Catalytic O- to N-Alkyl Migratory Rearrangement: Transition Metal-Free Direct and Tandem Routes to N-Alkylated Pyridones and Benzothiazolones

Article abstract of DOI:10.1002/adsc.201800664

The present study reports the synthesis of N-alkylated pyridones and benzothiazolones via O- to N-alkyl group migration under transition metal-free TfOH-catalyzed reaction conditions for the first time, to the best of our knowledge. Primary as well as secondary alkyl groups smoothly migrate under the present reaction conditions. Moreover, a minor modification of the protocol used in this study is found to be applicable for an entirely new tandem synthesis of 2-alkoxy-N-heterocycles from the simplest starting materials in a solvent-free reaction conditions. Density Functional Theory (DFT) calculation identifies the energy species associated with the rearrangement, whereas, mechanistic experiments explore the role of the catalyst as the alkyl group transfer mediator. (Figure presented.).

Full text of DOI:10.1002/adsc.201800664

Title: Catalytic O- to N-Alkyl Migratory Rearrangement: Transition
Metal-Free Direct and Tandem Routes to N-Alkylated Pyridones
and Benzothiazolones
Authors: Abhishek Mishra, Nelson Henrique Morgon, Suparna Sanyal,
Aguinaldo Robinson de Souza, and Srijit Biswas
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800664
Link to VoR: http://dx.doi.org/10.1002/adsc.201800664

10.1002/adsc.201800664
Advanced Synthesis & Catalysis
Very Important Publication
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Catalytic O- to N-Alkyl Migratory Rearrangement: Transition
Metal-Free Direct and Tandem Routes to N-Alkylated
Pyridones and Benzothiazolones
Abhishek Kumar Mishra,a Nelson Henrique Morgon,b Suparna Sanyal,c Aguinaldo
Robinson de Souza,d* and Srijit Biswasa*
a
Division of Molecular Synthesis and Drug Discovery, Centre of Bio-Medical Research (CBMR), SGPGIMS Campus,
Lucknow 226014, Uttar Pradesh, India, E-mail: srijit.biswas@cbmr.res.in, srijit_biswas@yahoo.co.in, Phone: +91 867
0848 007, Fax: +91 522 2668 215
Department of Physical Chemistry, Institute of Chemistry, Campinas State University, UNICAMP, Campinas, São
b
Paulo, 13083-970, Brazil
Department of Cell and Molecular Biology, BMC, Uppsala University, 751 24 Uppsala, Sweden
School of Science, São Paulo State University, UNESP, Bauru, São Paulo, 17033-360, Brazil, E-mail:
c
d
arobinso@fc.unesp.br, Phone: +55 14 3103 9815, Fax: +55 14 3103 6000
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. The present study reports the synthesis of N- Density Functional Theory (DFT) calculation identifies the
alkylated pyridones and benzothiazolones via O- to N-alkyl energy species associated with the rearrangement, whereas,
group migration under transition metal-free TfOH-catalyzed mechanistic experiments explore the role of the catalyst as
reaction conditions for the first time, to the best of our the alkyl group transfer mediator.
knowledge. Primary as well as secondary alkyl groups
smoothly migrate under the present reaction conditions.
Moreover, a minor modification of the protocol used in this
study is found to be applicable for an entirely new tandem
synthesis of 2-alkoxy-N-heterocycles from the simplest
starting materials in a solvent-free reaction conditions.
Keywords: Benzothiazolones; Metal-free; Pyridones;
Rearrangement; Tandem; DFT
Introduction
Catalysis without using transition metals is emerging
as a widely applicable and sustainable alternative
owing to the increasing awareness of environmental
aspects and limited resources of many transition
metals, particularly in pharmaceutical industries,
where a very low limit for heavy metal impurities are
allowed in the drugs produced.[1a] This has recently
been acknowledged by AstraZeneca, and it has been
documented that some precious metal resources will
be exhausted in 30 years.[1b] One of the major
interests of our research group is the development of
transition metal-free catalytic methods of aryl C–O
bond cleavages of phenols and its simplest
derivatives, such as, aryl methyl ethers.[2] Previous
studies on nucleophilic ipso-substitution of aryl
methyl ethers,[2b] showed a different reactivity when
Scheme 2. Catalytic synthesis of N-substituted-2-
alkylation due to the aromaticity of pyridine pyridones.
2-methoxypyridine (1a) was used as an electrophile
(Scheme 1). Aromatic electrophile, such as 2-
methoxynaphthalene (1’a), when treated with an O-
centered nucleophile, such as, 1-hexanol (4a),
generated the expected ipso-substitution product 3’a.
However, hetero aromatic electrophile, such as 2-
Scheme 1. The new reactivity of 2-methoxypyridine.
1
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10.1002/adsc.201800664
Advanced Synthesis & Catalysis
Table 1. Optimization of reaction parameters.[a]
methoxypyridine (1a) generated
a
completely
different product 1-methylpyridin-2(1H)-one (2a),
whereas no ipso-substitution product was observed.
This interesting result prompted us to explore the
reaction further owing to the prominence of N-
alkylated pyridones in natural products[3] and
medicinal targets.[4]
entry
1
Catalyst (mol-
%)
p-TSA·H2O
(20)
Solvent
(mL)
Conversion[b]
20%
Literature survey revealed the lack of general and
efficient methods of synthesizing N-alkylated
pyridones.[5] Alkylations of ambivalent aromatic
imidates often suffer from competitions between O-
and N-alkylation because of the aromaticity of the
pyridine ring.[6] By comparison, O- to N-alkyl
migratory rearrangement of O-alkyl pyridines are
more practical due to have relatively easier access to
the starting materials via nucleophilic aromatic
substitution reactions. Stoichiometric version of such
reaction was reported by Anderson and co-workers
where, the O- to N-alkyl migration was promoted by
LiI;[7] whereas, only two catalytic versions are
available using heavy transition metal catalysts, such
as, Ru by Dong (Scheme 2A)[8] and Ir, by Shibata
DCE (0.5)
2
3
4
5
6
7
8
9
10
11
12
13
14
CH3SO3H (20)
TfOH (20)
H3PO2 (20)
H3PO3 (20)
TfOH (20)
TfOH (20)
TfOH (20)
TfOH (20)
TfOH (20)
TfOH (20)
TfOH (10)
TfOH (5)
DCE (0.5)
DCE (0.5)
DCE (0.5)
DCE (0.5)
DMF (0.5)
THF (0.5)
PhCH3 (0.5) 43%
H2O (0.5)
DCE (0.3)
22%
50%
5%
0%
35%
41%
15%
83%
DCE (0.15) 85%
DCE (0.15) ˃99% (98%)[c]
DCE (0.15) 76%
TfOH (10)
no catalyst
Neat
DCE (0.15) 0%
52%[d]
(Scheme 2B).[9]
These catalytic methods were
15
remarkable on this area but urged for consequential
synthetic advancement for addressing concerns such
as use of heavy metals, ligands, and stoichiometric
amounts of bases/additives. Inspired by this, and in
agreement with our interest to develop transition
metal-free catalytic transformations, we herein report
the first transition metal-free catalytic strategy to
achieve O- to N- alkyl migratory rearrangements in a
very small amount of solvent (Scheme 2C). Density
Functional Theory (DFT) calculation has been
performed, which identifies the lower energy species
associated with the catalytic cycle while revealing the
role of the catalyst. As an important and practical
application, a minor modification of the protocol is
found to work for an entirely new tandem synthesis
of N-alkylated pyridones and benzothiazolones,
directly from the simplest starting materials, such as
2-chloropyridine or 2-chlorobenzothiazole, and
alcohols (Scheme 2D), without using any organic
solvent.
