Gold-catalysed cycloisomerisation reactions of 2-(2-propynyl)pyridine N-oxides leading to indolizinones

Article abstract of DOI:10.1039/c2cc32628k

Gold(i)-catalysed tandem oxygen-transfer/cycloisomerisation reaction of 2-(2-propynyl)pyridine N-oxides provides an atom-economical route to indolizinone frameworks.

Full text of DOI:10.1039/c2cc32628k

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COMMUNICATION
Gold-catalysed cycloisomerisation reactions of 2-(2-propynyl)pyridine
N-oxides leading to indolizinonesw
Masahito Murai, Sachie Kitabata, Kazuhiro Okamoto and Kouichi Ohe*
Received 13th April 2012, Accepted 7th June 2012
DOI: 10.1039/c2cc32628k
Gold(I)-catalysed tandem oxygen-transfer/cycloisomerisation
reaction of 2-(2-propynyl)pyridine N-oxides provides an atom-
economical route to indolizinone frameworks.
Indolizinones, the structure of which is closely related to that
of indolizines which exhibit strong anti-inflammatory, anti-HIV,
and anti-leukemia activity, have been exploited as privileged
structural motifs in the development of biologically active
molecules.1 Development of efficient and selective construc-
tions of these heterocycles with different substitution patterns
from readily available starting materials under mild conditions
remains an important task in synthetic chemistry. In this
Scheme 1 Transition metal-induced oxygen-transfer in pyridine
regard, transition metal-catalysed cycloisomerisation reaction
N-oxides involving an alkyne moiety.
of heteroatom-functionalized alkynes has received consider-
their precursors.13 In the course of our continuing studies on
able attention, since they provide a wide variety of complexed
heterocycles with high atom-efficiency.2 p-Alkyne metal com-
plexes are key intermediates capable of undergoing a wide
such reactive intermediates, we have found a novel method for
the generation of carbene complexes bearing a pyridyl group
range of reactions. Perhaps most commonly, they induce the
from pyridine N-oxides having alkyne moieties. When pyri-
dine N-oxide 1a was treated with 5 mol% of AuCl(PtBu3)/
addition of internal nucleophiles with a suitable length of tethers
leading to zwitterion (or metallocarbenoid) intermediates. A
AgSbF6 in ClCH2CH2Cl at rt (Scheme 2), b-pyridylenone 2
(E : Z = 92 : 8) and indolizinone 3a were obtained in 59%
variety of oxygen species may serve as the nucleophiles:
carbonyl (CQO),2,3 epoxides,2,4 amine N-oxides (R3N+–Oꢀ),5
and 41% yields, respectively. The relative stereochemistry of
nitrones,6 nitro,7 and sulfoxides (R2SQO)8 have been employed
with various transition-metal catalysts. In line with our recent
interest in the development of facile and efficient cycloisomeri-
sation reactions leading to heterocycles,9 we applied oxygen
transfer from pyridine N-oxides10 to alkynes activated with
transition metals A to the generation of zwitterions B or
metallocarbenoids C (Scheme 1).11 Since the resulting metallo-
carbenoids C possess reactive pyridyl groups, they might be
further converted into nitrogen-containing heterocycles.
Herein, we wish to report gold-catalysed cycloisomerisation
of 2-(2-propynyl)pyridine N-oxides leading to indolizinones
via acyl[(2-pyridyl)methyl]carbenoid complexes.12
3a was established by X-ray crystallography.14 When the
reaction was carried out at 50 1C, the total yield of 2 decreased
to 25%, whereas the yield of 3a raised up to 75%. These
results indicate that 3a might be formed by the cycloisomeri-
sation of 2 under the reaction conditions.
This interesting result stimulated us to optimize conditions
for the cycloisomerisation of 1a leading to indolizinone 3a.
The results are summarized in Table 1. First, reactions of 1a in
the presence of other gold catalysts were examined. While
reactions were generally sluggish in the presence of neutral gold
catalysts, such as AuCl, AuCl3, and AuCl(PtBu3) (entries 1–3),
cationic gold species prepared in situ from the reaction of
We reported the atom-economical generation of (2-furyl)-
carbene complexes using carbonyl–ene–yne compounds as
Department of Energy and Hydrocarbon Chemistry,
Graduate School of Engineering, Kyoto University, Katsura,
Nishikyo-ku, Kyoto 615-8510, Japan. E-mail: ohe@scl.kyoto-u.ac.jp;
Fax: +81 75-383-2499; Tel: +81 75-383-2495
w Electronic supplementary information (ESI) available: Experimental
details and analytical data. CCDC 869885 and 869886. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c2cc32628k
Scheme 2 Gold(I)-catalysed cycloisomerisation of 1a.
