A new route to tricyclic 2-pyridone frameworks via formation of bicyclic N-alkenyl alkynylamides followed by gold-catalyzed cycloisomerization

Article abstract of DOI:10.1246/cl.2009.1152

A cationic gold(I)/PPh₃ complex catalyzes cycloisomerizations of bicyclic N-alkenyl alkynylamides leading to tricyclic 2-pyridone derivatives at room temperature in good yields. The bicyclic N-alkenyl alkynylamides are readily prepared starting from commercially available 2-substituted cycloalkanones.

Full text of DOI:10.1246/cl.2009.1152

1152
Chemistry Letters Vol.38, No.12 (2009)
A New Route to Tricyclic 2-Pyridone Frameworks via Formation of Bicyclic N-Alkenyl
Alkynylamides Followed by Gold-catalyzed Cycloisomerization
Hidetomo Imase and Ken Tanakaꢀ
Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology,
Koganei, Tokyo 184-8588
(Received September 24, 2009; CL-090861; E-mail: tanaka-k@cc.tuat.ac.jp)
A cationic gold(I)/PPh3 complex catalyzes cycloisomeriza-
fully prepared starting from ketone 1a in four steps without pu-
rification of each intermediate (Table 1, Entry 1). Intermediate
azide 2a was prepared via alkylation of ketone 1a with 1-bro-
mo-3-chloropropane followed by treatment with NaN3. The
azide 2a was treated with PPh3 to form the corresponding
imine,10 which reacted with alkynoyl chloride 3a to furnish the
desired 1,5-enyne 4aa. Various 1,5-enynes 4 were then prepared
starting from 2-substituted cycloalkanones 1a–1d by following
the above optimized procedure. Both ethoxycarbonyl- (1a and
1b, Entries 1–6) and phenyl-substituted cycloalkanones (1d,
Entries 8 and 9) could be transformed to the corresponding
1,5-enynes in fair to good yields, while benzoyl-substituted cy-
clohexanone 1c was transformed to the corresponding 1,5-enyne
4ca in low yield due to the competitive aza-Wittig reaction in the
benzoyl carbonyl group (Entry 7). With respect to alkynoyl
chlorides, both aryl- (Entries 1–3 and 6–8) and alkyl-substituted
alkynoyl chlorides (Entries 4, 5, and 9) could be employed.
Thus obtaining the bicyclic 1,5-enynes 4, these were sub-
jected to the cationic gold(I)/PPh3 complex-catalyzed cycloiso-
merizations as summarized in Table 2. The cycloisomerizations
of bicyclic 5–6 fused 1,5-enynes smoothly proceeded to give the
desired tricyclic 2-pyridones in high yields (Entries 1–6). Not
only 5–6 fused 1,5-enynes but also 6–6 fused 1,5-enynes (Entries
7–10) could participate in this reaction, although product yields
were moderate and prolonged reaction times were required.
With respect to the substituents (R1) at the bridged carbon atom,
tions of bicyclic N-alkenyl alkynylamides leading to tricyclic
2-pyridone derivatives at room temperature in good yields.
The bicyclic N-alkenyl alkynylamides are readily prepared start-
ing from commercially available 2-substituted cycloalkanones.
As 2-pyridone frameworks are important core units in bio-
logically active compounds and functional organic materials,
their efficient synthesis has been extensively pursued to date.1
For the synthesis of bicyclic 2-pyridones, transition metal medi-
ated [2 þ 2 þ 2] cycloadditions of diynes with isocyanates
(eq 1)2 and alkynylisocyanates with alkynes (eq 2)3 are highly
efficient and convergent methods.4
O
transition-metal
catalyst
3
1
O
•
R
R
R
1
2
R
R
N
+
ð1Þ
n
2
N
3
R
n
O
O
1
2
•
transition-metal
catalyst
R
R
1
2
R
R
N
N
ð2Þ
+
n
n
3
R
3
R
Recently, we have reported that a cationic gold(I)/PPh3
complex catalyzes the cycloisomerization of N-alkenyl alkynyl-
amides (amide-linked 1,5-enynes) that can be readily prepared
starting from the corresponding cycloalkanones leading to 5–6
and 6–6 fused bicyclic 2-pyridones (n ¼ 1 and 2, eq 3).5–7 In this
letter, we describe the synthesis of tricyclic 2-pyridones (pyrido-
quinolinone derivatives8) that cannot be synthesized by
[2 þ 2 þ 2] cycloadditions via formation of bicyclic N-alkenyl
alkynylamides starting from the corresponding 2-substituted
cycloalkanones followed by the gold-catalyzed cycloisomeriza-
tion (eq 4).
Table 1. Synthesis of bicyclic N-alkenyl alkynylamides 4a
N
O
3
1) NaH
Br(CH ) Cl
O
N
3) PPh
2
2 3
3
O
1
2
R
R
2) NaN
4) R CCCOCl (3)
3
1
1
n
R
R
Et N
3
n
1
n
4
2
Product 4,
Yieldc/%
Entry Substrate 1
Substrate 3b
O
O
1
1
1a (n ¼ 1, R1 ¼ CO2Et) 3a (R2 ¼ Ph)
4aa, 35
4ab, 36
4ac, 31
4ad, 47
4ae, 57
4ba, 51
cationic
Au(I) catalyst
O
1
H
R
R
N
2
1a (n ¼ 1, R1 ¼ CO2Et) 3b (R2 ¼ 4-MeOC6H4)
1a (n ¼ 1, R1 ¼ CO2Et) 3c (R2 ¼ 2-ClC6H4)
1a (n ¼ 1, R1 ¼ CO2Et) 3d (R2 ¼ Me)
1a (n ¼ 1, R1 ¼ CO2Et) 3e (R2 ¼ Cy)
1b (n ¼ 2, R1 ¼ CO2Et) 3a (R2 ¼ Ph)
N
ð3Þ
ð4Þ
2
R
2
3
R
n
4
n
n
5
6d
7d
8
O
O
cationic
Au(I) catalyst
O
1c (n ¼ 2, R1 ¼ Bz)
1d (n ¼ 2, R1 ¼ Ph)
1d (n ¼ 2, R1 ¼ Ph)
3a (R2 ¼ Ph)
3a (R2 ¼ Ph)
3d (R2 ¼ Me)
4ca,
9
H
N
N
1
R
4da, 45
4dd, 27
2
R
2
R
9
1
n
1
R
R
n
n
aSee Supporting Information for detailed reaction conditions.9 bCarboxylic
acid chloride 3 were prepared in situ by the reaction of the corresponding
carboxylic acid and 1-chloro-N,N,2-trimethyl-1-propenylamine. cIsolated
yield. d1-Chloro-3-iodopropane was used instead of 1-bromo-3-chloropro-
pane.
We first investigated the synthesis of bicyclic N-alkenyl al-
kynylamides 4 starting from the commercially available 2-sub-
stituted cycloalkanones 1. After screening synthetic routes and
optimization of reaction conditions, 1,5-enyne 4aa was success-
Copyright Ó 2009 The Chemical Society of Japan