[a]
1.0 mmol 1a and catalyst in solvent, heated at 90 °C for
24 h. [b] NMR conversion w. r. t. 1a. [c] Isolated yield in the
parenthesis. [d] Isolated yield.
Table 2. Substrate scope towards N-alkylated pyridones
and quinolone.[a]
Results and Discussion
The simplest substrate, 2-methoxypyridine (1a), was
used to optimize the reaction parameters (Table 1).
The reaction temperature and time were fixed at
90 °C and 24 h after an initial screening. Different
commercially available Brønsted acid catalysts, such
as para-toluenesulfonic acid monohydrate (p-
TSA·H2O), methanesulfonic acid (CH3SO3H),
trifluoromethanesulfonic acid (TfOH), phosphinic
acid (H3PO2), and phosphorous acid (H3PO3) were
tested in 0.5 mL dry 1,2-dichloroethane (DCE)
solvent (table 1, entries 1–5). TfOH was found to be
the best catalyst in DCE. Changing the solvent made
the reaction sluggish, whereas, reducing the amount
of solvent to 0.3 mL largely increased the conversion
[a] 1.0 mmol 1, 10 mol-% TfOH in 0.15 mL DCE (∼7 M
conc.), heated at 90 °C for 24 h. Yields refer to pure and
isolated products.
2
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10.1002/adsc.201800664
Advanced Synthesis & Catalysis
Table 3. Solvent-free tandem synthesis of N-alkylated
of 2a from 50% to 83% (table 1, entries 3 and 10).
Finally, the best result was obtained using 10 mol-%
TfOH in only 0.15 mL DCE (∼7 M conc.), which
generated the product 2a in 98% isolated yield (table
1, entry 12).
pyridones and benzothiazolones.[a]
The optimized reaction conditions were applied to
a variety of 2-alkoxypyridine derivatives (Table 2).
Primary aliphatic groups at the R-position of the
substrates underwent the rearrangement reaction
smoothly to generate the N-alkylpyridone derivatives
in high yields (entries 1–3). The desired
rearrangement was observed for the substrate having
benzyl group at the
R
position (entry 4).
Electronically different substituents at different
aromatic positions of the benzyl group also tolerated
the reaction conditions and generated the products in
good to excellent yields (entries 5–8). Similarly,
excellent yield of the product was obtained when R
was a 2-naphthyl group (entry 9). The rearrangement
occurred for the substrate having O-allylic and
propargylic substituents (entries 10–12), where the
stereochemistry around the double bond was retained
in case of cis- and trans- allylic systems (entries 10–
11).[10] Unlike the reported Ru-catalyzed method,[8]
the present protocol worked successfully for
substrates having more challenging secondary benzyl
and allylic substituents at the R position (entries 13–
15). Presence of methyl and nitro substituents at the
pyridine ring did not interfere with the rearrangement
process and the desired products were generated in
67–75% yields (entries 16–19). Moreover, 2-
(benzyloxy)quinoline took part in the reaction
producing the N-benzyl-2-quinolone (2t) in 75%
yield (entry 20).
[a] 1.0 mmol 3, 1.5 mmol 4, 10 mol % TFA, 130 °C for 24
h.
revealed that the reaction proceeded in a tandem
fashion, where, TfOH promoted the aromatic
nucleophilic substitution reaction to generate the
intermediate 1d, which was converted in situ to the
product 2d. To the best of our knowledge, this is the
first report of tandem synthesis of N-alkylated
pyridones from such simple precursors. A brief
optimization of the tandem reaction conditions was
performed where trifluoroacetic acid (TFA) worked
the best instead of TfOH under a noteworthy solvent-
free reaction conditions (Table 3). Different
substituents at different positions of the benzyl ring
of 4, such as 4-Et, 3-Br, and 3,4-di-Cl, were
compatible with the modified protocol furnishing the
products 2u–2w directly from 2-chloropyridine (3a)
and alcohols (4u, 4v, 3w) in one pot (entries 2–4).
Allylic alcohol 4k (Z) reacted smoothly and
generated the products 2k (entry 5). More
challenging 2° alcohol, such as 4n, succeeded in
following the tandem reaction sequences to generate
the product 2n in 60% yields (entry 6). Most
importantly, when 2-chlorobenzothiazole (3b) was
exposed to the tandem catalytic reaction conditions
instead of 2-chloropyridine (3a), it reacted with 4-
methoxybenzylic alcohol 4f smoothly to generate the
corresponding benzothiazolone derivative 2x in 73%
yield (entry 7). This is certainly a crucial result as the
corresponding 2-alkoxy benzothiazole could not be
synthesized as starting material (of Table 2) using
Scheme 3. Traditional vs. tandem one pot synthesis of N-
alkylated pyridones.
Except substrate 1a (commercially available), all
the remaining substrates (1b–1t) were prepared via
reported[8,11] nucleophilic substitution reaction of the
corresponding chloro-pyridine derivatives with
alcohols. Excess amounts of alcohols and bases were
necessary for this traditional synthetic process. The
reaction time was 48 h, and the work-up and
purification procedures were tedious and generated
stoichiometric amounts of salts as by-products
(Scheme 3A). Interestingly, when 2-chloropyridine
(3a) and benzyl alcohol (4d) were exposed under the
present catalytic reaction conditions, it generated the
same product 2d with an overall yield of 62% at
130 °C (Scheme 3B). Controlled experiments and
GS-MS analysis of the crude reaction mixture
reported
nucleophilic
substitution
of
2-
chlorobenzothiazole 3b.[8,11] Piperonyl alcohol 4y, as
well as sterically and electronically more demanding
diphenylmethanol 4z also reacted with 3b, furnishing
the products 2y and 2z in 76% and 63% of the yields
respectively (entry 8–9). It is important to mention
that the core benzothiazolone motif has recently
received attention for its anti HIV activity.[12] To the
best of our knowledge, this is the first report of
tandem synthesis of N-alkylated pyridones and
benzothiazolones from such simples precursors.