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Table 1 Transition metal-catalysed cycloisomerisation of 1aa
Entry
Catalyst
Yield of 3ab (%)
Scheme 3 Gold(I)-catalysed isomerisation of 1i.
1
2
3
4
AuCl
AuCl3
6
11
29
50
24
86
86
AuCl(PtBu)3
terminus produced the corresponding 9-benzyloxyindolizinones
3e and 3f in moderate yields, respectively (entries 4 and 5). In
contrast, terminal alkyne 1g decomposed under the reaction
conditions and no products being able to characterize were
observed (entry 6). The reaction of alkyne-substituted 5,6,7,8-
tetrahydroquinoline N-oxide 1h proceeded to give nitrogen-
containing tricycle 3h in good yield (entry 7).
AuCl(PPh)3/AgSbF6
(IPr)AuCl/AgSbF6
AuCl(PtBu)3/AgSbF6e
AuCl(PtBu)3/AgSbF6
5
6c
7c,d
a
Reaction conditions: 1a (0.20 mmol) in ClCH2CH2Cl (2.5 mL) was
b
heated at 50 1C in the presence of catalyst (5 mol%) for 17 h. Isolated
yields. At 80 1C. (Z)-2 was obtained in 14% yield. 2 mol%.
IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene.
c
d
e
Interestingly, 1i which has a hydrogen atom at the propargyl
position afforded b-pyridylenone 4 in 37% yield as a
mixture of stereoisomers without the formation of indolizi-
none (Scheme 3). The formation of 4 can be rationalized by
invoking 1,2-hydride shift of the acyl[(2-pyridyl)methyl]-
carbene complex generated from 1i. This observation indicates
that the migration of a benzoyloxy group to the carbene
carbon is essential in the cycloisomerisation of 1 leading to
the indolizinone.
equimolar amounts of gold and silver salts exhibited much
higher catalytic activity (entries 4 and 5). The combination
of AuCl(PtBu3)/AgSbF6 was the catalyst of choice for this
cycloisomerisation and the yield of 3a improved to 86% when
the reaction temperature was increased to 80 1C (entry 6).
Furthermore, we found that reducing the catalyst loading to
2 mol% did not influence the selectivity and efficiency of
the reaction (entry 7).15 The use of other metal catalysts
decreased the reaction efficiency.16 Screening of solvents also
identified ClCH2CH2Cl to be optimal.17 It is noteworthy
that the (Z)-isomer of b-pyridylenone 2 was obtained in
14% yield as a by-product under the optimized reaction
conditions (entry 7).
When the reaction of alcohols without a benzoyl moiety was
carried out, diketones 5a and 5b were obtained in 33% and
31% yields, respectively (Scheme 4). Diketones were formed
via the domino process that includes the generation of carbene
species and 1,2-rearrangement of H or Me followed by
protodemetalation. This result supports that the present reac-
tion proceeds through 6-endo-dig cyclization via the nucleo-
philic attack of the oxygen atom of pyridine N-oxides to
alkyne moieties.
On the basis of the aforementioned observations,18 the most
plausible mechanism for the cycloisomerisation of 1a is
proposed in Schemes 5 and 6. First, acyl[(2-pyridyl)methyl]-
carbene complex F is formed through 6-endo-dig cyclization
via the nucleophilic attack of the oxygen atom of pyridine
N-oxides to alkyne moieties activated by the cationic gold
catalyst followed by N–O bond cleavage (oxygen-transfer).10
Carbene complex F is then converted to (E)-2 through the
migration of a benzoyloxy group to the carbene center via the
transient Fz.19 The fact that (E)-2 was obtained as a major
isomer at room temperature can be explained by assuming the
With the optimized reaction conditions in hand, we next
examined the substrate scope of the present cycloisomerisation
reaction. The results are summarized in Table 2. Both pivalate
1b and acetate 1c can serve as substrates for this reaction,
affording the corresponding indolizinones 3b and 3c in 82%
and 71% yields, respectively (entries 1 and 2). An excellent
yield of the product was obtained in the reaction of ethyl
group substituted pyridine N-oxide 1d (entry 3). The reaction
of 1e and 1f having 2-naphthyl and butyl groups at the alkyne
Table 2 Gold(I)-catalysed cycloisomerisation of 1a
Entry R1
R2
R3
R4
Product Yieldb (%)
1c
2
3
4
5
6
7
H
H
H
H
H
H
Me
Me
Et
Me
Me
Me
tBu Ph
Me Ph
1b 3b
1c 3c
1d 3d
82
71
96
66
64
0
Ph
Ph
Ph
Ph
Ph
Ph
2-Naph 1e 3e
nBu
H
1f
3f
1g 3g
1h 3h
–(CH2)3–
Ph
78
a
Reaction conditions: 1 (0.40 mmol) in ClCH2CH2Cl (5.0 mL) was
heated at 80 1C in the presence of AuCl(PtBu)3/AgSbF6 (2 mol%).
