A copper-catalyzed domino reaction to construct functionalized indolizinones

Article abstract of DOI:10.1039/c5ra20119e

An efficient copper-catalyzed domino reaction to 3,8a-disubstituted indolizinones has been firstly developed, and the protocol uses pyridine ketones and terminal alkynes as the starting materials, overriding the isolation of propargylic alcohols.

Full text of DOI:10.1039/c5ra20119e

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
A copper-catalyzed domino reaction to construct
functionalized indolizinones†
Cite this: RSC Adv., 2015, 5, 100097
b
b
b
a
Ben-Quan Hu,ab Li-Xia Wang, Gang Shen, Ya-Lin Tang and Luo Yang
*
*
*
Received 29th September 2015
Accepted 5th November 2015
DOI: 10.1039/c5ra20119e
www.rsc.org/advances
An efficient copper-catalyzed domino reaction to 3,8a-disubstituted or tetrabutylammonium uoride (TBAF) catalyst8 in dry solvents.
indolizinones has been firstly developed, and the protocol uses pyri- Here, we rstly reported copper-catalyzed domino reaction to
dine ketones and terminal alkynes as the starting materials, overriding construct 3,8a-disubstituted indolizinones starting from pyridine
the isolation of propargylic alcohols.
ketones and terminal alkynes, overriding the preparation and
isolation of propargylic alcohols (Scheme 1).
Our initial studies focused on identifying the optimal
conditions (Table 1). Di-2-pyridyl ketone 1a and phenylacetylene
2a could be smoothly converted to indolizinone 3aa in 57%
yield with 10 mol% of CuBr2 as the catalyst, 2 equiv. of NEt3 as
the base, and dioxane as the solvent at 110 ꢀC during 24 hours
(entry 1). Without the participation of NEt3, the yield decreased
to 38% (entry 2), so was catalyzed by CuI (comparing to entry 5),
indicating that the base could accelerate the reaction rate.
While without the addition of CuBr2, the reaction couldn't
happen (entry 3), showing that copper-salt as the catalyst was
necessary. We screened other catalysts, and found Cu(OAc)2 was
the best, which led to 95% yield aer 4 hours (comparing
entries 1 and 5–8). To our delight, the reaction conditions were
easily handled. For example, the reaction operated in freshly
dried dioxane under 1 atm nitrogen atmosphere also provided
94% yields aer 4 hours (entry 9). Besides of dioxane, acetoni-
trile or toluene as the solvent also provided excellent yields
(entries 10 and 11), albeit the inexpensive “green” water led to
a low yield of 25% (entry 12).
The development of efficient and versatile strategies for the
synthesis of heterocycles has always been an active research
topic in organic chemistry.1 In this regard, transformations that
employ readily available substrates and go through a “one-pot”
reaction to provide access to multiply functionalized heterocy-
cles are highly desirable. Indolizinones are N-heterocycles that
have only recently appeared in the chemical literature,2–5 and
are useful precursors to indolizidine natural products, phar-
maceutical agents and new materials.2b Methods for the
synthesis of indolizinones have been reported by other groups
with salts or complexes of platinum,2 copper,3 silver,6 gold6 and
iodine.4 This transformation is proposed to proceed by a cycli-
zation/1,2-migration process of propargylic pyridines. Indolizi-
nones are also accessible from propargylic alcohols using
a greener protocol. Kim group5c and Sarpong group2b discovered
that heating tertiary alcohols in ethanol afforded indolizinone
products in excellent yields. The preparation of propargylic
alcohols, utilizing basic lithium reagents under special condi-
tions, was necessary in all of the previous reports. Other methods
for synthesizing propargylic alcohols would employ heavy metal
catalysts such as zinc or indium in the presence of bulky ligands,7
aKey Laboratory for Environmental Friendly Chemistry and Application, Department of
Chemistry, Xiangtan University, Hunan 411105, PR China. E-mail: yangluo@xtu.edu.
cn; Fax: +86-731-5829-2251; Tel: +86-731-5829-8351
bBeijing National Laboratory for Molecular Sciences (BNLMS), Center for Molecular
Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable
Species, Institute of Chemistry Chinese Academy of Sciences, Beijing 10080, P. R.
