A chiral pool strategy for the synthesis of enantiopure hydroxymethyl-substituted pyridine derivatives

Article abstract of DOI:10.1002/ejoc.201100681

A simple procedure for the synthesis of enantiopure hydroxymethyl- substituted pyridine derivatives is presented. The developed method is based on TMSOTf-promoted cyclocondensations of β-ketoenamides, leading to differently substituted 4-hydroxypyridine/4-pyridone derivatives. The required β-ketoenamides were prepared by acylation ofeasily available enamino ketones with suitably protected enantiopure carboxylic chlorides. Most of the experiments were performed with D-mandelic acid as starting material. It has been shown that all steps occur essentially without racemisation. Several of the prepared 4-pyridone derivatives were transformed into the corresponding pyrid-4-yl nonaflates and subjected to a series of palladium-catalysed transformations, such as Suzuki, Heck or Sonogashira reactions. In addition, regioselective side-chain functionalisation of unsymmetrically 2,6-disubstituted pyridine derivatives was accomplished by application of Boekelheide rearrangements of the corresponding pyridine N-oxides. The presented methods allow a flexible, rapid and scalable approach to highly substituted, enantiopure pyridine derivatives. A new route to hydroxymethyl-substituted pyridine derivatives, starting from enantiopure α-hydroxy carboxylic acids, is described. The synthetic value of the method is demonstrated by multifaceted functionalisation reactions of the prepared pyridine derivatives, leading to a series of highly substituted enantiopure pyridine derivatives.

Full text of DOI:10.1002/ejoc.201100681

FULL PAPER
DOI: 10.1002/ejoc.201100681
A Chiral Pool Strategy for the Synthesis of Enantiopure Hydroxymethyl-
Substituted Pyridine Derivatives
Christian Eidamshaus[a] and Hans-Ulrich Reissig*[a]
Keywords: Enantiopure pyridines / 4-Pyridones / Cyclocondensation / β-Ketoenamides / Nitrogen heterocycles / Palladium
catalysis / Chiral pool
A simple procedure for the synthesis of enantiopure hy- cemisation. Several of the prepared 4-pyridone derivatives
droxymethyl-substituted pyridine derivatives is presented.
The developed method is based on TMSOTf-promoted cy-
clocondensations of β-ketoenamides, leading to differently
substituted 4-hydroxypyridine/4-pyridone derivatives. The
required β-ketoenamides were prepared by acylation of
easily available enamino ketones with suitably protected
enantiopure carboxylic chlorides. Most of the experiments
were transformed into the corresponding pyrid-4-yl nona-
flates and subjected to a series of palladium-catalysed trans-
formations, such as Suzuki, Heck or Sonogashira reactions.
In addition, regioselective side-chain functionalisation of un-
symmetrically 2,6-disubstituted pyridine derivatives was ac-
complished by application of Boekelheide rearrangements of
the corresponding pyridine N-oxides. The presented meth-
ods allow a flexible, rapid and scalable approach to highly
were performed with D-mandelic acid as starting material. It
has been shown that all steps occur essentially without ra- substituted, enantiopure pyridine derivatives.
starting materials are rare, and only a very few examples
Introduction
have been reported in the literature.[9,10] Obviously, in many
The pyridine core is ubiquitous in natural products,
cases the preparation of the required enantiopure starting
drugs and agrochemicals. Its ability to coordinate metal
materials is too difficult to make this approach a competi-
ions makes it an ideal ligand for transition-metal-catalysed
tive alternative. We have recently been able, however, to de-
processes and also for the construction of supramolecular
velop a new route to highly functionalised enantiopure pyr-
architectures.[1] Pyridines with side chains bearing stereo-
genic centres are widely used in asymmetric transformations
and, as a consequence, many well-established ligand frame-
works feature this heteroaromatic nucleus.[2] In particular,
enantiopure hydroxymethyl-substituted pyridine derivatives
have attracted great attention, because they are efficient cat-
alysts for a series of asymmetric transformations. Enantio-
selective additions of organometal compounds to aldehydes
are efficiently catalysed by chiral pyridines of this type, for
instance.[3] Moreover, structurally related phosphinites are
excellent P,N ligands for asymmetric iridium-catalysed hy-
drogenations of olefins.[4] Further examples include palla-
dium-catalysed allylic substitution reactions,[5] nickel-cata-
lysed additions of organozinc compounds to enones[6] and
asymmetric alkynylations of aldehydes.[7] Typically, enantio-
pure (hydroxymethyl)pyridine derivatives are prepared
through asymmetric reductions of the corresponding
ketones, diastereoselective additions of lithiated pyridine
derivatives to chiral ketones or through resolution of race-
mic compounds.[8] De novo pyridine syntheses using chiral
idine derivatives that essentially overcomes this problem.[11]
With the aid of TMSOTf-mediated cyclocondensation reac-
tions of β-ketoenamides, leading to 4-hydroxypyridines (or
their 4-pyridone tautomers), we successfully prepared a
series of enantiopure 4-hydroxy-3-methoxypyridine deriva-
tives from readily available chiral carboxylic acid or nitrile
starting materials in only two steps.[11] The employed β-ke-
toenamides 6 (Scheme 1) were synthesised through intri-
[a] Institut für Chemie und Biochemie, Freie Universität Berlin,
Takustr. 3, 14195 Berlin, Germany
Scheme 1. Approaches to the β-ketoenamides 6 and cyclocondensa-
tions to afford the 4-pyridones
7 or 4-hydroxypyridines 8.
Fax: +49-30-83855367
(a) TMSOTf (3.0 equiv.), NEt3 (3.0 equiv.), CH2Cl2 or 1,2-DCE
(0.05 m), reflux, 16–48 h. TMSOTf = trimethylsilyl trifluorometh-
anesulfonate; NEt3 = triethylamine; 1,2-DCE = 1,2-dichloroethane.
E-mail: hans.reissig@chemie.fu-berlin.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100681.
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Synthesis of Enantiopure Hydroxymethyl-Substituted Pyridine Derivatives
guing three-component reactions of the lithiated alkoxyall- Table 1. Preparation of β-ketoenamides through acylations of en-
amino ketones. Variation of the enamino ketone components.
enes 1, the nitriles 2 and the carboxylic acids 3 (Scheme 1,
upper pathway).
Although this approach is highly flexible and offers rapid
access to a broad range of differently substituted pyridine
derivatives it suffers from the fact that in the multicompo-
nent process the reacting carboxylic acid generally has to
be used in excess. This disadvantage clearly limits the reac-
tion scale and makes it difficult to prepare larger quantities.
Alternatively, the β-ketoenamides 6 are also available
through condensations between the enamino ketones 4 and
the carboxylic acids 5 (Scheme 1, lower pathway), with sub-
sequent cyclocondensation providing the pyridine deriva-
tives 7/8 with different substitution patterns.[12] So far this
method has been applied to the synthesis of a series of novel
bi- and terpyridine derivatives, but more complex or chiral
substrates had not been examined.
The subject of this report is the expansion of the scope
of this process and the development of a practical route to
enantiopure hydroxymethyl-substituted pyridine derivatives
starting from readily available enantiopure α-hydroxy car-
boxylic acids. Moreover, we disclose our results on subse-
quent functionalisations of the prepared pyridine deriva-
tives – in particular through regioselective Boekelheide re-
[a] Yields of purified products. [b] 10 g scale. [c] Prepared by start-
ing from l-mandelic acid.
arrangements of unsymmetrically 2,6-disubstituted pyridine
derivatives.
test the potential for scaling up of this process, the reaction
between 12 and mandelic acid (9) was performed on a 10 g
scale. Although the yield dropped significantly, the process
Results and Discussion
As was revealed in previous investigations, silyl-ether- still remained fairly efficient, and the desired coupling prod-
protected alcohols are tolerated well under the established uct could be isolated in a good yield of 66%.
cyclisation conditions for β-ketoenamides. To explore the
The employed enamino ketones 12 and 14 are easily ac-
scope of these reactions with respect to the enamino ketone cessible and were prepared by a literature procedure
components, a readily available silylated mandelic chloride through treatment of the corresponding 1,3-diketones with
was selected as the acyl chloride component and condensed an ammonia source.[14] The enamino ketone 16 was pre-
with different enamino ketones to provide the correspond- pared by means of a modified Blaise reaction.[15] In the case
ing β-ketoenamides 13, 15 and 17 (Table 1). It is noteworthy of 16 a mixture of (E) and (Z) isomers was obtained, but,
that no prior hydrolysis of the silyl mandelate for the gener- as previous results clearly demonstrate, the double bond
ation of the acyl chloride was necessary when oxalyl dichlo- geometries of the β-ketoenamides do not affect the outcome
ride and catalytic amounts of N,N-dimethylformamide of the subsequent cyclocondensation reactions.[11h,15b]
(DMF) were used.
Next, the scope of the coupling reactions with respect to
The efficacies of the coupling reactions seem to depend the carboxylic acid components was investigated. Besides
strongly on the electronic natures of the enamino ketone mandelic acid, the enantiopure α-hydroxy carboxylic acids
components. Whereas the reactions of the simple enamino 18 and 20 and the acetonide-protected tartaric acid deriva-
ketones 12 and 14 provided the corresponding β-ketoen- tive 22 were condensed with the enamino ketone 12 to af-
amides 13 and 15 in excellent yields (Entries 1 and 2), com- ford the β-ketoenamides 19, 21 and 23 in moderate to good
pound 17 was obtained in a very low yield of 13% (En- yields (Table 2, Entries 1–3). The desired α-hydroxy carbox-
try 3). This finding might be explained by the fact that the ylic acids 18 and 20 can easily be prepared in a one-step
nucleophilicity of 16 is substantially reduced by the ad- fashion from the corresponding amino acids l-valine and
ditional electron-withdrawing ethoxycarbonyl group. In l-tert-leucine by diazotization with NaNO2 in sulfuric
support of this result it should be noted that all peptide acid.[16] When the reaction with l-tert-leucine was con-
coupling reagents that were tried for the acylation of 12 or ducted in concd. HCl in place of sulfuric acid the α-chloro
16 either failed or gave only trace amounts of the desired carboxylic acid 24 was obtained,[17] and this could also be
coupling products. The nucleophilicity is apparently already converted into the expected β-ketoenamide 25 (Entry 4).
fairly low even in the case of the simple enamino ketone Unlike those of the protected α-hydroxy carboxylic acids,
12, which makes such vinylogous amides too unreactive to the preparation of the benzyl-protected pyrrolidyl-substi-
undergo coupling with active esters generated in situ.[13] To tuted β-ketoenamide 27 turned out to be more challeng-
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C. Eidamshaus, H.-U. Reissig
FULL PAPER
ing.[18] When the N-benzyl-protected proline 26 was sub- (Entry 3). When this precursor was subjected to the cycli-
jected to standard coupling conditions the desired product sation conditions no product formation was observed even
was isolated in only 7% yield. After tedious optimisation, after prolonged reaction times. For the 4-pyridone 28 we
however, we found that 4.7 equiv. of the sodium salt of the were able to demonstrate that the cyclisation process can
enamino ketone 12 (generated by deprotonation with so- also be performed on a 10 g scale without any loss in effi-
dium hydride) furnished the desired compound 27 in a satis- cacy, affording the product in excellent yield and perfect
factory yield of 60% (Entry 5).
optical purity. In general, the purification of the 4-pyrid-
ones is easy even on large scales. Typically, simple filtration
through a short silica gel pad is sufficient to provide the 4-
pyridones in high purities. The cyclisation of the β-ketoen-
amide 15, bearing ethyl substituents, proceeded almost as
well as in the case of 13 (Entry 4), but the cyclisation of the
ketoenamide 17, with an additional ethoxycarbonyl group,
was less efficient (Entry 5). This might again be the result
of the electron-withdrawing effect of this substituent or of
steric interactions of the phenyl substituent at C-1. More-
over, a significantly longer reaction time was required to
Table 2. Preparation of β-ketoenamides by acylation of the en-
amino ketone 12. Variation of the carboxylic acid components.
Table 3. Cyclisations of β-ketoenamides leading to the 4-pyridones
28–33.
[a] Yields of purified products. [b] The sodium salt of the enamino
ketone 12 (4.7 equiv.) was used.
The prepared β-ketoenamides were then subjected to the
cyclisation conditions, leading to the corresponding 4-pyr-
idone derivatives 28–33 (Table 3). As the first example, the
β-ketoenamide 13 was cyclised under the established condi-
tions to provide the corresponding 4-pyridone 28 in excel-
lent yield. No attempts to optimise the reaction conditions
further were made. With the pyridone 28 we were able to
demonstrate that the reaction sequence (coupling and
cyclisation) proceeds without detectable racemisation (see
the Supporting Information). It is therefore very likely that
this holds true for all other pyridones prepared according
to this method. However, the yields of the cyclisation pro-
cess varied strongly when other β-ketoenamides were tried
(Entries 1–3, Table 3). The efficacy of the cyclisation pro-
cess is apparently strongly influenced by the steric demand
of the amide substituent R. Whereas 13 could be cyclised
in excellent yield with a relatively short reaction time (En-
try 1), the condensation of 19 provided the corresponding
4-pyridone 29 in only 28% yield (Entry 2). This effect is
[a] Yields of purified products. [b] The reaction time was 7 d. [c] H2
even more pronounced in the case of β-ketoenamide 21 (balloon), Pd/C (100 wt.-%), MeOH, room temp., 12 h.
