Regioselective Functionalization of 3-Hydroxy-pyridine Carboxylates by Neighboring Group Assistance

Article abstract of DOI:10.1002/asia.201601111

Regioselective hydrolysis, transesterification, and aminolysis of unactivated, highly substituted pyridine esters were realized under mild conditions by employing neighboring group assisted catalysis. Excellent yields were achieved without active removal of the alcohol byproduct. Regioselective aminolysis had a considerable substrate scope ([hetero]aryl, alkyl and amino acid). A mechanism involving assistance by the deprotonated phenolic OH-group is suggested for hydrolysis and transesterification.

Full text of DOI:10.1002/asia.201601111

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Accepted Article
Title: Regioselective functionalization of 3-hydroxy-pyridine carboxylates by neigh-
boring group assistance
Authors: Hans-Dieter Arndt
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Regioselective functionalization of 3-hydroxy-pyridine
carboxylates by neighboring group assistance
K. Philip Wojtas, Jin-Yong Lu, Daniel Krahn, and Hans-Dieter Arndt*
Abstract: Regioselective hydrolysis, transesterification, and
aminolysis of unactivated, highly substituted pyridine esters were
realized under mild conditions by employing neighboring group
assisted catalysis. Excellent yields were achieved without active
removal of the alcohol byproduct. Regioselective aminolysis had a
considerable substrate scope ([hetero]aryl, alkyl and amino acid). A
mechanism involving assistance by the deprotonated phenolic OH-
group is suggested for hydrolysis and transesterification.
During the ensuing investigations it was found (Table 1) that
nBu NOH delivered the corresponding acid, albeit in moderate
yield (entry 1). We then turned our attention to transition metal
4
[7]
triflates. Yb(OTf)
(entry 2). In contrast, Sc(OTf)
3
did not show any activity in the hydrolysis
cleanly hydrolyzed the methyl
3
ester at position 2 of the pyridine ring at room temperature (entry
3). By elevating the temperature, the desired acid 2 was
obtained in good yield (entry 4). Further increase of the
temperature and concentration enhanced the conversion and
showed no side effect on the regioselectivity (entry 5). Lower
catalyst loading and high temperature lead to decomposition of
the pyridine 2 after long reaction time (entry 6). Further
screening of reaction conditions revealed that with 5 mol%
Carboxylic acid esters are ubiquitously present in natural
products and man-made molecules. They serve both as key
[
1]
intermediates and/or protecting groups in organic synthesis.
[
2]
[3]
Transesterification, ester-amide exchange, and saponification
are typically used to re-functionalize esters. Conventional
transesterifications with azeotropic removal of alcohol suffer
from quite harsh reaction conditions. The use of stoichiometric
amounts of activating reagents in stepwise manipulations
3
Sc(OTf) at pH 8.5 the reaction delivered at 60°C the desired
acid 2 in excellent yield and complete regioselectivity (entry 7).
However, in absence of Sc(III) salt similar results were obtained
(
entry 8). Hence, the metal ions were not necessary, and a
mode of activation different from chelation was likely to operate.
[
3a]
generally compromises transformation economy.
Therefore,
transition metal mediated or catalyzed transesterification and
ester-amide exchange reactions in homogeneous medium have
Table 1. Condition screening toward regioselective hydrolysis of diester 1.
[
2,3a+c,4]
attracted considerable interest.
However, regioselective
transformations of esters are typically limited to the hydrolysis of
entry
catalyst
nBu NOH
Yb(OTf)
Sc(OTf)
mol%
solvent
conditions
yield (2)
[
5]
symmetrical methyl esters when applying enzymes.
During our efforts toward a total synthesis of the thiopeptide
1
2
3
4
200
100
100
dioxane
r.t., 40 min
r.t., 24 h
r.t., 24 h
50%
[
6]
antibiotic nosiheptide, we were faced with the challenge of
regioselectively hydrolyzing one of the two methyl esters present
in the intermediate 1 (Scheme 1). Despite the apparent steric
and electronic differentiation of the methyl esters, many routine
methods typically used for ester cleavage such as LiOH showed
only negligible selectivity. Furthermore, product separation and
purification was demanding even by preparative HPLC.
[a]
3
dioxane/H
dioxane/H
2
O
-
[
[
a]
a]
3
2
O
>60% conv.
4
5
6
7
8
Sc(OTf)3
100
100
5
dioxane/H O
2
40 °C, 3 d
60 °C, 15 h
110 °C, 19 h
60 °C, 9 h
60 °C, 8 h
53%
92%
[a]
Sc(OTf)
3
2
dioxane/H O
[
a]
Sc(OTf)
3
dioxane/H
dioxane/H
dioxane/H
2
O
decomp.
