Preparation of N-alkyl 2-pyridones via a lithium iodide promoted oto N-alkyl migration: Scope and mechanism

Article abstract of DOI:10.1021/jo3015424

An efficient and inexpensive LiI-promoted O- to N-alkyl migration of 2-benzyloxy-, 2-allyloxy-, and 2-propargyloxypyridines and heterocycles is reported. The reaction produces the corresponding N-alkyl 2-pyridones and analogues under green, solvent-free conditions in good to excellent yields (30 examples, 20-97% yield). This method has been shown to be intermolecular and requires heat and lithium cation to occur.

Full text of DOI:10.1021/jo3015424

Article
pubs.acs.org/joc
Preparation of N‑Alkyl 2‑Pyridones via a Lithium Iodide Promoted O-
to N‑Alkyl Migration: Scope and Mechanism
Sarah Z. Tasker,† Michael A. Bosscher,† Christina A. Shandro,† Erica L. Lanni,‡ Keun Ah Ryu,†
Gregory S. Snapper,† Jarrad M. Utter,† Bruce A. Ellsworth,§ and Carolyn E. Anderson*,†
†Department of Chemistry and Biochemistry, Calvin College, 1726 Knollcrest Circle SE, Grand Rapids, Michigan 49546, United
States
‡Department of Chemistry, Pomona College, 645 North College Avenue, Claremont, California 91711, United States
§Department of Medicinal Chemistry, Research and Development, Bristol-Myers Squibb, Co., P.O. Box 5400, Princeton, New Jersey
08543-5400, United States
S
* Supporting Information
ABSTRACT: An efficient and inexpensive LiI-promoted O- to N-alkyl
migration of 2-benzyloxy-, 2-allyloxy-, and 2-propargyloxypyridines and
heterocycles is reported. The reaction produces the corresponding N-alkyl
2-pyridones and analogues under green, solvent-free conditions in good to
excellent yields (30 examples, 20−97% yield). This method has been shown
to be intermolecular and requires heat and lithium cation to occur.
that time, O-alkylated 2-hydroxypyridines have been utilized in
the presence of various catalysts as activated nucleophiles for
nitrogen alkylation.18,19 Even with activation, however, a
sufficiently nucleophilic heterocycle is still required, as initial
pyridinium salt formation occurs prior to C−O bond cleavage.
In the past few years, several metal-catalyzed benzyl migrations
leading to the formation of N-benzyl pyridones have also
appeared, including both LiI- and Ru-catalyzed methods.20,21
The former was developed in our laboratory and serves as the
basis for the following account. Additionally, several Pd- and Pt-
catalyzed procedures have also appeared for the preparation of
N-allyl 2-pyridones from 2-allyloxypyridines (eq 1, R =
allyl).22−26
Herein we report the use of LiI as an inexpensive catalyst for
the efficient O- to N-alkyl migration of 2-benzyloxy-, 2-allyloxy-,
and 2-propargyloxypyridines and heterocycles to provide N-
alkyl 2-pyridones. Due to the absence of solvent in these
transformations, this method represents a green alternative for
the synthesis of functionalized heterocyclic motifs. These
studies include both the scope of the LiI-catalyzed migration
as well as efforts to elucidate the mechanism of the benzyl
migration. The method reported achieves a formal [1,3]-alkyl
migration for a wide range of activated substituents in good to
excellent yields and with complete consumption of the starting
O-alkylated pyridines.
INTRODUCTION
■
Enolizable heterocycles, such as 2-pyridone, have provoked
significant interest in the chemical and biological communities
as a result of their ability to serve as models for hydrogen
bonding, tautomerization, and proton shuttling in both
chemical and biological processes.1−5 Furthermore, the
presence of N-alkylated 2-pyridones 3 in both natural
products6−9 and pharmacologically active structures renders
them important synthetic targets.10−12 As such, the develop-
ment of a simple method for selective nitrogen alkylation of 2-
pyridone motifs continues to be desirable. Although direct
intermolecular alkylation of either 2-hydroxypyridine or 2-
pyridone has been explored, O-alkylation is often a competing
process due to the aromatic character of the 2-oxypyridine
anion.13 Previous efforts by others in this area have utilized
salts14,15 or phase transfer catalysts16 to help control the
regiochemistry of the addition; however, these methods are
largely limited to activated electrophiles and often require
specific substituents on the pyridone for selectivity to be
observed.
In an attempt to circumvent these problems, O-alkylated
pyridines 2 have been explored as a means for accessing N-alkyl
pyridones 3 (eq 1). This is a particularly attractive strategy
RESULTS AND DISCUSSION
■
The synthesis of the required 2-alkyloxypyridines 6 was
generally accomplished, as previously described, by treating 2-
chloropyridine (4) (or a substituted analogue) with the
given that pyridines 2 can be accessed directly and in high yield
from 2-halopyridines 1 and an appropriate alcohol via
nucleophilic aromatic substitution. The first oxygen to nitrogen
migration in a 2-alkoxy-1N-heterocyclic system was reported by
Ikehara and Tanaka in 1974 within a nucleoside motif.17 Since
Received: July 26, 2012
© XXXX American Chemical Society
A
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requisite alcohol in the presence of potassium tert-butoxide
(Table 1).20 In this way, a variety of substituted benzyl, allyl,
and propargyl alcohols were readily incorporated into the
pyridine scaffolds.
Table 2. Optimization of Benzyl Migration
Table 1. Synthesis of 2-Alkoxypyridines
ab
,
entry
additive (equiv)
solvent (M)
temp (°C)
6a:7a
c
d
d
1
TFA (1.0)
BF3·Et2O (0.1)
LiI (3.0)
LiI (3.0)
LiI (1.5)
LiI (1.5)
LiI (1.5)
LiI (0.5)
LiI (0.25)
none
CH3CN (0.26)
CH3CN (0.26)
CH3CN (0.26)
CH3CN (0.26)
CH3CN (0.53)
CH3CN (0.53)
none
200
1:5
1.8:1
1:3
c
2
150
c
3
200
e
4
150
2.5:1
0:1
e
yield
5
150
a
,
(%)
e
b
6
100
1:6
entry
R
R′
R″
R‴ product
e
7
100
0:1
c
1
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
Me
H
6a
77
92
89
93
32
89
54
91
97
94
84
87
97
99
98
98
78
91
89
77
85
95
90
94
58
91
60
75
79
f
8
none
100
0:1
c
2
4-MeC6H5
6b
6c
e
9
none
100
1:3
c
c
3
4-MeOC6H5
4-ClC6H5
e
10
11
none
100
1:0
4
6d
6e
6f
g
LiI (0.5)
none
rt
1:0
5
4-CO2MeC6H5
4-CF3C6H5
a
b
1
Determined by either HPLC or H NMR analysis. Reference 20.
6
c
d
Microwave heating for 10 min. Benzylacetamide formed as a
7
4-CNC6H5
6g
6h
6i
e
f
byproduct. Conventional heating for 26 h. Conventional heating for
8 or 26 h rt = room temperature.
c
c
c
c
c
c
c
c
c
c
8
3-MeC6H5
g
9
3-MeOC6H5
3-ClC6H5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
6j
8 h with 0.5 equiv of LiI at 100 °C if the solvent was removed
completely (entry 8). Finally, entries 10 and 11 reveal that the
migration requires both LiI and heat to occur. Considering that
2-pyridones are known to be more thermodynamically stable
than their pyridine analogues, the absence of any thermally
promoted migration after 26 h at 100 °C is significant.28,29 It
should also be noted that while the removal of solvent was
initially implemented to improve the efficiency of the
migration, the absence of solvent also renders the reaction
more environmentally benign.
2-MeC6H5
6k
6l
2-MeOC6H5
2-ClC6H5
6m
6n
6o
6p
6q
6r
2,6-Cl2C6H4
2-naphthyl
Ph
Ph
Ph
c
α-Me-Ph
6s
(E)-CHCH(CH2)2Ph
(Z)-CHCH(CH2)2Ph
CC(CH2)4CH3
CC(CH2)2Ph
CCCy
E-6t
Z-6t
6u
6v
6w
6x
Substrate Scope. Applying the optimized reaction
conditions to a series of differently substituted 2-benzyloxypyr-
idine analogues 6 allowed for the rapid preparation of a variety
of substituted N-benzyl 2-pyridones 7 (Table 3). Monosub-
stitution at any position on the aryl ring was well tolerated,
providing the desired products in 60−97% yield (entries 1−
12). For substrates bearing electron-withdrawing groups, longer
reaction times (26 h versus 8 h) generally gave higher yields
(entries 4−6 and 9). Even in cases where the reactions were
complete in only 8 h, the N-benzyl pyridone products are stable
under the reaction conditions and can be isolated in similar
yields after more prolonged heating.20 Further, the reaction
proceeds efficiently even in the presence of substitution at the
ortho position, as shown by the reaction of 2-(2,6-
dichlorobenzyloxy)pyridine (6n), which undergoes alkyl
migration in 72% isolated yield after 26 h (entry 13). In this
case, the decrease in yield is likely attributable to the electron-
withdrawing ability of the two chlorine substituents rather than
a steric limitation and can be overcome by simply utilizing a full
equivalent of LiI (entry 14). Electron-rich 2-naphthyloxypyr-
idine (6o) underwent efficient conversion under the standard
reaction conditions to give N-2-naphyl-2-pyridone (7o) in 95%
yield after 8 h (entry 15).