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Synthesis of Enantiopure Hydroxymethyl-Substituted Pyridine Derivatives
achieve complete conversion of 17, resulting in the complete methyl iodide in acetonitrile did not lead to the formation
desilylation of the hydroxy group. Unfortunately, all of the desired product (Entry 1), and the use of Meerwein’s
attempts to cyclise the acetonide-protected tartaric-acid- salt as alkylating agent (Entry 2) was also unsuccessful and
derived ketoenamide 23 failed. Presumably, the acid-labile led only to the decomposition of 28. The best results were
protecting group is cleaved under the cyclisation conditions, obtained in aprotic polar solvents and with K2CO3 or
giving rise to the formation of various unidentified prod- Cs2CO3 as base (Entries 3–5). In none of these experiments
ucts. As well as the α-hydroxy-carboxylic-acid-derived β-ke- were products arising from competing N-alkylation iso-
toenamides, the proline derivative 27 was also successfully lated. However, partial desilylation occurred and limited the
cyclised to furnish the corresponding 4-pyridone 33 in mod- yields of the alkylation process. Deliberate desilylation of
erate yield (Entry 6). Subsequent cleavage of the benzyl pro- the product 39 was smoothly achieved with tetra-n-butyl-
tective group under reductive, heterogeneous conditions af- ammonium fluoride, furnishing the desired chiral pyridine
forded the debenzylated 4-pyridone derivative 34 in excel- derivative 40 in almost quantitative yield.
lent yield.
Table 4. Optimisation of the selective O-methylation of the 4-pyri-
done 28. (a) TBAF (1.0 m in THF), THF, room temp., 2 h. TBAF
= tetra-n-butylammonium fluoride.
The proposed mechanism of the cyclisations is depicted
in Scheme 2. In the first steps the disilylated species 35 are
likely to be formed. Two different pathways (A and B) are
then possible. The intermediates 35 can either cyclise di-
rectly, through formal 6π electrocyclisations, to give the di-
hydropyridine intermediates 37 (path A) or, after N-proton-
ation leading to 36, similar cyclisations, which can also be
regarded as intramolecular Mannich reactions, will afford
the cationic intermediates 38 (path B). Subsequent depro-
tonation should then also lead to 37, which after elimi-
nation of trimethylsilanol followed by protodesilylation of
the 4-hydroxy group would give the 4-hydroxypyridine de-
rivatives 8 and/or the 4-pyridones 7. In each of the examples
presented (Table 3) the pyridinol/pyridone equilibrium in
CDCl3 solution is completely on the side of the pyridone
tautomer. We speculate that intramolecular hydrogen bonds
between the pyridone N–H moiety and the α-OTBS, OH or
NH groups favour the pyridone tautomers.
[a] Yield of purified product.
Under the optimised alkylation conditions the 4-meth-
oxypyridines 41 and 44 were also prepared in moderate
yields (Scheme 3). When the pyridine 43, with an unprotec-
ted hydroxy group in the C-2 side chain, was alkylated the
4-methoxypyridine derivative 44 was isolated as the major
product. Deprotection of the silyl ether 41 with TBAF pro-
vided the corresponding hydroxymethyl-substituted pyr-
idine derivative 42.
Scheme 2. Proposed mechanism of the TMSOTf/base-mediated cy-
clisations of β-ketoenamides. (a) – TMSOH; (b) H2O, – TMSOH.
With the synthesised chiral pyridine derivatives to hand
we turned our attention to the further functionalisation of
the prepared substrates. We have recently demonstrated that
the hydroxy groups in 4-pyridinols can serve as useful han-
dles for the introduction of high structural diversity. Modi-
fication of the C-4 substituents should allow for fine-tuning
of the electronic properties and coordination abilities of the
resulting pyridines in applications as ligands in metal-cata-
Scheme 3. O-Selective methylation of the 4-pyridones 29 and 43.
(a) TBAF (1.0 m in THF), THF, room temp., 2 h; brsm = based on
recovered starting material.
As already demonstrated in numerous exam-
lysed processes. Firstly, O-selective alkylation was consid- ples,[11b,11d,11f] pyrid-4-yl nonaflates are excellent reaction
ered and optimised for the pyridone 28. As Table 4 shows, partners in cross-coupling reactions. Gratifyingly, our pre-
the efficiency of selective O-methylation is strongly influ- viously established nonaflation protocol for 4-hydroxypyr-
enced by the solvent and the base. Treatment of 28 with idines could also successfully be applied to the newly syn-
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C. Eidamshaus, H.-U. Reissig
FULL PAPER
thesised tautomeric 4-pyridones 28 and 31.[19] Deproton-
ation with NaH followed by treatment with nonafluorobut-
anesulfonyl fluoride (NfF) in THF afforded the pyrid-4-yl
nonaflates 45 and 46 in good yields (Scheme 4).[20]
Scheme 4. Nonaflation of the 4-pyridones 28 and 31.
The pyrid-4-yl nonaflates 45, ent-45 (prepared as de-
scribed for 45, by starting from l-mandelic acid via ent-13
and ent-28) and 46 were tested in a series of palladium-
catalysed transformations to achieve facile variation of the
C-4 substituent (Scheme 5). Suzuki couplings of 45 with
phenylboronic acid and (p-cyanophenyl)boronic acid pro-
vided the desired 4-aryl-substituted pyridine derivatives 47
and 49 in excellent yields. Subsequent desilylation led to the
unprotected (hydroxymethyl)pyridine derivatives 48 and 50.
Heck coupling between the pyridyl nonaflate ent-45 and
ethyl acrylate under Jeffery conditions afforded 51 in 66%
yield.[21] Reductions of aryl triflates or nonaflates to the
corresponding unsubstituted arenes under homogeneous
conditions are well established.[22] We were pleased to find
that these conditions can also be applied to the reduction
of the pyrid-4-yl nonaflate 45, affording the pyridine deriva-
tive 52, unsubstituted at C-4, in excellent yield. Again, desi-
lylation with TBAF efficiently afforded the free hy-
droxymethyl-substituted pyridine derivative 53. Sonoga-
shira coupling between the pyridyl nonaflate 46 and (triiso-
propylsilyl)acetylene smoothly delivered the 4-alkynylated
pyridine derivative 54. All these examples clearly demon-
strate that pyrid-4-yl nonaflates of this type easily lead to a
broad range of new chiral pyridine derivatives.
Scheme 5. Palladium-catalysed transformations of the pyrid-4-yl
nonaflates 45, ent-45 and 46. (a) C6H5B(OH)2 (1.1 equiv.),
Pd(OAc)2 (5%), PPh3 (20%), K2CO3 (1.0 equiv.), DMF, 80 °C,
16 h; (b) p-NCC6H4B(OH)2 (1.2 equiv.), Pd(OAc)2 (5%), PPh3
(20%), K2CO3 (1.2 equiv.), DMF, 80 °C, 16 h; (c) ethyl acrylate
(2.0 equiv.), Pd(OAc)2 (5%), TBAC (2.0 equiv.), NaHCO3
(2.1 equiv.), DMF, 70 °C, 4 h; (d) Pd(OAc)2 (16%), dppp (16%),
formic acid (3.2 equiv.), NEt3 (4.5 equiv.), DMF, 65 °C, 16 h;
(e) TIPS-acetylene (1.5 equiv.), PdCl2(PPh3)2 (5%), CuI (6%),
NEt3, 60 °C, 16 h; (f) TBAF (1.0 m in THF), THF, room temp., 1–
2 h. TBAC = tetra-n-butylammonium chloride; dppp = 1,3-bis(di-
phenylphosphanyl)propane; TIPS = triisopropylsilyl.
55 should allow easy variation of the substitution pattern
in a highly flexible manner and might thus result in even
better catalysts.
Scheme 6. Nucleophilic substitution of the pyrid-4-yl nonaflate ent-
45 with piperidine, leading to the chiral DMAP analogue 55.
Chiral 4-(dialkylamino)pyridines are widely used in ki-
So far we had been able to vary the C-4 substituents in
netic resolutions of racemic alcohols. We therefore ad- the prepared chiral pyridine derivatives widely, but selective
dressed the question of whether or not those structures transformations of the unavoidable C-6 alkyl groups in our
could be accessed through simple replacement of the non- compounds would also be highly desirable. A variety of
aflyl groups by amines. Cacchi and co-workers had devel- methods for the functionalisation of 2- or 6-methyl-substi-
oped a protocol for the synthesis of 4-amino-substituted tuted pyridine derivatives are known in the literature. Un-
quinolyl derivatives through nucleophilic substitution reac- fortunately, our attempts to oxidise the methyl group in 28
tions between quinol-4-yl triflates or nonaflates and various directly with SeO2 (Riley oxidation) gave the desired alde-
amines.[23] Gratifyingly, when ent-45 and piperidine were hyde 59 (Scheme 8, below) only in trace amounts. Further-
subjected to the reported conditions, the 4-amino-substi- more, deprotonation at the methyl group followed by trap-
tuted pyridine derivative 55 was efficiently obtained ping of the resulting anion with different electrophiles also
(Scheme 6). Vedejs and co-workers reported on a structur- did not lead to the formation of the anticipated products.
ally closely related pyridine derivative that efficiently acts as Gratifyingly, though, the C-6 methyl group in 39 can be
an enantiopure DMAP analogue in the resolution of chiral indirectly oxidised through
a Boekelheide rearrange-
secondary alcohols.[24] Our approach to compounds such as ment.[25] The required pyridine N-oxide 56 (Scheme 7) was
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Synthesis of Enantiopure Hydroxymethyl-Substituted Pyridine Derivatives
prepared in excellent yield by treatment of 39 with m-chlo- momethyl side chain may be used for the introduction of
roperbenzoic acid. Heating of 56 in acetic anhydride pro- amino substituents through nucleophilic substitution reac-
vided the acetoxymethyl-substituted pyridine derivative 57 tions, as demonstrated by the reaction between 60 and (S)-
almost quantitatively. Surprisingly, the rearrangement pro- diphenylprolinol (61), to afford 62 (Scheme 9). The fact that
ceeds with very high regioselectivity, furnishing 57 with compound 62 was obtained as single diastereomer again
complete preservation of the enantiopurity (Ͼ95% ee, see shows that the entire sequence including the oxidation to
the Supporting Information). The observed regioselectivity the aldehyde 59 proceeds without (partial) racemisation.
could be due to conformational constraints, strongly lower-
The formyl group in the pyridine derivative 59 was sub-
ing the kinetic acidity of the hydrogen atom in the C-2 side jected to Seyferth–Gilbert homologation[26] with the Best-
chain.
mann–Ohira reagent 63[27] to afford the alkynyl-substituted
pyridine derivative 64 under mild conditions and in good
yield (Scheme 10). The alkynyl group is certainly an excel-
lent tool with which to perform cycloadditions or Sonoga-
shira reactions and should hence allow the introduction of
additional structural diversity at C-6 in these chiral pyridine
derivatives.
Scheme 7. Formation of the pyridine N-oxide 56 and Boekelheide
rearrangement leading to the acetoxymethyl-substituted pyridine
57. m-CPBA = m-chloroperbenzoic acid; Ac2O = acetic anhydride.
Scheme 10. Seyferth–Gilbert homologation of the aldehyde 59,
leading to the alkynyl-substituted pyridine derivative 64.
For further transformations the acetoxy group in the pyr-
idine derivative 57 was hydrolysed by treatment with K2CO3
in methanol (Scheme 8). Oxidation of the hydroxymethyl-
substituted pyridine derivative 58 to aldehyde 59 was ac-
complished by Swern oxidation or alternatively by oxi-
dation with IBX.
Conclusions
We have developed a simple approach to chiral pyridine
derivatives, starting from enantiopure carboxylic acids. In
particular, the use of α-hydroxy carboxylic acids, leading
to (hydroxymethyl)pyridine derivatives, was investigated in
great detail. A procedure for O-selective alkylation of the
synthesised 4-pyridones was developed, and a series of 4-
methoxy-substituted pyridines was prepared by this
method. We were able to demonstrate that the correspond-
ing pyrid-4-yl nonaflates are excellent reaction partners in
palladium-catalysed transformations, allowing easy varia-
tion of the C-4 substituents. Moreover, we found that re-
gioselective oxidation of the less hindered substituents in
unsymmetrical 2,6-disubstituted pyridine N-oxides through
rearrangements in the presence of acetic anhydride is pos-
sible, allowing smooth subsequent reactions of these side
chains. Investigations of the prepared substrates as ligands
in asymmetric transformations are ongoing and will be the
subject of future reports.[28]
Scheme 8. Hydrolysis of 57 and subsequent oxidation of the (hy-
droxymethyl)pyridine 58 to the corresponding aldehyde 59.
(a) (COCl)2 (1.1 equiv.), DMSO (2.0 equiv.), NEt3 (5.0 equiv.),
CH2Cl2, –60 °C to room temp., 97%; (b) IBX (1.1 equiv.), CH2Cl2/
DMSO, 98%. IBX = iodooxybenzoic acid.
The new functional groups in the pyridine derivatives 58
and 59 are ideal for subsequent reactions. Compound 58,
for instance, was transformed into the corresponding bro-
momethyl-substituted pyridine 60 (Scheme 9) by treatment
with CBr4 and PPh3 (Appel reaction). The reactive bro-
Experimental Section
General Methods: Reactions were generally performed under argon
in flame-dried flasks. Solvents and reagents were added by syringe.
Solvents were purified with the MB SPS-800-dry solvent system.
NEt3 was distilled from CaH2 and stored over KOH under argon.
Pyridine was stored over KOH under argon. Other reagents were
purchased and used as received without further purification unless
otherwise stated. Products were purified by flash chromatography
on silica gel (230–400 mesh, Merck or Fluka). Unless otherwise
stated, yields refer to analytically pure samples. NMR spectra were
Scheme 9. Appel reaction of the pyridyl alcohol 58 to afford the
bromide 60 and subsequent reaction with (S)-diphenylprolinol (61),
leading to the pyridine derivative 62 with two stereogenic centres.