To understand the mechanism of the TfOH
catalyzed O- to N-alkyl rearrangement,[13]
mechanistic investigation was performed by DFT
3
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10.1002/adsc.201800664
Advanced Synthesis & Catalysis
Table 4. Proton Affinity (in kJ mol-1) in gas-phase
calculated at G4 theory.
calculations. Formation of 1-methylpyridin-2(1H)-
one (2a) from 2-methoxypyridine (1a) via TfOH
catalyzed O- to N- methyl migratory rearrangement
was chosen for computational modeling using the
DFT B3LYP/6-311++G(3df,2p) method. The
reaction mechanism was studied in 1,2-
dichloroethane (DCE) solution using SMD method.
The dispersion corrections were included using
semiempirical atom pairwise interactions (DFT-D3).
The reaction was assumed to begin with
abstraction of the acidic proton (from TfOH) by the
nucleophilic oxygen or nitrogen centers of 1a. To
understand the preference between these two centers,
theoretical calculations of proton affinity (PA) was
carried out (See SI for the electrostatic potential map
EPM of 1a). Table 4 shows the values of PAs for
triflate anion (TfO-), O- and N-centers of 1a. The
molecular systems were obtained at modified G4
theory[14] by including the solvent effects from the
IEFPCM model. While in the gas phase, the TfO- ion
has a higher proton affinity (1250.28 kJ mol-1) in the
presence of DCE solvent, and the protonation is more
preferable at the N-center of 1a (1113.56 kJ mol-1).
Thus, the reaction was initiated by protonation at the
N- center of 1a by TfOH catalyst leading to the
intermediate INT1, which was stable with respect to
1a and TfOH by -80.90 kJ mol-1 (See Figure 1 for
energy profile, optimized molecular structures, and
possible mechanism). A methyl group transfer from
the O-center of the substrate to the O-center of the
catalyst occurred via the transition state TS1, where
the planarity of the methyl group with partially
positive sp2-hybridized carbon center could be
observed (56.07 kJ mol-1).[15] After the transfer of the
methyl group, an intermediate INT2, which was a
van der Waals complex of TfOMe and the N-
protonated-2-pyridone was formed. The methyl group
transfer from TfOMe to the N-center of the pyridone
occurred via TS2 leading to INT3 having a relative
energy of 7.04 kJ mol-1. Subsequently, a proton
transfer from the N-center of pyridone to O-center of
the catalyst occurred via the transition state TS3,
which had a relative energy of 7.23 kJ mol-1, leading
to the intermediate INT4, at -66.27 kJ mol-1. The
energy difference between INT3 and TS3 was very
small because of the involvement of an
intramolecular proton transfer having an imaginary
frequency value of 78.30 cm-1. The product 1-
methylpyridin-2(1H)-one (2a) was formed at the final
step with regeneration of the catalyst. The overall
process is exothermic having ΔG at 298.15 K (-50.32
kJ mol-1).
entry protonation
reaction
proton affinity (PA)
calculated
experimental
1
TfO- + H+
1250.28
1278.0 ±
9.2
–
(1063.72)[a]
781.24
2
1a + H+
protonation at O-
center
(968.33)[a]
3
1a + H+
932.65
–
protonation at N-
center
[a] PA including solvent effect within the parenthesis using
a modified version of G4 theory.
(1113.56)[a]
To elucidate the mechanism of the reaction further,
some experiments were conducted (Scheme 4).
Complete conservation of deuterium at benzylic
position of 2d-D (90% D) was observed when 1d-D
(90% D) was treated with 40 mol-% TfOH (Scheme
4A).[16] Chirality was lost (mostly) when enantio-
enriched 1m (∼84% ee) was exposed to the optimum
reaction conditions to generate 2m having ∼10% ee
Figure 1. Energy profile (upper), optimized molecular
structures (middle), and possible mechanism (lower) for
TfOH catalysed conversion of 1a to 2a.
4
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10.1002/adsc.201800664
Advanced Synthesis & Catalysis
(Scheme 4B). The conservation of deuterium pointed
towards a mechanism that did not involve C-H bond
a minor modification of the protocol allows access to
the products from the simplest precursors in an
entirely new transition metal- and solvent-free
tandem reaction conditions.
Experimental Section
1
General considerations: H and 13C NMR spectra were
recorded with a 400 MHz spectrometer as solutions in
CDCl3. Chemical shifts are expressed in parts per million
(ppm, δ) and are referenced to CHCl3 (δ = 7.28 ppm) as an
internal standard. All coupling constants are absolute
values and are expressed in Hz. The description of the
signals include: s = singlet, d = doublet, t = triplet, q =
quadrate, m = multiplet, dd = doublet of doublets, dq =
doublet of quadrate, ddd = doublet of doublet of doublets,
td = triplet of doublet, and br. s. = broad singlet. 13C NMR
spectra were recorded as solutions in CDCl3 with complete
proton decoupling. Chemical shifts are expressed in parts
per million (ppm, δ) and are referenced to CDCl3 (δ =
77.16 ppm) as an internal standard. The molecular
fragments in High Resolution Mass Spectra (HRMS) are
quoted as the relation between mass and charge (m/z). The
routine monitoring of reactions was performed with silica
gel pre-coated Al plate, which was analyzed with iodine
Scheme 4. Experimental studies for mechanistic
investigations.
cleavage, which was in agreement with the results
obtained from theoretical calculations. However, the
racemization experiment (Scheme 4B) suggested an
SN1-type mechanism from INT2 to INT3 in the case
of the secondary benzylic group, probably owing to
the stability of the carbocation intermediate. A
crossover experiment was performed, where
intermolecular O- to N-allyl and benzyl group
migrations were observed when 1k and 1q together
were exposed to the TfOH-catalyzed optimized
reaction conditions, which generated a mixture of the
products 2k, 2q, 2d, 2qʹ (Scheme 4C). Most
importantly, the stereochemistry around the double
bond was retained in the products 2k and 2qʹ. This
observation ruled out the possibility of formation of
carbocation for primary allylic group migration.
Nonetheless, the observed crossover could be
explained by anticipating the formation of an allyl
triflet intermediate, which could have assisted the
intermolecular allylic group transfer without the loss
of olefin geometry. To support this hypothesis,
another experiment was carried out using substrate 1k
in presence of excess (1 eqv) of methyl triflate
(Scheme 4D). Exclusive formation of 2a was
observed under the optimized reaction conditions.
This experiment clearly documented the ability of
alkyl triflate to transfer alkyl groups under the present
reaction conditions which is in agreement with the
DFT calculations.
1
and/or uv light, H NMR analysis, and GCMS analysis of
the crude reaction mixture. All reactions were executed
with oven-dried glassware under nitrogen atmosphere.
