Palladium-Catalyzed Dearomative Allylic Alkylation of Indoles with Alkynes to Synthesize Indolenines with C3-Quarternary Centers

Article abstract of DOI:10.1021/acs.orglett.6b01947

A palladium-catalyzed dearomative allylic alkylation of indoles with alkynes to construct indolenines with C3-quarternary centers was reported. The in situ formed arylallene intermediate omitted the need to install leaving groups on the allylic compounds and employ extra oxidants to oxidize the allylic C-H bonds. The reaction exhibited good functional group tolerance and high atom economy. Moreover, the reaction was further expanded to synthesize pyrroloindolines and furanoindolines.

Full text of DOI:10.1021/acs.orglett.6b01947

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Dearomative Allylic Alkylation of Indoles with
Alkynes To Synthesize Indolenines with C3-Quarternary Centers
Shang Gao,† Zijun Wu,† Xinxin Fang, Aijun Lin,* and Hequan Yao*
State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, School of Pharmacy, China
Pharmaceutical University, Nanjing 210009, P. R. China
S
* Supporting Information
ABSTRACT: A palladium-catalyzed dearomative allylic alky-
lation of indoles with alkynes to construct indolenines with C3-
quarternary centers was reported. The in situ formed arylallene
intermediate omitted the need to install leaving groups on the
allylic compounds and employ extra oxidants to oxidize the
allylic C−H bonds. The reaction exhibited good functional
group tolerance and high atom economy. Moreover, the reaction was further expanded to synthesize pyrroloindolines and
furanoindolines.
ndolenine motifs and their derivatives are widely distributed
in natural products and bioactive compounds,1 such as
Scheme 1. Strategies for Dearomative Allylic Alkylation of
Indoles
I
potent monoamine oxidase inhibitor strictamine,2 ( )-chartel-
line C,3 analgesic agent (+)-koumine,4 and (−)-tubifoline5
(Figure 1). To construct the indolenine skeletons, the
Ag2CO3 as an extra oxidant (Scheme 1c).9 Despite the fact that
the aforementioned methods were very interesting to achieve
the allylic alkylation of indoles at the C3-position, the
development of a more efficient method with facile accessible
substrates and higher atom economy is still desirable.
π-Allylmetal complexes are very important intermediates in
the transition-metal-catalyzed allylic alkylation reaction
(namely, the Tsuji−Trost-type reaction).10 From an atom-
and redox-economic point of view, arylpropynes were ideal
precursors to form the π-allylmetal complex, and much research
has been reported to construct C−C bonds and C−X (X = N,
O, S) bonds.11 To the best of our knowledge, the dearomative
allylic alkylation of indoles at the C3-position with arylpropynes
has never been reported. As a continuation of our previous
work on the transition-metal-catalyzed dearomative reactions of
Figure 1. Selected natural products containing indolenine cores.
transition-metal-catalyzed dearomative reaction of indoles has
been studied intensively over the past few years.6 However, the
dearomative allylic alkylation of indoles at the C3-position
represents a significant challenge due to the potential N1/C3
and branch/linear selectivity. To date, three general strategies
have been developed as shown in Scheme 1, among which Pd-,
Ir-, and Cu-based catalytic systems with allylic agents have been
abundantly documented (Scheme 1a).7 The introduction of
leaving groups such as ester, halide, or hydroxyl to the allylic
compounds was necessary to complete the transformation.
Bandini’s group reported the allylic alkylation reactions
between indoles and electron-rich allenamides with Brønsted
acids or gold as catalysts (Scheme 1b).8 Very recently, Yang’s
group developed a palladium-catalyzed dearomative allylic
alkylation of indoles with allylbenzene through an C−H
activation/dearomatization process employing a stoichiometric
Received: July 5, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01947
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Organic Letters
Letter
indoles,12 herein we report a palladium-catalyzed dearomative
allylic alkylation of indoles with alkynes to construct
indolenines with C3-quarternary centers.
a,b
Scheme 2. Substrate Scope of Indoles
We commenced our reaction with 5-methoxyl-2,3-dimethy-
lindole 1a and phenylpropyne 2a as substrates and benzoic acid
as an additive in 2.0 mL of anhydrous toluene at 100 °C under
argon for 24 h as shown in Table 1. Screening of palladium
a,b
Table 1. Optimization of Reaction Conditions
entry
catalyst
Pd(PPh3)4
additive
PhCO2H
ligand
yield (%)
1
PPh3
PPh3
PPh3
PPh3
69
2
Pd/C
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
nr
3
Pd2(dba)3
Pd2(dba)3·CHCl3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
trace
nr
4
5
23
6
Ph3PO
dppp
dppm
Cy3P
tBu3P
Cy3P
Cy3P
Cy3P
Cy3P
Cy3P
Cy3P
Cy3P
Cy3P
Cy3P
trace
51
7
8
79
9
91
10
11
12
13
14
15
16
64
27
AcOH
50
PivOH
54
4-MeC6H4CO2H
4-FC6H4CO2H
4-MeOC6H4CO2H
4-FC6H4CO2H
4-FC6H4CO2H
4-FC6H4CO2H
92
a
Reaction conditions: 1 (0.25 mmol, 1.0 equiv), 2a (0.50 mmol, 2.0
equiv), Pd(PPh3)4 (10 mol %), Cy3P (20 mol %), and 4-FC6H4CO2H
(10 mol %) in anhydrous toluene (2.0 mL) at 100 °C under argon for
c
95 (91)
76
82
73
nr
d
b
17
24 h. Isolated yields.
