Convergent and rapid assembly of substituted 2-pyridones through formation of N-alkenyl alkynylamides followed by gold-catalyzed cycloisomerization

Article abstract of DOI:10.1021/ol801466f

(Chemical Equation Presented) A new method for the convergent and rapid assembly of substituted 2-pyridones was developed through the formation of N-alkenyl alkynylamides (amide-linked 1,5-enynes) by N-acylation of !mines with alkynoyl chlorides and the subsequent cationic Au(l)/PPh₃-catalyzed cycloisomerization.

Full text of DOI:10.1021/ol801466f

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3563-3566
Convergent and Rapid Assembly of
Substituted 2-Pyridones through
Formation of N-Alkenyl Alkynylamides
Followed by Gold-Catalyzed
Cycloisomerization
Hidetomo Imase,† Keiichi Noguchi,‡ Masao Hirano,† and Ken Tanaka*,†
Department of Applied Chemistry, Graduate School of Engineering, and
Instrumentation Analysis Center, Tokyo UniVersity of Agriculture and Technology,
Koganei, Tokyo 184-8588, Japan
tanaka-k@cc.tuat.ac.jp
Received June 11, 2008
ABSTRACT
A new method for the convergent and rapid assembly of substituted 2-pyridones was developed through the formation of N-alkenyl alkynylamides
(amide-linked 1,5-enynes) by N-acylation of imines with alkynoyl chlorides and the subsequent cationic Au(I)/PPh3-catalyzed cycloisomerization.
2-Pyridones constitute important core units in a large number
of pharmaceuticals, agrochemicals, and functional materials.
The development of their efficient synthesis is, therefore,
an important target in current organic synthesis.1 Recent
advances in transition-metal-catalyzed reactions allow de-
velopment of new strategies for the synthesis of these
compounds.2 As such, the transition-metal-catalyzed [2 + 2
+ 2] cycloaddition of two alkynes with an isocyanate has
proven to be an efficient method for the convergent and rapid
assembly of substituted 2-pyridones.3,4 However, due to
toxicity and instability of isocyanates, an alternative catalytic
synthesis of 2-pyridones from nontoxic and stable starting
materials would also be of great value.
In this respect, we anticipated that N-alkenyl alkynyla-
mides (amide-linked 1,5-enynes) bearing an electron-rich
(3) For recent reviews of the synthesis of azaheterocycles including
2-pyridones by transition-metal-catalyzed [2 + 2 + 2] cycloadditions, see:
(a) Heller, B.; Hapke, M. Chem. Soc. ReV. 2007, 36, 1085. (b) Chopade,
P. R.; Louie, J. AdV. Synth. Catal. 2006, 348, 2307. (c) Varela, J. A.; Saa`,
C. Chem. ReV. 2003, 103, 3787.
(4) For selected recent examples of the 2-pyridone synthesis by
transition-metal-catalyzed [2 + 2 + 2] cycloadditions, see: (a) Yamamoto,
Y.; Kinpara, K.; Saigoku, T.; Takagishi, H.; Okuda, S.; Nishiyama, H.;
Itoh, K. J. Am. Chem. Soc. 2005, 127, 605. (b) Duong, H. A.; Cross, M. J.;
Louie, J. J. Am. Chem. Soc. 2004, 126, 11438. (c) Kondo, T.; Nomura, M.;
Ura, Y.; Wada, K.; Mitsudo, T. Tetrahedron Lett. 2006, 47, 7107. (d)
Tanaka, K.; Wada, A.; Noguchi, K. Org. Lett. 2005, 7, 4737. (e) Bonaga,
L. V. R.; Zhang, H.-C.; Gauthier, D. A.; Reddy, I.; Maryanoff, B. E. Org.
Lett. 2003, 5, 4537. For Zr-mediated reactions, see: (f) Takahashi, T.; Tsai,
F.-Y.; Li, Y.; Wang, H.; Kondo, Y.; Yamanaka, M.; Nakajima, K.; Kotora,
M. J. Am. Chem. Soc. 2002, 124, 5059.
† Department of Applied Chemistry.
