Alkylation of pyridone derivatives by nickel/Lewis acid catalysis

Article abstract of DOI:10.1002/anie.201200922

MAD as an additive: The [Ni(cod)₂], (2,6-tBu₂-4- MeC₆H₂O)₂AlMe (MAD), and N-heterocyclic carbene (NHC) catalytic system effected a highly regioselective alkylation of pyridone derivatives (see scheme). Substituted pyridones and related heterocycles react with both terminal and internal alkenes to selectively give a range of nitrogen-containing heterocycles with linear alkyl substituents. Copyright

Full text of DOI:10.1002/anie.201200922

Angewandte
Chemie
DOI: 10.1002/anie.201200922
À
C H Activation
Alkylation of Pyridone Derivatives By Nickel/Lewis Acid Catalysis**
Ryuichi Tamura, Yuuya Yamada, Yoshiaki Nakao,* and Tamejiro Hiyama*
Pyridone derivatives are found in many pharmaceuticals and
biologically active natural products (Scheme 1).[1] In addition,
they often serve as synthetic precursors for nitrogen-contain-
ing six-membered-ring compounds, including substituted
pyridines and piperidines. Methods for the efficient synthesis
of substituted pyridones have thus attracted the interest of
synthetic organic and medicinal chemists. In this regard, the
have effected C6-alkenylation through regioselective inser-
À
tion of alkynes into the C(6) H bond, using electron-rich
nickel(0) and Lewis acidic aluminum compounds as cooper-
ative catalysts.[5] Additionally, we also reported preliminary
results on the alkylation of the C6-position to give branched
alkylated pyridones through insertion of 1,3-dienes and
[5]
À
vinylarenes into the Csp2 H bond. Herein, we wish to
report the alkylation of pyridone derivatives with unactivated
alkenes that selectively gives pyridones with linear alkyl
groups through the use of nickel/Lewis acid cooperative
catalysis modulated by N-heterocyclic carbene (NHC)
ligands.
Toward finding optimal reaction conditions for the C6-
selective alkylation of pyridones with unactivated alkenes, we
investigated the reaction of 1-methyl-2-pyridone (1a) with
1-tridecene (2a) in toluene at 808C, in the presence of
[Ni(cod)2] (5 mol%),
a range of ligands, and AlMe3
(20 mol%) as a co-catalyst (Table 1). When P(iPr)3, the
ligand of choice in our previously reported alkenylation
reaction,[5] was used, 1-methyl-6-(tridec-1-yl)-2-pyridone
(3aa) was indeed obtained, albeit in a low yield (Table 1,
entry 1). The use of P(tBu)3 only led to a slight increase in
yield (Table 1, entry 2). We next examined NHC ligands to
improve the yield of 3aa. Although we have previously shown
Scheme 1. Pyridone derivatives found in pharmaceuticals and natural
products.
regioselective and direct functionalization of the pyridone
core would be a significantly valuable synthetic method for
the rapid access to substituted pyridone derivatives.[2] The
enaminone substructure of 2-pyridone derivatives, for exam-
ple, has been amenable to regioselective electrophilic chlori-
nation at the C5-position.[3] This type of reactivity has been
Table 1: C6-Alkylation of 1-Methyl-2-pyridone (1a) with tridecene (2a).[a]
À
used for palladium-mediated C C bond formation at the C5-
position, possibly through electrophilic palladation of the
enaminone functionality.[4] We have previously developed
complementary protocols that enable the functionalization of
the C6-position of 2-pyridone derivatives. For example, we
Entry
Ligand
LA
T
[8C]
t
[h]
Yield of 3aa
[%][b]
1
2
3
4
5
6
7
8
P(iPr)3
P(tBu)3
IMes
IPr
IPr
IPr
IPr
IPr
IPr
IPr
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
AlEt3
AlMe2Cl
AlPh3
MAD
BEt3
80
80
80
80
60
60
60
60
60
80
80
80
80
6
6
6
1
8
12
76
36
47
34
7
62
2
1
[*] R. Tamura, Y. Yamada, Dr. Y. Nakao
6
Department of Material Chemistry
12
12
12
12
12
6
Graduate School of Engineering, Kyoto University
Katsura, Nishikyo-ku, Kyoto 615-8510 (Japan)
E-mail: yoshiakinakao@npc05.mbox.media.kyoto-u.ac.jp
9
Prof. Dr. T. Hiyama
10
11
12
13
Research & Development Initiative, Chuo University
Bunkyo-ku, Tokyo 112-8551 (Japan)
E-mail: thiyama@kc.chuo-u.ac.jp
IPr
ItBu
IAd
none
AlMe3
AlMe3
6
6
6
7
7
[**] This work has been supported financially by MEXT in the form of
a Grant-in-Aid for Scientific Research on Innovative Areas “Molec-
ular Activation Directed toward Straightforward Synthesis” (to Y.N.,
No. 22105003), and JSPS in the form of the award Scientific
Research (S) (to T.H., No. 21225005).
