Synthesis of Cyclopentadiindolyl Spirooxindoles via Palladium-catalyzed Intramolecular Oxidative Indole-Indole Coupling Reaction

Full text of DOI:10.1002/bkcs.11432

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DOI: 10.1002/bkcs.11432
BULLETIN OF THE
D. Y. Seo et al.
KOREAN CHEMICAL SOCIETY
Synthesis of Cyclopentadiindolyl Spirooxindoles via Palladium-
catalyzed Intramolecular Oxidative Indole-Indole Coupling Reaction
*
Da Young Seo, Gieun Kim, Hwi Yul Jo, and Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju
500-757, South Korea. *E-mail: kimjn@chonnam.ac.kr
Received January 5, 2018, Accepted February 13, 2018
Keywords: Spirooxindoles, Cyclopentadiindole, Oxidative coupling, Palladium
Spirooxindoles exist in a huge number of natural substances
and pharmaceutically interesting compounds.1 Thus, tremen-
dous efforts have been devoted to development of efficient
protocols to access these important motifs over the past
years.1–3 Recently, we reported the synthesis of various spir-
ooxindoles2 including spiroindeno[1,2-b]indolyloxindoles.3
The spiroindeno[1,2-b]indolyloxindoles were synthesized
from isatin and 2-arylindole in the presence of TiCl4 via
sequential inter- and intramolecular Friedel-Crafts reactions,
as shown in Scheme 1.3 Structurally similar spirocyclopenta
[b]indolyl-2-oxindoles have been synthesized by Shi and co-
workers from 3-indolyl-2-oxindoles and 3-vinylindoles via
chiral phosphoric acid-catalyzed [3 + 2] cyclization
(Scheme 1).4a–c Holz and co-workers also reported TfOH-
catalyzed synthesis of spirocyclopenta[b]indolyl-2-oxindoles
from isatin, indole, and styrene.4d In addition, Chen and co-
workers reported the synthesis of similar polycyclic spiroox-
indoles by [3 + 2] annulations of Morita-Baylis-Hillman
carbonates and 3-nitro-7-azaindoles.4e In these respects, we
examined the synthesis of spirocyclopenta[2,1-b;3,4-b’]diin-
dolyl-2-oxindole derivative 2a by oxidative coupling reac-
tion of 3,3-diindolyl-2-oxindole 1a, as shown in Scheme 1.
Similar intramolecular oxidative indole-indole coupling
reactions have been carried out under various reaction
conditions5–9 including 2,3-dichloro-5,6-dicyanobenzoqui
none (DDQ)/p-TsOH,5 DDQ/CF3COOH,6 K3Fe(CN)6,7
Pd(OAc)2,8 and other methods.9 The reaction of 1a under
the reported intramolecular oxidative coupling reaction
conditions employing DDQ/p-TsOH or DDQ/CF3COOH
afforded N,N-dimethylisoindigo in low yields (5–25%),
unexpectedly,10 as shown in Scheme 2.
We failed to obtain the desired compound 2a in any trace
amount. The reaction of 1a in the presence of K3Fe(CN)6
in alkaline solution also did not produce 2a. Thus, we
examined the synthesis of 2a by palladium-catalyzed oxida-
tive arene-arene coupling reaction conditions.8,11
As shown in Table 1, the reaction of 1a in the presence of
Pd(OAc)2, Cu(OAc)2, and K2CO3 in N,N-dimethylacetamide
ꢀ
(DMA) at 100 C afforded 2a in low yield (37%) for 18 h
(entry 1).8a When we elevated the reaction temperature to
140 ꢀC, the yield of 2a decreased (entry 2).
To our delight, 2a was obtained in good yield (88%)
when we used AgOAc as an oxidant in pivalic acid
(PivOH, entry 3) in short time (3 h).11a–d The use of
Cs2CO3 (entry 4) afforded 2a in better yield (90%). The
yield was slightly lower by using cesium pivalate (entry 5),
and the yield decreased slightly in the absence of a base
(entry 6). With lesser amount of AgOAc (2.0 equiv), the
yield decreased slightly (entry 7). When we carried out the
reaction under O2 balloon atmosphere, the yield was also
reasonable (entry 8). However, the reaction was ineffective
when we replaced pivalic acid with AcOH (entry 9), tolu-
ene (entry 10), and DMF (entry 11). The use of Pd(TFA)2
(entry 12) afforded 2a in good yield (90%). The use of
PdCl2 (entry 13) and PdCl2(PPh3)2 (entry 14) were less
effective. Among the examined conditions, we selected the
condition of entry 4 based on the yield and clearness of the
reaction.