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C. Eidamshaus, H.-U. Reissig
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recorded with Bruker (AC 250, AC 500, AVIII 700) and JOEL
(ECX 400, Eclipse 500) instruments. Chemical shifts are reported
relative to solvent residual peaks or TMS [1H: δ = 0.00 ppm (TMS),
cal procedure, with TBSCl (3.17 g, 21.0 mmol) and imidazole
(1.44 g, 21.2 mmol). The crude product (3.81 g, 10.0 mmol) was
then treated with (COCl)2 (1.27 g, 10.0 mmol) and DMF in CH2Cl2
δ = 7.26 ppm (CDCl3); 13C: δ = 77.0 ppm (CDCl3)]. Integrals are (50 mL) to give the desired acyl chloride. Treatment of the crude
in accordance with assignments, and coupling constants are given
acyl chloride with the enamino ketone 14 (2.58 g, 20.3 mmol) and
NEt3 (1.39 mL, 10.0 mmol) in CH2Cl2 (30 mL) gave 15 (3.87 g) to-
in Hz. All 13C NMR spectra are proton-decoupled. For detailed
peak assignments 2D spectra were measured (COSY, HMQC, gether with unreacted enamino ketone as a 4:1 mixture [as judged
HMBC). 13C NMR signals of CF3(CF2)3 groups are not given,
because unambiguous assignment is not possible, due to strong
splitting by coupling with the 19F nuclei. IR spectra were measured
with a Nicolet 5 SXC FT-IR spectrometer or with a Nexus FT-IR
spectrometer fitted with a Nicolet Smart DuraSample IR ATR. MS
and HRMS analyses were performed with Varian Ionspec QFT-7
(ESI-FT ICRMS) instruments. Elemental analyses were carried out
with a CHN-Analyzer 2400 (Perkin–Elmer) or with a Vario EL or
Vario EL III. Melting points were measured with a Reichert appa-
ratus (Thermovar) and are uncorrected. Optical rotations were de-
termined with a Perkin–Elmer 241 polarimeter at the temperatures
given.
by NMR (calculated yield: 92%) after flash column chromatog-
raphy (silica gel, hexane/EtOAc, 95:5)] as a colourless oil.
1
[α]2D2 = +131 (c = 3.2, CHCl3). H NMR (500 MHz, CDCl3): δ =
0.05, 0.11, 0.94 (3 s, 3 H, 3 H, 9 H, OTBS), 1.05 (t, X part of an
ABX3 system, JAX = JBX = 7.4 Hz, 3 H, 1Ј-H), 1.09 (t, J = 7.7 Hz,
3 H, 7Ј-H), 2.40 (dq, J = 1.5, 7.7 Hz, 2 H, 6Ј-H), 2.67, 2.77 (AB
part of an ABX3 system, JAX = JBX = 7.4 Hz, JAB = 14.6 Hz, 2 H,
2Ј-H), 5.12 (s, 1 H, 2-H), 5.38 (s, 1 H, 4Ј-H), 7.23–7.27 (m, 1 H,
Ph), 7.31–7.34, 7.50–7.54 (2 m, 2 H each, Ph) ppm. 13C NMR
(101 MHz, CDCl3): δ = –5.11, –4.96 (2 q, OTBS), 8.6 (q, C-7Ј),
12.5 (q, C-1Ј), 18.4, 25.7 (s, q, OTBS), 27.2 (q, C-2Ј), 36.5 (q, C-
6Ј), 76.7 (d, C-2), 104.3 (d, C-4Ј), 126.1, 128.0, 128.3, 139.5 (3 d, s,
Ph), 158.1 (s, C-3Ј), 172.1 (s, C-1), 201.9 (s, C-5Ј) ppm. HRMS
(ESI-TOF): calcd. for C21H33NO3Si 376.2308 [M + H]+; found
376.2312.
Typical Procedure for Acylations of Enamino Ketones with α-Hy-
droxy Carboxylic Acids. (R,Z)-2-(tert-Butyldimethylsiloxy)-N-(4-
oxopent-2-en-2-yl)-2-phenylacetamide (13): TBSCl (3.32 g, 22.0 mmol)
and imidazole (1.63 g, 24.0 mmol) were added to a solution of (R)-
mandelic acid (1.52 g, 10.0 mmol) in THF (50 mL). The resulting
mixture was stirred at room temp. for 16 h. The precipitate was
filtered off and thoroughly washed with THF. The combined solu-
tions were concentrated, and the residual material was dissolved in
Et2O (50 mL) and washed with water (2ϫ50 mL) and brine. The
organic layer was dried with Na2SO4 and filtered, and the solvent
was removed under reduced pressure to provide the corresponding
silyl ether/ester, which was used as obtained. (COCl)2 (1.52 g,
12.0 mmol) was added dropwise to a solution of the silyl ether/ester
(3.79 g, 9.97 mmol) in anhydrous CH2Cl2 (50 mL), followed by a
Ethyl (R)-2-{[2-(tert-Butyldimethylsiloxy)-2-phenylacetamido]phen-
ylmethylene}-3-oxobutanoate (17): (R)-Mandelic acid (426 mg,
2.80 mmol) was converted into the corresponding silyl ether/ester
according to the typical procedure, with TBSCl (886 mg,
5.88 mmol) and imidazole (457 mg, 6.72 mmol). The crude product
(max. 2.80 mmol) was then treated with (COCl)2 (391 mg,
3.08 mmol) and DMF in CH2Cl2 (30 mL) to give the desired acyl
chloride. Treatment of the crude acyl chloride with the enamino
ketone 16 (800 mg, 3.43 mmol) and NEt3 (390 μL, 2.81 mmol) in
CH2Cl2 (25 mL) gave 17 (172 mg, 13 %) after flash column
chromatography (silica gel, hexane/EtOAc, 9:1) as a colourless oil.
few drops of DMF. The resulting mixture was stirred at room temp. Compound 17 was obtained as a 3:1 mixture of (E) and (Z) iso-
for 4 h. All volatile components were then removed under reduced
pressure to afford the crude acyl chloride, which was used in the
next step without further purification. The acyl chloride was dis-
solved in anhydrous CH2Cl2 (10 mL) and added dropwise at 0 °C
mers. [α]2D2 = –57 (c = 0.8, CHCl3). Only characteristic signals of
the major isomer are given. 1H NMR (CDCl3, 500 MHz): δ = 0.00,
0.06, 0.90 (3 s, 3 H, 3 H, 9 H, OTBS), 0.81 (t, J = 7.2 Hz, 3 H, 3Ј-
H), 2.31 (s, 3 H, 4-H), 3.80 (q, J = 7.2 Hz, 2 H, 2Ј-H), 5.05 (s, 1
H, CHPh), 7.10–7.45 (m, 10 H, Ph) ppm. 13C NMR (CDCl3,
101 MHz): δ = –3.57 (q, OTBS), 14.7 (q, C-3Ј), 19.7, 27.1 (s, q,
OTBS), 31.1 (q, C-4), 62.6 (t, C-2Ј), 117.7 (s, C-2), 127.4, 128.5,
129.2, 129.5, 129.8, 130.0, 135.5, 140.3 (6 d, 2 s, Ph), 154.5 (s, C-
1Ј), 185.5, 197.9, 223.0 (3 s, CONHR, C-1, C-3) ppm. IR (ATR):
to
a
solution of (Z)-4-aminopent-3-en-2-one (12, 1.97 g,
19.9 mmol) and NEt3 (1.38 mL, 9.97 mmol) in CH2Cl2 (10 mL).
The mixture was stirred under argon for 16 h, during which it was
allowed slowly to reach room temp. The reaction was quenched by
addition of water (30 mL). The organic layer was separated, and
the aqueous layer was extracted with CH2Cl2 (3ϫ20 mL). The ν = 3050–2850 (=C–H, C–H), 1720–1560 (C=O, C=C) cm–1
.
˜
combined organic layers were dried with Na2SO4 and filtered, and
the solvent was evaporated under reduced pressure. The crude
product was purified by flash column chromatography (silica gel,
hexane/EtOAc, 9:1) to afford 13 (2.90 g, 84%) as a yellow oil.
HRMS (ESI-TOF): calcd. for C27H35NO5Si 482.2363 [M + H]+;
found 482.2414.
(S,Z)-2-(tert-Butyldimethylsiloxy)-3-methyl-N-(4-oxopent-2-en-2-
yl)butanamide (19): (S)-2-Hydroxy-3-methylbutanoic acid (7.61 g,
50.0 mmol) was converted into the corresponding silyl ether/ester
according to the typical procedure, with TBSCl (15.8 g, 100 mmol)
and imidazole (8.17 g, 120 mmol). This silyl ether/ester (17.5 g) was
then treated with (COCl)2 (6.35 g, 50.0 mmol) and DMF in CH2Cl2
(200 mL) to give the desired acyl chloride. Treatment of the crude
acyl chloride with the enamino ketone 12 (9.70 g, 100 mmol) and
NEt3 (6.97 mL, 50.0 mmol) in CH2Cl2 (100 mL) gave 19 (10.5 g,
67 %) after flash column chromatography (silica gel, hexane/
1
[α]2D2 = –248 (c = 1.65, CHCl3). H NMR (500 MHz, CDCl3): δ =
–0.06, 0.11, 0.94 (3 s, 3 H, 3 H, 9 H, OTBS), 2.13, 2.30 (2 s, 3 H
each, 5Ј-H, 1Ј-H), 5.12 (s, 1 H, 2-H), 5.34 (s, 1 H, 3Ј-H), 7.31–7.33
(m, 3 H, Ph), 7.51–7.53 (m, 2 H, Ph), 12.81 (s, 1 H, NH) ppm. 13
C
NMR (101 MHz, CDCl3): δ = –4.9, –3.6, 18.3 (2 q, s, OTBS), 21.7
(q, C-1Ј), 25.8 (q, OTBS), 30.5 (q, C-5Ј), 76.9 (d, C-2), 106.9 (d, C-
3Ј), 126.1, 128.1, 128.4, 139.4 (3 d, s, Ph), 153.1 (s, C-2Ј), 172.7 (s,
C-1), 198.5 (s, C-4Ј) ppm. IR (ATR): ν = 3140 (NH), 2955–2860
˜
(=C–H, C–H), 1710–1590 (C=O, C=C) cm–1. HRMS (ESI-TOF):
calcd. for C19H29NO3Si 370.1814 [M + Na]+; found 370.1812.
C19H29NO3Si (347.5): calcd. C 65.67, H 8.41, N 4.03; found C
65.84, H 8.48, N 4.02.
EtOAc, 9:1) as a colourless oil. [α]2D2 = –101 (c = 1.03, CHCl3). H
1
NMR (400 MHz, CHCl3): δ = 0.00, 0.05, 0.90 (3 s, 3 H, 3 H, 9 H,
OTBS), 0.90 (mc, 6 H, iPr), 1.95 (mc, 1 H, iPr), 2.07, 2.31 (2 s, 3
H each, 5Ј-H, 1Ј-H), 3.86 (mc, 1 H, 2-H), 5.28 (s, 1 H, 3Ј-H), 12.45
(S,Z)-2-(tert-Butyldimethylsiloxy)-N-(5-oxohept-3-en-3-yl)-2-phen- (br. s, 1 H, NH) ppm. 13C NMR (101 MHz, CDCl3): δ = –5.3, –4.9
ylacetamide (15): (S)-Mandelic acid (1.52 g, 10.0 mmol) was con-
verted into the corresponding silyl ether/ester according to the typi-
(2 q, OTBS), 17.1, 18.2 (2 q, iPr), 18.7 (s, OTBS), 21.8 (q, C-1Ј),
25.8 (q, OTBS), 30.4 (q, C-5Ј), 33.4 (d, iPr), 79.3 (d, C-2), 106.3
6062
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6056–6069

Synthesis of Enantiopure Hydroxymethyl-Substituted Pyridine Derivatives
(d, C-3Ј), 152.8 (s, C-2Ј), 174.1 (s, C-1), 198.2 (s, C-4Ј) ppm. IR temp. The mixture was diluted with CH2Cl2, and water was added.
(ATR): ν = 3490 (NH), 2960–2860 (=C–H, C–H), 1725–1480 The phases were separated, and the aqueous layer was extracted
˜
(C=O, C=C) cm–1. HRMS (ESI-TOF): calcd. for C16H31NO3Si
336.1965 [M + Na]+; found 336.1966.
with CH2Cl2 (3ϫ20 mL). The combined organic layers were dried
with Na2SO4 and filtered, and the solvent was removed under re-
duced pressure. The crude product was purified by flash column
chromatography (silica gel, hexane/EtOAc, 4:1) to provide 25
(430 mg, 53%) as a colourless oil. [α]2D2 = –105 (c = 0.5, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 1.13 (s, 9 H, tBu), 2.16 (s, 3 H,
1Ј-H), 2.38 (s, 3 H, 5Ј-H), 4.07 (s, 1 H, 2-H), 5.40 (s, 1 H, 3Ј-H),
12.8 (br. s, 1 H, NH) ppm. 13C NMR (101 MHz, CDCl3): δ = 21.6
(q, C-1Ј), 26.7, 35.3 (q, s, tBu), 30.2 (q, C-5Ј), 70.8 (d, C-2), 106.6
(d, C-3Ј), 153.6 (s, C-2Ј), 167.8 (s, C-1), 199.5 (s, C-4Ј) ppm. IR
(S,Z)-2-(tert-Butyldimethylsiloxy)-3,3-dimethyl-N-(4-oxopent-2-en-
2-yl)butanamide (21): (S)-2-Hydroxy-3,3-dimethylbutanoic acid
(1.81 g, 13.7 mmol) was converted into the corresponding silyl
ether/ester according to the typical procedure, with TBSCl (4.13 g,
27.4 mmol) and imidazole (1.87 g, 27.4 mmol). The crude product
(4.78 g) was then treated with (COCl)2 (1.71 g, 13.5 mmol) and
DMF in CH2Cl2 (45 mL) to give the desired acyl chloride. Treat-
ment of the crude acyl chloride with the enamino ketone 12 (2.00 g,
20.3 mmol) and NEt3 (1.88 mL, 13.5 mmol) in CH2Cl2 (30 mL)
gave 21 (3.52 g, 80%) after flash column chromatography (silica
gel, hexane/EtOAc, 9:1) as a colourless oil. [α]2D2 = –52.7 (c = 1.25,
CHCl3). The NMR spectra show the presence of rotamers; for the
OTBS and tBu groups only characteristic signals are given. 1H
NMR (400 MHz, CDCl3): δ = 0.03, 0.85, 0.98 (3 s, 6 H, 9 H, 9 H,
OTBS/tBu), 2.07, 2.31 (2 s, 3 H each, 1Ј-H/5Ј-H), 3.70 (s, 1 H, 2-
H), 5.27 (s, 1 H, 3Ј-H), 12.3 (br. s, 1 H, NH) ppm. 13C NMR
(101 MHz, CDCl3): δ = –5.4, –5.1 (2 q, OTBS), 18.1 (s, OTBS),
21.9 (q, C-1Ј), 25.6, 25.8 (2 q, OTBS/tBu), 30.3 (q, C-5Ј), 35.1 (s,
tBu), 82.6 (d, C-2), 106.1 (d, C-3Ј), 152.9 (s, C-2Ј), 173.1 (s, C-1),
(ATR): ν = 3035–2820 (=C–H, C–H), 1705–1580 (C=O, C=C)
˜
cm–1. HRMS (ESI-TOF): calcd. for C11H18ClNO2: 254.0918 [M +
Na]+; found 254.0933. C11H18ClNO2 (231.7): calcd. C 57.02, H
7.83, N 6.04; found C 56.34, H 7.75, N 6.09.