China. E-mail: wlx8825@iccas.ac.cn; tangyl@iccas.ac.cn; Fax: +86-10-6252-2090;
Tel: +86-10-6252-2090
† Electronic supplementary information (ESI) available: Synthetic procedures of
indolizinones, and copies of NMR spectra of all new compounds. CCDC
1428333 and 1428334. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c5ra20119e
Scheme 1 Methods for the synthesis of indolizinone derivatives.
RSC Adv., 2015, 5, 100097–100101 | 100097
This journal is © The Royal Society of Chemistry 2015

View Article Online
RSC Advances
Communication
a
Table 1 Optimization of conditions for copper-catalyzed domino Table 2 Substrate scope for terminal alkynes catalyzed by Cu(OAc)2
reaction of di-2-pyridyl ketone 1a with phenylacetylene 2a to form
indolizinone 3aaa
Entry
1
2
3
Temp.
110
Time
4
Yieldb [%]
95
Entry Cat.
Base Solvent Time [h] Temp. [ꢀC] Yieldb [%]
3aa
1
CuBr2
NEt3 Dioxane 24
Dioxane 24
NEt3 Dioxane 24
— Dioxane 24
110
110
110
110
110
110
110
110
110
110
110
110
57
38
nr
42
69
80
65
95
94
89
86
25
2
3
CuBr2
—
—
4
CuI
2
3
3ab
3ac
110
110
4
100
85
5
CuI
NEt3 Dioxane 24
NEt3 Dioxane 24
6
CuBr
7
Cu(NO3)2 NEt3 Dioxane 24
8
Cu(OAc)2 NEt3 Dioxane
Cu(OAc)2 NEt3 Dioxane
Cu(OAc)2 NEt3 CH3CN
Cu(OAc)2 NEt3 Toluene
Cu(OAc)2 NEt3 H2O
4
4
4
4
4
9c
10
11
12
24
a
Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), catalyst (0.03
b
4
3ad
110
24
78
mmol), base (0.6 mmol), solvent (2 ml) in sealed tube. Isolated yield.
c
Under highly pure nitrogen atmosphere and in freshly dried dioxane.
5
6
3ae
3af
110
110
24
4
93
93
With optimized conditions in hand, we rst examined the
scope of terminal alkynes with 1a (Table 2). Excellent yields of
the desired products were obtained with substituted phenyl-
acetylene bearing electron-donating or electron-withdrawing
groups. Strangely, para-substituted groups (except of methyl
group shown as in entry 2) at the benzene ring made the reac-
tion proceed slowly (entry 3–5, and 8). For example, the para-
chloride substrate provided the corresponding indolizinone 3ae
in 93% yields aer 24 hours (entry 5), but meta-chloride (entry 6)
and ortho-chloride (entry 7) substrates gave indolizinones 3af
and 3ag in 93% and 96% yields respectively, just aer 4 hours.
The structure of indolizinone 3af was conrmed by the X-ray
single crystal method (see Fig. S2†). Pyridylacetylene with N
atom at different positions (entries 9–11), and 2-naph-
thylacetylene (entry 12), and 4-phenyl phenylacetylene (entry 13)
led to good yields from 61% to 100%, but in need of longer
times and/or increasing temperature to 130 ꢀC. Aliphatic
alkynes such as cyclohexylacetylene (entry 14), 4-phenyl-1-
butyne (entry 15), and 1-octyne (entry 16) all afforded prod-
ucts with excellent yields in 1 hour.