CCPh
CC(CH2)4CH3
CC(CH2)4CH3
CC(CH2)4CH3
CCCH2OTIPS
6y
6z
6aa
6bb
d
a
Conditions: 2-chloropyridine or a substituted analogue (1.0 equiv),
ROH (1.5 equiv), KOtBu (1.5 equiv), 1,4-dioxane (0.22 M), 98 °C,
b
c
d
overnight. Isolated yields. Reference 20. Conditions: 2-fluoropyr-
idine (1.0 equiv), ROH (1.5 equiv), KOtBu (1.5 equiv), 1,4-dioxane
(0.66 M), 98 °C, overnight.
Optimization. Initial efforts to convert 2-benzyloxypyridine
(6a) to pyridone 7a focused on the use of various additives at
elevated temperature (Table 2). Using microwave heating,
TFA, BF3·OEt2, and LiI were each examined as possible
catalysts for the transformation (entries 1−3). While all three
species were found to facilitate the formation of the desired
product 7a, benzylacetamide was observed as a byproduct in
the presence of either TFA or BF3·OEt2.27 As this byproduct
was not observed in the LiI-promoted case, LiI was targeted for
further development.
Utilizing conventional heating, the efficiency of the LiI-
catalyzed reaction improved with increased concentration,
allowing for both the temperature and LiI loading to be
decreased (Table 2, entries 4−9). Under optimum conditions,
complete conversion to pyridone 7a could be achieved in only
In contrast, when the heterocycle or benzylic position was
substituted, the reaction was less robust. Whereas 5-methyl-
substituted pyridine 6q afforded a 93% yield of product 7q
under the standard migration conditions, the 3-methyl- and 6-
methyl-substituted cases gave reduced yields (entries 16−18).
Interestingly, 6-methyl pyridine 6r, which has been found by
others to be unreactive in this type of transformation,21
B
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provided 59% yield of the desired pyridone 7r after 26 h (entry
18). However, 3-methyl pyridine 6p required both 26 h and a
full equivalent of LiI to give comparable results (entry 16). In a
similar manner, 2-(α-methylbenzyloxy)pyridine (6s), which
bears substitution at the benzylic position, undergoes migration
more slowly than the unsubstituted case, affording only 34%
yield after 26 h (entry 19). While this yield is low, the
occurrence of the transformation is significant, given that
substrates with benzylic substituents have failed to react under
other established protocols.21 The reduced yield in each of
these cases is likely the result of a negative steric interaction
imposed by the appended methyl group.
Application of these conditions to other N-heterocycles,
including heterocycles with additional nitrogen atoms, resulted
in less successful migration reactions (Table 4). While dibenzyl
pyridazine derivative 8 was found to undergo mono- and
dimigration when subjected to 0.5 equiv LiI for 26 h in 63%
and 6% yields, respectively, heterocycles 11, 13, 15, and 17
showed little or no reactivity under these conditions. By
increasing the amount of LiI and the temperature, quinolone 12
and pyrimidone 14 could be isolated in 71% and 61% yields,
respectively (entries 2 and 3). Unfortunately, the reaction of
pyrazine 15 and quinoxaline 17 produced far greater amounts
of unidentified byproducts, leading to lower overall yields of the
migration products 16 and 18 (entries 4 and 5). 3-Pyridyl-
substituted pyridine 19 was the least productive of these
analogues, providing an array of unidentified byproducts and
none of the desired pyridone 20 (entry 6). In these cases, the
Table 3. Preparation of Substituted N-Benzyl 2-Pyridones
ab
,
entry substrate
Ar
R
R′
R″ product yield
c
c
c
1
6a
6b
6c
6d
6f
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
7a
7b
7c
7d
7f
91
97
84
2
4-MeC6H5
4-MeOC6H5
4-ClC6H5
4-CF3C6H5
4-CNC6H5
3-MeC6H5
3-MeOC6H5
3-ClC6H5
2-MeC6H5
2-MeOC6H5
2-ClC6H5
2,6-Cl2C6H4
2,6-Cl2C6H4
2-naphthyl
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
3
cd
,
4
90
d
5
84
d
6
6g
6h
6i
7g
7h
7i
60
c
7
96
94
c
8
cd
,
9
6j
7j
93
c
10
11
12
13
14
15
16
17
18
19
6k
6l
7k
7l
91
c
c
88
79
6m
6n
6n
6o
6p
6q
6r
7m
7n
7n
7o
7p
7q
7r
cd
,
72
85
ce
,
c
95
cde
,
,
57
c
Ph
93
59
d
Ph
cd
,
6s
α-Me-Ph
7s
34
a
b
c
Conditions: substrate (1.0 equiv), LiI (0.5 equiv), 100 °C, 8 h.
Isolated yields. Mean values from duplicate experiments ( 3%).
d
e
Reference 20. Reaction duration = 26 h. 1.0 equiv of LiI used.
Table 4. Evaluation of Heterocyclic Analogues
a
Conditions: (A) substrate (1.0 equiv), LiI (0.5 equiv), 100 °C, 26 h. (B) substrate (1.0 equiv), LiI (1.0 equiv), 110 °C, 26 h. (C) substrate (1.0
b
equiv), LiI (1.0 equiv), 100 °C, 26 h. (D) substrate (1.0 equiv), LiI (2.0 equiv), 110 °C, 26 h. Isolated yields. Mean values from duplicate
experiments ( 3%). Reference 20. NP = no product identified.
c
d
C
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The Journal of Organic Chemistry
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inclusion of an additional basic nitrogen away from the alkoxy
substituent seems to hinder the desired alkyl migration.
In an attempt to extend our methodology to other activated
groups, 2-allyloxypyridines 6t were also evaluated and shown to
migrate in good yields (Scheme 1). When geometrically pure E-
many of the substrates required superstoichiometric amounts of
LiI to proceed efficiently.
In general, utilizing 1.0 equiv LiI at 100 °C for 26 h
represents good initial conditions for the propargyl migration;
however, the ideal amount of LiI can be optimized
independently for each substrate (Table 5). Using this
technique, conditions were identified in which a variety of 2-
propargyloxypyridines 6 underwent migration to give the
desired pyridone products 7 in good to excellent yields (66−
85%, entries 1−10). The reaction tolerates a range of
substitution on the alkyne terminus, including some with
significant steric bulk, including cyclohexyl substrate 6w. In
these sterically congested systems, the yield was found to
increase when more LiI was used (entries 3 and 7). The
migration was also found to occur in the presence of extended
conjugation, as phenyl substrate 6x undergoes migration to give
pyridone 7x in 66% yield in the presence of 2.0 equiv of LiI
(entry 10).
As with the benzyl migration, added substitution on the
pyridine ring was met with mixed results. While methyl
substitution at C5 on the pyridine ring was found to have a
minimal effect on the migration (64% yield, entry 13),
methylation at either C3 or C6 was significantly more
detrimental with no more than 15% of the desired pyridone
isolated (entries 11 and 15). In these cases, it is assumed that
the additional substitution interferes with coordination of
lithium to the heteroatoms and thus impedes the migration.
Throughout these studies, it was observed that a small
amount of β-iodo N-alkenyl pyridone 22 was generally formed
in addition to the desired N-propargyl pyridone 7. This
byproduct was first observed in 2-octynyl substrate 6u, and a
full report detailing the synthesis of this class of compounds has
appeared elsewhere.30 Interestingly, in the case of silyl ether
6bb, N-alkenyl pyridone 22bb was observed as the only
product of the reaction in low isolated yields (entries 16−18).
In this case, increasing the amount of LiI did little to improve
the reaction yield but did decrease the amount of starting
pyridine 6bb that was recovered (0.5 equiv LiI: 13% 22bb, 70%
6bb recovered; 1.0 equiv LiI: 16% 22bb, 55% 6bb recovered;
1.5 equiv LiI: 16% 22bb, <10% 6bb recovered).