(S,Z)-1-Benzyl-N-(4-oxopent-2-en-2-yl)pyrrolidine-2-carboxamide
(27): (S)-N-Benzylpyrrolidine-2-carboxylic acid (26, 2.06 g,
10.0 mmol) was dissolved in anhydrous CH2Cl2 (100 mL) in a
flame-dried two-neck flask fitted with a gas outlet and a rubber
septum. The mixture was cooled to –20 °C, and (COCl)2 (1.40 g,
11.0 mmol) was added, followed by catalytic amounts of DMF.
Stirring at –20 °C was continued for 2 h. Then, the Na salt of the
enamine 12 (5.65 g, 46.7 mmol, generated by addition of an equi-
molar amount of NaH to a solution of 12 in THF, followed by
evaporation of the solvent) was added in portions at –30 °C. Stir-
ring under argon was continued overnight, during which the mix-
ture was allowed to warm slowly to room temp. The reaction mix-
ture was diluted with CH2Cl2 and water. The phases were sepa-
rated, and the aqueous layer was extracted with CH2Cl2
(3 ϫ 100 mL). The combined organic layers were dried with
Na2SO4 and filtered, and the solvent was removed under reduced
pressure. The residual material was purified by flash column
chromatography (neutral Al2O3; hexane/EtOAc, 7:3) to afford 27
(1.73 g, 60%) as a colourless oil. [α]2D2 = –196 (c = 0.25, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 1.74–1.97, 2.20–2.23 (2 m, 3 H,
1 H, 3-H/4-H), 2.17, 2.26 (2 s, 3 H, 1Ј-H/5Ј-H), 2.38–2.44 (m, 1 H,
5-H), 3.17 (dd, J = 10.4, 4.8 Hz, 1 H, 5-H), 3.26–3.30 (m, 1 H, 2-
H), 3.67, 3.82 (AB system, JAB = 13.0 Hz, 2 H, Bn), 5.31 (s, 1 H,
3Ј-H), 7.19–7.29 (m, 3 H, Ph), 7.38 (d, J = 6.9 Hz, 2 H, Ph), 12.83
(br. s, 1 H, NH) ppm. 13C NMR (101 MHz, CDCl3): δ = 23.9, 30.5
(2 t, C-3/C-4), 21.7, 31.0 (2 q, C-1Ј/C-5Ј), 53.9 (t, C-5), 59.5 (t,
CH2Ph), 68.4 (d, C-2), 106.1 (d, C-3Ј), 127.0, 128.0, 129.2, 137.9
(3 d, s, Ph), 153.5 (s, C-2Ј), 175.8 (s, C-1), 198.4 (s, C-4Ј) ppm. IR
198.3 (s, C-4Ј) ppm. IR (ATR): ν = 3470 (NH), 2970–2840
˜
(=C–H, C–H), 1710–1480 (C=O, C=C) cm–1. HRMS (ESI-TOF):
calcd. for C17H34NO3Si 328.2302 [M + H]+; found 328.2309.
(4S,5S)-2,2-Dimethyl-N4,N5-bis[(Z)-4-oxopent-2-en-2-yl]-1,3-di-
oxolane-4,5-dicarboxamide (23): Sodium (4S,5S)-2,2-dimethyl-1,3-
dioxolane-4,5-dicarboxylate (500 mg, 2.14 mmol) was dissolved in
THF (5 mL), and TMSCl (816 μL, 6.41 mmol) was added.[29] After
having been stirred under argon at room temp. for 16 h, the mixture
was filtered, and the solvent was removed under reduced pressure.
The obtained residue was re-dissolved in CH2Cl2 (7 mL), and
(COCl)2 (543 mg, 4.28 mmol) and DMF (catalytic amounts) were
added. The mixture was stirred at ambient temperature until the
gas evolution stopped. At that point, the mixture was cooled to
0 °C, and NEt3 (0.60 mL, 4.3 mmol) and the enamino ketone 12
[445 mg, 4.49 mmol, dissolved in CH2Cl2 (3 mL)] were added. Stir-
ring at room temp. was continued overnight. The reaction was
quenched with H2O (15 mL), and the aqueous layer was extracted
with CH2Cl2 (3ϫ20 mL). The combined organic layers were dried
with Na2SO4 and filtered, and the solvent was removed under re-
duced pressure. The crude product was purified by flash column
chromatography (silica gel, hexane/EtOAc, 3:2) to provide 23 as a
colourless solid (461 mg, 61%), m.p. 79 °C. [α]2D2 = +410 (c = 0.14,
CHCl3). 1H NMR (500 MHz, CDCl3): δ = 1.52 (s, 6 H, Mediox),
2.06 (s, 6 H, 5Ј-H), 2.31 (s, 6 H, 1Ј-H), 4.63 (s, 2 H, 4-H), 5.35 (s,
2 H, 3Ј-H) ppm. 13C NMR (101 MHz, CDCl3): δ = 21.4 (q, C-1Ј),
26.3 (q, Mediox), 30.3 (q, C-5Ј), 78.3 (d, C-4/5), 107.0 (d, C-3Ј),
113.9 (s, C-2), 152.7 (s, C-2Ј), 169.7 (s, C-6), 199.1 (s, C-4Ј) ppm.
(ATR): ν = 3140 (NH), 2975–2805 (=C–H, C–H), 1705–1470
˜
(C=C) cm–1. HRMS (ESI-TOF): calcd. for C17H23N2O2: 287.1760
[M + H]+; found 287.1760. C17H23N2O2 (286.4): calcd. C 71.30, H
7.74, N 9.78; found C 71.28, H 7.44, N 9.50.
Typical Procedure for Cyclisations of the β-Ketoenamides to 4-Pyr-
idones. (R)-2-[(tert-Butyldimethylsiloxy)(phenyl)methyl]-6-meth-
ylpyridin-4-one (28): NEt3 (0.24 mL, 1.71 mmol) and TMSOTf
(0.31 mL, 1.71 mmol) were added to a solution of the β-ketoenam-
ide 13 (200 mg, 0.57 mmol) in CH2Cl2 (12 mL). The mixture was
heated to reflux for 16 h. After cooling to room temp., the reaction
was quenched by addition of H2O (10 mL), and the mixture was
IR (ATR): ν = 3130 (NH), 3000–2930 (C–H), 1720, 1650–1590
˜
(C=O, C=C) cm–1. HRMS (ESI-TOF): calcd. for C17H24N2O6:
375.1527 [M + Na]+; found 375.1540. C17H24N2O6 (352.4): calcd.
C 57.94, H 6.86, N 7.95; found C 57.83, H 6.50, N 7.90.
(S,Z)-2-Chloro-3,3-dimethyl-N-(4-oxopent-2-en-2-yl)butanamide diluted with CH2Cl2. The phases were separated, and the aqueous
(25): (COCl)2 (448 mg, 3.53 mmol) and DMF (a few drops) were
added dropwise to a solution of (S)-2-chloro-3,3-dimethylbutanoic
layer was extracted with CH2Cl2 (3ϫ20 mL). The combined or-
ganic layers were dried with Na2SO4 and filtered, and the solvent
acid (24, 532 mg, 3.53 mmol) in CH2Cl2 (12 mL). After having been was removed under reduced pressure. The crude material was puri-
stirred at room temp. for 4 h, the reaction mixture was cooled to
0 °C, and NEt3 (448 mg, 3.53 mmol) and the enamino ketone 12
(684 mg, 6.91 mmol) were added. The mixture was stirred under
argon for 16 h, during which it was allowed to slowly reach room
fied by flash column chromatography (silica gel, CH2Cl2/MeOH,
90:10) to afford 28 (171 mg, 91%) as a colourless solid, m.p. 93–
95 °C. [α]2D2 = –48.2 (c = 0.1, CHCl3). 1H NMR (500 MHz, CDCl3):
δ = –0.04, 0.08, 0.92 (3 s, 3 H, 3 H, 9 H, OTBS), 2.32 (s, 3 H, Me),
Eur. J. Org. Chem. 2011, 6056–6069
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6063

C. Eidamshaus, H.-U. Reissig
FULL PAPER
5.71 (s, 1 H, PhCH), 6.24 (s, 1 H, 3-H), 6.40 (s, 1 H, 5-H), 7.30– ν = 3340 (OH), 3065–2895 (=C–H, C–H), 1725–1560 (C=O, C=C)
˜
7.35 (m, 5 H, Ph) ppm. 13C NMR (101 MHz, CDCl3): δ = –5.2,
–4.9, 18.2 (2 q, s, OTBS), 19.3 (q, Me), 25.7 (q, OTBS), 73.0 (d,
PhCH), 110.7 (d, C-5), 114.5 (d, C-3), 126.5, 128.7, 128.9, 140.5 (3
d, s, Ph), 150.3 (s, C-2), 156.1 (s, C-6) ppm. The signal of C-4 could
cm–1. HRMS (ESI-TOF): calcd. for C21H18NO4: 372.1206 [M +
Na]+; found 372.1218.
(S)-2-(1-Benzylpyrrolidin-2-yl)-6-methylpyridin-4-one (33): The β-
ketoenamide 27 (1.77 g, 6.18 mmol) was cyclised according to the
typical procedure, with TMSOTf (3.25 mL, 18.0 mmol) and NEt3
(2.50 mL, 18.0 mmol) in CH2Cl2 (120 mL) at reflux for 48 h. The
crude product was purified by flash column chromatography (silica
gel, CH2Cl2/MeOH, 80:20) to afford 33 (849 mg, 53%) as a yellow
oil. [α]2D2 = –68.0 (c = 0.25, CHCl3/MeOH, 1:1). 1H NMR
(400 MHz, CDCl3): δ = 1.70–1.93 (m, 4 H, 2-H/3-H), 2.44 (s, 3 H,
not be detected. IR (KBr): ν = 3280 (NH), 2950–2860 (=C–H, C–
˜
H), 1630–1470 (C=C) cm–1. HRMS (ESI-TOF): calcd. for
C19H27NO2Si 330.1889 [M + H]+; found 330.1906.
(S)-2-[1-(tert-Butyldimethylsiloxy)-2-methylpropyl]-6-methylpyridin-
4-one (29): The β-ketoenamide 19 (1.62 g, 5.18 mmol) was cyclised
according to the typical procedure, with TMSOTf (2.80 mL,
15.5 mmol) and NEt3 (2.15 mL, 15.5 mmol) in CH2Cl2 (100 mL) Me), 3.30–3.39 (m, 1 H, 1-H/1Ј-H), 3.84 (s, 2 H, CH2Ph), 4.04–
at reflux for 48 h. The pyridone 29 was purified by flash column
chromatography (silica gel, CH2Cl2/MeOH, 90:10) to afford
435 mg (28%) as a colourless oil. [α]2D2 = –54.2 (c = 1.0, CHCl3).
4.10 (m, 1 H, 1-H/ 1Ј-H), 6.53, 6.81 (2 d, J = 1.9 Hz, 1 H each, 3-H/
5-H), 7.20–7.35 (m, 5 H, Ph) ppm. 13C NMR (175 MHz, CDCl3): δ
= 19.7 (q, Me), 23.1, 33.5 (2 t, C-2Ј/C-3Ј), 54.5 (t, C-4Ј), 59.0 (t,
1H NMR (500 MHz, CDCl3): δ = –0.09, 0.10 (2 s, 3 H each, CH2Ph), 65.4 (d, C-1Ј), 110.8, 113.9 (2 d, C-3/C-5), 128.1, 128.6,
OTBS), 0.83 (d, J = 6.8 Hz, 3 H, iPr), 0.91 (s, 9 H, OTBS), 0.94
(d, J = 6.8 Hz, 3 H, iPr), 1.95 (dsept, J = 4.6, 6.8 Hz, 1 H, iPr),
2.49 (s, 3 H, Me), 4.58 (d, J = 4.6 Hz, 1 H, 1Ј-H), 6.53, 6.67 (2 d,
J = 1.9 Hz, 1 H each, 3-H/5-H) ppm. 13C NMR (101 MHz,
CDCl3): δ = –5.3, –5.0 (2 q, OTBS), 16.1 (q, iPr), 18.0 (s, OTBS),
19.0 (q, iPr), 19.3 (q, Me), 25.7 (q, OTBS), 35.3 (d, iPr), 74.5 (d,
C-1Ј), 110.9, 113.9 (2 d, C-3/C-5), 150.1, 156.6 (2 s, C-2/C-6), 177.1
129.2, 135.9 (3 d, s, Ph), 151.5, 154.5 (2 s, C-2/C-6), 175.8 (s, C-4)
ppm. IR (ATR): ν = 3260 (NH), 2980–2820 (=C–H, C–H), 1625–
˜
1485 (C=C) cm–1. HRMS (ESI-TOF): calcd. for C17H21N2O
269.1648 [M + H]+; found 269.1624.
(S)-2-Methyl-6-(pyrrolidin-2-yl)pyridin-4-one (34): Compound 33
(320 mg, 1.19 mmol) was added to a suspension of palladium on
charcoal (10% Pd, 330 mg) in MeOH (12 mL), and hydrogen was
bubbled through the solution for 30 min. The mixture was stirred
under hydrogen (balloon) at room temp. for 16 h. Filtration
through a short pad of Celite and concentration of the solution to
dryness afforded crude 34, which was purified by preparative TLC
(silica gel, CH2Cl2/MeOH, 8:2) to provide 33 (215 mg, 99%) as a
(s, C-4) ppm. IR (neat): ν = 3280 (NH), 2960–2860 (=C–H, C–H),
˜
1630–1500 (C=C) cm– 1 . HRMS (ESI-TOF): calcd. for
C16H29NO2Si 296.2046 [M + H]+; found 296.2053.