General procedure for TfOH catalyzed O- to N- alkyl
migration to synthesize the N-alkylated pyridones (2a–
2t) (Table 2 in the manuscript): Catalyst TfOH (15 mg,
10 mol-%), 2-alkoxypyridines 1a–1t (1.0 mmol) and 1,2-
dichloroethane solvent (0.15 mL) were taken in a 5 mL
VWR reaction vial containing a small magnet without
using inert atmosphere. The cap of the vial was closed and
the reaction mixture was stirred at 90 °C for 24 h. After
completion of the reaction (by TLC, GC or NMR), the
crude was directly purified by silica-gel (230–400 mess)
column chromatography (flash) using ethyl acetate /
hexane solution to afford the desired products 2a–1t.
Experimental procedures and characterisation data of
all products described in Scheme 3:
1-Methylpyridin-2(1H)-one (2a):[9] Catalyst TfOH (15
mg, 10 mol %) and 2-methoxypyridines 1a (109 mg, 1.00
mmol) were treated following the general procedure to
1
obtain 2a as a brown oil (107 mg, 0.98 mmol, 98%). H
NMR (400 MHz, CDCl3): δ = 3.40 (s, 3 H), 6.03 (td, J =
6.66, 1.34 Hz, 1 H), 6.41 (dd, J1 = J2 = 9.78, 1.22 Hz, 1
H), 7.14–7.25 (m, 2 H) ppm; 13C NMR (100 MHz, CDCl3):
δ = 37.4, 105.8, 120.3, 138.3, 139.5, 162.9 ppm.
1-Phenethylpyridin-2(1H)-one (2b):[8] Catalyst TfOH (15
mg, 10 mol %) and 2-phenethoxypyridine 1b (199 mg,
1.00 mmol) were treated following the general procedure
to obtain 2b as a white solid (141 mg, 0.71 mmol, 71%).
1H NMR (400 MHz, CDCl3): δ = 3.08 (t, J = 7.04 Hz, 2 H),
4.16 (t, J = 7.34 Hz, 2 H), 6.01 (dd, J1 = J2 = 6.46 Hz, 1
H), 6.60 (d, J = 9.39 Hz, 1 H), 6.86–6.96 (m, 1 H), 7.16 (d,
J = 7.04 Hz, 2 H), 7.21–7.36 (m, 4 H) ppm; 13C NMR (100
MHz, CDCl3): δ = 35.1, 52.1, 105.6, 121.1, 126.8, 128.8,
129.1, 138.0, 138.1, 139.6, 162.7 ppm.
Conclusion
In summary, we have developed a transition metal-
free catalytic protocol for the first time, to the best of
our knowledge, for accessing N-alkylated pyridones
and benzothiazolones via O- to N- alkyl group
migration. Density Functional Theory (DFT)
calculation and mechanistic experiments elucidate the
role of the catalyst and the possible reaction
mechanism via alkyl triflate intermediate. In addition,
1-Hexylpyridin-2(1H)-one (2c):[17] Catalyst TfOH (15 mg,
10 mol %) and 2-(hexyloxy)pyridine 1c (179 mg, 1.00
mmol) were treated following the general procedure to
1
obtain 2c as a brown liquid (175 mg, 0.98 mmol, 98%). H
NMR (400 MHz, CDCl3): δ = 0.82–0.92 (m, 3 H), 1.25–
1.38 (m, 6 H), 1.67–1.79 (m, 2 H), 3.91 (t, J = 7.46 Hz, 2
H), 6.14 (td, J = 6.60, 1.22 Hz, 1 H), 6.55 (d, J = 9.05 Hz,
1 H), 7.19–7.37 (m, 2 H) ppm; 13C NMR (100 MHz,
CDCl3): δ = 13.9, 22.4, 26.3, 29.2, 31.4, 49.9, 105.7, 121.1,
137.5, 139.1, 162.6 ppm.
5
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10.1002/adsc.201800664
Advanced Synthesis & Catalysis
1-Benzylpyridin-2(1H)-one (2d):[9] Catalyst TfOH (15 mg, NMR (100 MHz, CDCl3): δ = 13.7, 22.1, 34.3, 50.5, 106.1,
10 mol %) and 2-(benzyloxy)pyridine 1d (185 mg, 1.00
121.0, 124.3, 136.0, 136.9, 139.3, 162.6 ppm.
mmol) were treated following the general procedure to
1
obtain 2d as a brown oil (133 mg, 0.72 mmol, 72%). H
(Z)-1-(Pent-2-en-1-yl)pyridin-2(1H)-one (2k): Catalyst
TfOH (15 mg, 10 mol %) and (Z)-2-(hex-2-en-1-
yloxy)pyridine 1k (177 mg, 1.00 mmol) were treated
following the general procedure to obtain 2k as a brown
NMR (400 MHz, CDCl3): δ = 5.17 (s, 2 H), 6.17 (dd, J1 =
J2 = 6.65 Hz, 1 H), 6.64 (d, J = 9.39 Hz, 1 H), 7.21–7.45
(m, 7 H) ppm; 13C NMR (100 MHz, CDCl3): δ = 52.0,
106.4, 121.4, 128.1, 128.3, 129.0, 136.5, 137.4, 139.6,
162.9 ppm.
1
liquid (133 mg, 0.75 mmol, 75%). H NMR (400 MHz,
CDCl3): δ = 1.03 (t, J = 7.46 Hz, 3 H), 2.13–2.29 (m, 2 H),
4.56–4.68 (m, 2 H), 5.46 (dtt, J = 10.70, 7.12, 7.12, 1.59,
1.59 Hz, 1 H), 5.65–5.80 (m, 1 H), 6.16 (td, J = 6.66, 1.34
Hz, 1 H), 6.57 (d, J = 9.05 Hz, 1 H), 7.21–7.39 (m, 2 H)
ppm; 13C NMR (100 MHz, CDCl3): δ = 14.1, 20.8, 45.2,
106.2, 120.9, 122.9, 136.7, 137.2, 139.3, 162.7 ppm;
1-(4-Methylbenzyl)pyridin-2(1H)-one (2e):[9] Catalyst
TfOH
(15
mg,
10
mol
%)
and
2-((4-
methylbenzyl)oxy)pyridine 1e (199 mg, 1.00 mmol) were
treated following the general procedure to obtain 2e as a
yellow oil (195 mg, 0.98 mmol, 98%). 1H NMR (800 MHz, HRMS (ESI) calcd. for C10H14NO [M+H]+ m/z 164.1070
CDCl3): δ = 2.34 (s, 3 H), 5.12 (s, 2 H), 6.14 (td, J = 6.75,
1.37 Hz, 1 H), 6.62 (dd, J1 = J2 = 9.00 Hz, 1 H), 7.16 (m,
J = 7.83 Hz, 2 H), 7.21 (m, J = 8.22 Hz, 2 H), 7.26 (dd, J =
6.65, 1.57 Hz, 1 H), 7.31 (ddd, J = 9.00, 6.65, 1.96 Hz, 1
H) ppm; 13C NMR (100 MHz, CDCl3): δ = 21.2, 51.7,
106.3, 121.3, 128.4, 129.7, 133.5, 137.2, 138.0, 139.4,
162.9 ppm.
found m/z 164.1059.