Then we investigated the scope of pyridine ketones, another
six different substrates were examined (Table 3), bis(5-methyl-2-
pyridyl)ketone 1b,9 triuoro-(2-pyridyl) ketone 1c and 2-pyridyl-
4-pyridyl ketone 1d all led to indolizinones with yields from 33%
to 82%, and bis(5-methyl-2-pyridyl) ketone 1b showed the
similar reactivity as 1a. Terminal alkynes in varied types could
react with 1b or 1c, providing the corresponding indolizinones
3ba–3cn with yields from 53% to 82%. However, the reaction
starting from the substrates phenyl-(2-pyridyl) ketone 1e,
methyl-(2-pyridyl) ketone 1f, and pyridine-2-carbaldehyde 1g
7
3ag
110
4
96
8
9
3ah
3ai
110
130
24
24
91
64
10
11
3aj
110
130
72
18
79
61
3ak
100098 | RSC Adv., 2015, 5, 100097–100101
This journal is © The Royal Society of Chemistry 2015

View Article Online
Communication
RSC Advances
a
Table 2 (Contd.)
Table 3 Substrate scope for pyridine ketones catalyzed by Cu(OAc)2
Entry
1
1
2
3
Temp.
110
Time
1
Yieldb [%]
Entry
12
2
3
Temp.
130
Time
5
Yieldb [%]
100
2a
3ba
77
3al
2
3
4
1b
1b
1b
2c
2l
2n
3bc
3bl
3bn
110
110
110
24
24
1
68
82
80
13
3am
3an
130
110
1
1
92
90
5
2a
3ca
110
20
70
6
7
1c
1c
2l
2n
3cl
3cn
110
110
36
96
57
53
14
15
8
9
2a
2a
3da
110
110
63
24
33
3ao
3ap
110
110
1
1
94
80
16
—
—
a
Reaction conditions: 1a (0.3 mmol), 2 (0.6 mmol), Cu(OAc)2 (0.03
mmol), NEt3 (0.6 mmol), dioxane (2 ml) in a sealed tube. b Isolated yield.
10
2a
2a
—
—
110
110
24
24
—
—
couldn't happen under the established conditions. These
results indicated that the structure of pyridine ketones played
a very important role in deciding whether the reaction could
happen. We deduced that two 2-pyridyl N atoms in the
substrates 1a or 1b chelating to the copper ion, especially
comparing to the substrate 1d, thus facilitates nucleophilic
attack of the terminal alkyne, while CF3À in the substrate 1c as
a strong electron-withdrawing group played the similar role.
In order to conrm the chelation between 1a and Cu(OAc)2,
we obtained the gem–diol complex in 36% yield by the slow
volatilization at room temperature (note: all the reagents were
used without any purication aer purchase and the exclusion
of water was not required), from the solution of 1a and Cu(OAc)2
in the ratio of 1 : 1 in dioxane. In the solid state, the gem–diols
was formed through Cu2+-promoted in-situ hydration, and each
OH group O atom chelated to Cu2+ cooperating with two pyri-
dine N atoms, and nally provided an mononuclear inclined
octahedron with the ligand and metal salts in the ratio of 2 : 1
(Fig. 1). The gem–diol form (Py)2C(OH)2 from pyridine ketone 1a
11
a
Reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol), Cu(OAc)2 (0.03
mmol), NEt3 (0.6 mmol), dioxane (2 ml) in a sealed tube. b Isolated yield.
3aa qualitatively, when treated with phenylacetylene 2a.
Besides, previous reports have shown that di-2-pyridyl ketone
could coordinate with metal ions including Cu2+, providing
a dinuclear complex in dry solvents.13 The specic coordination
chemistry of di-2-pyridyl ketone to Cu2+ lent itself to form the
important intermediate propargylic alcohols bearing pyridine
rings, which might be converted further into indolizinone.
On the basis of these preliminary results, we speculated that
propargylic pyridine was a key intermediate. We isolated the
propargylic pyridine 4aa in 31% yield aer 0.5 hour during the
reaction process (Scheme 2A), under the established conditions,
and it would be converted into 3aa further quantitatively
À
À
11
was reported to be stabilized at the presence of BF4 , ,
10 ClO4
and here CH3COOÀ, indicating that the hydrolysis was inde-
pendent on the relative basicity of a counter-ion.12 We isolated
the crystal sample, and it was further converted to indolizinone
This journal is © The Royal Society of Chemistry 2015
RSC Adv., 2015, 5, 100097–100101 | 100099

View Article Online
RSC Advances
Communication
Scheme
3
Possible mechanism for Cu(OAc)2-catalyzed domino
synthesis of 3,8a-disustituted indolizinones.