(S)-2-[(tert-Butyldimethylsiloxy)(phenyl)methyl]-6-ethyl-3-methyl-
pyridin-4-one (31): The β-ketoenamide 15 (3.44 g, 9.16 mmol) was
cyclised according to the typical procedure, with TMSOTf yellow oil. [α]2D2 = –28.6 (c = 0.5, CHCl3/MeOH, 1:1). 1H NMR
(4.99 mL, 27.5 mmol) and NEt3 (3.81 mL, 27.5 mmol) in CH2Cl2
(180 mL) at reflux for 48 h. The pyridone 31 was purified by flash
column chromatography (silica gel, CH2Cl2/MeOH, 97:3) to afford
(500 MHz, CD3OD): δ = 1.95–2.16, 2.40–2.48 (2 m, 3 H, 1 H, 3Ј-
H/4Ј-H), 2.39 (s, 3 H, Me), 3.28–3.51 (m, 2 H, 5Ј-H), 4.54–4.56 (m,
1 H, 2Ј-H), 6.47, 6.54 (2 s, 1 H each, 3-H/5-H) ppm. 13C NMR
(176 MHz, CD3OD): δ = 22.3 (q, Me), 24.8, 32.3 (2 t, C-3Ј/C-4Ј),
1
2.46 g (75%) as a colourless oil. [α]2D2 = +3.7 (c = 1.4, CHCl3). H
NMR (400 MHz, CDCl3): δ = –0.03, 0.08, 0.90 (3 s, 3 H, 3 H, 9 47.0 (t, C-5Ј), 62.4 (d, C-2Ј), 109.8, 113.5 (2 d, C-3/C.5), 153.2,
H, OTBS), 1.24 (t, J = 7.5 Hz, 3 H, CH3), 1.89 (s, 3 H, CH3), 2.54 157.8 (2 br. s, C-2/C-6) ppm; the signal for C-4 could not be de-
(q, J = 7.5 Hz, 2 H, CH2), 5.82 (s, 1 H, CHPh), 6.18 (s, 1 H, 5-H), tected. IR (ATR): ν = 3335 (NH), 2945–2835 (=C–H), 1640–1405
˜
7.22–7.33 (m, 5 H, Ph), 8.88 (br. s, 1 H, NH) ppm. 13C NMR (C=O, C=C) cm–1. HRMS (ESI-TOF): calcd. for C10H14N2O
(127 MHz, CDCl3): δ = –5.2, –5.0 (2 q, OTBS), 9.9, 12.2 (2 q,
CH3), 18.1, 25.6 (s, q, OTBS), 26.4 (t, CH2), 71.4 (d, CHPh), 112.4
(d, C-5), 120.4 (s, C-3), 126.4, 128.2, 128.6, 140.1 (3 d, s, Ph), 145.7,
179.1179 [M + H]+; found 179.1166.
Typical Procedure for the O-Selective Methylation of 4-Pyridones.
(R)-2-[(tert-Butyldimethylsiloxy)(phenyl)methyl]-4-methoxy-6-
methylpyridine (39): K2CO3 (5.80 g, 42.0 mmol) and methyl iodide
(2.17 g, 15.3 mmol) were added to a solution of 28 (4.64 g,
13.3 mmol) in anhydrous DMF (50 mL). The mixture was stirred at
room temp. for 48 h until the starting materials had been consumed
(TLC). The mixture was diluted with EtOAc (100 mL), and water
149.4 (2 s, C-2/C-6), 179.3 (s, C-4) ppm. IR (ATR): ν = 3260 (NH),
˜
3065–2855 (=C–H, C–H), 1625 (C=O), 1520–1380 (C=C) cm–1
.
HRMS (ESI-TOF): calcd. for C21H31NO2Si 358.2202 [M + H]+;
found 358.2192.
(R)-Ethyl 6-[Hydroxy(phenyl)methyl]-4-oxo-2-phenyl-1,4-dihydro-
pyridine-3-carboxylate (32): The β-ketoenamide 17 (124 mg, (50 mL) was added. The phases were separated, and the aqueous
0.25 mmol) was cyclised according to the typical procedure, with layer was extracted with EtOAc (3ϫ100 mL). The combined or-
TMSOTf (135 μL, 0.74 mmol) and NEt3 (104 μL, 0.75 mmol) in ganic layers were washed with a brine/water mixture (1:1,
1,2-dichloroethane (5 mL) at 60 °C for 3 d. Because conversion was
still incomplete after 3 d, additional TMSOTf (135 μL, 0.74 mmol)
was added, and stirring was continued for 4 d. The crude product
was purified by flash column chromatography (silica gel, CH2Cl2/
MeOH, 95:5) to afford the pyridone 32 (35 mg, 40%) as colourless
crystals, m.p. 195 °C. [α]2D2 = –163 (c = 0.75, CHCl3). Several signals
in the NMR spectra are broadened due to the pyridinol/pyridone
equilibrium, and signals for a few C atoms could not be detected.
2ϫ100 mL) and brine (100 mL), dried with Na2SO4 and filtered.
Evaporation of the solvent afforded 39 (4.17 g, 91%) as a slightly
yellow solid, m.p. 94–96 °C. [α]2D2 = +31.8 (c = 1.1, CHCl3). 1H
NMR (700 MHz, CDCl3): δ = 0.03, 0.04, 0.97 (3 s, 3 H, 3 H, 9 H,
OTBS), 2.48 (s, 3 H, Me), 3.81 (s, 3 H, OMe), 5.85 (s, 1 H, PhCH),
6.52, 6.98 (2 d, J = 2.3 Hz, 1 H each, 3-H/5-H), 7.05–7.23, 7.29–
7.31, 7.51–7.52 (3 m, 1 H, 2 H, 2 H, Ph) ppm. 13C NMR (175 MHz,
CDCl3): δ = –4.9, 18.2 (q, s, OTBS), 24.5 (q, Me), 25.8 (q, OTBS),
1H NMR (500 MHz, CDCl3+CD3OD): δ = 0.96 (t, J = 7.2 Hz, 3 54.8 (q, OMe), 77.2 (d, PhCH), 102.8 (d, C-5), 107.7 (d, C-3),
H, CH3), 4.02 (q, J = 7.2 Hz, 2 H, CH2), 5.71 (s, 1 H, CHPh), 6.57 126.1, 127.0, 128.0 (3 d, Ph), 143.9 (s, Ph), 158.6, 165.7 (2 s, C-6,
(br. s, 1 H, 5-H), 7.43–7.45 (m, 10 H, Ph) ppm. 13C NMR C-2), 166.6 (s, C-4) ppm. IR (neat): ν = 2955–2855 (C–H), 1595–
(175 MHz, CDCl3+CD3OD): δ = 11.8 (q, CH3), 60.2 (t, CH2), 71.4
(br. d, CHPh), 112.2 (br. s, C-5), 125.8, 127.20, 127.23, 127.51,
˜
1575 (C=C) cm–1. HRMS (ESI-TOF): calcd. for C20H29NO2Si
344.2040 [M + H]+; found 344.2097. C20H29NO2Si (343.2): calcd.
127.53, 129.1, 140.0 (6 d, s, Ph), 166.5 (s, CO2Et) ppm. IR (ATR): C 69.92, H 8.51, N 4.08; found C 69.39, H 8.39, N 4.12.
6064 Eur. J. Org. Chem. 2011, 6056–6069
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Synthesis of Enantiopure Hydroxymethyl-Substituted Pyridine Derivatives
(S)-2-[1-(tert-Butyldimethylsiloxy)-2-methylpropyl]-4-methoxy-6-
methylpyridine (41): The 4-pyridone 29 (435 mg, 1.47 mmol) was
treated with methyl iodide (227 mg, 1.60 mmol) and K2CO3
(613 mg, 4.42 mmol) in DMF (5 mL) according to the typical pro-
cedure. The crude material was purified by flash column
chromatography (silica gel, hexane/EtOAc, 4:1) to provide 41
(219 mg, 48%) as a colourless oil. [α]2D2 = –102 (c = 0.7, CHCl3).
1H NMR (500 MHz, CDCl3): δ = –0.18, 0.03, 0.89 (3 s, 3 H, 3 H,
9 H, OTBS), 0.74, 0.90 (2 d, J = 6.7 Hz, 3 H each, iPr), 1.95 (dsept,
J = 4.2, 6.7 Hz, 1 H, iPr), 2.43 (s, 3 H, Me), 3.77 (s, 3 H, OMe),
4.50 (d, J = 4.2 Hz, 1 H, 1Ј-H), 6.47, 6.77 (2 d, J = 2.2 Hz, 1 H
each, 3-H/5-H) ppm. 13C NMR (101 MHz, CDCl3): δ = –5.1, –4.6,
18.1 (2 q, s, OTBS), 16.0, 19.8 (2 q, iPr), 24.5 (q, Me), 25.9 (q,
OTBS), 34.9 (d, iPr), 54.8 (q, OMe), 79.9 (d, C-1Ј), 103.6, 107.4 (2
ring was continued for 16 h. Flash column chromatography (silica
gel, gradient elution hexane to hexane/EtOAc, 9:1) provided 46
(236 mg, 52%) as a colourless oil. [α]2D2 = –55.8 (c = 0.52, CHCl3).
1H NMR (500 MHz, CDCl3): δ = –0.14, 0.11, 0.92 (3 s, 3 H, 3 H,
9 H, OTBS), 1.43 (t, X part of an ABX3 system, JAX = JBX
=
7.7 Hz, 3 H, Me), 2.10 (s, 3 H, Me), 2.85, 2.89 (AB part of an
ABX3 system, JAB = 2.3 Hz, 1 H each, CH2), 6.14 (s, 1 H, CHPh),
7.01 (s, 1 H, 5-H), 7.20–7.35 (m, 5 H, Ph) ppm. 13C NMR
(101 MHz, CDCl3): δ = –5.3, –5.0 (2 q, OTBS), 10.6 (q, 3-Me),
13.8 (q, Me), 18.2, 25.8 (s, q, OTBS), 31.0 (t, CH2), 79.7 (d, CHPh),
112.8 (d, C-5), 122.5 (s, C-3), 125.2, 126.9, 128.0, 141.9 (3 d, s,
Ph), 156.8 (s, C-4), 161.1 (s, C-6), 163.8 (s, C-2) ppm. 19F NMR
(376 MHz): δ = –128.0, –120.7, –109.5, –80.5 ppm. IR (ATR): ν =
˜
2960–2860 (C–H), 1600–1430 (C=C) cm–1. HRMS (ESI-TOF):
d, C-3/C-5), 158.2 (s, C-4), 165.7, 166.1 (2 s, C-2/C-6) ppm. IR calcd. for C25H30F9NO4SSi 640.1594 [M + H]+; found 640.1596.
(neat): ν = 2960–2855 (C–H), 1600, 1575 (C=C) cm–1. HRMS (ESI-
˜
(R)-2-[(tert-Butyldimethylsiloxy)(phenyl)methyl]-6-methyl-4-phen-
ylpyridine (47): Phenylboronic acid (77 mg, 0.63 mmol), Pd(OAc)2
(7 mg, 0.03 mmol), PPh3 (31 mg, 0.12 mmol) and K2CO3 (88 mg,
0.62 mmol) were added to a solution of the pyrid-4-yl nonaflate 45
(380 mg, 0.62 mmol) in anhydrous DMF (2 mL). The mixture was
heated to 80 °C under argon for 16 h. The mixture was filtered,
and EtOAc (15 mL) and water (15 mL) were added to the filtrate.
The layers were separated, and the aqueous layer was extracted
with EtOAc (3ϫ20 mL). The combined organic layers were washed
consecutively with a brine/water mixture (1:1) and brine, dried with
Na2SO4 and filtered, and the solvents were evaporated. The crude
product was purified by flash column chromatography (SiO2, hex-
ane/EtOAc, 90:10) to provide 47 (243 mg, 99%) as a colourless so-
lid, m.p. 98 °C. [α]2D2 = –2.5 (c = 0.08, CHCl3). 1H NMR (500 MHz,
CDCl3): δ = 0.03, 0.04, 0.96 (3 s, 3 H, 3 H, 9 H, OTBS), 2.58 (s, 3
H, Me), 5.93 (s, 1 H, CHPh), 7.18–7.21 (m, 2 H, Ph, 5-H), 7.27–
7.30 (m, 2 H, Ph), 7.40–7.47 (m, 3 H, Ph), 7.52–7.54 (m, 2 H, Ph),
7.60–7.63 (m, 3 H, Ph, 3-H) ppm. 13C NMR (126 MHz, CDCl3):
δ = –4.8, 18.3 (q, s, OTBS), 24.5 (q, Me), 25.9 (q, OTBS), 77.8 (d,
CHPh), 115.2, 119.7 (2 d, C-3/C-5), 126.1, 127.0, 128.1, 128.7,
128.9 (5 d, Ph)*, 138.9, 144.0 (2 s, Ph), 149.2, 157.5, 164.4 (3 s, C-
2/C-4/C-6) ppm; * the signal of one carbon atom could not be de-
TOF): calcd. for C17H31NO2Si 310.2202 [M + H]+; found 310.2207.
(S)-(6-Ethyl-4-methoxy-3-methylpyridin-2-yl)(phenyl)methanol (44):
The 4-pyridone 43 (590 mg, 2.42 mmol) was treated with methyl
iodide (412 mg, 2.90 mmol) and K2CO3 (680 mg, 4.95 mmol) in
DMF (6 mL) according to the typical procedure. The crude mate-
rial was purified by flash column chromatography (silica gel, hex-
ane/EtOAc, 4:1) to provide 44 (297 mg, 52%) as a colourless oil.