1-(3-Phenylprop-2-yn-1-yl)pyridin-2(1H)-one
(2l):[7b]
Catalyst TfOH (15 mg, 10 mol %) and 2-((3-phenylprop-2-
yn-1-yl)oxy)pyridine 1l (209 mg, 1.00 mmol) were treated
following the general procedure to obtain 2l as a brown oil
(182 mg, 0.87 mmol, 87%). 1H NMR (400 MHz, CDCl3): δ
= 4.97 (s, 2 H), 6.23 (td, J = 6.72, 1.22 Hz, 1 H), 6.51–6.64
(m, 1 H), 7.25–7.38 (m, 4 H), 7.40–7.52 (m, 2 H), 7.72 (dd,
J1 = J2 = 6.97, 1.59 Hz, 1 H) ppm; 13C NMR (100 MHz,
CDCl3): δ = 38.6, 82.1, 87.3, 106.5, 120.7, 122.1, 128.5,
129.1, 132.0, 136.0, 139.9, 162.3 ppm.
1-(4-Methoxybenzyl)pyridin-2(1H)-one (2f):[9] Catalyst
TfOH
(15
mg,
10
mol
%)
and
2-((4-
methoxybenzyl)oxy)pyridine 1f (215 mg, 1.00 mmol) were
treated following the general procedure to obtain 2f as a
brown oil (172 mg, 0.80 mmol, 80%). 1H NMR (400 MHz,
CDCl3): δ = 3.81 (s, 3 H), 5.10 (s, 2 H), 6.15 (dd, J1 = J2 =
6.48 Hz, 1 H), 6.62 (d, J = 9.29 Hz, 1 H), 6.89 (d, J = 8.56
Hz, 2 H), 7.25–7.35 (m, 4 H) ppm; 13C NMR (100 MHz,
CDCl3): δ = 51.6, 55.4, 106.3, 114.4, 121.3, 128.5, 129.9,
137.1, 139.5, 160.0, 162.9 ppm.
1-(1-Phenylethyl)pyridin-2(1H)-one (2m):[11] Catalyst
TfOH (15 mg, 10 mol %) and 2-(1-phenylethoxy)pyridine
1m (199 mg, 1.00 mmol) were treated following the
general procedure to obtain 2m as a brown oil (136 mg,
1
0.68 mmol, 68%). H NMR (400 MHz, CDCl3): δ = 1.74
(d, J = 7.09 Hz, 3 H), 6.12 (dd, J1 = J2 = 6.60 Hz, 1 H),
6.48 (q, J = 6.85 Hz, 1 H), 6.63 (d, J = 9.05 Hz, 1 H), 7.11
(d, J = 5.62 Hz, 1 H), 7.23–7.44 (m, 7 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 19.1, 52.5, 106.5, 120.8, 127.6,
128.1, 128.9, 134.4, 138.9, 140.3, 162.6 ppm.
1-(3,4-Dimethoxybenzyl)pyridin-2(1H)-one
(2g):
Catalyst TfOH (15 mg, 10 mol %) and 2-((3,4-
dimethoxybenzyl)oxy)pyridine 1g (245 mg, 1.00 mmol)
were treated following the general procedure to obtain 2g
1
as a brown oil (179 mg, 0.73 mmol, 73%). H NMR (400
MHz, CDCl3): δ = 3.83–3.91 (m, 6 H), 5.08 (s, 2 H), 6.14
(td, J = 6.66, 1.35 Hz, 1 H), 6.54–6.67 (m, 1 H), 6.78–6.96
(m, 3 H), 7.19–7.40 (m, 2 H) ppm; 13C NMR (100 MHz,
CDCl3): δ = 51.7, 56.0 (2 C), 106.2, 111.3, 117.8, 120.9,
121.2, 129.0, 137.1, 139.4, 149.1, 149.5, 162.8 ppm;
HRMS (ESI) calcd. for C14H16NO3 [M+H]+ m/z 246.1125
found m/z 246.1112.
1-(1-(4-Chlorophenyl)ethyl)pyridin-2(1H)-one
(2n):
Catalyst TfOH (15 mg, 10 mol %) and 2-(1-(4-
chlorophenyl)ethoxy)pyridine 1n (234 mg, 1.00 mmol)
were treated following the general procedure to obtain 2n
as a white solid (140 mg, 0.60 mmol, 60%). 1H NMR (400
MHz, CDCl3): δ = 1.72 (d, J = 7.09 Hz, 3 H), 6.14 (dd, J1
= J2 = 6.60 Hz, 1 H), 6.43 (q, J = 6.93 Hz, 1 H), 6.61 (d, J
= 9.05 Hz, 1 H), 7.05–7.13 (m, 1 H), 7.21–7.31 (m, 3 H),
7.31–7.40 (m, 2 H) ppm; 13C NMR (100 MHz, CDCl3): δ =
19.2, 51.9, 106.7, 120.9, 128.9, 129.1, 134.0, 134.0, 138.9,
139.0, 162.5 ppm; HRMS (ESI) calcd. for C13H13ClNO
[M+H]+ m/z 234.0680 found m/z 234.0669.
1-(4-Chlorobenzyl)pyridin-2(1H)-one (2h):[9] Catalyst
TfOH
(15
mg,
10
mol
%)
and
2-((4-
chlorobenzyl)oxy)pyridine 1h (220 mg, 1.00 mmol) were
treated following the general procedure to obtain 2h as a
1
white solid (194 mg, 0.88 mmol, 88%). H NMR (400
MHz, CDCl3): δ = 5.09 (s, 2 H), 6.15 (td, J = 6.72, 1.22 Hz,
1 H), 6.59 (d, J = 9.29 Hz, 1 H), 7.17–7.39 (m, 6 H); 13C
NMR (100 MHz, CDCl3): δ = 51.6, 106.5, 121.5, 129.2,
129.6, 134.1, 135.0, 137.2, 139.7, 162.7 ppm.
(E)-1-(4-phenylbut-3-en-2-yl)pyridin-2(1H)-one
(2o):
Catalyst TfOH (15 mg, 10 mol %) and (E)-2-((4-
phenylbut-3-en-2-yl)oxy)pyridine 1o (225 mg, 1.00 mmol)
were treated following the general procedure to obtain 2o
1
as a brown oil (178 mg, 0.79 mmol, 79%). H NMR (400
1-(Naphthalen-2-ylmethyl)pyridin-2(1H)-one
(2i):[9]
MHz, CDCl3): δ = 1.58 (d, J = 6.85 Hz, 3 H), 5.98 (ddd, J
= 6.85, 5.01, 1.83 Hz, 1 H), 6.21 (td, J = 6.72, 1.47 Hz, 1
H), 6.32 (dd, J = 16.02, 5.01 Hz, 1 H), 6.59–6.69 (m, 2 H)
7.30–7.38 (m, 4 H), 7.39–7.43 (m, 2 H) ppm; 13C NMR
(100 MHz, CDCl3): δ = 19.2, 51.2, 106.5, 121.0, 126.7,
128.3, 128.8, 129.0, 132.6, 134.2, 136.2, 139.1, 162.4 ppm.
