Ir(I)-catalyzed synthesis of N-substituted pyridones from 2-alkoxypyridines via C-O bond cleavage

Article abstract of DOI:10.1021/ol400557z

A cationic Ir(I) complex-catalyzed O-to-N-alkyl migration in 2-alkoxypyridines bearing a secondary alkyl group on the oxygen atom by C-O bond cleavage is described. The present transformation gave various N-alkylpyridones in moderate to good yields. The addition of sodium acetate played a key role in suppressing β-hydrogen elimination.

Full text of DOI:10.1021/ol400557z

ORGANIC
LETTERS
2013
Vol. 15, No. 8
1902–1905
Ir(I)-Catalyzed Synthesis of N‑Substituted
Pyridones from 2‑Alkoxypyridines via
CꢀO Bond Cleavage
Shiguang Pan,† Naoto Ryu,† and Takanori Shibata*,†,‡
Department of Chemistry and Biochemistry, School of Advanced Science and
Engineering, Waseda University, Shinjuku, Tokyo 169-8555, Japan, and JST, ACT-C,
4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
tshibata@waseda.jp
Received February 28, 2013
ABSTRACT
A cationic Ir(I) complex-catalyzed O-to-N-alkyl migration in 2-alkoxypyridines bearing a secondary alkyl group on the oxygen atom by CꢀO bond
cleavage is described. The present transformation gave various N-alkylpyridones in moderate to good yields. The addition of sodium acetate
played a key role in suppressing β-hydrogen elimination.
N-Alkylpyridone is an important structural unit and is
widely found in heterocyclic compounds with biological
activities and medicinal applications.1 Although the direct
NꢀH alkylation of pyridone has been explored under
the basic conditions, O-alkylation is a competing process
because of the aromatic character of 2-oxypyridine.2
Thus, the synthetic protocols that begin with 2-alkoxypyr-
idines via O-to-N-alkyl migration have attracted significant
attention for the efficient synthesis of N-alkylpyridone
because 2-alkoxypyridines can be easily synthesized by the
nucleophilic aromatic substitution of 2-halopyridines.3 Var-
ious salts have been used in these migration reactions;
typically, stoichiometric amounts of metal salts are
required.4 Pt and Pd complexes realized catalytic reactions,
but they were Claisen rearrangements and the substrates
were limited to 2-allyloxypyridines.5,6 Therefore, a more
general method for O-to-N-alkyl migration is required.
Recently, Dong published a useful protocol using a Ru
† Waseda University.
‡ JST, ACT-C.
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Hynd, G.; Wiley, J. L.; Martin, B. R. Bioorg. Med. Chem. 2001, 9, 2863.
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Org. Chem. 2005, 9, 1757 and references therein.
r
10.1021/ol400557z
Published on Web 03/29/2013
2013 American Chemical Society