[a] The reactions were carried out using 1a (0.50 mmol), 2a
(0.55 mmol), nC11H24 (internal standard, 125 mmol), [Ni(cod)2]
(3.0 mol%), ligand (6.0 mol% for phosphines and 3.0 mol% for NHCs),
and Lewis acid (12 mol%) in toluene (0.50 mL). [b] Determined by GC
based on 1a as the limiting reagent. cod=1,5-cyclooctadiene, LA=
Lewis acid.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200922.
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Table 2: Alkylation of pyridone derivatives with 2a catalyzed by Ni/MAD.
that the use of 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-yli-
dene (IMes) was effective for the alkylation of pyridones with
2-vinylnaphthalene,[5] this was not the case here for the
alkylation with 2a (Table 1, entry 3). Instead, we found that
1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) was
optimal, thus giving 3aa in 76% yield, as estimated using
GC analysis (Table 1, entry 4). We then screened other Lewis
acids in the reaction, while maintaining the presence of the
ligand IPr. Whereas the use of most of the aluminum-based
Lewis acids examined gave similarly modest yields of 3aa at
lower reaction temperatures (Table 1, entries 5–8), the use of
(2,6-tBu2-4-Me-C6H2O)2AlMe (MAD) afforded 3aa in 62%
yield even at 608C (Table 1, entry 9). The reaction in which
BEt3 was used (Table 1, entry 10) and the reaction not
containing a Lewis acid co-catalyst (Table 1, entry 11) gave
only trace amounts of 3aa, thus demonstrating the operation
of significant cooperative catalysis. When other NHCs,
including 1,3-diadamant-1-ylimidazol-2-ylidene (IAd) and
1,3-di-tert-butylimidazol-2-ylidene (ItBu), were used only
low yields were obtained (Table 1, entries 12 and 13).
With the most favorable combination of catalysts estab-
lished, we next studied the reaction of various pyridone
derivatives with 2a on a 1.0 mmol scale (Table 2). The
preparation of 3aa on this scale was successful (92%) but
the reaction also gave a small amount (2%) of the 4,6-
dialkylation product (Table 2, entry 1). However, the C4-
monoalkylation product was not observed in an amount
detectable by NMR spectroscopy, thus suggesting that the
primary reaction occurs at the C6-position exclusively.
Furthermore, no branched alkylation product was observed
in this particular example. Indeed, linear alkylation products
were selectively formed in most reactions in this study. The N-
benzyl variant 1b also reacted with 2a, in the presence of the
Ni/IPr/AlMe3 catalyst, to give 3ba in 64% yield, together with
the 4,6-dialkylation product in 16% yield (Table 2, entry 2).
The presence of a methyl substituent at 3-, 4-, or 5-position of
the 2-pyridone core did not adversely affect the alkylation
reaction and the respective products 3ca–3ea were obtained
in good yields (Table 2, entries 3–5). As anticipated from the
observation of minor amounts of the 4,6-dialkylation products
of 1a, 1b, and 1e, 1,6-dimethyl-2-pyridone (1j) was alkylated
at the C4-position when the reaction was conducted at 1008C
[Eq. (1)]. Similarly, 2-quinolone 1k underwent alkylation at
the C4-position [Eq. (2)]. 1-Methylisoquinolone (1 f),
Entry Starting material 1
t
[h]
Major product 3
Yield
[%][a]
1[b]
2[d,e,f]
3
1a
1b
1c
15
10
9
3aa 92[c]
3ba 64[c]
3ca 82
4
1d
1e
1 f
8
9
3da 94
3ea 62[c]
3 fa 83
3ga 65[c,j]
3ha 85
5[e,g]
6
16
9
7[g,h,i]
1g
1h
8
5
9[d]
1i
5
3ia
80[k]
[a] Yield of isolated product based on 1. [b] Reaction run at 608C.
[c] Dialkylation product was also obtained (entry 1: 2%; entry 2: 16%;
entry 5: 13%; entry 7: 8%). [d] AlMe3 was used instead of MAD.
