Mild and Regioselective N-Alkylation of 2-Pyridones in Water

Article abstract of DOI:10.1021/acs.orglett.5b01628

A mild and regioselective N-alkylation reaction of 2-pyridones in water has been developed. Tween 20 (2% w/w) was added to create a micellar system for improved solubility of starting materials, which leads to enhanced reaction rates. The protocol demonstrated a wide substrate scope with good isolated yields (40-94%) for all of the 24 examples evaluated. High regioselectivity favoring N-alkylation over O-alkylation was observed for benzyl halides (>5:1), primary alkyl halides (>6:1), and bulky and less reactive secondary alkyl halides (>2.4:1).

Full text of DOI:10.1021/acs.orglett.5b01628

Letter
pubs.acs.org/OrgLett
Mild and Regioselective N‑Alkylation of 2‑Pyridones in Water
Xin Hao, Zhongmiao Xu, Hongfu Lu, Xuedong Dai, Ting Yang, Xichen Lin, and Feng Ren*
Research and Development, GlaxoSmithKline, 898 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai 201203, China
S
* Supporting Information
ABSTRACT: A mild and regioselective N-alkylation reaction
of 2-pyridones in water has been developed. Tween 20 (2% w/
w) was added to create a micellar system for improved
solubility of starting materials, which leads to enhanced
reaction rates. The protocol demonstrated a wide substrate
scope with good isolated yields (40−94%) for all of the 24
examples evaluated. High regioselectivity favoring N-alkylation over O-alkylation was observed for benzyl halides (>5:1), primary
alkyl halides (>6:1), and bulky and less reactive secondary alkyl halides (>2.4:1).
N-Alkylated 2-pyridones and close analogues are important
components both in natural products1−4 and in many active
pharmaceuticals.5 Due to their ambident nucleophilic nature,
regioselective control of N- versus O-alkylation of 2-pyridones
has intrigued chemists for over half a century.6 Even though
impressive progress has been made in the development of new
methodologies (vide infra) to induce regioselectivity for N-
alkylated 2-pyridones as well as in the mechanistic understanding
of these alkylations,7 there are no reports of a general and
straightforward method on selective N-alkylation of 2-pyridones,
especially with bulky secondary alkyl groups.
Alkylation has been traditionally performed by treating alkyl
halides with metal salts of 2-pyridones, either preformed or
formed in situ.8 The regioselectivity of N- versus O-alkylation
depends on a variety of factors including the nature of the metals,
the structure of the alkyl halides, substituents on the 2-pyridone
ring, solvents,9 and temperature. Modifications of the reaction
conditions have been developed to improve the conversion and
regioselectivity of these alkylations. The use of CsF furnished N-
alkylated products from activated alkyl halides (benzyl or allyl
chlorides) with the N-/O-alkylation ratios of up to 13:1 under
mild conditions (DMF, 30 °C). However, O-alkylation was
favored for unactivated secondary alkyl halides.10 Addition of
LiBr to mixtures of NaH, DMF, and DME afforded N-
propargylated products with alkylation ratios of up to 12:1.
However, the ratio was low for benzyl and alkyl halides under the
same reaction conditions.11
Mitsunobu reaction conditions do not provide improved
regioselectivity for N-alkylated products. N-/O-alkylation ratios
of up to 4:1 were obtained for activated primary alcohols such as
benzyl alcohol. Unactivated primary alcohols generally yielded
mixtures of N- and O-alkylated products, while secondary
alcohols favored O-alkylation instead.12,13
Several other strategies have been reported to give high
regioselectivity. However, the requirements for special catalysts
or starting materials limit the substrate scopes and render these
methods less practical. Metal-catalyzed N-allylation of 2-
pyridone14,15 proved high yielding. Selective N-alkylation of 2-
pyridones was observed for alkoxypyridines16,17 with activated
alkyl halides. A cationic Ir(I) complex catalyzes O- to N-alkyl
migration for 2-alkoxypyridines.18 In the presence of Mg(Ot-
Bu)2, N-selective alkylation of 2-pyridones was achieved with 2-
halo-carboxylic acids.19 N-Alkylated 2-pyridones could be
obtained through nucleophilic ring opening of oxazolinium
intermediates, which are tedious to prepare.20
Herein, we report a mild, practical, and regioselective N-
alkylation reaction of 2-pyridones with both activated and
unactivated alkyl halides. In addition, the method has been
developed in water, the environmentally friendly solvent, which
makes the methodology even more attractive.
