A comparison of N- versus O-alkylation of substituted 2-pyridones under Mitsunobu conditions

Article abstract of DOI:10.1016/j.tetlet.2013.05.054

2-Pyridones are well-known ambident nucleophiles which are capable of reacting with electrophiles through either the nitrogen or oxygen atom to form N-alkyl-2-pyridones or 2-alkoxypyridines, respectively. It has been shown that the ratio of these products can be affected by a number of factors including the nature of the electrophile, the base used for deprotonation, and the solvent. We have now discovered a relationship between the ratio of N- and O-alkylation products and the nature of substituents on the pyridone ring when the Mitsunobu reaction is used to alkylate 2-pyridones.

Full text of DOI:10.1016/j.tetlet.2013.05.054

Tetrahedron Letters 54 (2013) 3926–3928
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Tetrahedron Letters
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A comparison of N- versus O-alkylation of substituted 2-pyridones
under Mitsunobu conditions
⇑
Matthew C. Torhan, Norton P. Peet, John D. Williams
Microbiotix Inc., One Innovation Drive, Worcester, MA 01605, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Pyridones are well-known ambident nucleophiles which are capable of reacting with electrophiles
through either the nitrogen or oxygen atom to form N-alkyl-2-pyridones or 2-alkoxypyridines,
respectively. It has been shown that the ratio of these products can be affected by a number of factors
including the nature of the electrophile, the base used for deprotonation, and the solvent. We have
now discovered a relationship between the ratio of N- and O-alkylation products and the nature of
substituents on the pyridone ring when the Mitsunobu reaction is used to alkylate 2-pyridones.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 24 April 2013
Accepted 7 May 2013
Available online 20 May 2013
Keywords:
2-Pyridone
Mitsunobu reaction
Ambident nucleophiles
N-alkylation
O-alkylation
Alkylated 2-pyridones are common structural motifs in a wide
range of biologically active compounds. N-alkylated pyridones
are commonly found in natural products such as camptothecin,1
cytisine,2,3 cerpegin,4 and amphimedine.5 O-alkylated pyridones
are found less commonly in nature, but are important substruc-
tures of biologically active compounds such as taranabant (a dis-
continued anti-obesity drug),6 pyriproxyfen (a pesticide),7
tafenoquine (an antiplasmodial),8 and lafutidine (a histamine H2
receptor antagonist).9 Synthesizing either N- or O-pyridones spe-
cifically, however, can be synthetically challenging because of the
ambident nature of the pyridone system.
Although it is well known that alkylation of 2-pyridones can re-
sult in formation of both N- and O-substituted products,10–13 rela-
tively few systematic studies of this phenomenon have been
published. Tieckelmann14 demonstrated that the reaction outcome
of pyridone alkylation was dependent in part on the counterion;
Na+ and K+ salts generally gave predominantly N-alkylation or mix-
tures of products, while Ag+ salts, following up on the work of
Kornblum,15 tend to favor O-alkylation. Tieckelmann also demon-
strated that the O-alkylation of 2-pyridone Ag+ salts was more
selective in nonpolar solvents, and that O-alkylation of hindered
electrophiles is favored regardless of solvent. In an excellent recent
study, Mayr16 has attempted to rationalize these findings based on
computational methods. Comins has demonstrated the utility of
the Mitsunobu reaction for producing alkylated 2-pyridones;10 by
eliminating the need for strong bases, a wider range of sensitive
substrates can be used in the reaction. Although hindered alcohols
were more selective for O-alkylation, primary alcohols tended to
form both O- and N-alkylated products; as in the case of pyridone
salts, the results varied greatly with the choice of solvent.
We became interested in using the Mitsunobu reaction to
synthesize a series of pyridyl-substituted lactate esters that we
required for the synthesis of a series of bacterial type three secre-
tion system (T3SS) inhibitors.17 Following the work of Lin et al.,6
who synthesized benzyl 2-(pyridin-2-yloxy)propionate under
Mitsunobu conditions en route to cannabinoid-1 receptor inverse
agonists, we attempted to make the corresponding ethyl 2-(3,5-
dichloropyridin-2-yloxy)propionate. Although Lin et al. noted the
formation of ‘some N-alkylated side products’; we observed that
the reaction with 3,5-dichloro-2-pyridone gave substantial
amounts of the undesired N-alkylated product in addition to the
desired O-alkylated product (see Supplementary data). Further-
more, repeating the reaction with the unsubstituted 2-pyridone
used by Lin produced nearly equal amounts of N- and O-alkylated
materials.
ethyl lactate
R3
R3
R3
O
DIAD
PPh3
O
O
O
O
OEt
+
N
NH
DMF
20 °C
N
R5
OEt
R5
R5
2
3
1
R3, R5: See Table 1.
⇑
Corresponding author. Tel.: +1 508 757 2800.
E-mail address: jwilliams@microbiotix.com (J.D. Williams).
Scheme 1. Mitsunobu reaction of substituted 2-pyridones and methyl lactate.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.054