‡ Instrumentation Analysis Center.
(1) For recent reviews of the 2-pyridone synthesis, see: (a) Torres, M.;
Gil, S.; Parra, M. Curr. Org. Chem. 2005, 9, 1757. (b) Rigby, J. H. Synlett
2000, 1.
(2) For a recent review of the transition-metal-catalyzed synthesis of
azaheterocycles including 2-pyridones, see: Nakamura, I.; Yamamoto, Y.
Chem. ReV. 2004, 104, 2127.
10.1021/ol801466f CCC: $40.75
Published on Web 07/18/2008
2008 American Chemical Society

alkene moiety and an electron-deficient alkyne moiety, that
might be available from the corresponding alkynoyl chlorides
and imines, would cyclize to give substituted 2-pyridones
by using a π-electrophilic transition-metal complex as a
catalyst (Scheme 1).5–10 Although several heterocycle syn-
compounds 3, and primary amines 4 was investigated to
allow a high degree of structural diversity. The optimized
reaction conditions for the synthesis of 6 are shown in
Scheme 2. The reaction of crude imine 5, prepared by
Scheme 2
.
Optimized Reaction Conditions for the Synthesis of
Scheme 1
.
Our Plan for Convergent Synthesis of Substituted
2-Pyridones
N-Alkenyl Alkynylamides 6
theses through transition-metal-catalyzed cycloisomerizations
of heteroatom-linked 1,5-enynes have been reported, ap-
plication to the 2-pyridone synthesis has not been ex-
plored.5–7 As alkynoyl chlorides can be readily prepared from
the corresponding alkynoic acid and imines can be readily
prepared from the corresponding carbonyl compounds and
primary amines (Scheme 1), this protocol would serve as an
attractive new method for the convergent and rapid assembly
of substituted 2-pyridones.
dehydration between 3 and 4 under microwave heating, and
crude alkynoyl chloride 2, prepared by chlorination of 1, at
0 °C in the presence of Et3N furnished the desired amide
6.11
Various N-alkenyl alkynylamides 6 were prepared in fair
to good yields by the above optimized reaction conditions.
Aryl- (entries 1-9), alkyl- (entry 10), and trimethylsilyl-
(entry 11) substituted alkynoic acids, cyclic (entries 1-5 and
10) and acyclic (entries 6-9 and 11) carbonyl compounds,
and benzylamine (entries 1-3 and 5-11) and neopenty-
lamine (entry 4) could be used as summarized in Table 1.12
The choice of the base is critical, and the use of pyridine
instead of Et3N did not furnish amide 6 at all (entries 1 vs
2). On the other hand, both thionyl chloride and 1-chloro-
N,N-2-trimethyl-1-propenylamine could be employed as a
chlorination reagent (entries 1 vs 3). All these reactions could
be conducted using a reagent grade solvent and completed
for 0.5-3 h, which might be attractive for the combinatorial
synthesis.
Gratifyingly, the reaction of N-cyclopentenyl phenylethy-
nylamide 6aaa with a catalytic amount of π-electrophilic
transition-metal complexes,13 such as Rh(I), Pd(II), Pt(II),
and Cu(II) complexes, at elevated temperature gave 4-phenyl-
2-pyridone 7aaa through endo cyclization (Table 2, entries
1-6).14 A cationic Ag(I) complex is more active, which
The convergent synthesis of N-alkenyl alkynylamides 6
starting from the corresponding alkynoic acid 1, carbonyl
(5) For the Au(I)-catalyzed cycloisomerization of N-propargyl silyl
ketene amides leading to substituted dehydro-δ-lactams, see: Minnihan,
E. C.; Colletti, S. L.; Toste, F. D.; Shen, H. C. J. Org. Chem. 2007, 72,
6287
.
(6) For the Au(I)-catalyzed cycloisomerization of propargyl vinyl ethers
leading to substituted dihydropyrans, see: Sherry, B. D.; Maus, L.; Laforteza,
B. N.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 8132
.