[α]2D2 = +123.7 (c = 1.1, CHCl3). 1H NMR (500 MHz, CDCl3): δ =
1.36 (t, J = 8.0 Hz, 3 H, Me), 1.89 (s, 3 H, 3-Me), 2.84 (q, J =
8.0 Hz, 2 H, CH2), 3.82 (s, 3 H, OMe), 5.71 (s, 1 H, PhCH), 6.61
(s, 1 H, 5-H), 7.22–7.29 (m, 5 H, Ph) ppm. 13C NMR (101 MHz,
CDCl3): δ = 9.5, 13.6 (q, t, 6-Et), 31.1 (q, 3-Me), 55.3 (q, OMe),
72.0 (d, CHPh), 103.2, 115.7 (2 d, C-3/C-5), 127.3, 127.5, 128.3,
143.1 (3 d, s, Ph), 157.2, 160.1 (2 s, C-2/C-.6), 164.6 (s, C-4) ppm.
IR (ATR): ν = 3320 (OH), 3085–2855 (=C–H, C–H), 1590–1480
˜
(C=C) cm–1. HRMS (ESI-TOF): calcd. for C16H19NO2: 240.1383
[M – H2O + H]+; found 240.1382. C16H19NO2 (257.3): calcd. C
74.68, H 7.44, N 5.44; found C 74.60, H 7.43, N 5.47.
Typical Procedure for the Nonaflation of 4-Pyridones. (R)-2-[(tert-
Butyldimethylsiloxy)(phenyl)methyl]-6-methylpyridin-4-yl Nonaflate
(45): NaH (60 wt.-% in mineral oil, 103 mg, 2.57 mmol) was added
to a solution of the 4-pyridone 28 (706 mg, 2.14 mmol) in THF
(21 mL). After the mixture had been stirred at room temp. under
argon for 30 min, NfF (785 mg, 2.60 mmol) was added, and stirring
was continued for 12 h. The reaction was quenched by slow ad-
dition of methanol (10 mL). All volatile components were evapo-
rated, and the residue was purified by flash column chromatog-
raphy (silica gel, gradient elution hexane to hexane/EtOAc, 9:1) to
provide 45 (1.02 g, 78%) as a colourless oil. [α]2D2 = –7.4 (c = 0.7,
tected. IR (ATR): ν = 3085–2855 (=C–H, C–H), 1600–1570 (C=C)
˜
cm–1. HRMS (ESI-TOF): calcd. for C25H31NOSi 390.2253 [M +
H]+; found 390.2244.
(R)-4-{2-[(tert-Butyldimethylsiloxy)(phenyl)methyl]-6-methylpyridin-
4-yl}benzonitrile (49): p-Cyanophenylboronic acid (302 mg,
2.04 mmol), Pd(OAc)2 (18 mg, 0.08 mmol), PPh3 (84 mg,
0.32 mmol) and K2CO3 (284 mg, 2.04 mmol) were added to a solu-
tion of the pyrid-4-yl nonaflate 45 (1.04 g, 1.69 mmol) in anhydrous
DMF (8 mL). The mixture was heated at 80 °C under argon for
16 h. The mixture was filtered, and EtOAc (30 mL) and water
(30 mL) were added to the filtrate. The layers were separated, and
the aqueous layer was extracted with EtOAc (3ϫ30 mL). The com-
bined organic layers were washed consecutively with a brine/water
mixture (1:1) and brine, dried with Na2SO4 and filtered, and the
solvents were evaporated. The crude product was purified by flash
column chromatography (SiO2, hexane/EtOAc, 85:15) to provide
49 (619 mg, 88%) as a colourless oil. [α]2D2 = –43.2 (c = 0.25,
1
CHCl3). H NMR (500 MHz, CDCl3): δ = 0.00, 0.03, 0.94 (3 s, 3
H, 3 H, 9 H, OTBS), 2.55 (s, 3 H, Me), 5.88 (s, 1 H, CHPh), 6.90,
7.41 (2 d, J = 2.0 Hz, 1 H each, 3-H/5-H), 7.17–7.19, 7.29–7.31,
7.48–7.50 (3 m, 1 H, 2 H, 2 H, Ph) ppm. 13C NMR (101 MHz,
CDCl3): δ = –5.2, –4.9, 18.1 (2 q, s, OTBS), 24.6 (q, Me), 25.6 (q,
OTBS), 77.2 (d, CHPh), 109.3, 113.6 (2 d, C-3/5), 126.3, 127.5,
128.3, 142.9 (3 d, s, Ph), 157.5, 160.8, 167.8 (3 s, C-2/C-4/C-6) ppm.
19F NMR (376 MHz, CDCl3): δ = –125.7, –120.8, –108.6,
–80.6 ppm. IR (neat): ν = 2955–2860 (C–H), 1595–1550 (C=C)
˜
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 0.03, 0.04, 0.95 (3 s, 3
cm–1. HRMS (ESI-TOF): calcd. for C23H25F9NO4SSi 612.1286 [M
+ H]+; found 612.1280. C23H25F9NO4SSi (611.6): calcd. C 45.17,
H 4.28, N 2.33; found C 45.29, H 4.28, N 2.23.
H, 3 H, 9 H, OTBS), 2.59 (s, 3 H, Me), 5.93 (s, 1 H, CHPh), 7.16
(s, 1 H, 3-H or 5-H), 7.18–7.20, 7.27–7.31, 7.51–7.54 (3 m, 1 H, 2
H, 2 H, Ar), 7.59 (s, 1 H, 3-H or 5-H), 7.65–7.67, 7.73–7.75 (2 m,
2 H, 2 H, Ar) ppm. 13C NMR (101 MHz, CDCl3): δ = –4.7, 18.4
(q, s, OTBS), 24.6 (q, Me), 25.9 (q, OTBS), 77.8 (d, CHPh), 112.5
(s, C-4Ј), 115.1 (d, C-3 or C-5), 118.6 (s, CϵN), 119.6 (d, C-3 or
C-5), 126.2, 127.3, 127.8, 128.2, 132.8 (5 d, Ar), 143.5, 143.8, 147.3,
(S)-2-[(tert-Butyldimethylsiloxy)(phenyl)methyl]-6-ethyl-3-methyl-
pyridin-4-yl Nonaflate (46): The pyridone 31 (254 mg, 0.71 mmol)
was treated with NaH (85 mg, 2.13 mmol) and NfF (634 mg,
2.10 mmol) in THF (7 mL) according to the typical procedure. Af-
ter 16 h, additional NfF (393 mg, 1.30 mmol) was added, and stir-
158.2, 165.1 (5 s, Ar, C-2/C-6) ppm. IR (ATR): ν = 3020–2860
˜
Eur. J. Org. Chem. 2011, 6056–6069
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6065

C. Eidamshaus, H.-U. Reissig
FULL PAPER
(=C–H, C–H), 2360–2280 (CN), 1710–1600 (C=C) cm–1. HRMS
(ESI-TOF): calcd. for C26H31N2OSi 415.2200 [M + H]+; found
415.2194.
H, 3 H, 9 H, OTBS), 1.10 (mc, 21 H, TIPS), 1.31 (t, X part of an
ABX3 system, JAX = JBX = 7.6 Hz, 3 H, Me), 2.21 (s, 3 H, 5-Me),
2.76, 2.81 (AB part of an ABX3 system, JAB = 1.9 Hz, 1 H each,
CH2), 6.09 (s, 1 H, CHPh), 7.15–7.38 (m, 6 H, 5-H, Ph) ppm. 13C
NMR (176 MHz, CDCl3): δ = –4.81, –4.80 (2 q, OTBS), 11.3 (d,
TIPS), 11.4 (q, Me), 14.2 (q, 6-Me), 15.4 (s, OTBS), 18.6 (q, TIPS),
25.9 (q, OTBS), 30.8 (t, CH2), 80.0 (d, CHPh), 98.9, 104.0 (2 s,
ϵC), 123.4 (s, C-3), 125.5 (d, Ph), 126.5 (d, C-5), 127.8, 131.1,
142.9 (2 d, s, Ph), 133.6, 158.7, 160.1 (3 s, C-2/C-4/C-6) ppm. IR
Ethyl (S,E)-3-{2-[(tert-Butyldimethylsiloxy)(phenyl)methyl]-6-meth-
ylpyridin-4-yl}acrylate (51): Pd(OAc)2 (5 mg, 0.02 mmol), tetra-n-
butylammonium chloride (137 mg, 0.98 mmol), NaHCO3 (90 mg,
1.03 mmol) and ethyl acrylate (98 mg, 0.98 mmol) were added to a
solution of the pyrid-4-yl nonaflate ent-45 (300 mg, 0.49 mmol) in
DMF (4 mL). The resulting mixture was heated at 70 °C under
argon for 4 h. The mixture was filtered through a short plug of
silica, and all volatile components were removed under reduced
pressure. The crude product was purified by flash column
chromatography (silica gel, hexane/EtOAc, 9:1) to afford 51
(133 mg, 66%) as a colourless solid, m.p. 55–58 °C. [α]2D2 = +50.4
(c = 0.75, CHCl3, 80% ee).[30] 1H NMR (500 MHz, CDCl3): δ =
0.02, 0.01, 0.93 (3 s, 3 H, 3 H, 9 H, OTBS), 1.33 (t, J = 7.0 Hz, 3
H, Me), 2.52 (s, 3 H, Me), 4.26, 4.27 (2 q, J = 7.0 Hz, 1 H each,
CH2), 5.86 (s, 1 H, CHPh), 7.03 (s, 1 H, 3-H or 5-H), 6.52, 7.54 (2
(ATR): ν = 3005–2850 (=C–H, C–H), 2200 (CϵC), 1645–1380
˜
(C=C) cm–1. HRMS (ESI-TOF): calcd. for C32H51NOSi2: 522.3587
[M + H]+; found 522.3621.
(S)-2-[(tert-Butyldimethylsiloxy)(phenyl)methyl]-6-methyl-4-
(piperidin-1-yl)pyridine (55): Piperidine (136 mg, 1.60 mmol) was
added to a solution of the pyrid-4-yl nonaflate ent-45 (198 mg,
0.32 mmol) in DMSO (1.6 mL), and the resulting mixture was
heated to 60 °C for 90 min. Water (10 mL) and EtOAc (30 mL)
were then added, the phases were separated, and the aqueous layer
d, J = 16.0 Hz, 1 H each, =CH), 7.18–7.21, 7.26–7.29 (2 m, 1 H, 2 was extracted with EtOAc (3ϫ30 mL). The combined organic lay-
H, Ph), 7.44–7.49 (m, 3 H, Ph, 3-H or 5-H) ppm. 13C NMR ers were washed consecutively with brine/water mixture (1:1) and
(101 MHz, CDCl3): δ = –4.89 (q, OTBS), 14.2 (q, Me), 18.3, 25.8
(s, q, OTBS), 24.4 (q, 6-Me), 60.8 (t, CH2), 77.6 (d, CHPh), 115.4,
119.7 (2 d, C-3/C-5), 122.1 (d, =CH), 126.0, 127.1, 128.1, 142.5 (3
brine, dried with Na2SO4 and filtered, and the solvents were evapo-
rated. The crude product was purified by flash column chromatog-
raphy (silica gel, hexane/EtOAc, 4:1 + 2 vol-% NEt3) to afford 55
d, s, Ph), 143.7 (d, =CH), 158.0, 164.9 (2 s, C-2/C-6), 166.3 (s, (101 mg, 80%) as a colourless solid, m.p. 71–73 °C. [α]2D2 = +34.0
CO R) ppm; the C-4 signal could not be detected. IR (ATR): ν =
(c = 0.5, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 0.01, 0.02, 0.94
(3 s, 3 H, 3 H, 9 H, OTBS), 1.60 (mc, 6 H, 3Ј-H/4Ј-H/5Ј-H), 2.40
(s, 3 H, Me), 3.29 (mc, 4 H, 2Ј-H/6Ј-H), 5.77 (s, 1 H, CHPh), 6.37,
6.84 (2 d, J = 2.4 Hz, 1 H each, 3-H/5-H), 7.15–7.19, 7.24–7.28,
7.49–7.51 (3 m, 1 H, 2 H, 2 H, Ph) ppm. 13C NMR (101 MHz,
CDCl3): δ = –4.9, –4.8, 18.2 (2 q, s, OTBS), 24.4 (q, Me), 24.7 (t,
C-4Ј), 25.1 (t, C-3Ј/C-5Ј), 25.8 (q, OTBS), 47.4 (t, C-2Ј/C-6Ј), 77.7
(d, CHPh), 101.9, 106.2 (2 d, C-3/C-5), 126.1, 126.7, 127.8, 144.4
(3 d, s, Ph), 156.1, 157.3, 164.2 (3 s, C-2/C-4/C-6) ppm. IR (ATR):
˜
2
3065–2855 (=C–H, C–H), 1775–1470 (C=O, C=C) cm–1. HRMS
(ESI-TOF): calcd. for C24H33NO3Si 434.2122 [M + Na]+; found
434.2208. C24H33NO3Si (411.6): calcd. C 70.03, H 8.08, N 3.40;
found C 70.00, H 8.06, N 3.34.
(R)-2-[(tert-Butyldimethylsiloxy)(phenyl)methyl]-6-methylpyridine
(52): Pd(OAc)2 (74 mg, 0.33 mmol), 1,3-bis(diphenylphosphanyl)-
propane (134 mg, 0.33 mmol), NEt3 (1.3 mL, 9.3 mmol) and formic
acid (0.26 mL, 6.9 mmol) were added to a solution of the pyrid-4-
yl nonaflate 45 (1.26 g, 2.06 mmol) in DMF (8 mL). The resulting
mixture was heated to 65 °C under argon for 16 h. After complete
consumption of the starting material (as indicated by TLC), all
volatile components were removed under reduced pressure, and the
residue was purified by flash column chromatography (silica gel,
hexane/EtOAc, 90:10) to provide 52 (630 mg, 98%) as a colourless
ν = 2950–2810 (C–H), 1590–1450 (C=C) cm–1. HRMS (ESI-TOF):
˜
calcd. for C24H36N2OSi 397.2670 [M + H]+; found 397.2671.
C
24H36N2OSi (396.6): calcd. C 72.67, H 9.15, N 7.06; found C
72.57, H 8.94, N 7.03.
