Construction of indoloquinolinones via Pd(II)-catalyzed tandem CC/CN bond formation: Application to the total synthesis of isocryptolepine

Article abstract of DOI:10.1016/j.tetlet.2014.11.008

Construction of indoloquinolinone skeleton via Pd-catalyzed tandem CC/CN bond formation has been achieved in moderate to good yields. The method was applied toward the total synthesis of the bioactive natural product isocryptolepine in good overall yields.

Full text of DOI:10.1016/j.tetlet.2014.11.008

Tetrahedron Letters 55 (2014) 7114–7117
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Construction of indoloquinolinones via Pd(II)-catalyzed tandem
CAC/CAN bond formation: application to the total synthesis
of isocryptolepine
⇑
⇑
Xuebing Chen, Peng Sun, Jinyi Xu, Xiaoming Wu, Lingyi Kong, Hequan Yao , Aijun Lin
State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Construction of indoloquinolinone skeleton via Pd-catalyzed tandem CAC/CAN bond formation has been
achieved in moderate to good yields. The method was applied toward the total synthesis of the bioactive
natural product isocryptolepine in good overall yields.
Received 27 August 2014
Revised 28 October 2014
Accepted 3 November 2014
Available online 6 November 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Indoloquinolinone
Tandem
Pd(II)-catalyzed
CAC/CAN bond formation
Isocryptolepine
O
Indole-containing polycyclic compounds are widely found in
natural products and many are clinically used as therapeutic drugs
(Fig. 1).1 Reserpine, an effective hypotensive agent, exists in many
species of Rauvolfia Linn.2 Fumitremorgin C is described as a
potent ABCG2/BCRP inhibitor that reverses multidrug resistance.3
Indoloquinolinones are found in numerous versatile synthetic mol-
ecules, many of which exhibit a wide range of biological activities
(Fig. 1A1 and A2).4 Moreover, the indoloquinolinone structure is
always employed as an important building block to the synthesis
of natural products, such as isocryptolepine.5 Several methods
have been reported for the construction of the indoloquinolinone
skeleton.6
N
MeO
OMe
OMe
NH
R
MeO
N
H
H
H
N
H
H
MeOOC
O
O
OMe
Indoloquinolinones
A1 R = H
Reserpine
O
O
A2 R = Cl
H
N
N
H
Me
N
MeO
N
H
N
Me
Me
In the past few years, transition-metal catalyzed tandem CAC/
CAN bond coupling reactions have been reported for the formation
of nitrogenous compounds.7 Among them, rhodium or ruthenium
catalyzed CAH/NAH cyclization reactions were the mainstream,
while most of the reported cases were limited to the substituted
phenyl derivatives with alkynes or diazo esters.8 Recently, the
cyclization reactions were extended to indole ring derivatives. In
2010, Jiao’s group reported a Pd(II)-catalyzed direct dehydrogena-
tive annulation of indolecarboxamides with internal alkynes via
CAH/NAH bond cleavage (Scheme 1a).9 In 2014, Cui and coworkers
Isocryptolepine
Fumitremorgin
C
Figure 1. Examples of bioactive indole-containing polycyclic compounds.
developed a Rh(III)-catalyzed tandem coupling of N-methoxy-1H-
indole-1-carboxamide and aryl boronic acids (Scheme 1b).10 To
the best of our knowledge, no example of the construction of
indoloquinolinones
from
N-methoxy-1-methyl-1H-indole-3-
carboxamide has been reported. Continuing our interest in palla-
dium-catalyzed CAH functionalization of indole ring,11 herein,
we will report the Pd(II)-catalyzed tandem CAC/CAN bond
formation for the construction of indoloquinolinones and apply
our approach toward the total synthesis of the bioactive natural
alkaloid isocryptolepine (Scheme 1c).
⇑
Corresponding authors. Tel.: +86 25 83271042; fax: +86 25 83301606.
E-mail addresses: hyao@cpu.edu.cn (H. Yao), ajlin@cpu.edu.cn (A. Lin).
http://dx.doi.org/10.1016/j.tetlet.2014.11.008
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