Mechanistic Studies. Unlike the allyl migration, benzyl
migration does not appear to proceed through a carbocation
intermediate. This conclusion stems from the initial optimiza-
tion studies in which no benzylacetamide byproduct was
observed in the presence of LiI, as compared to either TFA or
BF3·OEt2, (see Table 2). The formation of benzylacetamide is
expected to occur upon Ritter reaction between benzyl cation
and the acetonitrile solvent. Further, 2-(α-methylbenzyloxy)-
pyridine (6s) would be predicted to undergo a more facile
migration if a stable secondary benzylic carbocation was being
formed; however, this substrate proceeds with much lower
efficiency than the corresponding unsubstituted case (Scheme
2). Thus, additional benzylic substitution appears to inhibit
product formation rather than accelerate it.
Given this departure from our initial expectation, a Hammett
plot was constructed for the migration of para-substituted 2-
benzyloxypyridines 6. In this way, we hoped to gain an
understanding of the type of intermediates that were involved
in the reaction. Utilizing seven different para-substituted
benzyloxypyridines 6, the required kinetic data was obtained
by 1H NMR analysis of reaction aliquots. Reactions were
performed at 90 °C (standard conditions = 100 °C) in order to
decrease the reaction rate and allow for reproducible data to be
Scheme 1. LiI-Catalyzed Allyloxypyridine Migration
allyloxypyridine E-6t was subjected to the migration conditions,
a 2:1 mixture of E- and Z-N-alkylated 2-pyridone 7t was
observed in 87% yield. A similar result was observed when the
Z-isomer was utilized (2:1 ratio E-7t:Z-7t, 88% yield). These
results suggest the formation of a common carbocation
intermediate in the allyl migration. Further, although a [3,3]-
sigmatropic rearrangement can also be envisaged at these
temperatures, no spectral evidence for terminal alkene 21 was
observed after heating alkene 6t in either the presence or
absence of lithium iodide. The preference for formation of
linear product 7t over branched product 21 is expected to be
largely thermodynamically driven.
Propargyloxypyridines 6u−6bb were also subjected to the
alkyl migration conditions (LiI (0.5−2.0 equiv), 100 °C, neat,
26 h, Table 5). In all cases, 2-propargyloxypyridines 6 were
found to undergo migration more slowly than the correspond-
ing benzyl-substituted analogues (26 versus 8 h). In addition,
Table 5. Formation of N-Propargyl 2-Pyridones
LiI
yield 7
a
entry substrate
R
R′
R″
R‴ (equiv)
(%)
1
6u
6v
pentyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
0.5
0.5
0.8
1.0
0.5
0.8
1.2
0.5
1.4
2.0
0.5
0.5
1.0
1.5
0.5
0.5
1.0
1.5
81
55
85
84
36
56
77
19
53
66
2
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
Cy
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
3
6v
H
4
6v
H
5
6w
6w
6w
6x
H
6
Cy
H
7
Cy
H
8
Ph
H
9
6x
Ph
H
10
11
12
13
14
15
16
17
18
6x
Ph
H
b
6y
pentyl
H
NP
6z
pentyl
Me
Me
Me
H
57
64
56
15
−c
−d
−e
6z
pentyl
6z
pentyl
6aa
6bb
6bb
6bb
pentyl
CH2OTIPS
CH2OTIPS
CH2OTIPS
H
H
H
a
b
Isolated yields. Mean value of duplicate runs ( 3%). NP = no
c
d
product identified. 13% yield 22bb; 70% 6bb recovered. 16% yield
22bb; 55% 6bb recovered. 16% yield 22bb; <10% 6bb recovered.
e
D
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Article
In order to provide further evidence against an intra-
molecular process, crossover experiments between methylated
pyridine 6q and para-substituted methyl-, methoxy-, and
chloro-substituted benzyloxypyridines 6b−6d were conducted
(Scheme 3A). In each case, all four possible crossover products
were observed, eliminating the possibility that the migration is
intramolecular. Perhaps most interesting, however, was the
close to equimolar amounts of all four crossover products
observed in each of these transformations as determined by 1H
NMR. This is particularly intriguing since the methoxybenzyl
substrate 6c and chlorobenzyl substrate 6d migrate at
significantly different rates, as demonstrated in the Hammett
plot in Figure 1. Further control experiments in which either
equimolar amounts of benzyloxypyridine 6a and substituted
pyridone 7q or alternatively pyridones 7b and 7q were
subjected to the reaction conditions provided no products
resulting from crossover (Scheme 3B). These results suggest
that exchange must occur during the initial alkyl migration and
that this migration is not reversible under the reaction
conditions. Further, these observations stand in contrast to
the intramolecular Ru-catalyzed benzyl migration reported by
Dong and co-workers, in which no crossover is observed.21
Two distinct non-carbocation mechanisms appear to be
consistent with the observed data: (A) formation of a benzyl
iodide intermediate upon cleavage of the C−O bond by
nucleophilic iodide and then capture by an anionic pyridone
(Scheme 4A) or (B) nucleophilic cleavage of the C−O bond by
the nitrogen of another molecule of benzyloxypyridine (BOP)
6, either directly or through a more highly organized dimeric
complex (Scheme 4B). In each of these cases, it is assumed that
initial precoordination of lithium is required for migration to
take place. Complexes 23, 24, and 25, as proposed in
mechanistic possibility B, would in fact require lithium to
coordinate to two, three, or four heteroatoms rather than just a
single oxygen atom.31 The formation of more complex dimers
24 and 25 may be facilitated by the presence of one or more
edge-to-face aromatic−aromatic interactions (see green inter-
actions in Scheme 4B).32 In the case of mechanism B, iodide
Scheme 2. Impact of Benzylic Substitution on Migration
Efficiency
collected. Using this data, a Hammett plot was generated
displaying ρ = −2.60 (R2 = 0.89, Figure 1). This large negative
Figure 1. Hammett plot for the LiI-catalyzed migration of para-
substituted benzyloxypyridines 6.
ρ value strongly suggests that the reaction is proceeding
through an electrophilic intermediate and provides strong
evidence against mechanisms in which a negatively charged,
radical (neutral), or intramolecular (neutral) intermediate
would be required before or at the rate-determining step.
The large negative ρ value could be consistent with a number of
different electrophilic pathways, including nucleophilc benzyl
displacement or formation of a benzylic carbocation in the rate-
determining step.
Scheme 3. Crossover Experiments
E
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a
Scheme 4. Possible Non-Carbocation Mechanisms for Benzyl Migration
a
Potential edge-to-face aromatic−aromatic interactions are indicated in green.
may or may not serve as a ligand for lithium during the
migration.
To secure the importance of lithium in the migration, two
parallel studies were conducted. First, 2-benzylthiopyridine 26
was subjected to the migration conditions (0.5 equiv LiI, 100
°C, Scheme 5). In this case, the thiopyridone 27 was not
recovered. In order to ensure that this observation was not a
solvent effect, the reaction was performed with CH3CN or
THF as solvent at the same concentration. In these cases,
1
significant migration was observed by H NMR (1:5 and 1:40
6a:7a, respectively). The lack of reactivity of the sulfur analogue
26 and the recovery of pyridine 6a unchanged in the presence
of 12-crown-4 both, independently, confirm the importance of
lithium cation in the migration.
Scheme 5. Importance of Lithium Coordination to the Alkyl
Migration
The role of iodide in the reaction, however, remains less
clear. While the migration of pyridine 6j proceeds smoothly in
the presence of LiI, other iodide salts (KI and NBu4I) gave
none of the expected pyridone 7j (Scheme 6). In these
reactions, CH3CN was added to ensure the solubility of each
salt. Interestingly, migrations conducted under these conditions
in the presence of LiBr also yielded only recovered starting
material, suggesting that the unique dissociative properties of
Scheme 6. Evaluation of Various Metal Salts
observed, although sulfur analogue 26 was recovered
unchanged. Given the lower affinity of sulfur for lithium, this
strongly suggests that lithium coordination to the oxygen is
required for migration to occur. Further evidence in support of
this result was garnered when benzyloxypyridine 6a was treated
with LiI in the presence of 2 equiv of 12-crown-4 (reaction
concentration = 3.1 M). In this case, only starting material was
F
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LiI may be as important to the reaction as the iodide
counterion.
