Tandem [5+1] annulation-isocyanide cyclization: Efficient synthesis of hydroindolones

Article abstract of DOI:10.1039/c1cc14916d

A new strategy for the rapid construction of functionalized reduced indoles starting from activated methylene isocyanides and 1,5-dielectrophilic 5-oxohepta-2,6-dienoates (and their equivalents) through a [5+1] annulation-isocyanide cyclization cascade un

Full text of DOI:10.1039/c1cc14916d

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COMMUNICATION
Tandem [5+1] annulation–isocyanide cyclization: efficient synthesis of
hydroindolonesw
He Wang, Yu-Long Zhao,* Chuan-Qing Ren, Aboubacar Diallo and Qun Liu*
Received 9th August 2011, Accepted 29th September 2011
DOI: 10.1039/c1cc14916d
A new strategy for the rapid construction of functionalized
reduced indoles starting from activated methylene isocyanides
and 1,5-dielectrophilic 5-oxohepta-2,6-dienoates (and their
equivalents) through a [5+1] annulation–isocyanide cyclization
cascade under basic conditions has been developed. This strategy
allows the synthesis of polysubstituted dihydroindolones and
tetrahydroindolones in high to excellent yields under extremely
mild conditions in a single step.
(monitored by TLC) when the reaction was carried out in
dichloromethane or toluene (entries 7 and 8).
Clearly, product 2a can be obtained in high yield in a short
time under the reaction conditions as in Table 1, entry 2.z
Under the optimal conditions, the scope of the reaction was
then investigated and the results are summarized in Table 2.
It is obvious that the tandem reaction showed broad tolerance
for various R substituents of 1. All selected substrates 1a–j,
bearing phenyl (entry 2), electron-rich (entries 3, 7 and 8),
electron-deficient (entries 1 and 4–6) aromatics, and hetero-
aromatic R groups (entries 9 and 10), reacted smoothly with
ethyl isocyanoacetate to give the corresponding tetrahydro-
indolones 2a–j in high to excellent yield under very mild
conditions over 18 to 60 min. In addition, the reaction of
substrate 1k bearing a phenylvinyl R group can give the
desired 2k in 74% yield in the presence of stoichiometric
amounts of NaOH in acetonitrile (entry 11). Similarly, the
desired tetrahydroindolones 2l and 2m could be prepared in high
yields from substrates 1l and 1m bearing an ethoxycarbonyl
(entry 12) and cyano groups (entry 13), respectively. According
to 1H and 13C NMR data of the products 2, it was found that the
tandem reaction proceeds in a highly regio- and diastereoselective
manner and creates simultaneously three adjacent stereocenters.7
The configuration of 2 was further confirmed by the X-ray
diffraction analysis of 2m (Fig. 1).8
Domino reactions are attractive to industry and research
laboratories because of their potential to save solvents, reagents,
time and energy.1,2 In our research to develop new domino
reactions using ethyl isocyanoacetate as Michael donors,3,4
two-carbon-tethered pyrrole/oxazole pairs4a and pyrrolizidines4b
were synthesized with a-alkenoyl ketene dithioacetals (Scheme 1,
box) as 1,5-dielectrophiles based on the [5+1] annulation
strategy.5 On the basis of these results4 combined with the
choice of suitable 1,5-dielectrophiles,2a,d,4,5 we envisioned that
compounds containing the indole core, for example tetrahydro-
indolones 2 and dihydroindolones 3, could be constructed through
a domino sequence involving an initial [5+1] annulation of the
1,5-dielectrophilic substrates 1 with activated methylene isocyanides,
followed by pyrrole ring formation (Scheme 1, EWG = electron-
withdrawing group). We report herein our preliminary results,
which have led to a practical method for the rapid construction
of these bicyclic systems (Scheme 1) in a single step.1
The tandem process mentioned above (Table 2) represents a
very simple and highly efficient methodology for the construction
of polyfunctionalized tetrahydroindolone derivatives from readily
available acyclic precursors under mild reaction conditions in an
In the present study, initially, the model reaction of 5-oxohepta-
2,6-dienoate 1a (1.0 mmol) with ethyl isocyanoacetate (1.2 mmol)
was examined to optimize the reaction conditions (Table 1).6
Indeed, the desired tetrahydroindolone 2a could be obtained in
high yields with either NaOH or t-BuOK as the catalyst in DMF
solvent at room temperature (entries 2–4). In comparison, K2CO3
was a less effective catalyst than NaOH or t-BuOK (entry 5).