[e] Reaction run with [Ni(cod)2] (5 mol%), IPr (5 mol%), and Lewis acid
(20 mol%). [f] 1.5 mmol of 2a was used. [g] Reaction run at 1008C.
[h] Reaction run with [Ni(cod)2] (10 mol%), IPr (10 mol%), and MAD
(40 mol%). [i] 1.3 mmol of 2a was used. [j] The branched isomer was
also isolated in 7% yield. [k] linear/branched=96:4. Bn=benzyl.
1-methyl-pyrimidone (1g), and 1-methyl-quinazolone (1h)
all participated in the alkylation reaction with 2a to give the
respective monoalkylation products in good yields (Table 2,
entries 6–8). The alkylation of 1,3-dimethyluracil (1i) also
occurred exclusively at the C6-position to give 3ia in 80%
yield (Table 2, entry 9).[6]
The scope of the reaction with respect to variation of the
alkene was also explored (Table 3). The presence of other
functional groups in the alkene substrate, including silyloxy,
ester, and alkenyl moieties, as well as bulky substituents such
as tert-butyl and trimethylsilyl groups, was tolerated under
these reaction conditions (Table 3, entries 1–6). The reaction
of hexa-1,5-diene (2d) also gave a 40% yield, based on 2d, of
a 1,6-double-addition adduct (Table 3, entry 3). Although
terminal double bonds were exclusively functionalized in the
presence of more substituted ones, as demonstrated in the
2
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Table 3: Alkylation of pyridone 1d with alkenes, catalyzed by Ni/MAD.
Entry Alkene
2
t
[h]
Major product 3
Yield
[%][a]
1
2
R=(CH2)3OSiMe2tBu 2b
6
3db
3dc
3dd
3de
3df
84
R=(CH2)3OPiv
2b 20
2d 19
81
3[b,c] R=(CH2)2CH CH2
45[d]
94
=
4
R=cyclohexen-4-yl
R=tBu
2e
2 f
4
5
5
95
88
6[c]
R=SiMe3
2g 19
3dg
7
8
2h
2i
7
9
3dh 92
Scheme 2. Plausible mechanism.
3di 84
A, wherein the 2-pyridone carbonyl oxygen atom coordinates
to the Lewis acidic aluminum catalyst. A related aluminum
adduct of an h2-pyridine nickel intermediate has recently
been identified by Ong et al.[7] Oxidative addition of the
[a] Yield of isolated product based on 1d. [b] Reaction run with [Ni(cod)2]
(5 mol%), IPr (5 mol%), and Lewis acid (20 mol%). [c] Reaction run at
1008C. [d] 1,6-Double-addition product was also obtained in 40% yield
based on 2d. Piv=pivaloyl.
À
C(6) H bond in A to a nickel(0) species would give the nickel
hydride B, to which the alkene substrate could then coor-
dinate, thus giving C. Subsequent migratory insertion would
afford the alkyl nickel species D, which, upon reductive
elimination, would give 6-alkyl-2-pyridones; A would then be
regenerated through ligand exchange reactions, thus com-
pleting the catalytic cycle. The selectivity toward oxidative
addition at the C6-position, the primary reaction site, could
stem from the electrophilicity of this position, which is located
a to the formally positively charged nitrogen atom in
intermediate A. The high selectivity for the linear product
could be derived from a regioselective migratory insertion,
which would favor the sterically less-hindered primary alkyl
nickel D rather than the secondary alkyl nickel species. The
reaction of 2-vinylnaphthalene has previously been shown to
give the opposite regioselectivity, thus giving the branched
adduct exclusively,[5] presumably because of the high stability
of a benzylic nickel intermediate.[8] The nickel hydride species
E and F, shown in Scheme 3, would be plausible intermediates
responsible for the C4- and C2-selective alkylation reactions
of 6-substituted 2-pyridones and 4-pyridones, respectively.
The necessity for a highly bulky carbene ligand suggests that it
may be crucial in promoting the reductive elimination, which
may be a rate-determining step.[8] We have yet to undertake
mechanistic studies to understand both the proposed catalytic
cycle in detail and the high efficiency of the MAD catalyst
compared with other aluminum-based Lewis acids.[9]
reaction of 4-vinylcyclohexene (2e; Table 3, entry 4), the
alkylation also proceeded with 1,1-disubstituted ethene 2h
and cyclohexene (2i) in good yield (Table 3, entries 7 and 8).
