Palladium(0)-Catalyzed Intermolecular Asymmetric Cascade Dearomatization Reaction of Indoles with Propargyl Carbonate

Article abstract of DOI:10.1002/chem.201900425

An intermolecular asymmetric cascade dearomatization reaction of indole derivatives with propargyl carbonate was developed. The challenges associated with both the chemoselectivity between the carbon and nitrogen nucleophile and the enantioselective control during the formation of an all-carbon quaternary stereogenic center were well addressed by a Pd catalytic system derived from the Feringa ligand. A series of enantioenriched multiply substituted fused indolenines were provided in good yields (71–86 %) with excellent enantioselectivity (91–96 % ee) and chemoselectivity (3/4>19:1 in most cases).

Full text of DOI:10.1002/chem.201900425

A Journal of
Accepted Article
Title: Palladium(0)-Catalyzed Intermolecular Asymmetric Cascade
Dearomatization Reaction of Indoles with Propargyl Carbonate
Authors: Lu Ding, Run-Duo Gao, and Shuli You
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Link to VoR: http://dx.doi.org/10.1002/chem.201900425
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Palladium(0)-Catalyzed Intermolecular Asymmetric Cascade
Dearomatization Reaction of Indoles with Propargyl Carbonate
Lu Ding,[b] Run-Duo Gao,[a] and Shu-Li You*[a,b,c]
Abstract: An intermolecular asymmetric cascade dearomatization
reaction of indole derivatives with propargyl carbonate was devel-
oped. The challenges on the chemoselectivity between carbon
nucleophile and nitrogen nucleophile, and the enantioselective
control during the formation of an all-carbon quaternary stereogenic
center were well addressed by a Pd catalytic system derived from
the Feringa ligand. A series of enantioenriched multiple substituted
fused indolenines were provided in good yields (71-86%) with excel-
lent enantioselectivity (91-96% ee) and chemoselectivity (3/4 >19:1
in most cases).
phile at the C2 position with propargyl carbonate (Scheme 1, eq
3).
Figure 1. Selected Natural Products Containing Multiple Substituted Fused
Indolenine Scaffolds.
Fused indolenines are important structural cores of natural
products and frequently appear in biologically active molecules
(Figure 1).[1] Accordingly, extensive efforts have been devoted to
develop efficient methods for the construction of these scaffolds
in a highly chemo- and enantio-selective manner. In this regard,
the recently emerging catalytic asymmetric dearomatization
(CADA) reactions provide a large array of methods allowing
efficient accesses to fused indolenines from readily available
indole derivatives.[2] Notably, transition-metal-catalyzed allylic
dearomatization reactions of indoles have witnessed significant
progresses in the past decade.[3,4,5]
Recently, we realized the construction of fused indolenine
skeletons in a cascade fashion.[6] In 2014, the Rawal group and
we independently reported an intermolecular cascade dearoma-
tization reaction of indole-based bisnucleophiles with propargyl
carbonate, leading to a series of spiroindolenines and spiroin-
dolines. Moderate enantioselectivity (≤ 77% ee) was achieved
for limited substrates (Scheme 1, eq 1).[6a,7,8] Rawal and cowork-
ers found that the indole N-H moiety could participate in the
cyclization process when the nucleophilic side chain was deco-
rated at the C2 position of the C3 methyl substituted indole
(Scheme 1, eq 2).[7,9] Herein, we report a chemo- and enantio-
selective synthesis of multi substituted fused indolenines by Pd-
catalyzed cascade dearomatization of indoles bearing a nucleo-
Scheme 1. Palladium-Catalyzed Intermolecular Cascade Reaction between
Indole Derivatives and Propargyl Carbonate.
We began our studies by examining the reaction of dimethyl
2-((3-benzyl-1H-indol-2-yl)methyl)malonate (1a) with methyl
prop-2-yn-1-yl carbonate (2) in DMA in the presence of Pd cata-
lyst derived from Pd2dba3. Firstly, several commercially available
chiral phosphorus ligands were tested (Scheme 2). The desired
product 3a was obtained in moderate yields when Feringa ligand
(S,S,Sa)-L1, BINAP (R)-L2, or Synphos (R)-L3 were used. How-
ever, Pd complex derived from PHOX ligand (S)-L4 could hardly
promote this reaction. It is worth noting that the reaction with L1
led to 3a in excellent enantioselectivity and good chemoselectivi-
ty (94% ee, 10/1 3a/4a). Encouraged by these results, phospho-
ramidite ligands L5-L9 were investigated, however, no better
results were obtained. Next, further optimization of the reaction
conditions was carried out using L1 (Table 1). Reactions in
varied solvents such as DMF, DCM and THF afforded compara-
ble yields and enantioselectivity albeit with lower 3a/4a ratios
(entries 2-4), while MeOH and PhMe led to almost no reaction
[a]
Dr. R.-D. Gao, Prof. Dr. S.-L. You
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
University of Chinese Academy of Sciences
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
E-mail: slyou@sioc.ac.cn
Homepage: http://shuliyou.sioc.ac.cn/
L. Ding, Prof. Dr. S.-L. You
School of Physical Science and Technology, ShanghaiTech Univer-
sity, 100 Haike Road, Shanghai 201210 (China)
Prof. Dr. S.-L. You
[b]
[c]
Collaborative Innovation Center of Chemical Science and Engineer-
ing, Tianjin 300072 (China)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201900425
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(entries 5-6). Further evaluation of the concentration (entries 7-
11) of 1a revealed that c = 0.2 mol/L was optimal in terms of
yield (entry 8). Pd2(4-OMe-dba)3 was a better palladium source
than Pd2dba3 and [Pd(allyl)Cl]2 (entries 12-13).[10] Furthermore,
some additives were tested. To our delight, both of the yield and
3a/4a ratio were improved remarkably when 4 Å molecular
sieves were used (82% yield, 95% ee, >19/1 3a/4a, entry 15).