M. C. Torhan et al. / Tetrahedron Letters 54 (2013) 3926–3928
3927
Given the differences in product distribution of the substituted
and unsubstituted pyridone substrates, we undertook a study of
the effect that different substituents on the 2-pyridone ring have
on the outcome of the reaction. Using racemic ethyl lactate as
our alcohol component, we performed a series of Mitsunobu reac-
tions with 2-pyridones substituted in either the 3- or 5-position
(Scheme 1) and determined the relative ratios of N- and O-substi-
tuted products produced by these reactions. By choosing a series of
2-pyridones with substituents that would provide a range of
electronic and steric properties, we hoped to elucidate the factors
which influence the ultimate product distribution under
Mitsunobu conditions.
Before we began our comprehensive study, we needed to assign
the spectrum of both O- and N-alkylated products so that the ratios
could be properly determined. Thus, we unambiguously
synthesized the O-substituted compound ethyl 2-(3,5-dichloro-
pyridin-2-yloxy)propionate via the nucleophilic displacement of
3,5-dichloro-2-fluoropyridine with the sodium alkoxide of ethyl
lactate (see Supplementary data). Although little difference was
found in the proton NMR spectra of N- and O-alkylated products
Figure 2. Plot of O-/N-ratio versus modified resonance constant R.
It is immediately evident that the substituent at the 3-positon
has very little effect on the product distribution of the reaction;
very little change is noted over the entire range of 3-substituted
compounds. It is somewhat surprising that even the presence of
a bulky –CF3 substituent at the 3-position did not bias the
alkylation toward the N-substituted products through steric
effects. Conversely, the substituent at the 5-position had a substan-
tial impact on the ultimate outcome of the reaction, with the
distribution ratio ranging from 0.70 (–CF3) to 5.90 (–OMe).
in DMSO-d6, the chemical shift of the lactate
a proton quartet of
the alkoxypyridine in CDCl3 was sufficiently distinct from the
a
proton quartet of the corresponding N-alkylpyridone to assign
the two isomers based on their respective NMR spectra.
After assigning the 1H NMR spectra to the proper isomer, we ran
Mitsunobu reactions on all of the different 2-pyridones in our test
set. By determining the effect that different substituents had on the
ultimate O-/N-substitution ratio (found by integration of the lac-
tate
a protons), it was our hope that we could draw some impor-
O
tant conclusions about the factors governing the outcome of the
alkylation reaction. The results of the study are found in Table 1.
N
H
O
Table 1
Ratio of O-/N- substitution for Mitsunobu reaction of 2-pyridonesa
base
Entry
R3
R5
O-/N-ratiob
O
O
O
O
O
O
1
2
3
4
5
6
7
8
9
–H
–Cl
–H
–H
–H
–H
–H
–H
–Cl
–CN
–CF3
–Me
–OMe
0.95
1.09
1.11
1.03
0.87
0.91
2.88
1.27
0.74
1.45
5.75
N
N
N
N
N
O
O
O
O
O
–CN
–CF3
–Me
–OMe
–H
–H
–H
–H
–H
10
11
N
O
a
DIAD (3.0 mmol) was added to a solution of pyridone (2.5 mmol), ethyl lactate
unstable adjacent
negative charges
stable distant
negative charges
stable distant
negative charges
(3.0 mmol), and PPh3 (3.0 mmol) in DMF (3.0 mL) at room temperature.
b
Ratio determined by integration of lactate 2-position proton in 1H NMR
spectrum.
RX
RX
RX
O
O
O
N
R
O
N
O
R
N
O
R
O
O
N
R
O
N
O
R
minor product
major product
Scheme 2. Proposed rationale for observed product distribution in 5-substituted 2-
Figure 1. Plot of O-/N-ratio versus modified field constant F.
pyridones.