Scheme 1. Examples of O-to-N-Alkyl Migration via CꢀO Bond
Scheme 2. Ir-Catalyzed O-to-N-Alkyl Migration of 2-Methoxy-
pyridine
Cleavage
catalyst in the presence of a stoichiometric amount of base,
which led to efficient O-to-N-alkyl migration in pyridines
and other related heterocycles by sp3 ethereal CꢀO bond
cleavage.7
Here, we discloseO-to-N-alkyl migration in pyridines by
sp3 CꢀO bond cleavage using a cationic iridium catalyst.
The reaction of 2-alkoxypyridines bearing a secondary
O-alkyl group could also be achieved to give the corre-
sponding N-alkylpyridones (Scheme 1). In contrast, the
Ru-catalyzed migration of a 2-alkoxypyridine bearing
a secondary O-alkyl group did not give the desired
N-substituted pyridone.7
We have focused on the development of cationic iridium-
catalyzed reactions initiated by CꢀH bond activation,8 and
we recently presented the cationic iridium-catalyzed enan-
tioselective activation of the secondary sp3 CꢀH bonds
adjacent to a nitrogen atom using pyridyl as a directing
group.9 Based on the reported protocol, we studied the
cationic iridium-catalyzed activation of sp3 CꢀH bond
adjacent to an oxygen atom in 2-methoxypyridine under
the same conditions (Scheme 2, eq 1). Although the desired
CꢀH alkylated product was not obtained, a trace amount
of N-methylpyridone was formed by CꢀO bond cleavage.
It is noteworthy that the yield of N-methylpyridone was
improved in the absence of the phosphine ligand, and
the yield reached 95% NMR yield, when tetrakis(3,5-bis-
(trifluoromethyl)phenyl)borate (BARF) was used as a
counteranion (Scheme 2, eq 2).
Table 1. Optimization of the Reaction Conditionsa
entry
catalyst
additive
yieldb (%)
1
[Ir(cod)2]BARF
[Ir(cod)2]BARF
[Ir(cod)2]BARF
[Ir(cod)2]BARF
[Ir(cod)2]BARF
[Ir(cod)2]BARF
[Ir(cod)2]BARF
[Ir(cod)2]BARF
[Ir(cod)2]BARF
[Ir(cod)2]BF4
none
23
15
2
pyridine
NEt3
3
24
4
Li2CO3
Na2CO3
K2CO3
Cs2CO3
NaOAc
PivONa
NaOAc
NaOAc
NaOAcc
64
5
94
6
45
7
n.r
95 (78)
95
8
9
10
11
12
<5
[Ir(cod)2]OTf
41
[Ir(cod)2]BARF
81
a Conditions: 2-(1-phenylethoxy)pyridine (1a) (0.1 mmol), catalyst
(0.01 mmol), additive (0.11 mmol), PhCl (0.5 mL), unless otherwise
noted. b NMR yield. Isolated yield was given in parentheses. c NaOAc
(20 mol %) was used.
determining the optimal reaction conditions (Table 1). When
[Ir(cod)2]BARF by itself was used as a catalyst in chloro-
benzene, alkoxypyridine 1a was completely consumed, but
only a low yield of the desired pyridone 2a was obtained
(entry 1). Next, we examined various organic and inorganic
additives for the present reaction (entries 2ꢀ9) and found
that sodium acetate and pivalate exhibited higher catalytic
efficiencies among them (entries 8 and 9). Next, we tuned the
counteranion of the iridium complex using NaOAc as an
additive, but did not get better results than when BARF was
used (entries 10 and 11). A catalytic amount of NaOAc was
sufficient to achieve an efficient transformation, but gave a
slightly decreased yield (entry 12); thus, we used the entry 8
conditions for further investigations.
O-to-N-alkyl migration in pyridines bearing a sec-
ondary O-alkyl group is more challenging, and we chose
2-(1-phenylethoxy)pyridine (1a) as a model substrate for
(7) Yeung, C. S.; Hsieh, T. H. H.; Dong, V. M. Chem. Sci. 2011,
2, 544.
(8) (a) Tsuchikama, K.; Kasagawa, M.; Hashimoto, Y.; Endo, K.;
Shibata, T. J. Organomet. Chem. 2008, 693, 3939. (b) Tsuchikama, K.;
Hashimoto, Y.; Endo, K.; Shibata, T. Adv. Synth. Catal. 2009, 351,
2850. (c) Tsuchikama, K.; Kasagawa, M.; Endo, K.; Shibata, T. Org.
Lett. 2009, 11, 1821. (d) Tsuchikama, K.; Kasagawa, M.; Endo, K.;
Shibata, T. Synlett 2010, 97. (e) Shibata, T.; Hashimoto, Y.; Otsuka, M.;
Tsuchikama, K.; Endo, K. Synlett 2011, 2075. (f) Shibata, T.; Hirashima,
H.; Kasagawa, M.; Tsuchikama, K.; Endo, K. Synlett 2011, 2171.
(g) Takebayashi, S.; Shibata, T. Organometallics 2012, 31, 4114.
(h) Pan, S.; Ryu, Y.; Shibata, T. J. Am. Chem. Soc. 2012, 134, 17474.
(9) (a) Pan, S.; Endo, K.; Shibata, T. Org. Lett. 2011, 13, 4692. (b)
Pan, S.; Matsuo, Y.; Endo, K.; Shibata, T. Tetrahedron 2012, 68, 9009.
(10) When 2a was subjected to the same reaction conditions, no H/D
exchange was observed.
A control experiment wasconductedtoclarifythe roleof
NaOAc (Scheme 3). The reaction of 1a was examined
Org. Lett., Vol. 15, No. 8, 2013
1903