e
18
19
in 77% yield. The electron-withdrawing groups such as chloro-,
fluoro-, and trifluoromethyl groups at the C5-position delivered
3ea−ga in 73%, 72%, and 43% yields. Besides, 7-Me-, 7-Et-, and
7-F-substituted 2,3-dimethylindoles afforded 3ha−ja in 53%−
72% yields. Moreover, 1,2-dimethyl-3H-benzo[e]indole 1k was
also tested and furnished 3ka in 56% yield. By changing the C3-
methyl to a benzyl group or the C2-methyl to an ethyl group,
3la and 3ma were obtained in 64% and 49% yields. Notably,
cyclic olefin-fused indoles were also investigated, and 3na and
3pa were obtained in 57% and 71% yields, while 3oa was only
observed in 24% yield due to the disfavored conformation of
the seven-membered ring.
Next, the scope of alkynes was investigated, and the results
are summarized in Scheme 3. The alkynes with electron-
donating groups such as methyl, methoxyl, and phenyl groups
at the para-position of the phenyl ring delivered 3ab−ad in
66%, 70%, and 72% yields. The electron-withdrawing groups
(−Cl, −F, −CF3) showed higher reactivity and furnished 3ae−
ag in 87%, 69%, and 80% yields. 3-Methyl-substituted alkyne 2i
gave 3ai in 75% yield, while 2-methyl-substituted alkyne 2h
afforded 3ah in lower yield due to the steric effect. When the
phenyl ring was displaced with a naphthalene ring, the
dearomative products 3aj and 3ak were obtained in 71% and
61% yields. Moreover, the heterocycles such as thiophene rings
were also tolerated under this catalytic system and afforded 3al
in 51% yield and 3am in 67% yield.
a
Reaction conditions: 1a (0.25 mmol), 2a (0.50 mmol), [Pd] (10 mol
%), ligand (20 mol %), and additive (10 mol %) in 2.0 mL of
b
anhydrous toluene at 100 °C under argon for 24 h. The yields were
1
determined by H NMR with dibromomethane as internal standard.
c
d
Isolated yield. 7.5 mol % of Pd(PPh3)4 and 15 mol % of Cy3P were
e
used. 5 mol % of Pd(PPh3)4 and 10 mol % of Cy3P were used. nr =
no reaction.
catalysts revealed that Pd(PPh3)4 could yield the dearomative
allylic alkylated product 3aa in 69% yield, while no product was
obtained with Pd/C, Pd2(dba)3, or Pd2(dba)3·CHCl3 as
catalysts (entries 1−4). A control experiment indicated that
ligand was essential to this reaction (entry 5). Varying different
ligands (entries 6−11) showed that Cy3P could afford 3aa in
t
91% yield, while dppp, dppm, and Bu3P exhibited inferior
performance and Ph3PO inhibited the reaction completely.
Further screening of acids suggested that small aliphatic acids
such as AcOH and PivOH furnished 3aa in 50% and 54% yields
(entries 12 and 13). The benzoic acids gave better results, and
3aa could be finally isolated in 91% yield when 4-fluorobenzoic
acid was selected (entries 14−16). Decreasing the amount of
Pd(PPh3)4 influenced the outcome slightly (entries 17 and 18).
With the catalyst dislodged, no reaction could be detected
(entry 19).
