Synthesis of Dihydropyridinone-Fused Indoles and α-Carbolines via N-Heterocyclic Carbene-Catalyzed [3 + 3] Annulation of Indolin-2-imines and Bromoenals

Article abstract of DOI:10.1021/acs.orglett.7b00820

The N-heterocyclic carbene catalyzed [3 + 3] annulation of indolin-2-imines and bromoenals was developed to give dihydropyridinone-fused indoles in good to high yields, which were transformed to α-carbolines with different 2-subsituents by a process of dehydrogenation, tosylation, and palladium catalyzed C-C or C-N coupling reaction.

Full text of DOI:10.1021/acs.orglett.7b00820

Letter
pubs.acs.org/OrgLett
Synthesis of Dihydropyridinone-Fused Indoles and α‑Carbolines via
N‑Heterocyclic Carbene-Catalyzed [3 + 3] Annulation of Indolin-2-
imines and Bromoenals
Liang Yi,†,‡ Yuyang Zhang,† Zhao-Fei Zhang,†,§ Dequn Sun,*,‡ and Song Ye*,†,§
†Beijing National Laboratory for Molecular Science, Key Laboratory of Molecular Recognition and Function, CAS
Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190, China
‡Marine College, Shandong University at Weihai, 180 Wenhua West Road, Weihai 264209, China
§University of Chinese Academy of Science, Beijing 100049, P. R. China
S
* Supporting Information
ABSTRACT: The N-heterocyclic carbene catalyzed [3 + 3] annulation of indolin-2-imines and bromoenals was developed to
give dihydropyridinone-fused indoles in good to high yields, which were transformed to α-carbolines with different 2-subsituents
by a process of dehydrogenation, tosylation, and palladium catalyzed C−C or C−N coupling reaction.
onstruction of heterocycles combining two biologically
indole-3-alkenyl oximes.10 In those methods, functional groups
at the 2-position, which is crucial to many naturally occurring α-
carbolines, had to be introduced in advance.
1
Cattractive motifs is highly desired in drug discovery. α-
Carbolines (pyrido[2,3-b]indoles), combining indole2 and
pyridine,3 are known to exhibit an array of biological activities,4
such as grossularine-1 and grossularine-2 as anticancer
compounds,4a−c mescengricin as the inhibitor of L-glutamate
excitotoxicity in neurons,4d and isoxazolo[5′,4′:5,6]pyrido[2,3-
b]indoles as a new kind of anticancer lead (Figure 1).4e Many
strategies have been developed for the synthesis of α-carbolines,
including Graebe Ullmann reactions,5 Diels−Alder reaction,6
Vilsmeier−Haack reaction,7 palladium-catalyzed C−C coupling8
and C−N-coupling reactions,9 and the 6π-electrocyclization of
In the past decades, N-heterocyclic carbene (NHC) catalyzed
annulation reactions emerged as a powerful tool for the synthesis
of various heterocycles.11 The NHC-catalyzed generation of α,β-
unsaturated acyl azolium and its [3 + 3] annulation with imines
afforded dihydropyridinones,12 which is a key motif for many
bioactive compounds.13 In this letter, we report the NHC-
catalyzed [3 + 3] annulation of indolin-2-imines with bromoenals
to give dihydropyridinones-fused indoles, which could be
transformed to carbolines with different 2-subsituents via later
modification.
Initially, the model reaction of indolin-2-imines 1a with
bromoenal 2a was carried out under NHC catalysis (Table 1).
We were encouraged to find that the reaction gave the desired
cycloadduct 3aa in 27% yield in the presence of 10 mol %
thiazolium NHC precursor A and 1.2 equiv of potassium acetate
as the base (entry 1). A series of NHC precursors A−G were then
tested for their ability to catalyze the reaction (entries 2−7).
While low yields were observed for thioazlium NHC precursors
A and B (entries 1−2), no or only trace of cycloadduct 3aa was
detected for imidazolium NHC precursors C and D, respectively
(entries 3−4). The yields were improved dramatically when
triazolium salt NHC precursors E−G were used (entries 5−7).
Several other organic and inorganic bases were screened but did
not perform as well as potassium acetate (entries 8−11). Besides
Received: March 19, 2017
Figure 1. Bioactive α-carbolines.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00820
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Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 1. Reaction Scope
b
entry
pre-NHC
base
solvent
THF
temp
rt
yield (%)
1
A
B
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
DBU
27
13
NR
trace
68
57
68
27
32
18
15
66
66
99
2