Scheme 8. Determination of the Stereochemical Outcome of
Benzyl Migration
Further efforts to discern the importance of iodide in the
reaction focused on the addition of methylated benzyl iodide
28 to the standard reaction with benzyloxypyridine 6a (Scheme
7A).33 When pyridine 6a and tagged benzyl iodide 28 were
Scheme 7. Incorporation of 4-Methyl Benzyl Iodide 28
benzyl pyridone d1-7a in 68% isolated yield. Interestingly,
pyridone d1-7a is formed as a 1:1 mixture of two rotational
isomers around the C−N bond, as determined by 13C NMR
analysis. This suggests that pyridone d1-7a is formed as a
racemate, as the nonlabeled pyridone 7a does not exhibit this
characteristic. Isotopically labeled pyridone d1-7a was then
treated with P2S5 to provide thiopyridone d1-30.37 Subsequent
exposure of compound d1-30 to MeI provided the thiomethyl
pyridinium salt,37 which was then treated with thiourea to
facilitate cleavage of the benzyl group via an expected SN2
process.38 Hydrolysis in aqueous base then provided the
deuterated benzyl mercaptan d1-31. Preparation and stereo-
1
mixed in a 1:1 ratio in the presence of 0.5 equiv of LiI, H
NMR analysis of the crude reaction mixture showed that both
methylated pyridone 7b and a smaller amount of unsubstituted
pyridone 7a had been formed. This reaction was then repeated
in the presence of benzyl iodide 28 at ambient temperature
with and without LiI and at 100 °C with no LiI (Scheme 7B−
D). Under each set of conditions, both methylated product 7b
as well as unsubstituted pyridone 7a were observed. That
pyridone products are formed in the absence of both LiI and
heat in the presence of an external benzyl electrophile, suggests
that the rate determining step in the migration is likely C−O
bond cleavage, as no migration is observed under these
conditions in the absence of a benzyl iodide source (see Table
2, entry 11 for comparison). Further, the reaction with iodide
28 shows that benzyl iodides are competent intermediates to
initiate the reaction cascade, although it does not prove that
such an intermediate is actually generated. The formation of
unsubstituted pyridone 7a in the reaction with external iodide
28, however, implies that once initial alkylation of the pyridine
nitrogen occurs, another molecule of benzyloxypyridine 6a is
competent to cleave the C−O bond to provide the
unsubstituted product 7a. This type of scenario would be
necessary if the migration were occurring through mechanism
B. As such, the presence of both methylated product 7b and
unsubstituted pyridone 7a imply that either mechanism A or B
could be operative.
In an effort to differentiate between these possibilities, an
enantioenriched monodeuterated 2-benzyloxypyridine d1-6a
was subjected to the reaction conditions (Scheme 8). Since
mechanism A is expected to proceed through two sequential
SN2 displacements and mechanism B would only require a
single SN2 displacement, subjecting such a labeled substrate to
the migration conditions was expected to allow these
mechanistic possibilities to be distinguished (see Scheme 4).
Using Noyori’s ruthenium transfer hydrogenation protocol,34,35
monodeuterated benzyl alcohol d1-29 was prepared in 90+%
ee, as determined by MTPA ester analysis.36 Incorporation of
alcohol d1-29 into chiral pyridine d1-6a and treatment under
the standard migration conditions provided deuterated N-
1
chemical analysis of the (R)-MPA thioester d1-32 by H NMR
revealed that the isolated benzyl mercaptan d1-31 was
racemic,39 as demonstrated by the presence of two singlets of
equal intensity at 3.94 and 4.02 ppm.40 While initially
unexpected, this result suggests that either the two nucleophilic
displacement mechanisms are operating in tandem to
accomplish the formal [1,3]-benzyl migration or that at some
point in the migration process a carbocation is in fact being
formed. Such a carbocation could result from the ionization of a
benzyl iodide intermediate under the reaction conditions (100
°C) or through the formation of a benzyl cation that has gone
undetected in our investigations due to rapid recombination. A
reversible migration could also produce this result, however,
since no crossover is observed when differently substituted
pyridones are subjected to the migration conditions, this seems
unlikely (see Scheme 3B).
In summary, the LiI-catalyzed benzyl migration has been
shown to proceed via an intermolecular process that relies on
the activation of the benzyloxypyridine by lithium. While two
distinct nucleophilic displacement mechanisms are possible and
would be expected to give two stereochemically distinct
products, isotopically labeled pyridine d1-6a was found to
undergo migration to afford pyridone d1-7a as a racemate,
suggesting that these two processes are either operating in
tandem or that the reaction proceeds through an otherwise
undetected carbocation.
CONCLUSION
We have reported an inexpensive and efficient LiI-catalyzed
alkyl migration of 2-benzyloxy-, 2-allyloxy-, and 2-propargyloxy-
■
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tert-butoxide (505 mg, 4.50 mmol) was added to 2-chloropyridine
(0.28 mL, 3.00 mmol) and 4-(hydroxymethyl)benzonitrile (601 mg,
4.50 mmol) in 1,4-dioxane (13.6 mL). After 20 h, the reaction was
worked up and purified by column chromatography (SiO2, 4:1
hexanes/ethyl acetate) to afford 342 mg (54% yield) of 6g as a white
solid: mp 53−55 °C; 1H NMR (400 MHz, CDCl3) δ 8.12 (app d, J =
3.0 Hz, 1H), 7.55−7.65 (m, 3H), 7.52 (d, J = 8.0 Hz, 2H), 6.88 (app t,
J = 7.0 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 5.42 (s, 2H); 13C NMR (100
MHz, CDCl3) δ 162.9, 146.8, 143.0, 138.9, 132.2, 127.9, 118.8, 117.4,
111.3, 111.2, 66.2; IR (neat) 3053, 2932, 2228, 1592, 1571, 1474,
1432, 1285 cm−1; HRMS (ESI-TOF) m/z 211.0870 [211.0871 calcd
for C13H11N2O (M + H)+].
(E)-2-(5-Phenyl-2-pentenyloxy)pyridine (E-6t). Following the
general procedure outlined above for the synthesis of compound 6r,
potassium tert-butoxide (1.97 g, 17.6 mmol) was added to 2-
chloropyridine (1.10 mL, 11.7 mmol) and (E)-5-phenyl-2-penten-1-
ol41 (2.85 g, 17.6 mmol) in 1,4-dioxane (54 mL). After 20 h, the
reaction was worked up and purified by column chromatography
(SiO2, 39:1 hexanes/ethyl acetate) to afford 2.16 g (77% yield) of E-6t
as a viscous oil: 1H NMR (400 MHz, CDCl3) δ 8.15 (ddd, J = 1.4, 2.2,
6.5 Hz, 1H), 7.56 (ddt, J = 0.5, 2.0, 6.0 Hz, 1H), 7.25−7.30 (m, 2H),
7.15−7.21 (m, 3H), 6.86 (ddd, J = 1.0, 5.0, 6.9 Hz, 1H), 6.75 (td, J =
0.8, 8.4 Hz, 1H), 5.85−5.94 (m, 1H), 5.75−5.83 (m, 1H), 4.78 (d, J =
6.1 Hz, 2H), 2.73 (t, J = 7.5 Hz, 2H), 2.40 (q, J = 7.2 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 163.8, 147.1, 142.0, 138.7, 134.6, 128.7,
128.5, 126.1, 125.9, 116.9, 111.4, 66.6, 35.7, 34.4; IR (neat) 3026,
2932, 1595, 1472, 1432, 1285 cm−1; HRMS (ESI-TOF) m/z 262.1204
[262.1208 calcd for C16H17NONa (M + Na)+].
(Z)-2-(5-Phenyl-2-pentenyloxy)pyridine (Z-6t). Following the
general procedure outlined above for the synthesis of compound 6r,
potassium tert-butoxide (426 mg, 3.80 mmol) was added to 2-
chloropyridine (0.24 mL, 2.50 mmol) and (Z)-5-phenyl-2-penten-1-
ol41,42 (566 mg, 3.80 mmol) in 1,4-dioxane (11.4 mL). After 18 h, the
reaction was worked up and purified by column chromatography
(SiO2, 32:1 hexanes/ethyl acetate) to afford 506 mg (85% yield) of Z-
6t as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 8.15−8.17 (m, 1H),
7.57 (dddd, J = 0.7, 2.0, 7.1, 8.3 Hz, 1H), 7.26−7.32 (m, 2H), 7.16−
7.24 (m, 3H), 6.86 (tdd, J = 0.8, 5.1, 7.0 Hz, 1H), 6.74 (ddd, J = 0.8,
1.7, 8.4 Hz, 1H), 5.67−5.80 (m, 2H), 4.85 (d, J = 6.0 Hz, 2H), 2.74 (t,
J = 7.8 Hz, 2H), 2.50 (q, J = 6.7 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 163.8, 160.3, 147.0, 141.8, 138.7, 133.4, 128.7, 128.6, 126.1,
125.8, 116.9, 111.5, 61.9, 36.0, 29.7; IR (neat) 3024, 2929, 1594, 1569,
1473, 1432, 1285 cm−1; HRMS (ESI-TOF) m/z 262.1212 [262.1208
calcd for C16H17NONa (M + Na)+].