93%
[
b]
b]
Sc(OTf)
3
5
2
O
[
NaHCO
3
400
2
O
95%
[
a] Apparent pH = 4.3 - 4.5 without buffer; [b] pH 8.5.
Scheme 1. Regioselective methyl ester hydrolysis of intermediate 1 in the total
synthesis of nosiheptide.
The influence of the 3-hydroxyl moiety on the regioselectivity of
the transformation was examined next. As test substrates the
highly substituted hydroxypyridines 3a-d (Scheme 2) were
[
6a]
used,
which contain three methyl ester groups at different
[
a]
Dipl.-Chem. K. Philip Wojtas, Dr. J.-Y. Lu, Dipl.-Chem. Daniel Krahn,
Prof. Dr. H.-D. Arndt
Friedrich-Schiller-Universität
Institut für Organische Chemie und Makromolekulare Chemie
Humboldtstraße 10, 07743 Jena, Germany
E-mail: hd.arndt@uni-jena.de
positions on the pyridine ring. Pyridine 3a was selected as the
prototype substrate for further manipulations, including
transesterification and aminolysis reactions (vide infra).
Under the conditions investigated, the hydroxypyridine
monoacid 4a (Scheme 2) was obtained in excellent yield. To
study the role of the 3-hydroxyl group, the 3-hydroxyl
functionality on the pyridine was blocked using sulfonate and
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ether groups. As a result, the reactivity of tosylate 3b was found
reduced, despite the electron-withdrawing substitution. The only
product apart from the unchanged pyridine 3b was the Ts-
deprotected acid 4a. Apparently, cleavage of the Ts group
occurred slowly, then triggering fast ester hydrolysis. However,
when using the less bulky Me ether (3c) to protect the phenol a
complex mixture of products was obtained upon saponification.
Moreover, methyl 3-methoxypicolinate was not hydrolysed under
these conditions at all (data not shown).
that Sc(OTf)
3
appeared to activate the carboxyl group in position
2 regioselectively (Table 1, entry 5), this Lewis acid was
screened for transesterification efficacy as well. We found that
5 mol% of Sc(OTf) were sufficient to promote the transformation.
3
However, in comparison to the tertiary amine its performance
was inferior in all cases studied.
Table 2. Transesterification of picolinate 3a.
entry
R
yield A/B (5)
quant./n.d.
98%/90%
a
b
c
Et
Allyl
iPr
[
a]
95% /88%
[
b]
d
e
f
2-Hydroxyethyl
Benzyl
84%/46%
78%/trace
Scheme 2. Regioselective methyl ester hydrolysis of picolinates 3. a) TsCl,
[
c]
p-Methoxybenzyl
o-Nitrobenzyl
tBu
trace /no conv.
no conv./ no conv.
no conv./ no conv.
EtNiPr
2
, DMAP, THF, r.t., 15 h, 94%; b) MeI, K
(4 equiv.), 60°C.
2 3
CO , DMF, 20 h, 99%; c) 1,4-
dioxane/water (2:1), NaHCO
3
g
h
i
In order to confirm the apparent regioselectivity, the isotopically
labelled 3-hydroxypyridine 3d was designed and synthesized by
using an 1-azadiene hetero-Diels-Alder reaction (see supp. inf.
[
c]
[6a]
Ph
no conv. / no conv.
for details).
After saponification under the conditions just
developed, high resolution mass spectrometry (HRMS)
confirmed regioselective hydrolysis at position 2, i.e. formation of
monoacid 4d.
[
c]
j
D-Glucose
no conv. / no conv.
[
a] Performed at 85 °C; [b] 69% based on recovered starting material; [c]
These data indicated that a free phenolic OH-group was
crucial for the transformation to occur. Interestingly, specific rate
enhancements have been reported for unprotected salicylates.
This effect was subject to several mechanistic studies that
showed a pH-dependent intramolecular assistance of the OH-
ROH/1,4-dioxane = 1:1; [d] D-Glucose (2 equiv.), 1,4-dioxane/H O = 1:1.
2
Transesterification of hydroxypyridine 3a with allyl alcohol and
iso-propanol gave excellent yields (Table 2, entry b and c). An
X-ray structure was obtained in case of pyridine 5b (Figure 1),
[
12]
[8]
group in nucleophilic reactions. Some applications of this
which fully confirmed the assignment of the regioisomers.
[
9]
transformation have been reported as well.
While 3-
is slightly more acidic than methyl
9.8), it is in the range of the pH of the medium
used. Our observation hence suggested a similar activation for
-hydroxypyridines as for salicylates, and furthermore, that this
[
10]
a
hydroxypyridine (pK 8.7)
[11]
salicylate (pK
a
3
effect may be utilized in a more general context.