(R)-2-[(tert-Butyldimethylsiloxy)(phenyl)methyl]-4-methoxy-6-
methylpyridine N-Oxide (56): m-CPBA (2.11 g, 8.78 mmol) was
added to a solution of 39 (1.44 g, 4.39 mmol) in CH2Cl2 (45 mL).
The mixture was stirred at room temp. for 16 h. Water (30 mL)
1
oil. [α]2D2 = –298 (c = 0.40, CHCl3). H NMR (400 MHz, CDCl3):
δ = –0.03, 0.00, 0.92 (3 s, 3 H, 3 H, 9 H, OTBS), 2.50 (s, 3 H, Me),
5.85 (s, 1 H, CHPh), 6.95 (d, J = 7.7 Hz, 1 H, 3-H/5-H), 7.17–7.20, was then added, and the aqueous layer was extracted with CH2Cl2
7.25–7.29 (2 m, 1 H, 2 H, Ph), 7.35 (d, J = 7.7 Hz, 1 H, 3-H/5-H), (3ϫ50 mL). The combined organic layers were washed with satd.
7.47–7.53 (m, 3 H, 4-H, Ph) ppm. 13C NMR (101 MHz, CDCl3): aq. NaHCO3 solution (3ϫ100 mL), dried with Na2SO4 and fil-
δ = –4.9, 18.2 (q, s, OTBS), 24.4 (q, Me), 25.8 (q, OTBS), 78.0 (d, tered. Evaporation of the solvent afforded 56 (1.43 g, 91 %) as
CHPh), 117.1, 121.5 (2 d, C-3/5), 126.1, 126.9, 128.0 (3 d, Ph), colourless crystals, m.p. 130–132 °C. [α]2D2 = –45.1 (c = 1.0, CHCl3).
136.8 (d, C-4), 144.1 (s, Ph), 156.9, 163.8 (2 s, C-2/C-6) ppm. IR
1H NMR (400 MHz, CDCl3): δ = –0.10, 0.03, 0.88 (3 s, 3 H, 3 H,
9 H, OTBS), 2.44 (s, 3 H, Me), 3.83 (s, 3 H, OMe), 6.36 (s, 1 H,
CHPh), 6.68 (d, J = 3.5 Hz, 1 H, 3-H or 5-H), 7.19–7.29 (m, 4 H,
Ph, 3-H or 5-H), 7.52–7.54 (m, 2 H, Ph) ppm. 13C NMR
(101 MHz, CDCl3): δ = –5.1, –4.9, 18.1 (2 q, s, OTBS), 18.2 (q,
Me), 25.7 (q, OTBS), 55.7 (q, OMe), 64.0 (d, CHPh), 106.2, 110.4
(2 d, C-3/C-5), 127.4, 127.5, 128.0, 141.1 (3 d, s, Ph), 149.5, 155.2,
(film): ν = 3010–2855 (=C–H, C–H), 1735–1545 (C=C) cm–1
.
˜
HRMS (ESI-TOF): calcd. for C19H27NOSi 314.1940 [M + H]+;
found 314.1940. C19H27NOSi (313.5): calcd. C 72.27, H 8.68, N
4.47; found C 72.70, H 8.51, N 4.39.
(S)-2-[(tert-Butyldimethylsiloxy)(phenyl)methyl]-6-ethyl-3-methyl-
4-[(triisopropylsilyl)ethynyl]pyridine (54): PdCl2(PPh3)2 (3 mg,
0.004 mmol), CuI (1 mg, 0.005 mmol) and (triisopropylsilyl)acetyl-
ene (22 mg, 0.12 mmol) were added to a solution of the pyrid-4-
yl nonaflate 46 (50 mg, 0.08 mmol) in NEt3 (1 mL). The resulting
mixture was heated to 60 °C under argon for 16 h. After complete
consumption of the starting materials, all volatile components were
removed under reduced pressure, and the residue was purified by
flash column chromatography (silica gel, hexane/EtOAc, 9:1) to af-
ford 54 (40 mg, 99%) as a colourless oil. [α]2D2 = –63.8 (c = 1.3,
157.0 (3 s, C-2/C-4/C-6) ppm. IR (ATR): ν = 2955–2855 (C–H),
˜
1635–1460 (C=C) cm– 1 . HRMS (ESI-TOF): calcd. for
C20H29NO3Si 360.1989 [M + H]+; found 360.2005. C20H29NO3Si
(359.5): calcd. C 66.81, H 8.13, N 3.90; found C 65.75, H 7.75, N
3.87.
(R)-{6-[(tert-Butyldimethylsiloxy)(phenyl)methyl]-4-methoxypyridin-
2-yl}methyl Acetate (57): The pyridine N-oxide 56 (1.87 g,
5.20 mmol) was dissolved in acetic anhydride (100 mL), and the
mixture was stirred at 90 °C for 2 h. After complete consumption
1
CHCl3). H NMR (400 MHz, CDCl3): δ = –0.13, 0.10, 0.94 (3 s, 3
6066
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6056–6069

Synthesis of Enantiopure Hydroxymethyl-Substituted Pyridine Derivatives
of the starting material (as indicated by TLC), all volatile compo-
nents were removed under reduced pressure to provide 57 (2.05 g,
98%) as a yellow oil. [α]2D2 = +37.9 (c = 1.2, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = –0.01, 0.91 (2 s, 6 H, 9 H, OTBS), 2.11 (s,
3 H, Me), 3.80 (s, 3 H, OMe), 5.11 (s, 2 H, CH2), 5.83 (s, 1 H,
CHPh), 6.68, 7.03 (2 d, J = 1.9 Hz, 1 H each, 3-H/5-H), 7.23–7.26,
7.44–7.47 (2 m, 3 H, 2 H, Ph) ppm. 13C NMR (101 MHz, CDCl3):
δ = –4.8, 18.4 (q, s, OTBS), 21.1 (q, Me), 25.9 (q, OTBS), 55.2 (q,
OMe), 66.8 (t, CH2), 77.1 (d, CHPh), 104.5, 106.8 (2 d, C-3/C-5),
126.2, 127.2, 128.2, 143.7 (3 d, s, Ph), 156.2 (s, C-4), 166.3, 167.2
3/C-5), 126.1, 127.4, 128.1, 143.2 (3 d, s, Ph), 153.6, 166.9, 167.2 (3
s, C-2/C-4/C-6), 193.6 (d, CHO) ppm. IR (ATR): ν = 3060–2860
˜
(=C–H, C–H), 1715 (C=O), 1595–1470 (C=C) cm–1. HRMS (ESI-
TOF): calcd. for C20H27NO3: 358.1833 [M + H]+; found 358.1820.
(R)-2-(Bromomethyl)-6-[(tert-butyldimethylsiloxy)(phenyl)methyl]-
4-methoxypyridine (60): CBr4 (98 mg, 0.29 mmol) and PPh3 (77 mg,
0.29 mmol) were added to a solution of 58 (88 mg, 0.25 mmol) in
CH2Cl2 (3 mL), and the resulting mixture was stirred at room temp.
for 5 h. All volatile components were removed under reduced pres-
sure, and the residue was purified by flash column chromatography
(silica gel, hexane/EtOAc, 9:1) to afford 60 (51 mg, 49 %) as a
colourless oil. [α]2D2 = +51.1 (c = 2.5, CHCl3). 1H NMR (700 MHz,
CDCl3): δ = 0.01, 0.02, 0.94 (3 s, 3 H, 3 H, 9 H, OTBS), 3.81 (s, 3
H, OMe), 4.44, 4.46 (AB system, JAB = 11.0 Hz, 1 H each, CH2Br),
5.84 (s, 1 H, CHPh), 6.79, 7.01 (2 d, J = 2.4 Hz, 1 H each, 3-H/5-
H), 7.19–7.22, 7.25–7.30, 7.47–7.49 (3 m, 1 H, 2 H, 2 H, Ph) ppm.
13C NMR (176 MHz, CDCl3): δ = –4.9, 18.2, 25.8 (q, s, q, OTBS),
34.1 (t, CH2Br), 55.2 (q, OMe), 77.3 (d, CHPh), 104.5, 108.3 (2 d,
C-3/C-5), 126.0, 127.1, 128.1, 143.5 (3 d, s, Ph), 157.0, 166.2, 167.1
(2 s, C-2/C-6), 170.7 (s, CO) ppm. IR (ATR): ν = 2950–2855
˜
(=C–H, C–H), 1745–1575 (C=O, C=C) cm–1. HRMS (ESI-TOF):
calcd. for C22H31NO4Si 402.2095 [M + H]+; found 402.2119.
(R)-{6-[(tert-Butyldimethylsiloxy)(phenyl)methyl]-4-methoxypyridin-
2-yl}methanol (58): The pyridine derivative 57 (1.90 g, 4.71 mmol)
was dissolved in MeOH (45 mL) and K2CO3 (3.26 g, 23.6 mmol)
was added. The resulting mixture was stirred at room temp. for 6 h.
The solvent was removed under reduced pressure and the residue
was dissolved in EtOAc (30 mL) and water (30 mL). The aqueous
phase was extracted with EtOAc (3ϫ50 mL). The combined or-
ganic layers were washed with brine, dried with Na2SO4 and fil-
tered, and the solvents were evaporated. The crude material was
purified by flash column chromatography (silica gel, hexane/
EtOAc, 3:2) to afford 58 (1.07 g, 63%) as a yellow oil. [α]2D2 = +11.6
(3 s, C-2/C-4/C-6) ppm. IR (ATR): ν = 3090–2855 (=C–H, C–H),
˜
1595–1460 (C=C) cm– 1 . HRMS (ESI-TOF): calcd. for
C20H28BrNO2Si 422.1145 [M + H]+; found 424.1099.
[(S)-1-({6-[(R)-(tert-Butyldimethylsiloxy)(phenyl)methyl]-4-meth-
oxypyridin-2-yl}methyl)pyrrolidin-2-yl]diphenylmethanol (62):
K2CO3 (33 mg, 0.24 mmol) and (S)-diphenylprolinol (61, 30 mg,
0.12 mmol) were added to a solution of 60 (50 mg, 0.12 mmol) in
EtOH (1 mL). The resulting mixture was stirred at room temp. for
3 d. The solvent was then removed under reduced pressure, the resi-
due was dissolved in EtOAc (10 mL), and water (10 mL) was
added. The phases were separated, and the aqueous layer was ex-
tracted with EtOAc (2ϫ15 mL). The combined organic layers were
dried with Na2SO4 and filtered, and the solvents were evaporated.
The crude product was purified by flash column chromatography
(silica gel, hexane/EtOAc, 9:1) to afford 62 (53 mg, 74 %) as a
colourless oil. [α]2D2 = +56.8 (c = 2.5, CHCl3). 1H NMR (500 MHz,
CDCl3): δ = 0.00, 0.02, 0.94 (3 s, 3 H, 3 H, 9 H, OTBS), 1.54–1.61,
1.63–1.75, 1.85–1.97 (3 m, 2 H, 1 H, 1 H, 3Ј-H/4Ј-H), 2.64 (dd, J
= 7.9, 17.2 Hz, 1 H, 2Ј-H), 2.98 (mc, 1 H, 5Ј-H), 4.13 (br. dd, J =
4.9, 9.0 Hz, 1 H, 5Ј-H), 3.26, 3.32 (AB system, JAB = 14.1 Hz, 1 H
each, 2-CH2), 3.78 (s, 3 H, OMe), 5.08 (br. s, 1 H, OH), 5.79 (s, 1
H, CHPh), 6.33, 6.92 (2 d, J = 2.4 Hz, 1 H each, 3-H/5-H), 7.02–
7.06, 7.13–7.30, 7.43–7.45, 7.52–7.54, 7.62–7.64 (5 m, 1 H, 8 H, 2
H, 2 H, 2 H, Ph) ppm. 13C NMR (101 MHz, CDCl3): δ = –4.8,
18.4, 26.0 (q, s, q, OTBS), 24.6, 29.9 (2 t, C-3Ј/C-4Ј), 55.1 (q, OMe),
55.5 (t, C-5Ј), 61.1 (t, CH2), 70.2 (d, C-2Ј), 77.5 (d, CHPyr), 78.0
(s, CPh2), 104.2, 107.1 (2 d, C-3/C-5), 125.8, 126.2, 126.3, 126.8,
127.7, 128.1, 144.0, 146.6, 148.0 (6 d, 3 s, Ph), 160.3, 165.4, 166.7
1
(c = 0.43, CHCl3). H NMR (400 MHz, CDCl3): δ = –0.02, 0.00,
0.92 (3 s, 3 H, 3 H, 9 H, OTBS), 3.80 (s, 3 H, OMe), 4.58, 4.64
(AB system, JAB = 23.5 Hz, 1 H each, CH2), 5.79 (s, 1 H, CHPh),
6.51, 7.03 (2 d, J = 3.5 Hz, 1 H each, 3-H/5-H), 7.21–7.26, 7.43–
7.46 (2 m, 3 H, 2 H Ph) ppm. 13C NMR (101 MHz, CDCl3): δ =
–4.1, –4.9, 18.3, 28.2 (2 q, s, q, OTBS), 55.2 (q, OMe), 63.6 (t,
CH2), 77.3 (d, CHPh), 104.0, 104.7 (2 d, C-3/C-5), 126.2, 127.2,
128.1, 143.5 (3 d, s, Ph), 159.2, 164.8, 167.1 (3 s, C-2/C-4/C-6) ppm.
IR (ATR): ν = 3235 (OH), 2950–2850 (=C–H, C–H), 1730–1460
˜
(C=C) cm–1. HRMS (ESI-TOF): calcd. for C20H29NO3Si 360.1995
[M + H]+; found 360.1998.