Among the solvents tested, DMF seemed to be the best choice
although comparable results were produced with acetonitrile
as the solvent (entry 6). No desired product 2a was detectable
Department of Chemistry, Northeast Normal University,
Changchun 130024, China. E-mail: zhaoyl351@nenu.edu.cn;
Fax: 86 431 85099759; Tel: 86 431 85099759
w Electronic supplementary information (ESI) available: Detailed
experimental procedures and analytical data. CCDC 824546 (2m).
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c1cc14916d
Scheme 1 Domino reactions based on [5+1] annulation.
c
12316 Chem. Commun., 2011, 47, 12316–12318
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Table 1 Optimization of reaction conditions
atom-economic manner. It should be emphasized that the
above reactions define a practical method for the construction
of the bicyclic systems by combining the [5+1] annulation
and pyrrole ring formation into one pot.1,3–5,9,10 To test the
generality of this new approach for the construction of the
indole core, the reactions of tosylmethyl isocyanide (TosMIC)
with selected 5-oxohepta-2,6-dienoates 1 were further examined
(Table 3, Tos = p-toluenesulfonyl). However, under the
optimized reaction conditions (Table 1, entry 2), the reaction
of 1a (1.0 mmol) with TosMIC (1.2 mmol) was very sluggish.
In this case, the desired product, dihydroindolone 3a, was
isolated only in 8% yield along with the [3+2] cycloaddition
adduct 4a in 5% yield (entry 1).11 It was found that the desired
product 3a could be obtained in 53% yield as the major
product when the above reaction was performed in the
presence of 1.5 equivalents of NaOH (entry 2). After further
optimization of the reaction conditions, fortunately, 3a was
produced in 80% yield under otherwise identical conditions as
above but with DBU (1.5 eq, DBU = 1,8-diazabicyclo[5.4.0]undec-
7-ene) as the base (entry 3). Under similar conditions, dihydro-
indolones 3b, 3c and 3i were prepared in high yields from the
reactions of 1b, 1c and 1i with TosMIC, respectively (entries 4–6).
On the basis of the above results (Tables 2 and 3) together
with previous observations,4,5 the possible mechanisms for the
formation of tetrahydroindolones 2 and dihydroindolones
3 are proposed in Scheme 2. The overall process may involve: (1)
the diastereoselective double Michael addition ([5+1] annulation)
of ethyl isocyanoacetate (or TosMIC) to 1,5-dielectrophile
1 under basic conditions to provide cyclohexanone anion
intermediate A;4,5 (2) subsequent intramolecular cyclization of
the resulting anion onto the isocyanide carbon and protonation
followed by isomerization to furnish tetrahydroindolones
2 (Table 2);3 (3) in the cases of using TosMIC as the isocyanide
component, a further elimination of tosylic acid resulting in the
formation of dihydroindolones 3 (Table 3) in the presence of
excess base.11
Entry
Base (equiv.)
Solvent
t/h
2aa (%)
1aa (%)
1
2
3
4
5
6
7
8
NaOH (0.1)
NaOH (0.2)
NaOH (0.3)
t-BuOK (0.2)
K2CO3 (0.2)
NaOH (0.2)
NaOH (0.2)
NaOH (0.2)
DMF
DMF
DMF
DMF
DMF
CH3CN
CH2Cl2
Toluene
12
0.3
0.3
0.3
5
1
12
12
70
90
87
89
70
87
0
16
0
0
0
20
0
93
97
0
a
Isolated yield.