(7) For the Ru(II)-catalyzed cycloisomerization of 3-azadienynes leading
to substituted pyridines via Ru-vinylidene intermediates, see: (a) Movas-
saghi, M.; Hill, M. D. J. Am. Chem. Soc. 2006, 128, 4592. Related recent
azaheterocycle syntheses, see: (b) Movassaghi, M.; Hill, M. D. J. Am. Chem.
Soc. 2006, 128, 14244. (c) Movassaghi, M.; Hill, M. D.; Ahmad, O. K.
J. Am. Chem. Soc. 2007, 129, 10096. (d) Liu, S.; Liebeskind, L. S. J. Am.
Chem. Soc. 2008, 130, 6918
.
(8) For recent examples of π-electrophilic transition-metal-catalyzed
cycloisomerizations of 1,5-enynes to form six-membered carbocycles by
Au(I) catalysts, see: (a) Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2004,
126, 11806. (b) Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2005, 127,
6962. (c) Sun, J.; Conley, M. P.; Zhang, L.; Kozmin, S. A. J. Am. Chem.
Soc. 2006, 128, 9705. (d) Shibata, T.; Ueno, Y.; Kanda, K. Synlett 2006,
411. (e) Nieto-Oberhuber, C.; MuNunez, M. P.; Nevado, C.; Herrero-Gomez,
E.; Raducan, M.; Echavarren, A. M. Chem.-Eur. J. 2006, 12, 1677. (f)
Grise, C. M.; Barriault, L. Org. Lett. 2006, 8, 5905. By Cu(I) catalysts,
see: (g) Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 2006, 45, 2901By
Hg(II) catalysts, see: (h) Imagawa, H.; Iyenaga, T.; Nishizawa, M. Org.
Lett. 2005, 7, 451. (i) Imagawa, H.; Iyenaga, T.; Nishizawa, M. Synlett
(11) Although N-acylation of imines with alkynoyl chlorides has not
been previously reported, N-acylation of imines with alkanoyl chlorides in
the presence of a base was reported. See: (a) Saito, M.; Matsuo, J.;
Uchiyama, M.; Ishibashi, H. Heterocycles 2006, 69, 69. (b) Lenz, G. R.;
Lessor, R. A.; Rafalko, P. W.; Ezell, E. F.; Kosarych, Z.; Meyer, L.;
Margaretha, P. HelV. Chim. Acta 2004, 87, 690.
2005, 703
.
(12) Alkynyl-NH-amides, structures of which are shown below, were
generated as byproducts.
(9) For examples of Ru(II)-catalyzed cycloisomerizations of 1,5-enynes
to form six-membered carbocycles via Ru-vinylidene intermediates, see:
(a) Merlic, C. A.; Pauly, M. E. J. Am. Chem. Soc. 1996, 118, 11319. (b)
Datta, S.; Odedra, A.; Liu, R.-S. J. Am. Chem. Soc. 2005, 127, 11606. (c)
Odedra, A.; Wu, C.-J.; Pratap, T. B.; Huang, C.-W.; Ran, Y.-F.; Liu, R.-S.
J. Am. Chem. Soc. 2005, 127, 3406
.
(13) For a review of π-electrophilic Lewis acid catalysts, see: Yamamoto,
Y. J. Org. Chem. 2007, 72, 7817.
(10) For recent reviews of cycloisomerization of 1,n-enynes, see: (a)
Michelet, V.; Toullec, P. Y.; Geneˆt, J.-P. Angew. Chem., Int. Ed. 2008, 47,
4268. (b) Zhang, L.; Sun, J.; Kozmin, S. A. AdV. Synth. Catal. 2006, 348,
2271. (c) Bruneau, C. Angew. Chem., Int. Ed. 2005, 44, 2328. (d) An˜orbe,
(14) The NH-amide (R1 ) Ph, R2 ) Bn in ref 12) was obtained as a
byproduct in ca. 35% yield (entry 2) and ca. 70% yield (entry 6). On the
other hand, unidentified complex mixtures were generated other than the
desired 2-pyridone in entries 1, 3, 4, 5, and 7.