HRMS (ESI) calcd. for C15H16NO [M+H]+ m/z 226.1226
found m/z 226.1227.
Catalyst TfOH (15 mg, 10 mol %) and 2-(naphthalen-2-
ylmethoxy)pyridine 1i (235 mg, 1.00 mmol) were treated
following the general procedure to obtain 2i as a brown oil
(212 mg, 0.90 mmol, 90%). 1H NMR (400 MHz, CDCl3): δ
= 5.32 (s, 2 H), 6.15 (dd, J1 = J2 = 6.60 Hz, 1 H), 6.67 (d,
J = 9.05 Hz, 1 H), 7.25–7.39 (m, 2 H), 7.44 (dd, J = 8.31,
1.47 Hz, 1 H), 7.47–7.56 (m, 2 H,) 7.75 (s, 1 H), 7.78–7.89
(m, 3 H) ppm; 13C NMR (100 MHz, CDCl3): δ = 52.0,
106.4, 121.3, 126.0, 126.4, 126.5, 127.3, 127.9, 128.9,
133.0, 133.4, 133.9, 137.3, 139.6, 162.9 ppm.
1-Hexyl-5-methylpyridin-2(1H)-one (2p): Catalyst TfOH
(15 mg, 10 mol %) and 2-(hexyloxy)-5-methylpyridine 1p
(193 mg, 1.00 mmol) were treated following the general
procedure to obtain 2p as a brown oil (129 mg, 0.67 mmol,
(E)-1-(Hex-2-en-1-yl)pyridin-2(1H)-one (2j):[18] Catalyst
TfOH (15 mg, 10 mol %) and (E)-2-(hex-2-en-1-
yloxy)pyridine 1j (177 mg, 1.00 mmol) were treated
following the general procedure to obtain 2j as a brown
1
67%). H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 6.36
Hz, 3 H), 1.26–1.34 (m, 6 H), 1.72 (t, J = 6.48 Hz, 2 H),
2.17 (s, 3 H), 3.88 (t, J = 7.46 Hz, 2 H), 5.96–6.08 (m, 1 H),
6.38 (s, 1 H), 7.14 (d, J = 6.85 Hz, 1 H) ppm; 13C NMR
(100 MHz, CDCl3): δ = 14.1, 21.3, 22.6, 26.4, 29.4, 31.6,
49.6, 108.6, 119.5, 136.6, 151.0, 162.8 ppm; HRMS (ESI)
calcd. for C12H20NO [M+H]+ m/z 194.1539 found m/z
194.1528.
1
liquid (127 mg, 0.72 mmol, 72%). H NMR (400 MHz,
CDCl3): δ = 0.81–0.93 (m, 3 H), 1.30–1.47 (m, 2 H), 1.96–
2.08 (m, 2 H), 4.50 (d, J = 6.85 Hz, 2 H), 5.48–5.62 (m, 1
H), 5.62–5.76 (m, 1 H), 6.15 (dd, J1 = J2 = 7.34 Hz, 1 H),
6.56 (d, J = 8.80 Hz, 1 H), 7.20–7.37 (m, 2 H) ppm; 13C
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800664
Advanced Synthesis & Catalysis
1-Benzyl-5-methylpyridin-2(1H)-one (2q):[9] Catalyst
TfOH (15 mg, 10 mol %) and 2-(benzyloxy)-5-
methylpyridine 1q (199 mg, 1.00 mmol) were treated
following the general procedure to obtain 2q as a brown oil
(149 mg, 0.75 mmol, 75%). 1H NMR (400 MHz, CDCl3): δ
= 2.18 (d, J = 0.98 Hz, 3 H), 5.13 (s, 2 H), 6.00 (dd, J =
6.97, 1.83 Hz, 1 H), 6.40–6.47 (m, 1 H), 7.15 (d, J = 7.09
Hz, 1 H), 7.25–7.41 (m, 5 H) ppm; 13C NMR (100 MHz,
CDCl3): δ = 21.3, 51.5, 108.9, 119.7, 128.0, 129.0, 136.2,
136.8, 151.2, 162.8 ppm.
Hz, 2 H), 4.80 (s, 2 H), 5.82 (td, J = 6.72, 1.22 Hz, 1 H),
6.30 (d, J = 9.05 Hz, 1 H), 6.79–7.05 (m, 6 H); 13C NMR
(100 MHz, CDCl3): δ = 15.6, 28.6, 51.8, 106.3, 121.3,
128.4, 128.5, 133.7, 137.3, 139.4, 144.3, 162.9 ppm;
C14H16NO [M+H]+ m/z 214.1226 found m/z 214.1225.
1-(3-Bromobenzyl)pyridin-2(1H)-one (2v):[20] Catalyst
TFA (11 mg, 10 mol %), 2-chloropyridine 3a (114 mg,
1.00 mmol) and (3-bromophenyl)methanol 4v (281 mg,
1.50 mmol, 90%) were treated following the general
procedure to obtain 2v as a white solid (238 mg, 0.90
1
5-Methyl-1-(4-methylbenzyl)pyridin-2(1H)-one
(2r):
mmol, 90%). H NMR (400 MHz, CDCl3): δ = 5.01 (s, 2
Catalyst TfOH (15 mg, 10 mol %) and 5-methyl-2-((4-
methylbenzyl)oxy)pyridine 1r (213 mg, 1.00 mmol) were
treated following the general procedure to obtain 2r as a
H), 6.08 (td, J = 6.72, 1.47 Hz, 1 H) 6.49–6.56 (m, 1 H),
7.07–7.20 (m, 3 H) 7.24 (ddd, J = 9.05, 6.72, 2.08 Hz, 1 H)
7.31–7.36 (m, 2 H) ppm; 13C NMR (100 MHz, CDCl3): δ =
51.2, 106.3, 120.8, 122.5, 126.4, 130.2, 130.6, 130.8, 137.2,
138.5, 139.6, 162.2 ppm.
1
white solid (160 mg, 0.75 mmol, 75%). H NMR (400
MHz, CDCl3): δ = 2.14 (s, 3 H), 2.30 (s, 3 H), 5.00–5.09
(m, 2 H), 5.95 (dd, J = 6.97, 1.83 Hz, 1 H), 6.39 (s, 1 H),
7.08–7.14 (m, 3 H), 7.14–7.20 (m, 2 H) ppm; 13C NMR
(100 MHz, CDCl3): δ = 21.2, 21.2, 51.2, 108.8, 119.5,
128.2, 129.6, 133.7, 136.1, 137.7, 151.0, 162.7 ppm;
HRMS (ESI) calcd. for C14H16NO [M+H]+ m/z 214.1226
found m/z 214.1222; Melting point observed: 75–78 °C.