X. Chen et al. / Tetrahedron Letters 55 (2014) 7114–7117
7115
(a) Jiao's work
N
shortened to 6 h, the reaction could also be completed smoothly
and promoted the yield to 55% (entry 9). We found that the strong
acidity of solvent leads to the decomposition of the starting mate-
rial at high temperatures,13 then we tested our reaction in mixed
solvents (entries 10–13). The results showed that the yield of 3a
increased to 83% when the reaction was carried out in AcOH/
DMA (3:1) under argon atmosphere (entry 13). Replacing Pd(OAc)2
with other commonly used Pd(II) catalysts gave unsatisfactory
results (entries 14 and 15). Without PPh3, the yield decreased to
20% (entry 16). When phenyl bromide was used instead of phenyl
iodide, no product was afforded (entry 17).
With the optimized conditions in hand, we then focused on the
substrate scope and generality of the reaction. To our delight, most
substrates in Table 2 could react smoothly to provide the desired
products 3a–3o in moderate to good yields. The C5-position of
the indoles bearing the methoxyl, methyl, or bromine group affor-
ded 3b, 3c, and 3d in 67%, 64%, and 58% yield. The yield of 3e
decreased to 46% due to steric hindrance. Unfortunately, the sub-
strate bearing –NO2 at the C5-position could not generate the
Ph
O
Ph
R
Ph
Pd(OAc)2 (10 mol %)
TBAB (1.0 equiv)
H
N
N
R
N
Me
DMA, air, 50 o
C
Me
O
Ph
(b) Cui's work
B(OH)2
[Cp*RhCl2]2 (2 mol %)
N
Ag2O (4 equiv)
MeOH, 60 oC
N
O
NHOMe
O
O
N
OMe
(c) This work
Pd(OAc)2 (10 mol %)
PPh3 (20 mol %)
Ag2CO3 (2 equiv)
O
I
OMe
N
NHOMe
N
Me
N
Me
AcOH/DMA (3:1)
Ar, 100 oC, 6 h
Scheme 1. Transition-metal catalyzed tandem CAC/CAN bond formation.
Our initial investigation focused on the coupling of N-methoxy-
1-methyl-1H-indole-3-carboxamide (1a) with phenyl iodide (2a),
the results were summarized in Table 1. When 1a was treated with
10 mol % Pd(OAc)2, 2 equiv of Ag2O in AcOH at 100 °C for 12 h, we
were delighted to find that the desired product 3a was afforded in
13% yield with the decomposition of 1a (Table 1, entry 1). Subse-
quent screening of oxidants suggested that the silver salts were
indispensable. Other oxidants such as K2S2O8, PhI(OAc)2, Cu(OAc)2
were all ineffective (Table 1, entries 2–4). Phosphine ligands are
usually employed to promote the palladium-catalyzed CAH activa-
tion reactions,12 then we added 20 mol % phosphine ligands to the
reaction system. Fortunately, the use of PPh3 or John Phos could
increase the yield of the desired product 3a to 32% and 20%, respec-
tively (entries 5 and 6). Then, some silver salts were screened, and
Ag2CO3 was the best choice (entry 8). When the reaction time was
Table 2
Investigation on the substrate scopea
Pd(OAc)2 (10 mol %)
O
O
I
PPh3 (20 mol %)
Ag2CO3 (2 equiv)
OMe
R2
N
R3
NHOMe
R3
N
N
AcOH/DMA (3:1)
Ar, 100 oC, 6 h
R1
R1
R2
2
1
3
O
O
O
OMe
MeO
OMe
N
Me
OMe
N
N
N
Me
N
N
Me
Me
3b (67%)
3a (71%)
3c (64%)
O
O
O
OMe
OMe
Br
OMe
N
N
N
N
N
N
N
Table 1
N
Me
N
Me Me
N
Me
Screening of reaction conditionsa
Me
O
3e (46%)b
3f (50%)
O
3d (58%)
I
OMe
NHOMe
N
conditions
O
O
O
MeO
OMe
OMe
F
OMe
Cl
N
N
N
N
Me
Me
N
Me
N
Me
N
Me
1a
2a
3a
Me
3g (62%)b
3h (45%)b
3i (73%)b
Entry
Catalyst
Ligand
Oxidant
Solvent (3:1)
Yieldb (%)
1
2
3
4
5
6
7
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
None
None
None
None
PPh3
John Phos
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
None
PPh3
Ag2O
K2S2O8
PhI(OAc)2
Cu(OAc)2
Ag2O
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
13d
Trace
Trace
Trace
32
20
36
50
55
O
O
O
OMe
Br
OMe
MeO
OMe
N
N
N
Bn
N
Me
N
Bn
Me
3j (82%)b
3k (67%)
3l (62%)
Ag2O
AgOAc
O
O
O
8
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3/Ar
Ag2CO3/Ar
Ag2CO3/Ar
Ag2CO3/Ar
Ag2CO3/Ar
Br
OMe
9c
AcOH
Br
OMe
OMe
N
N
10c
11c
12c
13c
14c
15c
16c
17c
AcOH/Tol
AcOH/DMF
AcOH/DMSO
AcOH/DMA
AcOH/DMA
AcOH/DMA
AcOH/DMA
AcOH/DMA
49
58
53
N
Bn
N
Bn
N
Bn
Me
Me
83(71)d
29
3o (64%)b
3n (66%)b
3m (64%)
O
O
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
36
OBn
Me
N
20
0e
N
N
Bn
Bn
a
Reaction conditions: Catalyst (10 mol %), Ligand (20 mol %), 1a (0.5 mmol), 2a
b
3p
3q
(0%)
(70%)
(1.5 mmol) in AcOH (3 mL) at 100 °C for 12 h.
b
1H NMR yields using dibromomethane (d = 4.80) as an internal standard.
The reaction time was 6 h.
Isolated yields.
Phenyl bromide was used.
a
Reaction conditions:
10 mol %), PPh3 (0.1 mmol, 20 mol %), Ag2CO3 (1 mmol, 2 equiv) in AcOH (3 mL)/
DMA (1 mL) under argon atmosphere at 100 °C for 6 h. Isolated yields.
1 (0.5 mmol), 2 (1.5 mmol), Pd(OAc)2 (0.05 mmol,
c
d
e
b
110 °C.