Fig. 1 ORTEP representation of the cation of gem–diol complex
between 1a and Cu(OAc)2.
Conclusion
(Scheme 2C). The formation of propargylic pyridine decided
whether the nal conversion to indolizinone could succeed, and
it was dependent on the structure of pyridine ketone. To explore
the importance of the propargylic alcohols during the reaction
process, we then prepared propargylic pyridine 4ea starting
from the phenyl-(2-pyridyl) ketone 1e by the participation of n-
BuLi (Scheme 2B). Under the established conditions the new
propargylic pyridine 4ea could be converted into 3ea efficiently,
with yields of 88%.
To the best of our knowledge, the work reported herein repre-
sents the rst example of copper-catalyzed domino reaction to
construct indolizinones starting from pyridine ketones and
terminal alkynes in one-pot. Pyridine ketones containing two 2-
pyridyl groups chelating to the copper ion or a strong electon-
À
withdrawing CF3
group promoted polarization of the
carbonyl C]O bond thus facilitated the nucleophilic attack of
the terminal alkyne, and provided the corresponding indolizi-
nones aer cyclization and 1,2-migration. The specic coordi-
nation chemistry of di-2-pyridyl ketone to metal ions endows its
carbonyl group with increased electrophilicity, which will lead
to a growing number of interests in the future.
As shown in Scheme 3, we proposed a reasonable mecha-
nism. Firstly, propargylic alcohol bearing pyridine rings I is
formed, through nucleophilic attack of a alkynylcopper(I)
species,15,16 with the assistance of copper ion and base. Coor-
dination of the carbonyl oxygen to a metal ion (direct polari-
zation) and coordination of the pyridyl group (induced
polarization) can promote such polarization of the carbonyl
Acknowledgements
C]O bond.10,14 Then, subsequent cyclization/1,2-migration The authors wish to thank the National Natural Science Fou-
processes of propargylic alcohol in the presence of Cu(I)3 or dation of China (Grant No. 21302188, 91027033) and Chinese
Cu(II)17 happen to afford the indolizinone 3 nally.
Academy of Sciences (Grant No. KJCX2-EW-N06-01 and
XDA09030307) for nancial support.
References
1 For a recent general review, see: J. A. Joule and K. Mills,
Heterocyclic Chemistry, Blackwell Science Ltd., Cambridge,
MA, 4th edn, 2000.
2 (a) C. R. Smith, E. M. Bunnelle, A. J. Rhodes and R. Sarpong,
Org. Lett., 2007, 9, 1169; (b) A. R. H. Narayan and R. Sarpong,
Org. Biomol. Chem., 2012, 10, 70; (c) S. T. Heller, T. Kiho,
A. R. H. Narayan and R. Sarpong, Angew. Chem., Int. Ed.,
2013, 52, 11129; (d) E. M. Bunnelle, C. R. Smith, S. K. Lee,
S. W. Singaram, A. J. Rhodes and R. Sarpong, Tetrahedron,
2008, 64, 7008.
3 B. Yan, Y. B. Zhou, H. Zhang, J. J. Chen and Y. H. Liu, J. Org.
Chem., 2007, 72, 7783–7786.
4 J. Choi, G. H. Lee and I. Kim, Synlett, 2008, 1243–1249.
5 (a) I. Kim and K. Kim, Org. Lett., 2010, 12, 2500; (b) H. Cho
and I. Kim, Tetrahedron, 2012, 68, 5464; (c) I. Kim, J. Choi,
S. Lee and G. H. Lee, Synlett, 2008, 15, 2334.
6 I. V. Seregin, A. W. Schammel and V. Gevorgyan, Org. Lett.,
2007, 9, 3433.
Scheme 2 (A) Isolation of propargylic pyridine 4aa. (B) Preparation of
propargylic pyridine 4ea. (C) Copper-catalyzed transformations of 4aa
and 4ea under the established conditions.