Table 2 Synthesis of tetrahydroindolones 2a
Entry
1
R
EWG
t/min
Yieldb (%)
1
2
3
4
1a
1b
1c
1d
1e
1f
1g
1h
1i
4-ClC6H4
C6H5
CO2Bun
CO2Bun
CO2Bun
CO2Bun
CO2Bun
CO2Bun
CO2Bun
CO2Bun
CO2Bun
CO2Bun
CO2Bun
CO2Et
18
18
20
18
18
60
30
40
30
30
40
20
30
2a (90)
2b (87)
2c (80)
2d (84)
2e (90)
2f (75)
2g (91)
2h (83)
2i (85)
2j (89)
2k (74)
2l (88)
2m (83)
4-MeOC6H4
2-ClC6H4
4-BrC6H4
4-NO2C6H4
4-MeC6H4
3,4-O2CH2C6H3
2-Furyl
2-Thienyl
PhCHQCH
4-ClC6H4
4-ClC6H4
5
6c
7
8
In conclusion, we have developed a new strategy for the
rapid and highly efficient synthesis of polysubstituted dihydro-
indolone and tetrahydroindolone derivatives. The domino
reaction combines [5+1] annulation with pyrrole ring formation
and allows the construction of the fused bicyclic systems in a
single step from the easily available acyclic substrates in high to
9c
10
11d
12
13
1j
1k
1l
1m
CN
a
Reaction conditions: 1 (1.0 mmol), isocyanoacetate (1.2 mmol),
b
NaOH (0.2 mmol), DMF (4.0 mL), room temperature. Isolated
c
d
yield. 0.3 equiv. NaOH was used. 1.0 equiv. NaOH was used in
CH3CN (4.0 mL) instead of DMF.
Table 3 Synthesis of dihydroindolones 3
Entry
1
Base (equiv.)
t/h
Yielda (%)
1b
2
3
4
5
6
1a
1a
1a
1b
1c
1i
NaOH (0.2)
NaOH (1.5)
DBU (1.5)
DBU (1.5)
DBU (1.5)
DBU (1.5)
12
0.5
1
1
1
3a (8)
4a (5)
4a (29)
4a (0)
4b (0)
4c (0)
4i (0)
3a (53)
3a (80)
3b (78)
3c (75)
3i (83)
3
a
b
Isolated yield. 1a was recovered in 65% yield.
Fig. 1 ORTEP drawing of 2m.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 12316–12318 12317

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2 (a) X. Bi, D. Dong, Q. Liu, W. Pan, L. Zhao and B. Li, J. Am.
Chem. Soc., 2005, 127, 4578; (b) Z. Zhang, Q. Zhang, S. Sun,
T. Xiong and Q. Liu, Angew. Chem., Int. Ed., 2007, 46, 1726;
(c) J. Meng, Y.-L. Zhao, C.-Q. Ren, Y. Li, Z. Li and Q. Liu,
Chem.–Eur. J., 2009, 15, 1830; (d) L. Zhang, X. Xu, J. Tan, L. Pan,
W. Xia and Q. Liu, Chem. Commun., 2010, 46, 3357;
(e) Y.-L. Zhao, S.-C. Yang, C.-H. Di, X.-D. Han and Q. Liu,
Chem. Commun., 2010, 46, 7614.
3 For a review on the synthetic utility of isocyanoacetate derivatives,
see: A. V. Gulevich, A. G. Zhdanko, R. V. A. Orru and
V. G. Nenajdenko, Chem. Rev., 2010, 110, 5235.
4 (a) Y. Li, X. Xu, J. Tan, C. Xia, D. Zhang and Q. Liu, J. Am.
Chem. Soc., 2011, 133, 1775; (b) J. Tan, X. Xu, L. Zhang, Y. Li and
Q. Liu, Angew. Chem., Int. Ed., 2009, 48, 2868.
5 For a review on the [5+1]-annulation strategy, see: (a) L. Pan and
Q. Liu, Synlett, 2011, 1073; (b) D. Zhang, X. Xu, J. Tan and
Q. Liu, Synlett, 2010, 917; (c) A. C. Silvanus, B. J. Groombridge,
B. I. Andrews, G. Kociok-Kohn and D. R. Carbery, J. Org.
¨
Chem., 2010, 75, 7491; (d) L.-L. Wang, L. Peng, J.-F. Bai,
L.-N. Jia, X.-Y. Luo, Q.-C. Huang, X.-Y. Xu and L.-X. Wang,
Chem. Commun., 2011, 47, 5593.