Finally, the optimized reaction conditions were established as
the following: Pd2(4-OMe-dba)3 (2.5 mol%), L1 (11 mol%), 4 Å
MS (100 mg) in DMA (1 mL) at 80 °C (entry 15). To be noted, 4a
can not be converted to 3a under the optimized conditions,
suggesting the formation of C-N is likely an irreversible process
here.
7
Pd2dba3
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
0.4
8.1/1
8.6/1
8.3/1
6/1
60
73
94
92
92
93
94
8
Pd2dba3
0.2
9
Pd2dba3
0.1
58
10
Pd2dba3
0.05
0.033
0.2
39
11
Pd2dba3
5.4/1
34
12
[Pd(allyl)Cl]2
Pd2(4-OMe-dba)3
Pd2(4-OMe-dba)3
Pd2(4-OMe-dba)3
Pd2(4-OMe-dba)3
Pd2(4-OMe-dba)3
N.R.
75
13[e]
14[f]
15[g]
16[h]
17[i]
0.2
10.4/1
8.6/1
94
93
95
94
0.2
84
0.2
>19/1
11.3/1
82
0.2
73
0.2
complex
[a] Reaction conditions: 1a (0.2 mmol), 2 (0.26 mmol), Pd source (0.005
mmol), and L1 (0.022 mmol) in solvent at 80 °C. [b] Determined by 1H NMR
analysis of the crude reaction mixture. [c] Isolated yield of 3a. [d] Determined
by HPLC analysis. [e] 4-OMe-dba: di(4-methoxybenzylidene)acetone. [f] 3 Å
MS (100 mg) was added. [g] 4 Å MS (100 mg) was added. [h] 5 Å MS (100
mg) was added. [i] Cs2CO3 (0.2 mmol) was added.
With the optimized conditions in hands, we then explored the
substrate scope of this reaction (Scheme 3). Firstly, substrates
with different substituents on the benzyl group were examined.
Both electron-donating groups (3b: 4-OMe, 3c: 4-Me, 3d: 3-Me)
and electron-withdrawing groups (3e: 4-F, 3f: 4-Cl) were found
to be well tolerated. The corresponding products were obtained
in good to excellent yields, with excellent chemo- and enantiose-
lectivities (3b-3f, 78-82% yields, 16.2:1 ~ >19:1 3/4, 93-95% ee).
When the benzyl group was changed to 2-thienyl or 2-naphthyl,
the desired products could also be obtained in gratifying results
(3g: 79% yield, 15.6:1 3g/4g, 96% ee, 3h: 85% yield, >19:1
3h/4h, 96% ee). Next, substrates with different substituents on
the indole ring were investigated. The dearomatized products
were afforded in excellent yields, chemo- and enantioselectivi-
ties when an electron-donating group (3i: 5-OMe, 3j: 5-Me) was
installed on the indole ring (3i: 84% yield, >19:1 3i/4i, 96% ee,
3j: 86% yield, >19:1 3j/4j, 92% ee). Remarkably, when an elec-
tron-withdrawing group was introduced on the indole ring (3k: 5-
F, 3l: 5-Cl, 3m: 5-Br, 3n: 6-F, 3o: 6-Cl), good to excellent yields,
C/N ratios and excellent enantioselectivity were obtained (3k-3o:
73-77% yields, 4.2:1 ~ 11.7:1 3/4, 92-94% ee). Notably, the
formation of allylic amination products was more favorable when
stronger electron-withdrawing group was introduced (from 5-F to
5-Br, 6-F to 6-Cl). These are probably due to the increased
acidity of the indole N-H and more easily formed N nucleophiles
caused by the electron-withdrawing substituent. When EWG
group on substrate 1 was changed from methyl carbonate to
ethyl carbonate, the desired product could also be obtained in
good results (3p: 71% yield, 18.3:1 3p/4p, 91% ee). Further-
more, when an aliphatic group was installed at the C3 position,
all substrates could be well tolerated (3q-3v: 71-85% yields,
>19:1 3/4 in all cases, 92-94% ee). The structure and absolute
configuration of product 3r were confirmed by an X-ray crystal-
lographic analysis of an enantiopure example (See the Support-
Scheme 2. Investigation of the ligands. Reaction conditions: 1a (0.2 mmol), 2
(0.26 mmol), Pd2dba3 (0.005 mmol), and L (0.011 or 0.022 mmol) in DMA (3.0
mL) at 80 °C. The ratios of 3a/4a were determined by 1H NMR analysis of the
crude reaction mixture. The ee values were determined by HPLC analysis.