Encouraged by the successful result, 3,3-diindolyl-2-
oxindoles 1a-1j were prepared from N-methylisatins and
indoles according to the reported methods.12 Various
Scheme 1. Synthesis of spirooxindoles bearing cyclopenta[b]indo-
lyl moiety.
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Scheme 2. Synthesis of spirooxindole 2a.
Table 1. Optimization of reaction conditions for the synthesis of 2a.a
Entry
Catalyst
Oxidant
Base
Solvent
Temp (ꢀC)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
Pd(OAc)2 (10 mol%)
Pd(OAc)2 (10 mol%)
Pd(OAc)2 (10 mol%)
Pd(OAc)2 (10 mol%)
Pd(OAc)2 (10 mol%)
Pd(OAc)2 (10 mol%)
Pd(OAc)2 (10 mol%)
Pd(OAc)2 (10 mol%)
Pd(OAc)2 (10 mol%)
Pd(OAc)2 (10 mol%)
Pd(OAc)2 (10 mol%)
Pd(TFA)2 (5 mol%)
PdCl2 (5 mol%)
Cu(OAc)2 (3.0 equiv)
Cu(OAc)2 (3.0 equiv)
AgOAc (3.0 equiv)
AgOAc (3.0 equiv)
AgOAc (3.0 equiv)
AgOAc (3.0 equiv)
AgOAc (2.0 equiv)
O2 balloon
AgOAc (3.0 equiv)
AgOAc (3.0 equiv)
AgOAc (3.0 equiv)
AgOAc (3.0 equiv)
AgOAc (3.0 equiv)
AgOAc (3.0 equiv)
K2CO3 (1.0 equiv)
K2CO3 (1.0 equiv)
K2CO3 (1.0 equiv)
Cs2CO3 (1.0 equiv)
CsOPiv (3.0 equiv)
no base
K2CO3 (1.0 equiv)
K2CO3 (1.0 equiv)
K2CO3 (1.0 equiv)
K2CO3 (1.0 equiv)
K2CO3 (1.0 equiv)
K2CO3 (1.0 equiv)
K2CO3 (1.0 equiv)
K2CO3 (1.0 equiv)
DMA
DMA
100
140
120
120
120
120
120
120
reflux
reflux
120
120
120
120
18
18
3
3
3
3
3
3
3
18
18
3
3
3
37
25
88
90
78
84
86
84
<5b
<5c
<5c
90
70
76
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
AcOH
toluene
DMF
9
10
11
12
13
14
a
PivOH
PivOH
PivOH
PdCl2(PPh3)2 (5 mol%)
Substrate 1a (0.5 mmol).
Decomposition of 1a.
Most of 1a was remained.
b
c
Table 2. Synthesis of cyclopentadiindolyl spirooxindoles.
xx
aThe reaction of 1j was carried out at 80 ꢀC (5 h).
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Scheme 4. Failed substrates 1n and 1o.
however, somewhat longer reaction time (12 h) was
required for the completion. Similarly, the reactions of 1l
and 1m afforded 2l (77%) and 2m (80%) in good yields.
The reaction might proceed via an initial electrophilic palla-
dation toward more reactive indole moiety and a following
intramolecular electrophilic palladation to benzene ring.
The oxidative coupling reaction of NH derivative 1n
failed, as we2h and other groups have already observed.13
The reason might be the formation of palladium interme-
diate III,14 as shown in Scheme 4, instead of electrophilic
palladation at the indole ring. Although the synthesis of
spirofluorenyl-2-oxindoles has been reported by other
methods,15 we examined the synthesis of 2o from 1o by
using our method. However, the reaction failed presumably
due to less favorable electrophilic palladation at the ben-
zene ring even at high temperature (160 ꢀC).