2-(4-Triisopropylsiloxy-2-butynyl)pyridine (6bb). Following
the general procedure outlined above for the synthesis of compound
6r, potassium tert-butoxide (253 mg, 2.25 mmol) was added to 2-
fluoropyridine (0.13 mL, 1.50 mmol) and 4-triisopropylsiloxy-2-butyn-
1-ol43 (545 mg, 2.25 mmol) in 1,4-dioxane (2.3 mL). After 16 h, the
reaction was worked up and purified by column chromatography
(SiO2, 32:1 hexanes/ethyl acetate) to afford 378 mg (79% yield) of
6bb as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 3.2 Hz,
1H), 7.55 (dt, J = 2.0, 7.0 Hz, 1H), 6.86 (app t, J = 5.1 Hz, 1H), 6.75
(d, J = 8.3 Hz, 1H), 4.98 (t, J = 1.7 Hz, 2H), 4.40 (t, J = 1.6 Hz, 2H),
0.96−1.16 (m, 21H); 13C NMR (100 MHz, CDCl3) δ 162.5, 146.7,
138.6, 117.2, 111.2, 84.9, 80.0, 53.6, 52.0, 17.8, 11.9; IR (neat) 2943,
2866, 1596, 1573, 1488, 1434, 1285, 1271 cm−1; HRMS (ESI-TOF)
m/z 342.1871 [342.1865 calcd for C18H29NO2SiNa (M + Na)+].
General Procedure for the LiI-Promoted Rearrangement of
2-Alkoxypyridines. (N)-(4-Trifluoromethylbenzyloxy)-2-pyri-
done (7f). To 2-(4-trifluoromethylbenzyloxy)pyridine (6f, 210 mg,
0.83 mmol) in a 1 dram vial was added LiI (56 mg, 0.42 mmol). The
sealed vial containing the mixture was placed in a 100 °C bath for 26 h.
Upon removal from the bath, the mixture was diluted with ethyl
acetate (2 mL), and the resulting solution was loaded onto silica gel
for purification by column chromatography (SiO2, 1:3 hexane/ethyl
acetate) to afford 176 mg (84%) of 7f as a white solid: mp 82−83 °C;
1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.8 Hz, 2H), 7.36 (d, J =
pyridines and heterocyclic analogues that proceeds under green
conditions to afford the corresponding N-alkyl 2-pyridones in
good to excellent yields. This method has been shown to
require heat and lithium cation to occur and proceeds through
either a combination of nucleophilic displacement mechanisms
or a short-lived carbocation. Despite some limitations, this
transformation provides an excellent means for the preparation
of N-alkyl pyridones and heterocyclic analogues and should find
wide synthetic application.
EXPERIMENTAL SECTION
■
All reagents were purchased from commercial venders and used as
1
received. H and 13C NMR spectra were obtained on either a 400
MHz or 500 MHz NMR spectrometer. Chemical shifts are reported in
ppm relative to CDCl3. Multiplicity is indicated as follows: s (singlet);
d (doublet); t (triplet); q (quartet); m (multiplet); dd (doublet of
doublets); dt (doublet of triplets); app (apparent).
General Experimental Procedure for the Synthesis of 2-
Alkoxypyridines. 2-Benzyloxy-6-methylpyridine (6r). To a
solution of benzyl alcohol (2.07 mL, 20.0 mmol) in 1,4-dioxane (45
mL) were added 2-chloro-6-methylpyridine (1.09 mL, 10.0 mmol) and
potassium tert-butoxide (1.68 g, 15.0 mmol). The reaction vessel was
equipped with an air condenser and warmed to 98 °C. After 19 h, the
reaction mixture was cooled to room temperature, and ethyl acetate
(10 mL) and H2O (10 mL) were added. The phases were separated,
and the aqueous phase was extracted with ethyl acetate (2 × 10 mL).
The combined organic phases were then washed successively with 1:1
brine/H2O (10 mL) and H2O (10 mL), dried (MgSO4), and
concentrated in vacuo. Purification by column chromatography (39:1
hexane/ethyl acetate) afforded 1.80 g (91% yield) of 6r as a white
1
solid: mp 39−40 °C; H NMR (400 MHz, CDCl3) δ 7.43−7.50 (m,
3H), 7.37 (tt, J = 1.2, 7.1 Hz, 2H), 7.28−7.34 (m, 1H), 6.72 (d, J = 7.2
Hz, 1H), 6.59 (d, J = 8.2 Hz, 1H), 5.37 (s, 2H), 2.47 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 163.1, 156.2, 138.8, 137.6, 128.4, 128.1,
127.7, 115.9, 107.6, 67.4, 24.2; IR (neat) 3065, 3032, 2952, 1599,
1575, 1451, 1304, 1232 cm−1; HRMS (ESI-TOF) m/z 222.0891
[222.0895 calcd for C13H13NONa (M + Na)+].
Methyl 4-(2-Pyridinyloxymethyl)benzoate (6e). Following the
general procedure outlined above for the synthesis of compound 6r,
potassium tert-butoxide (2.02 g, 18.0 mmol) was added to 2-
chloropyridine (1.13 mL, 12.0 mmol) and methyl 4-(hydroxymethyl)-
benzoate (2.99 g, 18.0 mmol) in 1,4-dioxane (54.5 mL). After 18 h,
the reaction was worked up and purified by column chromatography
(SiO2, 9:1 hexanes/ethyl acetate) to afford 923 mg (32% yield) of 6e
1
as a white solid: mp 48−50 °C; H NMR (400 MHz, CDCl3) δ 8.13
(d, J = 4.7 Hz, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.57 (t, J = 7.1 Hz, 1H),
7.49 (d, J = 8.0 Hz, 2H), 6.87 (t, J = 6.4 Hz, 1H), 6.81 (d, J = 8.3 Hz,
1H), 5.42 (s, 2H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
166.9, 163.2, 146.8, 142.7, 138.7, 129.7, 129.4, 127.3, 117.1, 111.2,
66.6, 52.1; IR (neat) 3032, 2952, 1722, 1598, 1474, 1434, 1278, 1109
cm−1; HRMS (ESI-TOF) m/z 244.0973 [244.0974 calcd for
C14H14NO3 (M + H)+].
2-(4-Trifluoromethylbenzyloxy)pyridine (6f). Following the
general procedure outlined above for the synthesis of compound 6r,
potassium tert-butoxide (1.01 g, 9.00 mmol) was added to 2-
chloropyridine (0.56 mL, 6.00 mmol) and 4-trifluoromethylbenzyl
alcohol (1.23 mL, 9.00 mmol) in 1,4-dioxane (27.3 mL). After 16 h,
the reaction was worked up and purified by column chromatography
(SiO2, 19:1 hexanes/ethyl acetate) to afford 1.35 g (89% yield) of 6f as
1
a white solid: mp 38−39 °C; H NMR (400 MHz, CDCl3) δ 8.16
(app dd, J = 2.0, 5.1 Hz, 1H), 7.55−7.65 (m, 5H), 6.90 (app dd, J =
5.1, 7.1 Hz, 1H), 6.83 (qd, J = 0.6, 8.4 Hz, 1H), 5.45 (s, 2H); 13C
NMR (100 MHz, CDCl3) δ 163.2, 146.8, 141.6, 138.8, 129.1 (q, J =
32.4 Hz), 127.8, 125.6 (q, J = 3.7 Hz), 122.8, 117.2, 111.2, 66.5; IR
(neat) 3016, 2939, 1594, 1569, 1473, 1432, 1325, 1270, 1121 cm−1;
HRMS (ESI-TOF) m/z 254.0789 [254.0793 calcd for C13H11F3NO
(M + H)+].
2-(4-Cyanobenzyloxy)pyridine (6g). Following the general
procedure outlined above for the synthesis of compound 6r, potassium
7.9 Hz, 2H), 7.29−7.35 (m, 1H), 7.22−7.26 (m, 1H), 6.60 (d, J = 9.1
Hz, 1H), 6.16 (t, J = 6.9 Hz, 1H), 5.17 (s, 2H); 13C NMR (125 MHz,
H
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CDCl3) δ 162.5, 140.4 (q, J = 1.3 Hz), 139.8, 137.3, 130.0 (q, J = 32.4
Hz), 128.1, 125.7 (q, J = 3.8 Hz), 123.9 (q, J = 274 Hz), 121.3, 106.6,
51.7; IR (neat) 3065, 2917, 1665, 1586, 1536, 1325, 1108 cm−1;
HRMS (ESI-TOF) m/z 276.0608 [276.0612 calcd for C13H10F3NONa
(M + Na)+].