To address ever-increasing environmental concerns,21
a
growing number of advances in chemical synthesis and catalysis
have been reported utilizing water as solvent. One focus of our
group is to develop reactions in aqueous reaction conditions;
these reactions can be facilitated by micelles formed in water
from readily available surfactants. We favor the choice of
polysorbates (also known as Tween) because of their low cost,
availability, high stability, and relatively nontoxic profile.22
Micelles form nanoreactor environments in water due to the
hydrophobic effects that favor the compartmentalization of
organic reagents thus improving the solubility and the local
concentration of reagents.23 As a consequence, unique enhance-
ment of reactivity, chemo-, region-, and stereoselectivities can be
achieved in aqueous micellar systems.24
Based on the C−H arylation using the Tween/water micellar
system we developed,25 we have explored the challenges in the
synthesis of N-alkylated 2-pyridones and exploited the effects of
this micellar system on the conversion and regioselectivity of the
alkylation of 2-pyridones. We started this endeavor by reacting 5-
bromo-2-pyridone (1a) with benzyl bromide (2a) using K2CO3
as the base (Table 1). To our delight, we observed high
conversion (76%) to the alkylated products (3a26 and 4a) after 3
h at ambient temperature in Tween 20/water (2% w/w). Based
on HPLC analysis, N-/O-alkylation ratio (3a/4a ratio) was 10:1
(entry 1). We then evaluated the effects of different bases
Received: March 9, 2015
© XXXX American Chemical Society
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Table 1. Optimization of Reaction Conditions for N-Alkylation of 2-Pyridone
b
b
entry
base (equiv)
surfactant
conversion (HPLC)
3a/4a ratio (HPLC)
1
2
3
4
5
6
7
8
K2CO3 (1.2 equiv)
Cs2CO3 (1.2 equiv)
Et3N (1.2 equiv)
Tween 20
Tween 20
Tween 20
Tween 20
Tween 80
none
76%
69%
57%
85%
84%
37%
94%
95%
10:1
8:1
5:1
i-Pr2NEt (1.2 equiv)
i-Pr2NEt (1.2 equiv)
i-Pr2NEt (1.2 equiv)
i-Pr2NEt (2.0 equiv)
i-Pr2NEt (5.0 equiv)
12:1
10:1
6:1
Tween 20
14:1
14:1
Tween 20
a
b
The same equivalent of benzyl bromide (2a) as the base was used. Conversion and N-/O-alkylation ratio were determined by HPLC peak areas at
214 nm for 2-pyridone and the regio-isomer products (3a and 4a) in the reaction mixture.
Table 2. Scope of 2-Pyridones and Benzyl Halides for the Regioselective N-Alkylation Reaction in Water
a
b
Conversion was determined by HPLC peak areas at 214 nm for 2-pyridone and the regio-isomer products in the reaction mixture. N-/O-alkylation
1
ratio was determined by comparing integrations of characteristic protons for product 3 and 4 in H NMR spectrum of the concentrated reaction
mixture
including Cs2CO3 (entry 2), Et3N (entry 3), and i-Pr2NEt (entry
4), and discovered that i-Pr2NEt provided the highest conversion
and regioselectivity (N-/O-alkylation ratio). Use of Tween 80 as
the surfactant provided similar conversion as that of Tween 20,
but with lower N-/O-alkylation ratio (10:1, entry 5). In the
absence of a Tween surfactant, the reaction was sluggish and the
regioselectivity was poor (entry 6), which is consistent with our
observations in previous studies25 and the reported benefits of
surfactants in solubility improvement and reaction rate
acceleration.24
micellar alkylation conditions, however, the nucleophilicity
reduction of 2-pyridone 1a was not observed, further
demonstrating the utility of the reaction environment created
by micelles relative to simple aqueous solutions. When the
amounts of i-Pr2NEt and benzyl bromide 2a were increased to 2
equiv, both the conversion and regioselectivity were improved
(entry 7). Further increasing the amounts of i-Pr2NEt and benzyl
bromide provided negligible improvement in conversion (entry
8).
With the optimized reaction condition identified, we evaluated
the substrate scope. As shown in Table 2 (entries 1−7), a variety
of substituted 2-pyridones (1a−1g) bearing both electron-
Interestingly, Mayr showed that the nucleophilicity of 2-
pyridone is greatly decreased in aqueous solution.7 Under
B
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Table 3. Scope of Aliphatic Halides and 2-Pyridones for the Regioselective N-Alkylation Reaction in Water
a
b
Conversion was determined by HPLC peak areas at 214 nm for 2-pyridone and the regio-isomer products in the reaction mixture. N-/O-alkylation
1
ratio was determined by comparing integrations of characteristic protons for products 6 and 7 in H NMR spectra of the concentrated reaction
mixture. Ten equivalents of halides (5) and ten equivalents of K2CO3 were used.
c
donating and electron-withdrawing substituents were well
tolerated with high conversion (>80%). The N-/O-alkylation
ratios ranged from 5:1 to >19:1 as determined by integration of
In addition, benzyl chloride (2e) also afforded N-alkylated
product with high yield (86%) and regioselectivity (8:1), albeit
the reaction rate was slower.