2
Scheme 3. Regioselective transesterification. a) 10 mol% EtNiPr , ROH,
3 2
60 °C; b) 5 mol% Sc(OTf) , ROH, cat. H O, 60 °C.
Therefore, after establishing the regioselective hydrolysis to the
2
3
-carboxylic acid, transesterification was studied next (Scheme
). Gratifyingly, 10 mol% of EtNiPr were found to give
2
[
12]
Figure 1. Ortep plot of an X-ray structure data of pyridine 5b. Heavy atom
ellipsoids are shown at the 35% confidence level.
quantitative yield of regioselective transesterification with
ethanol within 20 h (Table 2, entry a). Based on the observation
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Only mono-transesterification of glycol was observed leading to
alcohol 5d in good yield (entry d) with the second hydroxyl group
being left untouched. Further screening with synthetically useful
but less reactive benzyl alcohol led to lower efficacy (entry e).
Other benzylic alcohols could not be used (entry f and g).
Phenol and t-BuOH could not be transformed to the desired
esters either, even at elevated temperature (100 °C, sealed
tube). The hydrolyzed acid was the only product observed,
except of recovered starting material (entry h-i). D-glucose did
not give any detectable conversion (entry j), indicating the
limitations of this methodology.
Table 3. Hydroxyl-assisted ester-amide exchange of 3-hydroxypicolinates 3.
1
2
3
entry
SM
R
R
R
yield
7)
(
a
b
c
d
3a
3a
3a
3a
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
NHBn
NHBn
NHBn
NHCy
93%
[
a]
62%
99%
[b]
82%
91%
Interestingly, employing Sc(III) to 3-methoxypyridine 3c
under transesterification conditions gave the double ethyl ester 6
in quantitative yield (Scheme 4). This change in selectivity imply-
cates a participation of the phenol in the Lewis-acid catalyzed
transformation of pyridine 3a. Most likely a different mechanism
is active in case of 3c, such as tridentate chelation with
simultaneous activation of both ester groups in positions 2 and 6.
4
e
f
3a
3a
3a
3a
8
COOMe
COOMe
COOMe
COOMe
Ph
COOMe
COOMe
COOMe
COOMe
CN
R
5
[c]
R
57%
56%
92%
50%
60%
g
h
i
HSer(TBS)NH
HSerOMe
HSerOMe
HSerOMe
nPrNH
2
6
j
9
R
CN
7
[c]
k
l
10
11
Me-CO-
H
R
73%
8
[c,d]
R
nPrNH
72%
[
2 2
a] 100 mol% of BnNH was used; [b] dioxane/EtNiPr = 1:1, 20°C, 3 h; [c]
run at 60 °C; [d] 1,4-dioxane/DMSO = 3/2 was used; Cy = cyclohexyl.
In order to further explore the scope of this mild ester-amide
[
13]
exchange 6-cyanopyridines
esters 8 and 9 smoothly transformed into amides 7i and 7j
entries i-j), notably without any indication for nitrile hydrolysis. 3-
were additionally studied. Nitrile
(
Hydroxypyridines 10 and 11 containing keto groups were
converted to the corresponding amides 7k and 7l as well
(
entries k and l) without any appreciable indication of imine
formation or other side products attributable to the keto groups.
Scheme 4. 2,6-Selective transesterification and 2-selective aminolysis.
For a mechanistic explanation earlier reports on salicylates
have invoked intramolecular H-bond catalysis of the non-ionized
phenol A1 in aprotic solvent (Scheme 5, path a). Alternatively,
To investigate regioselective amide formation, 3-hydroxypyridine
[8c]
3
a was treated with diverse amines (Scheme 4, Table 3). A
clean transformation occurred with excess of benzyl amine
entry a). Equimolar amounts led to lower efficiency (entry b),
intramolecular assistance of a phenolate B1 generated in polar,
[8d-e]
protic solvent (path b) has been proposed.
It is likely that the
(
acidic 3-hydroxypyridines studied here will be deprotonated at
pH 8.5 in aqueous medium to generate a phenolic anion B1.
The phenolate anion could serve as an intramolecular base to
assist nucleophilic attack (B1), and then as a proton relay for
facilitating the breakdown of the tetrahedral intermediate B2. In
fact, a deeper coloration was observed during turnover of some
substrates with aqueous bicarbonate, indicative of ionization and
the anionic path b. Furthermore, attempts to induce selective
transesterification with acids (AcOH, TCA, TFA) were not suc-
cessful, disfavoring path a for hydrolysis and transesterification.
On the other hand, the neutral path a could still benefit from the
assistance of a base in nucleophile deprotonation (A1) or in
but nearly quantitative yield of amide 7a was obtained with
excess of additional tertiary amine (entry c), indicating that the
availability of sufficient base is important for complete turnover.