Table 1. Investigation of the Reaction Conditions[a]
c
yield
(%)[c]
ee
entry
[Pd]
solvent
3a/4a[b]
(mol/L)
(%)[d]
1
2
3
4
5
6
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
DMA
DMF
DCM
THF
0.067
0.067
0.067
0.067
0.067
0.067
10/1
48
46
94
93
94
93
4.8/1
2.6/1
1.2/1
51
47
MeOH
PhMe
trace
N.R.
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10.1002/chem.201900425
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ing Information for details). Moreover, substrate 1w bearing a
nucleophilic chain at the C3 position underwent the reaction
smoothly, affording the bridged indoline 3w in 71% yield and
96% ee.
to afford 6 in 91% yield. The relative configuration of 6 was
determined by NOE analysis (For details, see the Supporting
Information). Treatment of 6 with acetyl chloride and NaH pro-
duced 7 in quantitative yield. Finally, the double bond in 7 was
oxidized with ozone to give ketone 8 in 64% yield.
Scheme 4. Gram-Scale Reaction and Product Transformations
Scheme 3. Substrate Scope. Reaction conditions: 1 (0.2 mmol), 2 (0.26 mmol),
Pd2(4-OMe-dba)3 (0.005 mmol), L1 (0.022 mmol), and 4 Å MS (100 mg) in
DMA (1.0 mL) at 80 °C. The ratios of 3/4 were determined by 1H NMR analysis
of the crude reaction mixture. The ee values were determined by HPLC
analysis. [a] 4m was isolated in 14% yield. [b] After 1w was disappeared,
TsOH•H2O (0.02 mmol) was added at room temperature.
To demonstrate the utility of the current method, a gram-
scale reaction and several transformations of the product were
carried out (Scheme 4). The asymmetric cascade dearomatiza-
tion reaction of 1a with 2 on a 3.0 mmol scale provided product
3a in 84% yield and 95% ee. Under Pd/C hydrogenation condi-
tions, the exocyclic double bond of product 3a was reduced and
the benzyl group was also removed at the same time likely due
to the driving force of aromatization, giving 5 in 92% yield. The
imine moiety in 3a could be reduced by NaBH3CN in acetic acid
Scheme 5. A Plausible Catalytic Cycle
A proposed catalytic cycle is depicted in Scheme 5. The
propargyl carbonate is activated by Pd(0) to give intermediate I.
Then the nucleophilic side chain attacks intermediate I to gener-
ate π-allyl palladium species II. Upon the deprotonation of indole
N-H, the C3 position of indole in III attacks π-allyl palladium
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moiety to deliver IV. Finally, product 3 is provided upon the
liberation of palladium catalyst.
In conclusion, we have achieved an efficient palladium(0)-
catalyzed intermolecular asymmetric cascade dearomatization
reaction of indole derivatives with propargyl carbonate. A series
of multiple substituted fused indolenines were obtained in good
to excellent yields, excellent chemo- and enantio-selectivities.
This method features mild reaction conditions and broad sub-
strate scope. Further studies on the reaction mechanism are
currently underway in our laboratory.
Acknowledgements
We thank the National Key R&D Program of China
(2016YFA0202900), the National Basic Research Program of
China (2015CB856600), NSFC (21572252, 21821002), Program
of Shanghai Subject Chief Scientist (16XD1404300), and the
CAS (XDB20000000, QYZDY-SSW-SLH012) for generous
financial support.
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Keywords: allylic • asymmetric catalysis • cascade • dearomati-
zation • indole • palladium
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COMMUNICATION
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10.1002/chem.201900425
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Lu Ding, Run-Duo Gao, and Shu-Li You*
Page No. – Page No.
Palladium(0)-Catalyzed Intermolecular
Asymmetric Cascade Dearomatization
Reaction of Indoles with Propargyl Car-
bonate
An intermolecular asymmetric cascade dearomatization reaction of indole derivatives with
propargyl carbonate was developed. The challenges on the chemoselectivity between carbon
nucleophile and nitrogen nucleophile, and the enantioselective control during the formation of
an all-carbon quaternary stereogenic center were well addressed by a Pd catalytic system
derived from the Feringa ligand. A series of enantioenriched multiple substituted fused indole-
nines were provided in good yields (71-86%) with excellent enantioselectivity (91-96% ee) and
chemoselectivity (3/4 >19:1 in most cases).
This article is protected by copyright. All rights reserved.