6 Substrates 1a–m were easily prepared in high yields by Pd(OAc)2-
catalyzed CꢀC coupling reaction of a-iodo-a-cinnamoyl ketene
dithioacetals with terminal alkenes, see ESIw.
Scheme 2 Proposed mechanisms for formation of 2 and 3.
excellent yields under mild metal-free conditions. This strategy
exhibits a highly efficient use of the reactive sites of the
substrates and expands the synthetic potential of the [5+1]
annulation. Further studies are in progress.
Financial support of this research by the National Natural
Sciences Foundation of China (20972026 and 21172032), the
Department of Science and Technology of Jilin Province
(20080548) is greatly acknowledged.
7 In these reactions (Table 2), no diastereomers of 2a–m were
detected.
8 Crystal data for 2m: C21H19ClN2O3S2, white crystal, M = 446.82,
monoclinic, space group C2/c, a = 40.139(6), b = 9.4559(13), c =
11.1246(14) A, b = 100.587(2)1, V = 4150.5(10) A3, Z = 8, T =
293(2) K, F000 = 1856, R1 = 0.0486, wR2 = 0.1252. CCDC
824546.
9 For a recent review on isocyanides in the synthesis of nitrogen
heterocycles, see: A. V. Lygin and A. de Meijere, Angew. Chem.,
Int. Ed., 2010, 49, 9094.
Notes and references
z General procedure for the synthesis of 2 (taking 2a as an example):
To a solution of 5-oxohepta-2,6-dienoate 1a (1.0 mmol, 408 mg) and
ethyl isocyanoacetate (1.2 mmol, 0.13 ml) in DMF (4.0 ml) was added
NaOH (0.2 mmol, 8 mg) in one portion. The reaction mixture was
stirred for 18 min at room temperature. After 1a was consumed
(monitored by TLC), the reaction mixture was poured into ice-water
(45 mL) under stirring. The precipitated solid was collected by
filtration, and dried in vacuo to afford the crude product, which
was purified by flash chromatography (silica gel, petroleum ether–
acetone = 5 : 1, v/v) to give 2a (469 mg, 90%) as a white solid.
10 For the synthesis of indole rings, see: (a) G. W. Gribble, J. Chem.
Soc., Perkin Trans. 1, 2000, 1045; (b) C. S. Schindler, S. Diethelm
and E. M. Carreira, Angew. Chem., Int. Ed., 2009, 48, 6296;
(c) Y. Zeng, D. S. Reddy, E. Hirt and J. Aube, Org. Lett., 2004,
´
6, 4993; (d) M. Mori, K. Hori, M. Akashi, M. Hori, Y. Sato and
M. Nishida, Angew. Chem., Int. Ed., 1998, 37, 636; (e) J. H. Rigby
and W. Dong, Org. Lett., 2000, 2, 1673; (f) T. Kamikubo and
K. Ogasawara, Chem. Commun., 1998, 783; (g) M. Mori,
S. Kuroda, C.-S. Zhang and Y. Sato, J. Org. Chem., 1997,
62, 3263; (h) A. Padwa, M. A. Brodney, M. Dimitroff, B. Liu
and T. Wu, J. Org. Chem., 2001, 66, 3119.
1 For recent reviews on domino reactions, see: (a) L. F. Tietze,
P. H. Bell and G. Brasche, Domino Reactions in Organic Synthesis,
Wiley-VCH, Weinheim, 2006; (b) D. Enders, C. Grondal and
M. R. M. Huttl, Angew. Chem., Int. Ed., 2007, 46, 1570;
¨
(c) K. C. Nicolaou, T. Montagnon and S. A. Snyder, Chem.
Commun., 2003, 551; (d) A. Padwa and S. K. Bur, Tetrahedron,
2007, 63, 5341.
11 For a review on Van Leusen pyrrole synthesis (cyclization between
a Michael acceptor and TosMIC), see: D. Van Leusen and
A. M. van Leusen, Org. React., 2001, 57, 417.
c
12318 Chem. Commun., 2011, 47, 12316–12318
This journal is The Royal Society of Chemistry 2011