Isolated yields. For 5 h.
b
c
Scheme 4 Gold(I)-catalysed isomerisation of alcohols.
Chem. Commun., 2012, 48, 7622–7624 7623
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Scheme 5 Regioselective formation of b-pyridylenone 2.
9 (a) M. Murai, S. Kawai, K. Miki and K. Ohe, J. Organomet.
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and alkynes, see: (a) L. Ye, L. Cui, G. Zhang and L. Zhang,
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Scheme 6 Cycloisomerisation of (E)-2 leading to 3a.
facile attack of a carbonyl moiety to a carbenoid center in
rotamer F (via transition state Fz), which is kinetically favoured
(see also Scheme 2).20 On the other hand, the amount of (Z)-2
formed was slightly affected by the reaction temperature
(5–8%), at which migration of a benzoyloxy group takes place
via rotamer G and transient Gz. At further elevated temperature,
(E)-2 only undergoes cycloisomerisation via the intramolecular
attack of pyridyl nitrogen to the gold catalyst-activated carbonyl
group to furnish indolizinone 3a along with regeneration of the
catalyst (Scheme 6).21
11 For
a non-catalysed cycloisomerisation of 2-butenylpyridine
N-oxides leading to quinolizine and indolizine, see: W. Eberbach
and W. Maier, Tetrahedron Lett., 1989, 30, 5591.
12 For rhodium–carbene complexes containing a pyridyl group, see:
(a) H. M. L. Davies and R. J. Townsend, J. Org. Chem., 2001,
66, 6595; (b) S. Chuprakov, F. W. Hwang and V. Gevorgyan,
Angew. Chem., Int. Ed., 2007, 46, 4757; (c) S. Chuprakov and
V. Gevorgyan, Org. Lett., 2007, 9, 4463.
13 For selected examples, see: (a) K. Miki, F. Nishino, K. Ohe and
S. Uemura, J. Am. Chem. Soc., 2002, 124, 5260; (b) K. Miki,
T. Yokoi, F. Nishino, Y. Kato, Y. Washitake, K. Ohe and
S. Uemura, J. Org. Chem., 2004, 69, 1557.
14 For X-ray crystal analysis data of 3a, see ESIw (CCDC 869886).
15 When isolated tBu3PAuSbF6 was used as a catalyst, 3a was
obtained in 86% yield.
16 Other transition metal catalysts produced 3a in the following yields.
AgSbF6: 15%, PtCl2: 17%, [RuCl2(CO)3]2: 8%, [Rh(OAc)2]2: 0%.
17 3a was obtained in 31% yield in MeCN and 50% yield in MeNO2,
respectively, at 50 1C in the presence of 5 mol% of AuCl(PPh3)/
AgSbF6.
In conclusion, we have demonstrated gold-catalysed oxygen-
transfer and cycloisomerisation cascade of 2-(2-propynyl)-
pyridine N-oxides leading to 9-acyloxyindolizinones. It is
noted that the gold catalyst serves as a p- and a s-acid catalyst.
This work is financially supported by a Grant-in-Aid for
Scientific Research on Innovative Areas (No. 2105) from the
MEXT. M.M. thanks the JSPS Research Fellowships for
Young Scientists. The authors thank the referees for helpful
comments on the reaction mechanism.
Notes and references
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18 See ESIw for the further discussion into the reaction mechanism.
19 The possibility that pyridylenones
2 are formed through
1,2-rearrangement of a benzoyloxy group followed by oxygen-
transfer from pyridine N-oxide to the generated carbene com-
plexes, or 1,3-rearrangement of a benzoyloxy group followed by
oxygen-transfer from pyridine N-oxide to the terminal position of
the resulting allene cannot be ruled out completely. For the gold-
catalysed allene formation and oxygen-transfer from sulfoxides to
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´
20 Gold-catalysed isomerization of 1a at 0 1C selectively afforded
(E)-2 in 12% yield without forming (Z)-2. For X-ray crystal
analysis data of (E)-2, see ESIw (CCDC 869885).
21 For similar platinum-catalysed intramolecular cyclization of dienones,
see: B. G. Pujanauski, B. A. B. Prasad and R. Sarpong, J. Am. Chem.
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7624 Chem. Commun., 2012, 48, 7622–7624
This journal is The Royal Society of Chemistry 2012