6u30 (331 mg, 1.63 mmol) was treated with LiI (109 mg, 0.81 mmol)
for 26 h. Purification by column chromatography (SiO2, ethyl acetate)
afforded 270 mg (81% yield) of 7u as a yellow oil: H NMR (400
1
MHz, CDCl3) δ 7.70 (dd, J = 2.1, 6.9 Hz, 1H), 7.32 (ddd, J = 2.1, 6.6,
9.0 Hz, 1H), 6.55 (app d, J = 9.2 Hz, 1H), 6.21 (dt, J = 1.4, 6.8 Hz,
1H), 4.72 (t, J = 2.3 Hz, 2H), 2.23 (tt, J = 2.3, 7.2 Hz, 2H), 1.53
(pentet, J = 7.2 Hz, 2H), 1.26−1.40 (m, 4H), 0.89 (t, J = 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 162.4, 139.7, 136.0, 120.6, 106.1, 88.8,
73.0, 38.4, 31.3, 28.3, 22.4, 19.1, 14.2; IR (neat) 3458, 3078, 2932,
2856, 2228, 1659, 1588, 1534, 1462, 1350, 1259, 1142 cm−1; HRMS
(ESI-TOF) m/z 204.1390 [204.1388 calcd for C13H18NO (M + H)+].
5-Phenyl-1-(2-pyridonyl)pent-2-yne (7v). Following the gen-
eral procedure above for the preparation of compound 7f, 2-
propargyloxypyridine 6v30 (156 mg, 0.66 mmol) was treated with
LiI (65 mg, 0.48 mmol) for 26 h. Purification by column
chromatography (SiO2, 1:1 hexane/ethyl acetate) afforded 133 mg
(85% yield) of 7v as a brown oil: 1H NMR (400 MHz, CDCl3) δ 7.49
(dd, J = 2.1, 6.9 Hz, 1H), 7.19−7.35 (m, 6H), 6.54 (dt, J = 0.6, 9.2 Hz,
1H), 6.14 (app t, J = 6.6 Hz, 1H), 4.69 (t, J = 2.2 Hz, 2H), 2.85 (t, J =
7.4 Hz, 2H), 2.57 (tt, J = 2.4, 7.4 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 162.2, 140.2, 139.7, 135.9, 128.4, 126.3, 120.2, 106.2, 105.9,
87.6, 73.7, 38.2, 34.6, 20.8; IR (neat) 3028, 2928, 2235, 1667, 1651,
1538, 1454, 1353, 1261, 1145 cm−1; HRMS (ESI-TOF) m/z 260.1044
[260.1051 calcd for C16H15NONa (M + Na)+].
(N)-(4-Cyanomethylbenzyloxy)-2-pyridone (7g). Following
the general procedure above for the preparation of compound 7f, 2-
(4-cyanomethylbenzyloxy)pyridine (6g, 174 mg, 0.83 mmol) was
treated with LiI (55 mg, 0.41 mmol) for 26 h. Purification by column
chromatography (SiO2,1:1 hexanes/ethyl acetate) afforded 104 mg
1
(60%) of 7g as a white solid: mp 136−137 °C; H NMR (400 MHz,
CDCl3) δ 7.56 (d, J = 8.2 Hz, 2H), 7.28−7.36 (m, 3H), 7.24 (dd, J =
0.9, 6.7 Hz, 1H), 6.56 (d, J = 9.2 Hz, 1H), 6.16 (t, J = 6.7 Hz, 1H),
5.13 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 162.4, 141.7, 139.9,
137.2, 132.6, 128.3, 121.4, 118.5, 111.7, 106.7, 51.9; IR (neat) 3433,
3065, 2228, 1659, 1585, 1538 cm−1; HRMS (ESI-TOF) m/z 233.0699
[233.0691 calcd for C13H10N2ONa (M + Na)+].
(N)-Benzyloxy-6-methyl-2-pyridone (7r). Following the general
procedure above for the preparation of compound 7f, 2-benzyloxy-6-
methylpyridine (6r, 108 mg, 0.54 mmol) was treated with LiI (36 mg,
0.27 mmol) for 26 h. Purification by column chromatography
(SiO2,1:1 hexanes/ethyl acetate) afforded 65 mg (60%) of 7r as a
1
white solid: mp 103−105 °C; H NMR (400 MHz, CDCl3) δ 7.18−
7.31 (m, 4H), 7.12 (d, J = 7.1 Hz, 2H), 6.52 (d, J = 9.0 Hz, 1H), 6.00
(d, J = 6.9 Hz, 1H), 5.33 (s, 2H), 2.24 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 163.9, 146.6, 139.1, 136.4, 128.8, 127.3, 126.4, 117.8, 107.0,
47.1, 20.6; IR (neat) 3448, 3033, 2962, 1656, 1550, 1407, 1144 cm−1;
HRMS (ESI-TOF) m/z 222.0888 [222.0895 calcd for C13H13NONa
(M + Na)+].
1-Cyclohexyl-3-(2-pyridonyl)prop-1-yne (7w). Following the
general procedure above for the preparation of compound 7f, 2-
propargyloxypyridine 6w30 (149 mg, 0.69 mmol) was treated with LiI
(110 mg, 0.82 mmol) for 26 h. Purification by column chromatog-
raphy (SiO2, 1:1 hexane/ethyl acetate) afforded 114 mg (77% yield) of
1
(N)-Benzyl-6-benzyloxy-1-pyridazone (9) and (N,N)-Diben-
zyl-1,4-pyridazone (10). Following the general procedure above for
the preparation of compound 7f, 3,6-dibenzyloxypyridazine (8,21 104
mg, 0.39 mmol) was treated with LiI (27 mg, 0.20 mmol) for 26 h.
Purification by column chromatography (SiO2, 1:1 hexanes/ethyl
acetate) afforded 66 mg (63%) of 9 and 6 mg (6%) of 10. Compound
7w as a brown oil: H NMR (400 MHz, CDCl3) δ 7.73 (dd, J = 2.2,
7.0 Hz, 1H), 7.33 (ddd, J = 1.6, 8.6, 10.8 Hz, 1H), 6.56 (d, J = 9.1 Hz,
1H), 6.22 (t, J = 6.8 Hz, 1H), 4.74 (d, J = 2.0 Hz, 2H), 2.38−2.46 (m,
1H), 1.77−1.87 (m, 2H), 1.68−1.73 (m, 2H), 1.40−1.54 (m, 3H),
1.25−1.36 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 162.2, 139.4,
135.6, 120.3, 105.9, 92.7, 72.6, 38.1, 32.4, 29.1, 25.7, 24.8; IR (neat)
2930, 2855, 2235, 1668, 1574, 1538, 1449, 1351, 1258, 1144 cm−1;
HRMS (ESI-TOF) m/z 238.1203 [238.1208 calcd for C14H17NONa
(M + Na)+].
1-Phenyl-3-(2-pyridonyl)prop-1-yne (7x). Following the gen-
eral procedure above for the preparation of compound 7f, 2-
propargyloxypyridine 6x30 (102 mg, 0.49 mmol) was added to LiI
(130 mg, 0.97 mmol) for 26 h. Purification by column chromatog-
raphy (SiO2, 1:1 hexane/ethyl acetate) afforded 67 mg (77% yield) of
7x as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 1.8, 6.9
Hz, 1H), 7.48 (app dd, J = 1.6, 7.4 Hz, 2H), 7.40−7.27 (m, 4H), 6.61
(d, J = 9.2 Hz, 1H), 6.27 (dt, J = 1.3, 6.8 Hz, 1H), 5.00 (s, 2H); 13C
NMR (100 MHz, CDCl3) δ 162.4, 139.9, 136.1, 132.1, 129.1, 128.6,
122.2, 120.8, 106.5, 87.4, 82.2, 38.7; IR (neat) 3072, 3030, 2970, 2235,
1660, 1587, 1538, 1490, 1352, 1146 cm−1; HRMS (ESI-TOF) m/z
232.0731 [232.0738 calcd for C14H11NONa (M + Na)+].