7116
X. Chen et al. / Tetrahedron Letters 55 (2014) 7114–7117
desired product. Aryl iodides bearing the methyl group offered 3f,
3i, and 3j in 50%, 73%, and 82% yield, respectively. Aryl iodides
bearing the halogen group, such as –F and –Cl gave 3g and 3h in
62% and 45% yields. N-benzyl substituted indoles could also be
compatible in the reaction and offered 3k–3o in 62–67% yields.
Replacing the methoxy group with the benzyloxy group on the
amide yielded the product 3p in 70%, while N-methyl-1-methyl-
1H-indole-3-carboxamide could not offer the corresponding prod-
uct 3q under optimized conditions.
mechanism for our tandem CAC/CAN bond formation reaction as
illustrated in Figure 2. The reaction of 1a with Pd(OAc)2 formed
the five-membered palladacycle A, which was oxidized to the PdIV
species B by phenyl iodide.14 Reductive elimination gave arylated
product 4. Subsequent deprotonation of the NAH and CAH activa-
tion of 4 led to the seven-membered palladacycle C. Reductive
elimination of C afforded 3a and a Pd0 species, which was oxidized
by Ag2CO3 to regenerate the active PdII species for the next cata-
lytic cycle (Fig. 2).
During the screening of the reaction temperature, we observed
that when the reaction was carried out at 80 °C, the reaction fur-
nished 3a in 9% yield with 4 in 34% yield (Scheme 2). This phenom-
enon suggested that 3a may be generated from 4. Under optimized
reaction conditions, the 3a could be obtained in 86% yield from 4
(Scheme 2, I). Without PPh3, a decreased yield (66% vs 86%) was
achieved (Scheme 2, II). Without Pd(OAc)2 and PPh3, only a trace
product was monitored (Scheme 2, III). Without any catalysts
and additives, no reaction occurred (Scheme 2, IV). Based on these
results and previous reports,13,8a,8d here, we proposed a plausible
Application of this method was demonstrated with the synthe-
sis of the bioactive natural alkaloid isocryptolepine 6, which has
been isolated in 1995 from the West African plant Cryptolepis
sanguinolenta. Compound 3k was an appropriate platform for con-
version into isocryptolepine in two additional steps as shown in
Scheme 3. The removal of methoxyl, N-methylation of amide and
N-debenzylation of 3k could be completed in one pot to offer com-
pound 5 in 77% yield.6a,8f Reduction of 5 with NaBH4 and BF3ÁEt2O
furnished isocryptolepine 6 in 84% yield smoothly (Scheme 3).
Compared with other methods,15 our strategy represented the
Pd(OAc)2 (10 mol %)
PPh3 (20 mol %)
Ag2CO3 (2 equiv)
O
O
OMe
I
NHOMe
N
H
3a
N
Me
1a
N
Me
AcOH/DMA (3:1)
Ar, 80 oC, 6 h
2a
4
9%
(34%)
optimized conditions
3a (86%)
(,)
O
optimized conditions
3a
(66%)
NHOMe
(
)
without PPh3 ,,
N
Me
4
Ag2CO3 (2 eq)
3a
3a
(trace)
(N.R)
no Pd and no PPh3
(,,,)
(
)
none ,9
Scheme 2. Studies on reaction mechanism.
O
NHOMe
N
Me
1a
AcOH
O
AgI, H2O, CO2
Pd(OAc)2
OMe
N
O
Pd Ln
N
Me
C
N
Pd
Ln
OMe
Ag2CO3, AcOH
O
N
AcOH
O
NHOMe
Me
A
N
Me
4
PhI
2a
N
OMe
Ag2CO3
Pd
N
Me
Pd(OAc)2
I
Ag, H2O, CO2
O
Ph
B
OMe
N
N
Me
3a
Figure 2. Plausible reaction mechanism. Ln = Ligand.

X. Chen et al. / Tetrahedron Letters 55 (2014) 7114–7117
7117
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shortest and cheapest route to prepare isocryptolepine in 43%
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Generous financial support from the National Natural Science
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