1-(3,4-Dichlorobenzyl)pyridin-2(1H)-one (2w): Catalyst
TFA (11 mg, 10 mol %), 2-chloropyridine 3a (114 mg,
1.00 mmol) and (3,4-dichlorophenyl)methanol 4w (281 mg,
1.50 mmol) were treated following the general procedure
1
obtain 2w as a white solid (163 mg, 0.64 mmol, 64%). H
NMR (400 MHz, CDCl3): δ = 5.26 (s, 2 H), 6.21 (td, J =
6.72, 1.47 Hz, 1 H), 6.63 (d, J = 9.05 Hz, 1 H), 7.03–7.12
(m, 1 H), 7.17 (dd, J1 = J2 = 7.83 Hz, 1 H), 7.32 (dd, J =
6.85, 1.47 Hz, 1 H) 7.34–7.47 (m, 2 H) ppm; 13C NMR
(100 MHz, CDCl3): δ = 50.4, 106.5, 121.4, 127.9, 130.0,
131.6, 133.5, 136.0, 137.6, 140.0, 162.6 ppm; HRMS (ESI)
calcd. for C12H10Cl2NO [M+H]+ m/z 254.0134 found m/z
254.0131; Melting point observed: 89–92 °C.
1-Benzyl-5-nitropyridin-2(1H)-one (2s):[19] Catalyst
TfOH (15 mg, 10 mol %) and 2-(benzyloxy)-5-
nitropyridine 1s (230 mg, 1.00 mmol) were treated
following the general procedure to obtain 2s as a white
1
solid (170 mg, 0.74 mmol, 74%). H NMR (800 MHz,
CDCl3): δ = 5.20 (s, 2 H), 6.62 (d, J = 9.78 Hz, 1 H), 7.37
(d, J = 6.65 Hz, 2 H), 7.38–7.45 (m, 3 H), 8.09 (dd, J =
10.17, 3.13 Hz, 1 H), 8.60 (d, J = 2.74 Hz, 1 H) ppm; 13C
NMR (100 MHz, CDCl3): δ = 53.3, 119.8, 128.6, 129.1,
129.4, 130.9, 133.2, 134.4, 139.1, 161.6 ppm.
(Z)-1-(Pent-2-en-1-yl)pyridin-2(1H)-one (2k): Catalyst
TFA (11 mg, 10 mol %), 2-chloropyridine 3a (114 mg,
1.00 mmol) and (Z)-pent-2-en-1-ol 4k (129 mg, 1.50
mmol) were treated following the general procedure to
obtain 2k as a brown liquid (163 mg, 0.56 mmol, 56%).
1-Benzylquinolin-2(1H)-one (2t):[18] Catalyst TfOH (15
mg, 10 mol %) and 2-(benzyloxy)quinoline 1t (235 mg,
1.00 mmol) were treated following the general procedure
1
to obtain 2t as a yellow oil (176 mg, 0.75 mmol, 75%). H
1-(1-(4-Chlorophenyl)ethyl)pyridin-2(1H)-one
(2n):
NMR (400 MHz, CDCl3): δ = 5.59 (br. s., 2 H), 6.83 (d, J
= 9.54 Hz, 1 H), 7.16–7.36 (m, 7 H), 7.40–7.49 (m, 1 H),
7.59 (dd, J = 7.82, 1.47 Hz, 1 H), 7.77 (d, J = 9.54 Hz, 1
H) ppm; 13C NMR (100 MHz, CDCl3): δ = 46.1, 115.2,
121.1, 121.8, 122.4, 126.7, 127.4, 129.0, 129.0, 130.8,
136.5, 139.6, 139.7, 162.7 ppm.
Catalyst TFA (11 mg, 10 mol %), 2-chloropyridine 3a (114
mg, 1.00 mmol) and 1-(4-chlorophenyl)ethan-1-ol (4n)
(236 mg, 1.50 mmol) were treated following the general
procedure to obtain 2n as a white solid (140 mg, 0.60
mmol, 60%).
3-(4-Methoxybenzyl)benzo[d]thiazol-2(3H)-one
(2x):
General procedure for TFA catalyzed solvent free
tandem synthesize of N-alkylated pyridones 2d, 2u, 2v,
2w, 2k, 2n and benzothiazolones 2x, 2y, 2z (Table 3 in
the manuscript): Catalyst TFA (11 mg, 10 mol-%), 2-
chloropyridine 3a or 2-chlorobenzo[d]thiazole 3b (1.0
mmol), and alcohol 4 (1.5 mmol) were taken in a 5 mL
VWR reaction vial containing a small magnet without
using inert atmosphere. The cap of the vial was closed and
the reaction mixture was stirred at 130 °C for 24 h without
any external solvents. After completion of the reaction (by
TLC, GC or NMR), the crude was directly purified by
silica-gel (230–400 mess) column chromatography (flash)
using ethyl acetate / hexane solution to afford the desired
products 2d, 2u, 2v, 2w, 2k, 2n, 2x, 2y, 2z.
Catalyst
TFA
(11
mg,
10
mol
%),
2-
chlorobenzo[d]thiazole 3b (170 mg, 1.00 mmol) and (4-
methoxyphenyl)methanol (4f) (207 mg, 1.50 mmol) were
treated following the general procedure to obtain 2x as a
1
white solid (198 mg, 0.73 mmol, 73%). H NMR (400
MHz, CDCl3): δ = 3.79 (s, 3 H), 5.11 (s, 2 H), 6.84–6.90
(m, 2 H), 7.02 (d, J = 8.07 Hz, 1 H), 7.11–7.18 (m, 1 H),
7.21–7.31 (m, 3 H), 7.44 (dd, J = 7.70, 0.86 Hz, 1 H) ppm;
13C NMR (100 MHz, CDCl3): δ = 45.8, 55.3, 111.3, 114.3,
122.6, 122.7, 123.2, 126.4, 127.3, 128.7, 137.0, 159.3,
170.3 ppm; HRMS (ESI) calcd. for C15H14NO2S [M+H]+
m/z 272.0740 found m/z 272.0737; Melting point observed:
65–67 °C.
3-(Benzo[d][1,3]dioxol-5-ylmethyl)benzo[d]thiazol-
2(3H)-one (2y): Catalyst TFA (11 mg, 10 mol %), 2-
chlorobenzo[d]thiazole 3b (170 mg, 1.00 mmol) and
benzo[d][1,3]dioxol-5-ylmethanol (4y) (228 mg, 1.50
mmol) were treated following the general procedure to
Experimental procedures and characterisation data of
all products described in Scheme
5 (excluding
characterization data for those compounds already
given before):
1
obtain 2y as a white solid (217 mg, 0.76 mmol, 76%). H
1-Benzylpyridin-2(1H)-one (2d):[9] Catalyst TFA (11 mg,
10 mol %), and 2-chloropyridine 3a (114 mg, 1.00 mmol),
phenylmethanol (162 mg, 1.50 mmol) were treated
following the general procedure to obtain 2d as a brown oil
(135 mg, 0.73 mmol, 73%).