1-((5-Methyl)-2-pyridonyl)oct-2-yne (7z). Following the general
procedure above for the preparation of compound 7f, 2-propargylox-
ypyridine 6z30 (120 mg, 0.55 mmol) was treated with LiI (74 mg, 0.55
mmol) for 26 h. Purification by column chromatography (SiO2, 1:1
hexane/ethyl acetate) afforded 76 mg (64% yield) of 7z as a yellow oil:
1H NMR (400 MHz, CDCl3) δ 7.41 (broad s, 1H), 7.16 (dd, J = 2.2,
9.3 Hz, 1H), 6.47 (d, J = 9.1 Hz, 1H), 4.67 (s, 2H), 2.21 (app t, J = 7.1
Hz, 2H), 2.08 (s, 3H), 1.51 (pentet, J = 7.0 Hz, 2H), 1.24−1.39 (m,
4H), 0.88 (app t, J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
158.8, 139.6, 130.7, 117.4, 112.4, 85.4, 70.6, 35.4, 28.5, 25.6, 19.6, 16.2,
14.7, 11.4; IR (neat) 2952, 2929, 2861, 2254, 2230, 1673, 1596, 1532,
1461, 1259, 1142 cm−1; HRMS (ESI-TOF) m/z 218.1546 [218.1545
calcd for C14H20NO (M + H)+].
1
9: mp 83−84 °C; H NMR (400 MHz, CDCl3) δ 7.22−7.38 (m,
10H), 6.86−6.93 (m, 2H), 5.17 (s, 2H), 5.13 (s, 2H); 13C NMR (100
MHz, CDCl3) δ 158.8, 152.1, 136.4, 135.9, 133.1, 128.7, 128.51,
128.48, 128.3, 128.2, 127.7, 126.5, 68.8, 54.4; IR (neat) 3448, 3033,
2947, 1668, 1590, 1438, 1279 cm−1; HRMS (ESI-TOF) m/z 315.1102
1
[315.1110 calcd for C18H16N2O2Na (M + Na)+]. Compound 10: H
NMR (400 MHz, CDCl3) δ 7.20−7.35 (m, 6H), 7.02 (d, J = 7.3 Hz,
4H), 6.99 (s, 2H), 5.08 (s, 4H); 13C NMR (100 MHz, CDCl3) δ
157.4, 134.9, 134.7, 129.2, 128.2, 126.1, 48.2; IR (neat) 3484, 3033,
2924, 1641, 1595, 1455, 1285, 1136 cm−1; HRMS (ESI-TOF) m/z
315.1110 [315.1110 calcd for C18H16N2O2Na (M + Na)+].
5-Phenyl-1-(2-pyridonyl)pent-2-ene (7t). Following the general
procedure above for the preparation of compound 7f, (E)-2-(5-phenyl-
2-pentenyloxy)pyridine (E-6t, 354 mg, 1.48 mmol) was treated with
LiI (99 mg, 0.74 mmol) for 26 h. Purification by column
chromatography (SiO2, ethyl acetate) afforded 207 mg (58%) of E-
7t and 101 mg (29%) of Z-7t as viscous orange oils.44 Compound E-
7t: 1H NMR (400 MHz, CDCl3) δ 7.09−7.32 (m, 7H), 6.56 (ddd, J =
0.7, 1.3, 9.1 Hz, 1H), 6.11 (td, J = 1.4, 6.7 Hz, 1H), 5.67−5.76 (m,
1H), 5.52−5.61 (m, 1H), 4.48 (dd, J = 1.0, 6.3 Hz, 2H), 2.71 (t, J = 7.6
Hz, 2H), 2.39 (app q, J = 7.3 Hz, 2H); 13C NMR (100 MHz, CDCl3)
δ 162.7, 141.6, 139.5, 137.0, 135.2, 128.7, 128.6, 126.1, 125.2, 121.1,
106.2, 50.4, 35.5, 34.1; IR (neat) 3468, 3026, 2927, 1656, 1588, 1538,
1144 cm−1; HRMS (ESI-TOF) m/z 262.1201 [262.1208 calcd for
1
C16H17NONa (M + Na)+]. Compound Z-7t: H NMR (400 MHz,
CDCl3) δ 7.17−7.32 (m, 6H), 6.81 (ddd, J = 0.7, 2.1, 6.8 Hz, 1H),
6.52 (ddd, J = 0.6, 1.4, 9.2 Hz, 1H), 6.03 (td, J = 1.4, 6.7 Hz, 1H),
5.69−5.77 (m, 1H), 5.43−5.51 (m, 1H), 4.48 (dd, J = 1.6, 7.0 Hz,
2H), 2.74 (t, J = 7.3 Hz, 2H), 2.52 (app q, J = 7.3 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 162.8, 141.5, 139.4, 136.9, 134.1, 128.9, 128.7,
126.3, 124.8, 121.0, 106.2, 45.3, 35.7, 29.6; IR (neat) 3468, 3026, 2927,
1656, 1588, 1538, 1144 cm−1; HRMS (ESI-TOF) m/z 262.1201
[262.1208 calcd for C16H17NONa (M + Na)+].
3-Iodo-4-triisopropylsiloxy-2-(2-pyridonyl)but-2-en-1-ol
(22bb). LiI (45 mg, 0.33 mmol) was added to 2-propargyloxypyridine
6bb30 (107 mg, 0.33 mmol) in a 1 dram screw-top vial, and the
reaction was warmed to 100 °C for 26 h. Purification of the residue by
column chromatography (SiO2, 1:1 hexane/ethyl acetate) afforded 24
1
1-(2-Pyridonyl)oct-2-yne (7u). Following the general procedure
above for the preparation of compound 7f, 2-propargyloxypyridine
mg (16% yield) of 22bb as a white powder: mp 93−95 °C, H NMR
(400 MHz, CDCl3) δ 7.38 (t, J = 8.0 Hz, 1H), 7.17 (d, J = 6.4 Hz,
I
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Article
1H), 6.55 (d, J = 9.2 Hz, 1H), 6.19 (t, J = 6.6 Hz, 1H), 4.65 (dd, J =
7.2, 13.6 Hz, 1H), 4.37 (dd, J = 4.8, 13.6 Hz, 1H), 4.20 (d, J = 12.2 Hz,
1H), 4.13 (d, J = 12.2 Hz, 1H), 3.72 (app t, J = 6.2 Hz, 1H), 0.94−1.07
(m, 21H); 13C NMR (100 MHz, CDCl3) δ 162.7, 143.0, 140.8, 138.1,
121.2, 108.2, 106.3, 67.5, 66.7, 17.9, 11.9; IR (neat) 3216, 2941, 2865,
1647, 1571, 1534, 1458, 1284 cm−1; HRMS (ESI-TOF) m/z 486.0932
[486.0938 calcd for C18H30NO3ISiNa (M + Na)+].
128.0, 121.3/121.1, 106.24/106.19, 51.7 (t, J = 76.8 Hz)/51.5 (t, J
= 79.1 Hz).
(N)-(α-Deutrobenzyloxy)-2-thiopyridone (d1-30). To (N)-(α-
deutrobenzyloxy)-2-pyridone (d1-7a, 40 mg, 0.22 mmol) in a sealed
tube were added P2S5 (50 mg, 0.23 mmol) and pyridine (0.65 mL).
The tube was sealed and heated at 150 °C for 5 h before cooling and
adding H2O (3 mL) and CHCl3 (6 mL). The phases were separated,
and the aqueous layer was extracted with CHCl3 (3 × 6 mL). The
combined organic layers were dried (MgSO4), filtered, and
concentrated in vacuo. Purification by column chromatography
(SiO2, 7:3 hexanes/ethyl acetate) afforded 25 mg (58%) of d1-30 as
1:1 mixture of rotational isomers: 1H NMR (400 MHz, CDCl3) δ 7.71
(d, J = 8.7 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.25−7.37 (m, 5H), 7.12
(tt, J = 1.8, 8.8 Hz, 1H), 6.56 (tt, J = 1.4, 6.8 Hz, 1H), 5.76 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 180.9, 139.9/139.8, 136.4/136.3,
135.0, 133.7, 129.0 (broad), 128.4 (broad), 113.7/113.5, 105.0, 58.5
(t, J = 78.8 Hz)/58.2 (t, J = 74.4 Hz); IR (neat) 3443, 3033, 2927,
1618, 1532, 1459, 1419, 1267, 1128, 1095 cm−1.
General Procedure for Kinetic Studies Used To Generate the
Hammett Plot. To benzyloxypyridine 6a−6g (1.0 equiv) in a 1 dram
screw top vial was added LiI (0.5 equiv). The vial was closed and
placed in a 90 °C bath. Aliquots were then removed by pipet at
appropriate intervals until the reaction reached ∼90% completion, as
determined by comparing the benzylic hydrogen resonance of starting
1
material 6 to that of pyridone product 7 using H NMR. The initial
rate for each trial was determined using the linear segment of each
curve.