3928
M. C. Torhan et al. / Tetrahedron Letters 54 (2013) 3926–3928
ultimately leading to O-alkylated products have relatively more
O
O
stable, separated, negative charges; these two forms would be
more populated, and therefore produce predominantly the
O-alkylated product to a degree that is dependent on the resonance
contribution of the 5-substituent. This same behavior is not
observed for the 3-substituted pyridones (see Scheme 3 as illus-
trated for 3-methoxypyridone) because the corresponding high
energy resonance form with adjacent charges causes only one of
two possible oxygen-charged species to be underpopulated with
respect to the nitrogen-charged intermediate. With no substantial
barrier to N-alkylation, roughly equal mixtures of N- and O-alkyl-
ated products would be produced, regardless of the substituent at
the 3-position.
We have demonstrated that the Mitsunobu reaction of 2-pyri-
dones and ethyl lactate produces a range of possible outcomes
based on the nature of the substituents on the 2-pyridone ring.
By comparing the electronic properties of the substituents with
the ratio of O- and N-alkylation products, we have determined that
the Hammett resonance contribution (R) of the substituent at the
5-position has a profound impact on the ultimate product distribu-
tion, while neither the resonance contribution of the 3-substituent
nor the Hammett field constant (F) for either substituent causes a
significant effect.
N
H
base
O
O
O
O
O
O
N
N
N
N
N
O
O
O
O
O
O
N
stable distant
negative charges
stable distant
negative charges
unstable adjacent
negative charges
RX
O
RX
O
RX
O
Supplementary data
N
R
O
N
O
R
N
O
R
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.05.
054.
O
O
O
References and notes
1. Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.; McPhail, A. T.; Sim, G. A. J.
Am. Chem. Soc. 1966, 88, 3888–3890.
2. Partheil, A. Arch. Pharm. (Weinheim, Ger.) 1894, 232, 161.
3. Ing, H. R. J. Chem. Soc. 1932, 2778.
N
R
N
O
R
equal amounts of product
Scheme 3. Proposed rationale for observed product distribution in 3-substituted
2-pyridones.
4. Adibatti, N. A.; Thirugnanasambantham, P.; Kulothungan, C.; Viswanathan, S.;
Kameswaran, L.; Balakrishna, K.; Sukumar, E. Phytochemistry 1991, 30, 2449–
2450.
5. Schmitz, F. J.; Agarwal, S. K.; Gunasekera, S. P.; Schmidt, P. G.; Shoolery, J. N. J.
Am. Chem. Soc. 1983, 105, 4835–4836.
Given the electronic properties of these two substituents, it is
tempting to correlate the product distribution with the electron
donating/withdrawing capacities. Surprisingly, when the ratio of
products is plotted versus the modified field constant F,18 the
correlation is poor (Fig. 1). When the distribution ratio is plotted
versus the modified resonance constant R,18 however, the correla-
tion becomes clear (Fig. 2); substituents with a high resonance con-
tribution at the 5-position favor O-alkylation, while substituents
with little resonance contribution favor nearly even mixtures of
N- and O-substitution.
This behavior can be rationalized in terms of the resonance
structures available to the 5-substituted pyridones. After deproto-
nation of the 2-pyridone, three tautomeric forms can be drawn
(see Scheme 2 as illustrated for 5-methoxypyridone). After the
resonance contribution is taken into account, three corresponding
triply charged intermediates are possible. However, the resonance
form that is ultimately converted into the N-alkylated product
possesses relatively unstable adjacent negative charges, and would
thus be less populated. In contrast, the two resonance forms
6. Lin, L. S.; Lanza, T. J.; Jewell, J. P.; Liu, P.; Shah, S. K.; Qi, H.; Tong, X.; Wang, J.;
Xu, S. S.; Fong, T. M.; Shen, C.-P.; Lao, J.; Xiao, J. C.; Shearman, L. P.; Stribling, D.
S.; Rosko, K.; Strack, A.; Marsh, D. J.; Feng, Y.; Kumar, S.; Samuel, K.; Yin, W.;
Ploeg, L. H. T. V. D.; Goulet, M. T.; Hagmann, W. K. J. Med. Chem. 2006, 49, 7584–
7587.
7. Kawada, H.; Dohara, K.; Shinjo, G. Jpn. J. Sanit. Zool. 1987, 38, 317–322.
8. Peters, W.; Robinson, B. L.; Milhous, W. K. Ann. Trop. Med. Parasitol. 1993, 87,
547–552.
9. Hirakawa, N.; Matsumoto, H.; Hosoda, A.; Sekine, A.; Yamaura, T.; Sekine, Y.
Chem. Pharm. Bull. 1998, 46, 616–622.
10. Comins, D. L.; Jianhua, G. Tetrahedron Lett. 1994, 35, 2819–2822.
11. Sato, T.; Yoshimatsu, K.; Otera, J. Synlett 1995, 845–846.
12. Liu, H.; Ko, S.-B.; Josien, H.; Curran, D. P. Tetrahedron Lett. 1995, 36, 8917–8920.
13. Janin, Y. L.; Huel, C.; Flad, G.; Thirot, S. Eur. J. Org. Chem. 2002, 1763–1769.
14. Hopkins, G. C.; Jonak, J. P.; Minnemeyer, H. J.; Tieckelmann, H. J. Org. Chem.
1967, 32, 4040–4044.
15. Kornblum, N.; Smiley, R. A.; Blackwood, R. K.; Iffland, D. C. J. Am. Chem. Soc.
1955, 77, 6269–6280.
16. Breugst, M.; Mayr, H. J. Am. Chem. Soc. 2010, 132, 15380–15389.
17. Aiello, D.; Williams, J. D.; Majgier-Baranowska, H.; Patel, I.; Peet, N. P.; Huang,
J.; Lory, S.; Bowlin, T. L.; Moir, D. T. Antimicrob. Agents Chemother. 2010, 54,
1988–1999.
18. Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165–195.