100100 | RSC Adv., 2015, 5, 100097–100101
This journal is © The Royal Society of Chemistry 2015

View Article Online
Communication
RSC Advances
7 Selected references: (a) P. G. Cozzi, Angew. Chem., Int. Ed., 2003, 14 E. C. Constable, Metals and Ligand Reactivity, VCH,
42, 2895; (b) N. K. Anad and E. M. Carreira, J. Am. Chem. Soc., Weinheim, Germany, 1996, p. 46.
2001, 123, 9687; (c) X. Li, G. Lu, W. H. Kwok and A. S. Chan, J. 15 Copper(II) salts such as Cu(OAc)2 readily undergo reduction
Am. Chem. Soc., 2002, 124, 12636; (d) C. Wolf and S. Liu, J. Am.
Chem. Soc., 2006, 128, 10996; (e) D. E. Frantz, R. Fassler,
C. S. Tomooka and E. M. Carriera, Acc. Chem. Res., 2000, 33,
373; (f) Z. Xu, R. Wang, J. Xu, C. Da, W. Yan and C. Chen,
Angew. Chem., Int. Ed., 2003, 42, 5747.
8 V. R. Chintareddy, K. Wadhwa and J. G. Verkade, J. Org.
Chem., 2011, 76, 4482.
9 J. P. Collman, M. Zhong, Z. Wang and M. Rapta, Org. Lett.,
1999, 13, 2122.
to copper(I) in the presence of a terminal alkyne, and the
chelation of di-2-pyridyl ketone to Cu(II) may facilitate the
generation of Cu(I). The research about the conversion
from Cu(II) to Cu(I) in the presence of terminal alkynes
with pyridyl substrates, please see: (a) W. S. Brotherton,
H. A. Michaels, J. T. Simmons, R. J. Clark, N. S. Dalal and
L. Zhu, Org. Lett., 2009, 11, 4954; (b) G. C. Kuang,
P. M. Guha, W. S. Brotherton, J. T. Simmons,
L. A. Stankee, B. T. Nguyen, R. J. Clark and L. Zhu, J. Am.
Chem. Soc., 2011, 133, 13984; (c) Z. Yuan, G.-C. Kuang,
R. J. Clark and L. Zhu, Org. Lett., 2012, 14, 2590.
10 C. Q. Wan, H. J. Yan and T. C. W. Mak, Inorg. Chim. Acta,
2015, 432, 13.
11 V. Tangoulis, C. P. Raptopoulou, A. Terzis, S. Paschalidou, 16 We detected the 1,4-diphenylbutadiyne as one by-product by
P. Perlepes and E. G. Bakalbassis, Inorg. Chem., 1997, 36,
3996.
12 (a) C. Q. Wan and T. C. W. Mak, Inorg. Chim. Acta, 2008, 361,
1496; (b) C. Q. Wan, G. S. Li, X. D. Chen and T. C. W. Mak,
Cryst. Growth Des., 2008, 8, 3897.
GC-MS to testify indirectly the generation of the Cu(I)
species, aer the completion of the reaction between 1a
and 2a under the optimized conditions (see Fig. S1†). The
possible generation process of the Cu(I) species was shown
as in below, according to ref. 16a:
´
13 (a) R. A. Mariezcurrena, A. W. Mombru, L. Suescun,
´
E. Kremer and R. Gonzalez, Acta Crystallogr., Sect. C: Cryst.
Struct. Commun., 1999, 55, 1989; (b) A. Basu, A. R. Saple
and N. Y. Sapre, J. Chem. Soc., Dalton Trans., 1987, 1797; (c)
G. S. Papaefstathiou and S. P. Perlepes, Comments Inorg.
Chem., 2002, 23, 249.
17 As shown in Scheme 2c, Cu(II) salts could catalyze the
cyclization/1,2-migration of propargylic alcohol to
indolizinones.
This journal is © The Royal Society of Chemistry 2015
RSC Adv., 2015, 5, 100097–100101 | 100101