Chemistry Letters Vol.38, No.12 (2009)
1153
Table 2. Gold-catalyzed cycloisomerizations of bicyclic N-
alkenyl alkynylamides 4a
tigated. Fortunately, the desired cycloisomerization proceeded at
room temperature by using the cationic gold(I)/PPh3 complex
(5 mol %) to yield the expected tricyclic 2-pyridone 8 in 52%
yield (eq 5).
O
O
5 mol %
AuCl(PPh )/AgBF
N
3
4
N
2
R
2
(CH Cl) , rt
O
2
2
R
O
1
1
5 mol %
R
R
n
n
AuCl(PPh )/AgBF
3
4
N
N
5
4
ð5Þ
(CH Cl) , rt
Ph
2
2
Me
Ph
Me
12 h
Product 5,
Yieldb/%
Me
Me
8 52%
Entry Substrate 4
4aa (n ¼ 1, R1 ¼ CO2Et, R2 ¼ Ph)
Time/h
7
1
5
5
5aa, 82
5aa, 81
5ab, 87
5ac, 79
5ad, 71
5ae, 86
5ba, 71
5ca, 51
5da, 64
5dd, 60
In conclusion, a new route to tricyclic 2-pyridone deriva-
2c 4aa (n ¼ 1, R1 ¼ CO2Et, R2 ¼ Ph)
tives has been developed via formation of bicyclic N-alkenyl al-
kynylamides followed by the gold-catalyzed cycloisomerization.
Future work will focus on application of this methodology to the
total synthesis of natural products.
3
4
5
6
7
8
9
4ab (n ¼ 1, R1 ¼ CO2Et, R2 ¼ 4-MeOC6H4)
4ac (n ¼ 1, R1 ¼ CO2Et, R2 ¼ 2-ClC6H4)
4ad (n ¼ 1, R1 ¼ CO2Et, R2 ¼ Me)
4ae (n ¼ 1, R1 ¼ CO2Et, R2 ¼ Cy)
4ba (n ¼ 2, R1 ¼ CO2Et, R2 ¼ Ph)
4ca (n ¼ 2, R1 ¼ Bz, R2 ¼ Ph)
1
4
17
12
17
30
15
36
This work was supported partly by a Grant-in-Aid for Scien-
tific Research (No. 20675002) from MEXT, Japan.
4da (n ¼ 2, R1 ¼ Ph, R2 ¼ Ph)
10 4dd (n ¼ 2, R1 ¼ Ph, R2 ¼ Me)
References and Notes
aAuCl(PPh3)3 (0.010 mmol), AgBF4 (0.010 mmol), 4 (0.200 mmol), and
(CH2Cl)2 (1.0 mL) were used. See Supporting Information in detail.9
bIsolated yield. c(CH2Cl)2 (reagent grade) was used.
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1) LiAlH
4
N
2) TBDMSCl
3) Dess-Martin
periodinane
3
CO Me
2
O
O
O
Me
4) TBAF
5) MsCl, Et N
Me
ref. 9
Me
N
3
then NaN
3
1e
6
2e
3
4
5 mol %
AuCl(PPh )/
AgBF
4
O
O
3
1) PPh
3
N
Ar
(CH Cl) , rt
2
2
2) ArCCCOCl (3c)
Et N
Ar
5 h
Me
Me
4ec 20% from 6
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(Ar = 2-ClC H )
6
4
5ec 86%
5
6
Scheme 1. Synthesis of tricyclic 2-pyridone 5ec (See Support-
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stituents (R2) at the alkyne terminus, the reactions of aryl-substi-
tuted 1,5-enynes proceeded at higher reaction rates than those
of alkyl-substituted 1,5-enynes (Entries 1, 3, and 4 vs. 5 and 6;
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Although elaborate operations are required, tricyclic 2-pyr-
idone 5ec, bearing a methyl group at the bridged carbon atom,
could also be synthesized as shown in Scheme 1. 1,4-Addition
of methyl methacrylate to 2-methylcyclopentanone (1e) furnish-
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transformed into azide 2e in five steps. The azide 2e was treated
with PPh3 followed by reaction with alkynoyl chloride 3c to fur-
nish the desired 1,5-enyne 4ec. The gold-catalyzed cycloisome-
rization of 4ec proceeded to give the desired 2-pyridone 5ec in
high yield.
therein.
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Published on the web (Advance View) October 31, 2009; doi:10.1246/cl.2009.1152