In addition to 2-pyridones, 4-pyridone derivatives also
reacted selectively; 1-methyl-4-pyridone (1l) and 1-methyl-
4-quinolone (1m), were alkylated directly at the C2-position
exclusively through regioselective addition to 2a [Eqs. (3) and
(4)]. Under the newly developed reaction conditions, the C6-
alkylation of 1d was sluggish when using vinylarenes and
1,3-dienes (< 5% yield); under previously reported reaction
conditions, these reactions gave branched alkylation prod-
ucts.[5]
A possible catalytic cycle is shown in Scheme 2; it starts
with the formation of the h2-2-pyridone nickel intermediate
Scheme 3. Nickel hydride intermediates E and F.
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Angewandte
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corresponding products in yields listed in Table 2, Table 3, and
Equations (1)–(4).
In summary, we have developed an alkylation reaction of
pyridone derivatives with unactivated alkenes that employs
nickel/Lewis acid cooperative catalysis and selectively gives
the linear product. The protocols enable the otherwise
challenging direct functionalization of the heterocycles that
are found in many biologically active substances, in a predict-
able manner. Efforts to understand the mechanism of the
cooperative catalysis and the further application of the
reaction toward the functionalization of unreactive substrates
are currently in progress.
Received: February 2, 2012
Published online: && &&, &&&&
À
Keywords: alkenes · C H activation · Lewis acids · nickel ·
pyridones
.
[1] M. Torres, S. Gil, M. Parra, Curr. Org. Chem. 2005, 9, 1757.
À
[2] For reviews on direct C H functionalization of heteroarenes, see:
a) F. Bellina, R. Rossi, Tetrahedron 2009, 65, 10269; b) R. Rossi, F.
Bellina, M. Lessi, Synthesis 2010, 4143.
[3] L. A. Paquette, W. C. Farley, J. Org. Chem. 1967, 32, 2725.
[4] T. Itahara, F. Ouseto, Synthesis 1984, 488.
[5] Y. Nakao, H. Idei, K. S. Kanyiva, T. Hiyama, J. Am. Chem. Soc.
2009, 131, 15996.
[6] For C6-selective arylation of uracils, see: a) M. Cernovꢀ, R. Pohl,
M. Hocek, Eur. J. Org. Chem. 2009, 3698; b) M. Cernovꢀ, I.
Cerna, R. Pohl, M. Hocek, J. Org. Chem. 2011, 76, 5309.
[7] C.-C. Tsai, W.-C. Shih, C.-H. Fang, T.-G. Ong, G. P. A. Yap, J. Am.
Chem. Soc. 2010, 132, 11887.
[8] Y. Nakao, N. Kashihara, K. S. Kanyiva, T. Hiyama, Angew. Chem.
2010, 122, 4553; Angew. Chem. Int. Ed. 2010, 49, 4451.
[9] For a review of MAD, see: S. Saito, H. Yamamoto, Chem.
Commun. 1997, 1585.
Experimental Section
A general procedure for the nickel-catalyzed alkylation of pyridones:
In a glove box, pyridone (1.0 mmol), alkene (1.1–1.5 mmol), and
undecane or dodecane (internal standard, 0.25 mmol) were placed in
a 3 mL vial. A solution of [Ni(cod)2] (8.3 mg, 30 mmol) and IPr
(11.7 mg, 30 mmol) in toluene (0.50 mL) and a solution of MAD
(58 mg, 0.12 mmol) in toluene (0.50 mL) were then added to the
mixture. The vial was sealed with a screw-cap, taken out of the glove
box, and heated at 808C for the time specified in Table 2, Table 3, and
Equations (1)–(4). The resulting mixture was filtered through a silica
gel pad, concentrated in vacuo, and purified by medium pressure
chromatography on silica gel (ethyl acetate/hexane) to give the
4
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À
C H Activation
MAD as an additive: The [Ni(cod)2], (2,6-
tBu2-4-MeC6H2O)2AlMe (MAD), and N-
heterocyclic carbene (NHC) catalytic
system effected a highly regioselective
alkylation of pyridone derivatives (see
scheme). Substituted pyridones and
related heterocycles react with both ter-
minal and internal alkenes to selectively
give a range of nitrogen-containing het-
erocycles with linear alkyl substituents.
R. Tamura, Y. Yamada, Y. Nakao,*
T. Hiyama*
&&&& — &&&&
Alkylation of Pyridone Derivatives By
Nickel/Lewis Acid Catalysis
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5
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