(R)-6-[(tert-Butyldimethylsiloxy)(phenyl)methyl]-4-methoxypicolin-
aldehyde (59)
(A) By Swern Oxidation: DMSO (44 mg, 0.56 mmol) was added at
–60 °C to a solution of oxalyl dichloride (39 mg, 0.31 mmol) in
CH2Cl2 (1 mL). The resulting mixture was stirred at the same tem-
perature under argon for 5 min, after which 58 (100 mg, 0.28 mmol,
dissolved in 1.4 mL of CH2Cl2) was added, followed by NEt3
(196 μL, 1.40 mmol). Stirring at –60 °C was continued for 20 min,
after which the mixture was allowed to warm to room temp. over
2.5 h. All volatile components were then removed under reduced
pressure to provide 59 (97 mg, 97%) as a yellow oil. No further
purification was necessary.
(3 s, C-2/C-4/C-6) ppm. IR (ATR): ν = 3220 (br., OH), 3085–2850
˜
(B) By IBX Oxidation: IBX (398 mg, 1.42 mmol) was added to a
solution of 58 (446 mg, 1.29 mmol) in CH2Cl2 (10 mL) and DMSO
(1.4 mL) and the resulting mixture was stirred at room temp. for
16 h. Aq. Na2S2O3 solution (1m, 5 mL) and EtOAc (20 mL) were
then added, and the mixture was stirred until it became homogen-
eous (15 min). The phases were separated, and the aqueous layer
was extracted with EtOAc (3ϫ30 mL). The combined organic lay-
ers were dried with Na2SO4 and filtered, and all volatile compo-
nents were removed under reduced pressure to leave pure 59
(453 mg, 98%) as a colourless oil. [α]2D2 = +13.5 (c = 0.2, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 0.00, 0.01, 0.93 (3 s, 3 H, 3 H,
9 H, OTBS), 3.86 (s, 3 H, OMe), 5.91 (s, 1 H, CHPh), 7.27–7.33
(=C–H, C–H), 1655–1445 (C=C) cm–1. HRMS (ESI-TOF): calcd.
for C37H47N2O3Si 595.3351 [M + H]+; found 595.3392.
(R)-2-[(tert-Butyldimethylsilyloxy)(phenyl)methyl]-6-ethynyl-4-meth-
oxypyridine (64): Dimethyl (1-diazo-2-oxopropyl)phosphonate (63,
101 mg, 0.53 mmol) and K2CO3 (121 mg, 0.88 mmol) were added
to a solution of 58 (150 mg, 0.42 mmol) in MeOH (7 mL). The
resulting mixture was stirred at room temp. for 90 min. After con-
sumption of the starting material, satd. aq. NaHCO3 solution
(10 mL) and Et2O (20 mL) were added. The layers were separated,
and the aqueous layer was extracted with Et2O (2ϫ30 mL). The
combined organic layers were washed with brine, dried with
(m, 5 H, Ph, 3-H/5-H), 7.48–7.50 (m, 2 H, Ph), 9.95 (s, 1 H, CHO) Na2SO4 and filtered, and the solvents were evaporated. The crude
ppm. 13C NMR (101 MHz, CDCl3): δ = –4.9, –4.8, 18.2, 25.8 (2 q, material was purified by flash column chromatography on silica gel
s, q, OTBS), 55.5 (q, OMe), 77.2 (d, CHPh), 105.6, 110.3 (2 d, C-
(hexane/EtOAc, 4:1) to provide 64 (95 mg, 64%) as a colourless
Eur. J. Org. Chem. 2011, 6056–6069
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6067

C. Eidamshaus, H.-U. Reissig
FULL PAPER
solid, m.p. 102 °C. [α]2D2 = +109.6 (c = 0.52, CHCl3). 1H NMR
Me), 74.8 (d, CHOH), 116.4, 120.1 (2 d, C-3/C-5), 127.0, 127.1,
(500 MHz, CDCl3): δ = –0.01, 0.10, 0.93 (3 s, 3 H, 3 H, 9 H, 127.7, 128.5, 128.9 (5 d, Ph),* 138.2, 143.4, 149.7 (3 s, Ph, C-4),
OTBS), 3.08 (s, 1 H, ϵCH), 3.80 (s, 3 H, OMe), 5.86 (s, 1 H, 157.1, 160.6 (2 s, C-2/C-6) ppm; * the signal of one carbon atom
CHPh), 6.85, 7.10 (2 d, J = 2.5 Hz, 1 H each, 3-H/5-H), 7.18–7.21,
could not be detected. IR (ATR): ν = 3310 (OH), 3060–2850
˜
7.26–7.29, 7.48–7.50 (3 m, 1 H, 2 H, 2 H, Ph) ppm. 13C NMR (=C–H, C–H), 1605–1555 (C=C) cm–1. HRMS (ESI-TOF): calcd.
(101 MHz, CDCl3): δ = –4.9, 18.2, 25.8 (q, s, q, OTBS), 55.2 (q,
OMe), 76.4, 84.0 (s, d, ϵC), 77.3 (d, CHPh), 105.9, 112.6 (2 d, C-
3/C-5), 125.9, 127.1, 128.1, 143.3 (3 d, s Ph), 141.9, 166.3, 166.9 (3
for C19H17NO 276.1388 [M + H]+; found 276.1392. C19H17NO
(275.2): C 82.88, H 6.22, N 5.09; found C 82.53, H 5.95, N 5.23.
(R)-4-{2-[Hydroxy(phenyl)methyl]-6-methylpyridin-4-yl}benzo-
nitrile (50): Compound 49 (609 mg, 1.47 mmol) was treated with
TBAF (1 m in THF, 1.62 mL, 1.62 mmol) according to the typical
procedure to provide 50 (397 mg, 90%) as colourless crystals after
flash column chromatography (silica gel, hexane/EtOAc, 4:6), m.p.
s, C-2/C-4/C-6) ppm. IR (ATR): ν = 3315 (ϵC–H), 3005–2855
˜
(=C–H), 1585–1430 (C=C) cm–1. HRMS (ESI-TOF): calcd. for
C21H27NO2Si 354.1884 [M + H]+; found 354.1884. C21H27NO2Si
(353.5): calcd. C 71.34, H 7.70, N 3.96; found C 71.36, H 7.54, N
4.03.
1
156–158 °C. [α]2D2 = –13.8 (c = 0.50, CHCl3). H NMR (500 MHz,
CDCl3): δ = 2.70 (s, 3 H, Me), 5.42 (br. s, 1 H, OH), 5.81 (s, 1 H,
CHOH), 7.14, 7.27 (2 s, 1 H each, 3-H/5-H), 7.29–7.33, (m, 1 H,
Ph), 7.36–7.39, 7.44–7.45, 7.63–7.65, 7.73–7-75 (4 m, 2 H each, Ph,
Ar) ppm. 13C NMR (101 MHz, CDCl3): δ = 24.3 (q, Me), 74.5 (d,
CHOH), 112.6 (s, Ar), 116.3 (d, C-3 or C-5), 118.3 (s, CN), 120.1
(d, C-3 or C-5), 127.1, 127.8, 127.8, 128.6, 132.7 (5 d, Ph, Ar),
142.8, 143.0, 147.7, 157.7, 161.2 (5 s, Ph, Ar, C-2/C-4/C-6) ppm.
Typical Procedure for the Desilylation of TBS-Protected Hy-
droxymethyl-Substituted Pyridine Derivatives. (R)-(4-Methoxy-6-
methylpyridin-2-yl)(phenyl)methanol (40): TBAF (1 m in THF,
0.37 mL, 0.37 mmol) was added to a solution of 39 (106 mg,
0.31 mmol) in THF (3 mL), and the resulting mixture was stirred
at room temp. for 2 h, after which water (10 mL) and EtOAc
(20 mL) were added. The phases were separated, and the aqueous
layer was extracted with EtOAc (2ϫ20 mL). The combined organic
layers were dried with Na2SO4 and filtered, and the solvents were
evaporated. The crude product was purified by flash column
chromatography (silica gel, hexane/EtOAc, 7:3) to afford 40 (71 mg,
99%) as colourless crystals, m.p. 107–108 °C. [α]2D2 = –104.0 (c =
IR (ATR): ν = 3495 (OH), 2950–2800 (=C–H, C–H), 2230 (CN),
˜
1600–1390 (C=C) cm–1. HRMS (ESI-TOF): calcd. for C20H16N2O
301.1341 [M + H]+; found 301.1337. C20H16N2O (300.4): calcd. C
79.98, H 5.37, N 9.33; found C 78.65, H 5.47, N 9.46.
(R)-(6-Methylpyridin-2-yl)(phenyl)methanol (53): Compound 52
(623 mg, 1.99 mmol) was treated with TBAF (1 m in THF, 2.19 mL,
2.19 mmol) according to the typical procedure to provide 53
(366 mg, 92%) as colourless crystals after flash column chromatog-
raphy (silica gel, hexane/EtOAc, 1:1), m.p. 103–104 °C. [α]2D2 = –181
1
1.0, CHCl3). H NMR (500 MHz, CDCl3): δ = 2.52 (s, 3 H, Me),
3.72 (s, 3 H, OMe), 4.80 (br. s, 1 H, OH), 5.63 (s, 1 H, CHPh),
6.41, 6.56 (2 s, 1 H each, 3-H/5-H), 7.23–7.38 (m, 5 H, Ph) ppm.
13C NMR (126 MHz, CDCl3): δ = 24.3 (q, Me), 55.0 (q, OMe),
74.6 (d, CHOH), 104.2, 108.0 (2 d, C-3/C-5), 127.0, 127.6, 128.4,
143.4 (3 d, s, Ph), 158.1, 161.8, 166.7 (3 s, C-2/C-4/C-6) ppm. IR
1
(c = 0.60, CHCl3). H NMR (500 MHz, CDCl3): δ = 2.59 (s, 3 H,
Me), 5.69 (s, 1 H, CHOH), 6.88, 7.03 (2 d, J = 7.7 Hz, 1 H each,
3-H/5-H), 7.24–7.28, 7.30–7.39 (2 m, 1 H, 4 H, Ph), 7.48 (t, J =
7.7 Hz, 1 H, 4-H) ppm; the OH signal was not detected. 13C NMR
(101 MHz, CDCl3): δ = 24.2 (q, Me), 74.5 (d, CHOH), 118.3, 121.8
(2 d, C-3/C-5), 127.1, 127.7, 128.5 (3 d, Ph), 137.1 (d, C-4), 143.4
(ATR): ν = 3140 (OH), 2920–2850 (=C–H), 1600–1580 (C=C)
˜
cm–1. HRMS (ESI-TOF): calcd. for C14H15NO2: 230.1176
[M + H]+; found 230.1189. C14H15NO2 (229.1): calcd. C 73.34, H
6.59, N 6.11; found C 73.00, H 6.39, N 6.04.
(s, Ph), 156.6, 159.8 (2 s, C-2/C-6) ppm. IR (ATR): ν = 3200 (OH),
˜
(S)-1-(4-Methoxy-6-methylpyridin-2-yl)-2-methylpropan-1-ol (42):
Compound 41 (88 mg, 0.28 mmol) was treated with TBAF (1 m in
THF, 0.31 mL, 0.31 mmol) according to the typical procedure to
provide 42 [33 mg, 59%, starting material (20 mg) was reisolated,
yield based on recovered starting material 77%] as colourless crys-
tals after flash column chromatography (silica gel, hexane/EtOAc,
7:3), m.p. 96–97 °C. [α]2D2 = +30.0 (c = 0.12, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 0.76, 1.00 (2 d, J = 6.8 Hz, 3 H each, iPr),
1.97 (dsept, J = 4.1, 6.8 Hz, 1 H, iPr), 2.47 (s, 3 H, Me), 3.81 (s, 3
H, OMe), 4.42 (d, J = 4.1 Hz, 1 H, CHOH), 6.52, 6.55 (2 d, J =
2.2 Hz, 1 H each, 3-H/5-H) ppm; the OH signal was not detected.
13C NMR (101 MHz, CDCl3): δ = 15.9, 19.6 (2 q, iPr), 24.4 (q,
Me), 35.0 (d, iPr), 55.0 (q, OMe), 76.8 (d, CHOH), 103.6, 107.7 (2
d, C-3/C-5), 158.1 (s, C-4), 162.2, 166.4 (2 s, C-2/C-6) ppm. IR
2950–2840 (=C–H, C–H), 1685–1575 (C=C) cm–1. HRMS (ESI-
TOF): calcd. for C13H13NO 200.1075 [M + H]+; found 200.1082.
C13H13NO (199.2): calcd. for C 78.36, H 6.58, N 7.03; found C
78.33, H 6.53, N 6.95.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed description of Mosher ester formation and determi-
nation of the enantiomeric excess.
Acknowledgments
Support of this work by the Deutsche Forschungsgemeinschaft
(SFB 765), the Bayer Schering Pharma AG and the Studienstiftung
des Deutschen Volkes (Ph.D. fellowship to C. E.) is most gratefully
acknowledged. We also thank Dr. R. Zimmer for help during the
preparation of this manuscript and M. Hoppe (Freie Universität
Berlin) for experimental contributions.
(ATR): ν = 3165 (OH), 2970–2845 (=C–H, C–H), 1595–1465
˜
(C=C) cm–1. HRMS (ESI-TOF): calcd. for C11H17NO2: 196.1338
[M + H]+; found 196.1389. C11H17NO2 (195.3): calcd. C 67.66, H
8.78, N 7.17; found 67.69, H 8.58, N 6.99.
(R)-(6-Methyl-4-phenylpyridin-2-yl)(phenyl)methanol (48): Com-
pound 47 (183 mg, 0.47 mmol) was treated with TBAF (1 m in
THF, 0.52 mL, 0.52 mmol) according to the typical procedure to
provide 48 (124 mg, 96%) as colourless crystals after flash column
chromatography (silica gel, hexane/EtOAc, 7:3), m.p. 126–128 °C.
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[α]2D2 = –10.3 (c = 0.50, CHCl3). H NMR (500 MHz, CDCl3): δ =
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m, 7 H, 2 H, Ph) ppm. 13C NMR (101 MHz, CDCl3): δ = 24.3 (q,
6068
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Eur. J. Org. Chem. 2011, 6056–6069

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The pyridine derivatives 51 and 55 were prepared from a batch
of mandelic acid with 80% ee.
[30]
Received: May 13, 2011
Published Online: August 24, 2011
Eur. J. Org. Chem. 2011, 6056–6069
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6069