L.; Dom´ınguez, G.; Pe´rez-Castells, J. Chem.-Eur. J. 2004, 10, 4938
.
3564
Org. Lett., Vol. 10, No. 16, 2008

Table 1. Synthesis of N-Alkenyl Alkynylamides 6a
Table 2. Screening of Catalysts for Cycloisomerization of
N-Cyclopentenyl Phenylethynylamide 6aaaa
yield (%)b
conditions convn (%) 7aaa 8aaa
entry
catalyst
1
2
3
4
5
6
7
8
9
[Rh(PPh3)2]BF4
80 °C, 3 h
85
49
13
17
68
42
18
52
0
0
0
0
0
0
0
0
0
0
[Rh(P(OPh)3)2]BF4 80 °C, 3 h
50
PdCl2
80 °C, 3 h
76
[Pd(CH3CN)4](BF4)2 80 °C, 1 h
100
100
100
100
0
PtCl2
Cu(OTf)2
AgBF4
80 °C, 3 h
80 °C, 3 h
rt, 5 h
AuCl(PPh3)
80 °C, 6 h
AuCl(PPh3)/AgBF4 rt, 0.5 h
100
82
a Catalyst (0.0050 mmol, 5 mol %), 6aaa (0.10 mmol), and (CH2Cl)2
(1.0 mL) were used. b Isolated yield.
tries 1-8), while the reactions of alkyl- and trimethylsilyl-
substituted alkynylamides were slow (entries 9 and 10).15
Table 3. Cationic Au(I)/PPh3-Catalyzed Cycloisomerization of
N-Alkenyl Alkynylamides 6 to Form 2-Pyridones 7a
a 1 (5-10 mmol scale, 1.0 equiv), SOCl2 (3.0 equiv), 3 (1.0 equiv), 4
(1.0 equiv), TsOH (ca. 2 mg), and CH2Cl2 (reagent grade) were used. See
Supporting Information for details. b Isolated yield. c Pyridine was used
instead of Et3N. d 1-Chloro-N,N-2-trimethyl-1-propenylamine (1.1 equiv)
was used instead of SOCl2.
catalyzed the reaction at room temperature (entry 7).14
A
cationic Au(I)/PPh3 complex showed the highest catalytic
activity, which catalyzed the reaction at room temperature
for only 0.5 h (entry 9), while a neutral Au(I)/PPh3 complex
showed no catalytic activity even at elevated temperature
(entry 8). In all entries, the exo cyclization product 8aaa
was not generated at all.
The scope of the cationic Au(I)/PPh3-catalyzed cycloi-
somerization of N-alkenyl alkynylamides 6, leading to
2-pyridones 7, was examined as summarized in Table 3. Both
N-benzyl (entry 1) and N-neopentyl (entry 3) alkynylamides
furnished the corresponding 2-pyridones in high yields.
Alkynylamides bearing not only trisubstituted (entries 1-4
and 9) but also disubstituted (entries 5-7 and 10) and
monosubstituted (entry 8) alkene moieties could participate
in this reaction. With respect to the alkyne terminus, the
reactions of aryl-substituted alkynylamides were rapid (en-
a Reactions were conducted using AuCl(PPh3)/AgBF4 (0.010 mmol, 5
mol %), 6 (0.20 mmol), and (CH2Cl)2 (2.0 mL: anhydrous) at rt. b Isolated
yield. c (CH2Cl)2 (2.0 mL: reagent grade) was used.
Org. Lett., Vol. 10, No. 16, 2008
3565

The electronic nature of the aromatic substituents appears
to have a high impact on yields [more electron-rich (entry
6), higher yield; more electron-poor (entry 7), lower yield].16
Importantly, the present Au(I)-catalyzed cycloisomerization
can be conducted using a reagent grade solvent without
erosion of the yield (entry 2). The structure of the endo
cyclization product 7, not the exo cyclization product 8, was
unambiguously confirmed by X-ray crystallographic analysis
of the crystalline 2-pyridone 7aca.17
temperature were examined in the presence of the catioinic
Au(I) complex (5 mol %). However, 2-pyridones 7aba and
7cca were obtained in almost identical yields (81% and 44%,
respectively) as compared with entries 4 and 7 of Table 3,
and the expected MeOH adducts 9aba and 9cca (Figure 1)
Scheme 3 depicts a possible mechanism for the present
Figure 1. Expected MeOH adducts 9aba and 9cca.