General Procedure for Crossover Experiments. To pyridine
6q (1.0 equiv) and pyridine 6b−d (1.0 equiv) in a 1 dram screw top
vial was added LiI (1.0 equiv). The vial was closed and heated at 100
°C for 26 h. After cooling, CDCl31(1.5 mL) was added, and the crude
reaction mixture was analyzed by H NMR. Benzylic resonances were
assigned to compounds A−D by adding authentic samples of each
Benzyl (R)-Methoxyphenylthioacetate (d1-32). To (N)-(α-
deutrobenzyloxy)-2-thiopyridone (d1-30, 25 mg, 0.12 mmol) in
benzene (0.43 mL) was added MeI (0.04 mL, 0.62 mmol). The
reaction was warmed to reflux for 18 h, cooled, and concentrated in
1
1
species to the H NMR tube.
vacuo: H NMR (400 MHz, CDCl3) δ 9.36 (d, J = 5.8 Hz, 1H), 8.42
General Procedure for Salt Studies. To a solution of pyridine 6j
(1.0 equiv) in CH3CN (2.0 M) in a 1 dram screw top vial was added a
metal salt (3.0 equiv). The vial was closed and heated at 85 °C for 26
h. After cooling, CDCl3 (1.5 mL) was added, and the crude reaction
(t, J = 7.6 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.70 (t, J = 6.4 Hz, 1H),
7.22−7.34 (m, 5H), 5.91 (s, 1H), 2.83 (s, 3H).
To the crude pyridinium salt was added thiourea (11 mg, 0.15
mmol), and the neat mixture was heated at 160 °C. After 30 min, the
reaction was removed from the heat, and 10% (w/v) aq NaOH (1.2
mL) was added. The reaction was then heated to reflux for 3 h. After
cooling, the reaction was acidified with 6 M aq HCl and extracted with
Et2O (5 × 6 mL). The combined organic layers were dried (MgSO4),
filtered, and concentrated in vacuo. Partial purification by column
chromatography (SiO2, 39:1 hexanes/ethyl acetate) afforded 3 mg
(17%) of impure d1-31.
1
mixture was analyzed by H NMR.
2-Benzylthiopyridine (26). Following the general procedure
outlined above for the synthesis of compound 6r, potassium tert-
butoxide (842 mg, 7.50 mmol) was added to 2-chloropyridine (0.47
mL, 5.00 mmol) and benzyl mercaptan (0.97 mL, 7.50 mmol) in 1,4-
dioxane (22.7 mL). After 15 h, the reaction was worked up and
purified by column chromatography (SiO2, 19:1 hexanes/ethyl
1
acetate) to afford 914 mg (91% yield) of 26 as a colorless oil: H
To a solution of impure α-deutrobenzyl mercaptan (d1-31, 3 mg,
0.022 mmol) in CH2Cl2 (0.3 mL) in a conical vial were added (R)-
methoxyphenylacetic acid (5 mg, 0.026 mmol), 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide·HCl (5 mg, 0.026 mmol), and
N,N-dimethylaminopyridine (3 mg, 0.022 mmol). After 4.5 h, the
reaction was washed with H2O (3 mL), 1 M aq HCl (3 mL), H2O (3
mL), satd aq NaHCO3 (3 mL), and H2O (3 mL). The organic layer
was dried (Na2SO4), filtered, and concentrated in vacuo. Purification
by pipet column (SiO2, 19:1 hexanes/ethyl acetate) afforded thioester
NMR (400 MHz, CDCl3) δ 8.46 (app ddd, J = 1.0, 1.8, 4.9 Hz, 1H),
7.47 (ddd, J = 1.9, 7.4, 9.2 Hz, 1H), 7.39−7.43 (m, 2H), 7.27−7.33
(m, 2H), 7.20−7.25 (m, 1H), 7.16 (dtd, J = 0.4, 1.0, 8.1 Hz, 1H), 6.99
(ddd, J = 1.0, 5.0, 7.4 Hz, 1H), 4.45 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 160.3, 159.0, 149.6, 138.2, 136.2, 129.2, 128.7, 217.3, 122.3,
119.8, 34.6; IR (neat) 3063, 3028, 2997, 2927, 1578, 1556, 1453, 1413,
1123 cm−1; HRMS (ESI-TOF) m/z 202.0688 [202.0690 calcd for
C12H12NS (M + H)+].
1
1
Migration in the Presence of 4-Methyl Benzyl Iodide 28. To
pyridine 6a (1.0 equiv) and 4-methylbenzyl iodide (28, 1.0 equiv) in a
1 dram screw top vial was added LiI (0.5 equiv or none). The vial was
closed and either heated at 100 °C or maintained at room temperature
for 24 h. After cooling, CDCl3 (1.5 mL) was added, and the crude
d1-32 for H NMR analysis: H NMR (400 MHz, CDCl3) δ 7.14−
7.38 (m, 10H), 4.70 (s, 1H), 4.02 (s, 0.5H), 3.95 (s, 0.5H), 3.39 (s,
3H).
Benzyl (R)-Methoxyphenylthioacetate (32). To a solution of
benzyl mercaptan (0.01 mL, 0.073 mmol) in CH2Cl2 (1.0 mL) in a
conical vial were added (R)-methoxyphenylacetic acid (15 mg, 0.088
mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide·HCl (17 mg,
0.088 mmol) and N,N-dimethylaminopyridine (9 mg, 0.073 mmol).
After 7 h, the reaction was washed with H2O (3 mL), 1 M aq HCl (3
mL), H2O (3 mL), satd aq NaHCO3 (3 mL), and H2O (3 mL). The
organic layer was dried (Na2SO4), filtered, and concentrated in vacuo:
1H NMR (400 MHz, CDCl3) δ 7.39−7.44 (m, 2H), 7.28−7.38 (m,
3H), 7.16−7.27 (m, 5H), 4.75 (s, 1H), 4.09 (d, J = 13.7 Hz, 1H), 4.01
(d, J = 13.7 Hz, 1H), 3.44 (s, 3H).
1
reaction mixture was analyzed by H NMR.
2-(α-Deutrobenzyloxy)pyridine (d1-6a). Following the general
procedure outlined above for the synthesis of compound 6r, potassium
tert-butoxide (169 mg, 1.51 mmol) was added to 2-chloropyridine
(0.10 mL, 1.01 mmol) and α-deutrobenzyl alcohol34,35 (d1-29, 110
mg, 1.01 mmol) in 1,4-dioxane (4.6 mL). After 22 h, the reaction was
worked up and purified by column chromatography (SiO2, 19:1
hexanes/ethyl acetate) to afford 59 mg (31% yield) of d1-6a as a clear
1
liquid: H NMR (400 MHz, CDCl3) δ 8.17 (app d, J = 2.8 Hz, 1H),
7.57 (dt, J = 2.1, 8.8 Hz, 1H), 7.43−7.49 (m, 2H), 7.27−7.42 (m, 3H),
6.87 (t, J = 6.5 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 5.36 (app s, 1H);
13C NMR (100 MHz, CDCl3) δ 163.6, 146.8, 138.6, 137.3, 128.4,
128.0, 127.8, 116.9, 111.3, 67.2 (t, J = 89.1 Hz).
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all new compounds and
mechanistic analysis. This material is available free of charge
via the Internet at http://pubs.acs.org.
(N)-(α-Deutrobenzyloxy)-2-pyridone (d1-7a). Following the
general procedure above for the preparation of compound 7f, 2-(α-
deutrobenzyloxy)pyridine (d1-6a, 59 mg, 0.32 mmol) was treated with
LiI (21 mg, 0.16 mmol) for 24 h. Purification by column
chromatography (SiO2, 1:1 hexanes/ethyl acetate) afforded 40 mg
1
(68%) of d1-7a as a 1:1 mixture of rotational isomers: H NMR (400
AUTHOR INFORMATION
■
MHz, CDCl3) δ 7.20−7.38 (m, 7H), 6.58 (d, J = 9.2 Hz, 1H), 6.10 (t,
J = 6.8 Hz, 1H), 5.09 (app s, 1H); 13C NMR (100 MHz, CDCl3) δ
162.6, 139.42/139.35, 137.2/137.1, 136.3, 128.84/128.82, 128.1,
Corresponding Author
*E-mail: cea3@calvin.edu.
J
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The Journal of Organic Chemistry
Article
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
under CHE-0911264, awards from Research Corporation for
Science Advancement, Arnold and Mabel Beckman Foundation
Scholars Program, Donors of the American Chemical Society
Petroleum Research Fund, Calvin College, and Pomona
College. NMR spectrometers were provided by a Major
Research Instrumentation grant of the National Science
Foundation under CHE-0922973. We thank Ms. E. Rhude
and Mr. N. Romero (Calvin College) and Dr. J. Greaves (UC-
Irvine) for their work in support of this project and Drs. C. D.
Anderson (Pleotint, LLC), T. Hoye (U of Minnesota), J.
Johnson (Hope College), and J. Dinnocenzo (U of Rochester)
for helpful conversations regarding this work.
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