Several primary and secondary amines as well as amino
acid derivatives could be effectively employed as well.
Transformation of cyclohexyl amine and morpholine delivered
the corresponding amide in good yields (entries d-e). Even the
sterically hindered 1-adamantylamine could be regioselectively
introduced at elevated temperature (60°C, entry f), while at 20°C
conversion remained insignificant (TLC). Picolinic acid amide 7e
was obtained in acceptable yield from O-TBS-protected L-serine
[
14]
[
8c]
promoting the potentially rate-limiting
decomposition of the
amide. In comparison, L-serine methyl ester delivered amide
f with excellent yield, which might be a result of the reduced
steric hindrance of the free hydroxyl group in the serine residue
entries g-h). OH-induced reactions of the serine ester groups
neutral tetrahedral intermediate A2. This pathway cannot be
excluded at present for the aprotic conditions of the aminolysis
reaction. However, both mechanistic alternatives benefit from a
free phenolic OH-group in ortho position as an activating neigh-
boring group that renders the transformation regioselective.
7
(
were not observed, indicating the distinct activating potential of
the much more acidic phenolic OH group.
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In summary, we have shown 3-hydroxypicolinates to undergo
facile regioselective methyl ester hydrolysis, transesterification,
and aminolysis reactions with diverse amines. These
transformations occur preferentially ortho to the free phenolic
OH-group, indicating intramolecular assistance. Complete regio-
selectivity can be achieved by adjusting the medium. Scope and
functional group tolerance are remarkable, and neither inert
atmosphere nor anhydrous solvent are necessary. These trans-
formations offer hence new options for the synthesis and
medicinal chemistry of polyfunctional target molecules, and will
also be helpful for accessing novel pyridine donor ligands.
Keywords: amides • neighboring-group effects • regioselectivity
•
scandium • transesterification
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Scheme 5. Possible intramolecular assistance during the transformation of
salicylates and 3-hydroxypicolinic acid esters (simplified); B = external base,
SM = starting material, P = product, X = CH, N; Y = O, NH.
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General procedure A (GP A) for regioselective hydrolysis:
A mixture of the 3-hydroxypyridine (39 µmol) and NaHCO
[
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3
(13 mg,
156 µmol) in 1,4-dioxane (2 mL) and water (0.6 mL) was heated to 60 °C
for 8-10 h (HPLC control). Phosphate buffer (pH 2.5, 30 mL) was added,
and the mixture was extracted with ethyl acetate (3 × 50 mL). The
combined extracts were dried (Na
column chromatography (10 g silica gel, CH
2
SO
4
), concentrated, and purified by
Cl /MeOH).
2
2
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General procedure B (GP B) for transesterification:
A mixture of 3-hydroxypyridine 3a (14 mg, 52 µmol) and EtNiPr (5 µmol)
2
in the respective alcohol (2 mL) was heated to 60 °C until conversion was
complete (TLC/GC control). The mixture was concentrated and purified
by column chromatography (10 g silica gel, PE/EtOAc).
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1
,4-dioxane (0.5 mL) and stirred at room temperature or at 60 °C for the
given time (TLC control). Phosphate buffer (pH 3.0, 10 mL) was added,
and the mixture was extracted with CH Cl (3 × 10 mL). The combined
organic extracts were dried (Na SO ), concentrated, and purified by
column chromatography (10 g silica gel, PE/EtOAc or CH Cl /MeOH).
2
2
2
4
[10] A. Albert, J. N. Philipps, J. Chem. Soc. 1956, 1294-304.
2
2
[
[
11] F. E. Scully Jr., J. Hoigne, Chemosphere 1987, 16, 681-94.
12] CCDC 748382 (5b) contains the supplementary crystallographic data
for this publication. This data can be obtained free of charge from The
Further methods and characterization data of all compounds can be
found in the supporting information.
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
[
[
13] J.-Y. Lu, J. A. Keith, W.-Z. Shen, M. Schürmann, H. Preut, T. Jacob, H.-
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Acknowledgements
14] E.g. see: C. Melander, D. A. Horne, J. Org. Chem. 1997, 62, 9295-7.
We thank Dr. Hans Preut (TU Dortmund) for support in X-Ray
crystallography and anonymous reviewers for valuable
comments.
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Entry for the Table of Contents
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K. Philip Wojtas, Jin-Yong Lu, Daniel
Krahn, Hans-Dieter Arndt*
Page No. – Page No.
Regioselective functionalization of
3-hydroxy-pyridine carboxylates by
neighboring group assistance
An unexpected docking site. Free phenolic hydroxy groups in pyridine rings were
found to assist the regioselective transformation of proximal ester groups. Selective
hydrolysis, transesterification, and amide bond formation can such be realized at
very mild pH (8.5) even in the presence of water.
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