Scheme 3. Possible Mechanism for Cationic Au(I)/PPh3-
Catalyzed Cycloisomerization of N-Alkenyl Alkynylamides 6
were not obtained at all presumably due to the rapid
deprotonation from the intermediate A and/or the rapid
elimination of MeOH from the compounds 9 leading to the
conjugated structures 7.
In conclusion, we have established a new synthetic route
to substituted 2-pyridones through the formation of N-alkenyl
alkynylamides by N-acylation of imines with alkynoyl
chlorides and the subsequent cationic Au(I)/PPh3-catalyzed
cycloisomerization. The present synthesis serves as a versatile
new method for the convergent and rapid assembly of
substituted 2-pyridones in pharmaceutical, agricultural, and
material chemistry. Expansion of the substrate scope and an
asymmetric variant of this reaction are underway in our
laboratory.
cycloisomerization. We believe that the coordination of the
catioinic Au(I) complex to the alkyne moiety of N-alkenyl
alkynylamide 6 would induce the endo cyclization to generate
the iminium intermediate A.18–20 Subsequent deprotonation
gives substituted 2-pyridone 7 and regenerates the Au(I)
catalyst.
Acknowledgment. This work was supported partly by a
Grant-in-Aid for Scientific Research (Nos. 19350046 and
20675002) from the Ministry of Education, Culture, Sports,
Science and Technology, Japan. We thank Messrs. Goushi
Nishida, Takeshi Suda, and Yu Shibata (TUAT) for their
experimental assistance.
To intercept the cationic intermediate A, the reactions of
6aba and 6cca with MeOH (1 equiv) in 1,4-dioxane at room
(15) Although the product yields were moderate in entries 8 and 9, the
complete conversion of the starting material was observed, and the almost
pure 2-pyridones were obtained after removal of the gold catalyst by a short
silica gel column chromatography. Extremely polar decomposition products
might be generated other than the desired 2-pyridones. On the other hand,
an unidentified complex mixture was generated other than the desired
2-pyridone in entry 10.
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and an X-ray
crystallographic information file (PDF, CIF). This material
is available free of charge via the Internet at http://pubs.acs.org.
(16) Exo cyclization product 8cca was generated as a byproduct with
ca. 25% yield in entry 7, although it could not be isolated in a pure form.
OL801466F
(20) The electron-rich alkene moiety and the electron-deficient alkyne
moiety of 1 are essential to promote the present cycloisomerization. The
reaction of N-isopropenyl alkynylamide 6eca furnished the corresponding
pyridone 7eca at room temperature (Table 3, entry 10), while no reaction
was observed and the starting material remained unchanged in the reaction
of N-alkynyl isopropenylamide even at elevated temperature as shown
below.
(17) See Supporting Information.
(18) Toste and co-workers proposed the formation of the oxocarbenium
intermediate in their Au(I)-catalyzed synthesis of dihydropyrans from 1,5-
enynes; see ref 6
.
(19) Importantly, cyclopropane derivatives and alkyl migration products
were not detected at all in the crude reaction mixtures of the present Au(I)-
catalyzed cycloisomerization of amide-linked 1,5-enynes (Table 3). There-
fore, cationic cyclopropylcarbene-gold intermediates may not play a role
in this cycloisomerization. For examples, see: (a) Echavarren, A. M.;
Nevado, C. Chem. Soc. ReV. 2004, 33, 431. (b) Gagosz, F. Org. Lett. 2005,
7, 4129. (c) See also ref 10
.
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Org. Lett., Vol. 10, No. 16, 2008