Scheme 3. Investigation of the Role of NaOAc
Scheme 5. O-to-N-Alkyl Migration of 2-Alkoxypyridines with a
Primary Alkyl Group
NaOAc by β-hydrogen elimination after oxidative CꢀO
bond cleavage by the Ir complex. In contrast, the forma-
tion of pyridone 3 was not detected in the presence of
NaOAc. These results suggest that NaOAc completely
suppressed β-hydrogen elimination.
Scheme 4. O-to-N-Alkyl Migration of 2-Alkoxypyridines with a
Secondary Alkyl Groupa
Subsequently, the scope of 2-alkoxypyridines bearing a
secondary O-alkyl group was examined for the present
transformation (Scheme 4). 2-Alkoxypyridines 1bꢀd with
an electron-donating group on the benzene ring gave the
desired pyridones 2bꢀd in moderate to good yields. Sig-
nificant steric effects on the reactivities were observed from
substituents: o-methyl substituent on the aromatic moiety
deterred the reaction, giving low yield of the corresponding
product 2e. The reaction of 2-alkoxypyridine 1f with an
electron-withdrawing group required a long reaction time.
2-Benzyloxypyridines 1gꢀi possessing other alkyl groups at
the benzylic position could be also transformed into the
corresponding N-substituted pyridones 2gꢀi. Not only
1-arylalkyl groups, but also 1-alkylethyl groups, such as
isopropyl and sec-butyl, could be used as the migrating
group, and N-alkylpyridones 2k and 2l were obtained.
Methyl-substituted pyridines 1nꢀp were also investigated
and the yields varied depending on the position of the
methyl group. Almost no effect was observed from sub-
stitution at 3 and 5 positions, but 6-methyl-2-alkoxypyridine
did not give pyridone 2p. These results indicate that steric
bulkiness around the nitrogen atom is important and that
the coordination of the metal to the nitrogen atom is crucial.
The introduction of an electron-withdrawing group could
be possible, and chloropyridone 2q was obtained in good
yield. One of the two alkyl groups migrated to give product
2r in a moderate yield when 3,6-dialkoxypyridazine 1r was
used as the substrate.
For 2-alkoxypyridines bearing a primary O-alkyl group,
the migration proceeded efficiently without NaOAc or sol-
vent, and the reaction of 2-methoxypyridine and 2-benzyloxy-
pyridine gave N-methylpyridone 5a and N-benzylpyridone
5b, respectively, in good to excellent yields at low catalyst
loadings (Scheme 5). The protocol is a facile way of synthe-
sizing N-alkyl pyridones bearing primary alkyl groups.
A series of experiments were carried out as a preliminary
mechanistic study (Scheme 6). The reaction of 1a was
examined in the presence of D2O (30 equiv), followed by
quenching within 30 min (Scheme 6, eq 3). H/D exchange at
the benzylic position was observed in both of the migrated
product 2a and the recovered 1a.10 Next, chiral substrate 1a
a Conditions: 2-alkoxyheterocycles 1 (0.1 mmol), [Ir(cod)2]BARF
(0.01 mmol), NaOAc (0.11 mmol), PhCl (0.5 mL), 135 °C for 24 h,
unless otherwise noted. b The reaction time was 48 h. c [Ir(cod)2]BF4 were used
in place of [Ir(cod)2]BARF, and the reaction proceeded without NaOAc.
without and with NaOAc, followed by quenching after a
short reaction time, and the crude products were analyzed
by NMR. Pyridone 3 was generated in the absence of
(11) In the absence of NaOAc, the significant decrease of enantio-
meric excess was also observed in 1a and 2a, which means that the
racemization was not due to base.
1904
Org. Lett., Vol. 15, No. 8, 2013

Scheme 6. Investigation of Mechanism
Scheme 7. Proposed Mechanism
was subjected to the reaction (Scheme 6, eq 4). Interestingly, a
significant decrease of the enantiomeric excess was observed
in both of the migrated product 2a and the recovered 1a.11
Based on these results, we speculated the reaction mech-
anism (Scheme 7). First, two pathways lead to CꢀO
bond cleavage: (a) direct oxidative CꢀO bond cleavage to
give intermediate A, which does not induce racemization,
and (b) oxidative CꢀH bond cleavage along with carbene
formation and 1,2-hydride migration, which induce
racemization.12 The subsequent intramolecular O-to-N-
alkyl migration and reductive elimination processes do not
generate free radicals or ionic intermediates.13,14
elimination was completely suppressed by adding NaOAc.
Further studies on the scope of the substrate and the precise
mechanism are in progress in our laboratory.
In summary, we developed a protocol for the cationic Ir(I)-
catalyzed O-to-N-alkyl migration in 2-alkoxypyridines bear-
ing a secondary O-alkyl group to afford various N-substi-
tuted pyridones. In this transformation, the β-hydrogen
Acknowledgment. This research was supported by
Grant-in-Aid for Scientific Research on Innovative Areas,
“Molecular Activation Directed toward Straightforward
Synthesis,”MEXT, JST, ACT-C, and Grantsfor Excellent
Graduate Schools (Practical Chemical Wisdom), Waseda
University, MEXT, Japan.
(12) Cleavage of sp3 CꢀO bond via oxidative addition of CꢀH bond
with Ir pincer complexes: Choi, J.; Choliy, Y.; Zhang, X.; Emge, T. J.;
Krogh-Jespersen, K.; Goldman, A. S. J. Am. Chem. Soc. 2009, 131,
15627.
(13) We examined a crossover experiment where the 1:1 mixture of 1c
and 1o was submitted to the same reaction conditions: only trace
amounts of the crossover products (<5%) were observed by GCꢀMS
analysis.
Supporting Information Available. Experimental pro-
cedure and physical property of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) The [1s,4s]-sigmatropic rearrangement can also be a possible
€
mechanism: (a) Schollkopf, U.; Hoppe, I. Tetrahedron Lett. 1970, 4527.
(b) Bowman, W. R.; Bridge, C. F. Synth. Commun. 1999, 29, 4051 and ref 3d.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 8, 2013
1905