With the optimized conditions in hand, the substrate scope
was examined with various indoles (Scheme 2). The indoles
with electron-donating groups such as methoxyl, methyl, and
isopropyl groups at the C5-position afforded 3aa−ca in 91%,
80%, and 81% yield, respectively. 2,3-Dimethylindole gave 3da
Polycyclic skeletons embedded within pyrroloindoline or
furanoindoline frameworks represent important structure
motifs in numerous natural products and pharmaceuticals
exhibiting interesting biological properties.13 Therefore, we
B
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Letter
a
,b
a
Scheme 3. Substrate Scope of Alkynes
Scheme 5. Deuterated-Labeling Experiments
a
Reaction conditions: 1a (0.25 mmol, 1.0 equiv), 2 (0.50 mmol, 2.0
equiv), Pd(PPh3)4 (10 mol %), Cy3P (20 mol %) and 4-FC6H4CO2H
(10 mol %) in anhydrous toluene (2.0 mL) at 100 °C under argon for
a
The extent of deuterium incorporation was determined using 1H
NMR spectroscopy.
b
24 h. Isolated yields.
tried to build pyrroloindoline and furanoindoline cores with
tryptamine and tryptophol as substrates through cascade
dearomatization/allylic alkylation/cyclization process. Unfortu-
nately, no target products were detected under standard
conditions. According to our previous work,14 triethylborane
(Et3B) reacting with indoles could form the N-indolyltriethyl-
borate species, which has been proved to be a useful reagent for
dearomative C3-alkylation of 3-substituted indoles with both
activated and nonactivated alkyl halides due to the enhanced π-
nucleophilicity of indoles. Indeed, when 1.1 equiv of Et3B was
added to our catalytic system, 5aa and 5ab could be obtained in
78% and 91% yields (Scheme 4).
12% deuterium incorporation of C2-methyl was detected under
conditions A and B, respectively (Scheme 5c). According to
this result, we could conclude that 4-FC6H4CO2D was
produced when the reaction was conducted with 2a-d3,
suggesting the oxidation procedure of Pd(PPh3)4 with 4-
fluorobenzoic acid was reversible. Moreover, when 1a was
stirred with 10 mol % of Pd(OAc)2 and AcOH-d4 (Scheme 5d),
a slightly higher deuterated ratio of C2-methyl in 20% was
measured, which hinted that the existence of Pd(II) could
promote the deuterated procedure of C2-methyl and Pd(II)
should be involved in the total catalytic cycle.
On the basis of previous reports11,15 and our deuterated
labeling experiments, a plausible catalytic cycle is proposed as
shown in Scheme 6. First, oxidation of Pd(PPh3)4 with 4-
fluorobenzoic acid initiates the catalytic cycles and affords the
hydridopalladium species A.15a Hydropalladation of 2a with A
generates to the vinylpalladium intermediate B. β-Hydrogen
elimination of B produces the phenyl allene C and intermediate
A (catalytic cycle I). Next, hydropalladation of A with phenyl
Scheme 4. Construction of Fused Indolines
Scheme 6. Proposed Mechanism
To gain insight into the mechanism of this reaction, a
deuterated-labeling experiment with 2a-d3 was conducted
(Scheme 5a). The observed incorporation of hydrogen at the
γ-position of 3aa-dn indicated the procedure of insertion of 2a
to intermediate A and β-hydrogen elimination of intermediate
B during the formation of allene was reversible.11e It was
noteworthy that the C2-methyl was deuterated in 45% ratio,
and further experiments were conducted to explore this
phenomenon. When 3aa was stirred with AcOH-d4 under
conditions A or B, no incorporation of deuterium was observed
(Scheme 5b), suggesting that the deuterium at the C2-methyl
was not incorporated with 3aa. With 1a as substrate, 10% and
C
DOI: 10.1021/acs.orglett.6b01947
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Organic Letters
Letter
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with substituted indole 1a to give the dearomative product 3aa
together with Pd(0) (cycle II).
In summary, we have developed a palladium-catalyzed
dearomative allylic alkylation of indoles with alkynes to
construct indolenines with C3-quarternary centers. The in
situ formed arylallene intermediate omitted the need of
installing leaving groups to the allylic compounds and
employing extra oxidants to oxidize the allylic C−H bonds.
The reaction exhibited good functional group tolerance as well
as high atom economy. Moreover, our protocol was expanded
to synthesize pyrroloindoline and furanoindoline frameworks.
Further studies on the asymmetric synthesis are currently
underway in our laboratory.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01947.
1H and 13C NMR spectra for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ajlin@cpu.edu.cn.
*E-mail: hyao@cpu.edu.cn; cpuhyao@126.com.
Author Contributions
†S.G. and Z.W. contributed equally.
(9) Zhang, H.; Hu, R.-B.; Liu, N.; Li, S.-X.; Yang, S.-D. Org. Lett.
2016, 18, 28.
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(d) Engelin, C. J.; Fristrup, P. Molecules 2011, 16, 951. (e) Le Bras, J.;
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Generous financial support from the National Natural Science
Foundation of China (NSFC21572272 and NSFC21502232),
the Natural Science Foundation of Jiangsu Province
(BK20140655), the Foundation of State Key Laboratory of
Natural Medicines (ZZYQ201605), and the Innovative
Research Team in University (IRT_15R63) is gratefully
acknowledged.
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Khakyzadeh, V.; Bury, T.; Breit, B. J. Am. Chem. Soc. 2014, 136, 16124.
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