1
the characteristic protons for products 3 and 4 in H NMR
To further evaluate the efficiency of the reaction condition, we
examined the N-alkylation of 2-pyridones with unactivated
primary and secondary aliphatic halides. Not surprisingly,
reaction was sluggish under the aforementioned conditions
optimized for activated benzyl halides. The reaction could be
accelerated by elevating the temperature to 70 °C as well as
increasing the amount of both base and halides to five
equivalents. However, the elevated temperature resulted in the
formation of unknown side products. Fortunately, the formation
of side products could be suppressed by switching the base from
i-Pr2NEt to K2CO3. As shown in Table 3 (entries 1−4), 5-
bromo-2-pyridone (1a) reacted with primary bromide 5a and
primary iodides 5b−5d to afford N-alkylated products (6a−6c)
in high isolated yields. Except for iodide 5c, which afforded N-/
O-alkylation ratio of 6:1, N-alkylated products were the only
regio-isomers detected in 1H NMR spectra of the concentrated
reaction mixtures for halides 5a, 5b, and 5d. The reaction showed
high tolerability to the electronic properties of substitutions on 2-
pyridones, as demonstrated by the reactions between 2-
pyridones (1d−1h) and n-propyl iodide (5b) (entries 5−9).
Even though 2-pyridones 1f and 1g showed moderate yields
when reacting with benzyl bromide (2a) (Table 2, entries 6 and
spectra of the concentrated reaction mixtures. The desired N-
alkylated products (3a−3g) were isolated in good yields (52−
94%). The regiochemistry (N-alkylation) was confirmed by 2D
NMR for the representative compound 3a based on the
observation of ROESY cross-peaks between Ha and Hb in 3a
(Supporting Information). Electron withdrawing substituents at
the 3-position deactivate 2-pyridones (1d and 1e) toward
alkylation, and prolonged reaction time was required for good
conversions (entries 4 and 5). 2-Pyridones with electron
donating/neutral groups (1f and 1g) were also less reactive
and resulted in lower isolated yields with compromised
regioselectivities of the N-alkylated products, even after
prolonged reactions (entries 6 and 7). Limited scope of benzyl
halide was then explored (Table 2, entries 8−11) using 5-bromo-
2-pyridone (1a). para-Substituted benzyl bromides (2b−2d)
with electron-donating and electron-withdrawing substituents
were well tolerated yielding good conversions, alkylation ratios,
and isolated yields. N-Alkylated products (3h−3j) were the
predominant regioisomers isolated in high yields (90−94%) after
3 h of reaction at room temperature. The N-/O-alkylation ratios
were determined to range from 12:1 to 17:1 by 1H NMR analysis.
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7), excellent isolated yields (94%) were achieved when ten
equivalents of n-propyl iodide (5b) and K2CO3 were used with
the prolonged reaction time of 60 h at 70 °C (Table 3, entries 8
and 9). In order to further confirm the regio-chemistry (N-
versus O-alkylation), 2D NMR experiments have been
conducted for the representative compounds 6a and 6h. The
ROESY cross-peaks between Ha and Hb of both compounds
(entries 1 and 9) were observed (Supporting Information),
providing strong evidence for N-alkylation products. In addition,
13C NMR spectrum of 6h was observed to be identical to
literature data,27 which provided further evidence for our
regiochemistry assignments. We then further explored the
scope of unactivated secondary alkyl halides, which has presented
a long-lasting, unresolved challenge to the organic chemistry
community. To our delight, our reaction condition employing
the Tween/water micellar system was well tolerated for
unactivated secondary iodides (isopropyl iodide 5e and isobutyl
iodide 5f) with different substitutions on the 2-pyridone (Table
3, entries 10, 11, and 13). The desired N-alkylation products (6i,
6j, and 6l) were obtained in moderate to good isolated yields, and
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Corresponding Author
*E-mail: feng.q.ren@gsk.com.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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We thank Dr. Yi Li (GlaxoSmithKline) for HRMS analysis, Ms.
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DOI: 10.1021/acs.orglett.5b01628
Org. Lett. XXXX, XXX, XXX−XXX