NMR (400 MHz, CDCl3): δ = 5.07 (s, 2 H), 5.94 (s, 2 H),
6.74–6.79 (m, 1 H), 6.79–6.85 (m, 2 H), 6.98–7.04 (m, 1
H), 7.12–7.18 (m, 1 H), 7.22–7.28 (m, 1 H), 7.41–7.46 (m,
1 H); 13C NMR (100 MHz, CDCl3): δ = 46.1, 101.3, 107.9,
108.6, 111.4, 120.9, 122.8, 123.4, 126.5, 129.1, 137.1,
147.5, 148.3, 170.4 ppm. HRMS (ESI) calcd. for
C15H12NO3S [M+H]+ m/z 286.0532 found m/z 286.0536;
Melting point observed: 91–94 °C.
1-(4-Ethylbenzyl)pyridin-2(1H)-one (2u): Catalyst TFA
(11 mg, 10 mol %), and 2-chloropyridine 3a (114 mg, 1.00
mmol), (4-ethylphenyl)methanol 4u (204 mg, 1.50 mmol)
were treated following the general procedure to obtain 2u
3-Benzhydrylbenzo[d]thiazol-2(3H)-one (2z): Catalyst
TFA (11 mg, 10 mol %), 2-chlorobenzo[d]thiazole 3b (170
mg, 1.00 mmol) and diphenylmethanol (4z) (276 mg, 1.50
1
as a brown oil (146 mg, 0.70 mmol, 70%). H NMR (400
MHz, CDCl3): 0.91 (t, J = 7.70 Hz, 3 H), 2.32 (q, J = 7.74
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800664
Advanced Synthesis & Catalysis
mmol) were treated following the general procedure to
[4] a) J. A. Pfefferkorn, J. Lou, M. L. Minich, K. J.
Filipski, M. He, R. Zhou, S. Ahmed, J. Benbow, A.-G.
Perez, M. Tu, J. Litchfield, R. Sharma, K. Metzler, F.
Bourbonais, C. Huang, D. A. Beebe, P. J. Oates, Bioorg.
Med. Chem. Lett., 2009, 19, 3247–3252; b) J. W.
Huffman, J. Lu, G. Hynd, J. L. Wiley, B. R. Martin,
Bioorg. Med. Chem., 2001, 9, 2863–2870.
1
obtain 2z as a white solid (200 mg, 0.63 mmol, 63%). H
NMR (400 MHz, CDCl3): δ = 6.78 (dd, J = 8.19, 0.86 Hz,
1 H), 7.04 (td, J = 7.83, 1.47 Hz, 1 H), 7.10 (td, J = 7.64,
1.34 Hz, 1 H), 7.29–7.41 (m, 11 H), 7.42–7.48 (m, 1 H)
ppm; 13C NMR (100 MHz, CDCl3): δ = 61.0, 114.0, 122.5,
122.6, 123.0, 125.8, 128.1, 128.5, 128.8, 136.8, 137.0,
170.6 ppm; HRMS (ESI) calcd. for C20H16NOS [M+H]+
m/z 318.0947 found m/z 318.0943; Melting point observed:
162–163 °C.
[5] For reviews, see, a) M. D. Hill and M. Movassaghi,
Chem.–Eur. J., 2008, 14, 6836–6844 and references
cited therein.
Computational methods: Electronic and molecular
structures of compounds originated from the Brønsted acid
catalyzed O- to N-alkyl migratory rearrangement of 2-
methoxypyridine were investigated through theoretical
calculation. The calculations were performed using DFT
employing the hybrid exchange-correlation functional
(B3LYP). Geometry optimizations and evaluation of
harmonic frequencies were performed at the B3LYP/6-
311++G(2d,p) level of theory. The optimized structures
were confirmed to be minima by vibrational frequency
analysis. The single point energy calculations were carried
out at B3LYP/6-311++G(3df,2p) level on corresponding
optimized geometries. The solvent effects (of 1, 2-
dichloroethane, DCE) were included using the SMD
solvation model. The dispersion corrections were included
using semi empirical atom pair wise interactions. DFT-D3
method developed by Grimme et al was employed because
this methodology has been shown to give quite accurate
thermo chemistry for both covalently bonded systems and
systems containing dispersion forces.[21] All computations
were performed using the Gaussian 09, Revision D.01[22]
and Gamess 2014, Version R1[23] quantum chemistry
packages.
[6] a) M. Breugst, H. Mayr, J. Am. Chem. Soc. 2010, 132,
15380–15389; b) D. Conreaux, E. Bossharth, N.
Monteiro, P. Desbordes, G. Balme, Tetrahedron Lett.
2005, 46, 7917–7920.
[7] a) E. L. Lanni, M. Bosscher, B. D. Ooms, C. A.
Chandro, B. A. Ellsworth, C. E. Anderson, J. Org.
Chem. 2008, 73, 6425–6428; b) S. Z. Tasker, M. A.
Bosscher, C. A. Shandro, E. L. Lanni, K. A. Ryu, G. S.
Snapper, J. M. Utter, B. A. Ellsworth, C. E. Anderson,
J. Org. Chem. 2012, 77, 8220–8230.
[8] C. S. Yeung, T. H. H. Hsieh, V. M. Dong, Chem. Sci.
2011, 2, 544–551.
[9] S. Pan, N. Ryu, T. Shibata, Org. Lett. 2013, 15, 1902–
1905.
[10] a) For palladium catalyzed [3,3]-sigmatopic
rearrangement, see, A. Rodrigues, E. E. Lee, R. A.
Batey, Org. Lett. 2010, 12, 260–263; b) E / Z
stereochemistry was determined by NOESY NMR;
please refer to SI for spectra.
Acknowledgements
S.B. thanks DST-INSPIRE programme, Govt. of India for the
faculty award (DST/INSPIRE/04/2013/000017). AKM thanks
DST-INSPIRE for his project fellowship. We are thankful to the
Director, CBMR for infrastructural facility. We also thank Mr. A.
Verma and Dr. B. Baishya for their helps in 2D NMR. N.H.M.
and A.R.S. gratefully acknowledge financial supports from
Brazilian Science Funding Agencies (FAPESP and CNPq), as
well as the computational facilities of GridUNESP. We are
extremely thankful to the Editor and the Reviewers for their
valuable comments towards revision of the manuscript. AKM and
SB thank to Dr. S. Sengupta for helping us improve the language
quality of the manuscript.
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FULL PAPER
Catalytic O- to N-Alkyl Migratory Rearrangement:
Transition Metal-Free Direct and Tandem Routes
to N-Alkylated Pyridones and Benzothiazolones
Adv. Synth. Catal. Year, Volume, Page – Page
Abhishek Kumar Mishra,a Nelson Henrique
Morgon,b Suparna Sanyal,c Aguinaldo Robinson de
Souzad* and Srijit Biswasa*
10
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