Figure 1. Possible reaction pathway.
cyclopentadiindolyl spirooxindoles 2a-2j were synthesized
under the optimized reaction condition (entry 4 in Table 1),
and the results are summarized in Table 2. The reactions of
5-chloro-, 5-methyl-, 5-methoxy-, 6-chloro-, and 5,7-
dimethylisatin derivatives 1b-1f afforded 2b-2f in good
yields (82–89%). The reactions of 5-methyl- and
5-methoxyindole derivatives 1g-1j also afforded 2g-2j in
good to moderate yields (58–87%). When the reaction of
ꢀ
dimethoxy derivative 1j was carried out at 120 C, severe
decomposition was observed. Thus, the reaction 1j was car-
ried out at 80 ꢀC for a long time (5 h).
The reaction mechanism is proposed in Figure 1. An
electrophilic palladation of 1a with Pd(OAc)2 or Pd(OPiv)2
to form an intermediate I. A following intramolecular elec-
trophilic palladation to form palladacycle II, and a follow-
ing reductive elimination of palladium affords 2a. The
palladium is oxidized by AgOAc to generate a PdII species
to finish the catalytic cycle.
In summary, various cyclopentadiindolyl spirooxindoles
were synthesized in good yields by palladium-catalyzed
intramolecular oxidative indole-indole coupling reaction.
The coupling reaction could be also applied for the synthe-
sis of spiroindeno[1,2-b]indolyloxindoles.
In order to extend scope of the reaction, we examined
the synthesis of spiroindeno[1,2-b]indolyloxindole 2k,3 as
shown in Scheme 3. The required starting material 1k was
prepared from N-methylisatin by sequential introduction of
phenyl group with phenylmagnesium bromide (83%) and
N-methylindole in the presence of p-TsOH (88%).12 The
oxidative coupling reaction of 1k was carried out under the
standard condition to obtain 2k in good yield (79%);
Experimental
Typical synthetic procedure of 2a. A mixture of 1a
(203 mg, 0.5 mmol), Pd(OAc)2 (12 mg, 10 mol%), AgOAc
(250 mg, 3.0 equiv), and Cs2CO3 (164 mg, 1.0 equiv) in
PivOH (3.0 mL) was heated to 120 C for 3 h under N2
balloon atmosphere. The reaction mixture was diluted with
ꢀ
Scheme 3. Synthesis of 2k-2m.
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3. J. W. Lim, H. R. Moon, S. Y. Kim, J. N. Kim, Tetrahedron
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CH2Cl2 and filtered through a pad of Celite and washed
with CH2Cl2. After usual aqueous extractive workup and
column chromatographic purification process (n-hexane/
EtOAc, 2:1), compound 2a was isolated as a pale yellow
solid, 182 mg (90%). Other compounds were synthesized
similarly, and the selected spectroscopic data of 2a are as
follows.
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ꢀ
Compound 2a: 90%; pale yellow solid, mp 320–322 C;
IR (KBr) 1706, 1609, 1467, 1328 cm−1; 1H NMR
(DMSO‑d6 + CDCl3, 500 MHz) δ 3.40 (s, 3H), 4.19 (s, 6H),
6.62 (d, J = 7.4 Hz, 1H), 6.74 (d, J = 7.8 Hz, 2H), 6.81–6.91
(m, 3H), 7.05 (t, J = 7.5 Hz, 2H), 7.23 (d, J = 7.7 Hz, 1H),
7.33 (t, J = 7.7 Hz, 1H), 7.49 (d, J = 8.3 Hz, 2H); 13C NMR
(DMSO‑d6 + CDCl3, 125 MHz) δ 27.2, 33.3, 54.9, 109.1,
111.2, 116.7, 120.5, 121.0, 122.79, 122.82, 123.1, 125.6,
128.7, 129.4, 139.7, 140.7, 144.9, 175.6; ESIMS m/z
404 [M + H]+. Anal. Calcd for C27H21N3O: C, 80.37; H,
5.25; N, 10.41. Found: C, 80.19; H, 5.54; N, 10.17.
Acknowledgments. This work was supported by National
Research Foundation of Korea (NRF) grant funded by the
Korea government (NRF-2015R1A4A1041036). Spectro-
scopic data were obtained from the Korea Basic Science
Institute, Gwangju branch.
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Supporting Information. Additional supporting informa-
tion is available in the online version of this article.
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