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
ether
1,4-dioxane
THF
rt
3
C
D
E
rt
4
rt
5
rt
6
F
rt
7
G
G
G
G
G
G
G
G
rt
8
rt
9
DIPEA
K2CO3
KHCO3
KOAc
KOAc
KOAc
rt
10
11
12
13
14
rt
rt
rt
rt
40 °C
a
General conditions: 1a (0.2 mmol), 2a (1.2 equiv), cat. A−G (10 mol
b
%), base (1.2 equiv), solvent (2 mL). Isolated yield. NR = no
reaction.
THF, the reaction proceeded smoothly in ether and 1,4-dioxane
(entries 12−13). Finally, the yield was increased to 99% when the
reaction was carried out at 40 °C (entry 14).
With the optimized conditions in hand, a variety of substituted
indolin-2-imines and bromoenals were then explored (Scheme
1). It was found that both indolin-2-imines with substituents at
the 4-/5-position of electron-withdrawing groups (X = 4-Cl, 5-
Br) and electron-donating groups (X = 4-Me, 5-MeO) gave the
products (3ba−3ea) in good to high yields. Substitution at 6-
position (X = 6-Br) also resulted in good yield (3fa).
Furthermore, an N-benzyl indolin-2-imine worked just as well
as the N-methylsubstrates, giving cycloadduct 3ga in 85% yield.
Both β-aryl-α-bromoenals with electron-withdrawing group
(Ar = 4-FC6H4, 4-ClC6H4, 4-BrC6H4) and with electron-
donating group (Ar = 4-MeC6H4, 4-MeOC6H4) worked well,
although the later ones afforded better yields (3ab−3ac vs 3ae−
3af). All the reactions of arylbromoenals with meta-substituents
(Ar = 3-ClC6H4, 3-MeOC6H4), with ortho-substituents (Ar = 2-
BrC6H4, 2-MeOC6H4) and with disubstituents (Ar = 3-Br-4-
MeOC6H3) went smoothly to give the cycloadducts (3ag−3ak)
in high yields. Notably, the reaction of aliphatic α-bromoenal (R
= n-C2H5, n-C5H11) gave the desired product (3al−3am) in low
and moderate yield, respectively. In addition, β,β-disubstituted
bromoenals could also participate in the reaction to give the
cycloadducts 3an and 3ao with a quaternary carbon in moderate
to high yields.
The synthesis of α-carbolines from cycloadduct 3aa was then
investigated (Scheme 2). The dehydrogenation of 3aa with Pd/
C gave indole-fused pyridinone,14 which was tosylated to afford
compound 5.15 The palladium-catalyzed coupling reaction of
heteroaryl tosylate 5 with aniline, phenylboronic acid, and alkene
gave the corresponding α-carbolines 6−8 with 2-amino, 2-
phenyl, and alkenyl substituent, respectively.16
In addition, the dihydropyridinone is hydrolyzed with
methanol could be ring-opened to give the 2-amino-3-
substituted indole 9 in 61% yield (eq 1).
B
DOI: 10.1021/acs.orglett.7b00820
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Scheme 2. Synthesis of α-Carbolines
Figure 3. Plausible catalytic cycle.
The structure of cycloadduct 3da was established by the X-ray
analysis of its single crystal (Figure 2).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00820.
Experimental details and NMR spectra for obtained
compounds (PDF)
X-ray data for 3da (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: songye@iccas.ac.cn.
*E-mail: dequn.sun@sdu.edu.cn.
ORCID
Song Ye: 0000-0002-3962-7738
Notes
Figure 2. X-ray structure of 3da.
The authors declare no competing financial interest.
A plausible catalytic cycle for the reaction was depicted in
Figure 3. As previously reported,12a the key intermediate α,β-
unsaturated acyl azolium I is generated by nucleophilic addition
of NHC catalyst to bromoenal followed by elimination of
bromide. The addition of enamine anion 1′, generated from
indoline-2-imines in the presence of base, to α,β-unsaturated acyl
azolium intermediate I gives adduct II, which is transformed to
enamine anion III via proton transfer. Subsequent lactamization
yields the final [3 + 3] annulation product 3 and regenerates
NHC catalyst.
In conclusion, the N-heterocyclic carbene-catalyzed [3 + 3]
annulation of indolin-2-imines and bromoenals was developed to
give dihydropyridinone-fused indoles in good to high yields. The
cycloadduct could be transformed to α-carbolines with different
2-substituents by dehydrogenation, tosylation, and palladium-
catalyzed coupling reactions. Further development of NHC-
catalyzed [3 + 3] annulation reactions is underway in our
laboratory.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science Foundation
of China (Nos 21425207, 21521002) and the Chinese Academy
of Sciences is greatly acknowledged.
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