Metal-Free Dearomatization: Direct Access to Spiroindol(en)ines in Batch and Continuous-Flow

Article abstract of DOI:10.1002/chem.201805945

A metal-free, phosphine-catalyzed intramolecular “umpolung Michael addition” on alkynes to form spiroindol(en)ines is reported. This nucleophilic catalysis enables the formation of a wide scope of five- and six-membered spiroindol(en)ines in moderate to excellent yields in batch as well as under continuous-flow conditions. Triphenylphosphine-catalyzed nucleophilic activation of alkynes allows the exclusive formation of exo-product under mild reaction conditions.

Full text of DOI:10.1002/chem.201805945

A Journal of
Accepted Article
Title: Metal-Free Dearomatization: Direct access to Spiroindol(en)ines
in Batch and Continuous-Flow
Authors: Prabhat Ranjan, Gerardo M. Ojeda, Upendra K. Sharma, and
Erik Van der Eycken
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To be cited as: Chem. Eur. J. 10.1002/chem.201805945
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Metal-Free Dearomatization: Direct access to Spiroindol(en)ines in
Batch and Continuous-Flow
Prabhat Ranjan,[a] Gerardo M. Ojeda[a,b], Upendra K. Sharma,*[a] Erik V. Van der Eycken,*[a,c]
Abstract: We report herein a metal-free, phosphine-catalyzed
intramolecular “umpolung Michael addition” on alkynes to form
spiroindol(en)ines. This nucleophilic catalysis enables the formation
of a wide scope of five- and six-membered spiroindol(en)ines in
moderate to excellent yields in batch as well as under continuous-flow
conditions. Triphenylphosphine-catalyzed nucleophilic activation of
alkynes allows the exclusive formation of exo-product under mild
reaction conditions.
Dearomatization[1] is a robust strategy to synthesize three-
dimensional rigid molecular scaffolds from simple planar aromatic
molecules. The synthesis of spiroindol(en)ines and related
spirocarbocycles through dearomatization of indole and
substituted phenols has captured the close attention of chemist
due to their widespread presence in various natural products and
biologically relevant molecules.[2-3] Henceforth, greener and atom
economical syntheses of these structures have become
imperative for synthetic chemists (Scheme 1a-c).[4-8] Several
simple Lewis or -acidic catalysts were employed in the last
decades for the synthesis of spiroindolenines through
dearomatization of indole at the C-3 position, including nano-
metal catalysts.[9] In addition, a number of alternative methods
for the synthesis of spiroindolenines has also been developed in
the last decade, viz. the intramolecular version of the Prins
cyclization[10]
,
a
radical-oxidation[11] and acid-catalyzed
reactions.[12] However, several synthetic procedures are often
limited by exo/endo selectivity issues and side reactions such as
reopening of the spiro-ring through 1,2-migration to restore the
aromaticity, particularly prevalent with spiroindolenines. Apart
from these reports, an umpolung Michael-type synthesis of
spiroindol(en)ines with catalytic Lewis base (LB) is still elusive.
The uniqueness of nucleophilic phosphine catalysis has
already resulted in a plethora of reports in the last two decades[13]
after seminal work appearing in the 1960s.[14] In 1997, Trost
Scheme 1: Background on spiroindolenines framework.
described the phosphine-catalyzed -umpolung Michael reaction
of alkyl esters with sulfonyl amine or phthalimide to achieve  -
amino carbonyl compounds (Scheme 1d).[15] The reaction
proceeds through several intermediates, of which intermediate II
could be trapped with different nucleophiles.
[a]
P. Ranjan, Gerardo M. Ojeda , Dr. U. K. Sharma, and Prof. E. V. Van
der Eycken
With our enduring interest in spiroindol(en)ines,[16] we
planned to trap the intermediate II through an intramolecular
nucleophilic attack of the C-3 position of the indole (Scheme 1e).
This unique approach of LB-catalyzed umpolung reaction could
lead to highly functionalized spiroindol(en)ines and related
spirocarbocycles under mild reaction conditions. We commenced
our investigation on the dearomatization of propargylic amides 1a,
derived from tryptamine and propargylic acid, with
triphenylphosphine as nucleophilic catalyst. In the presence of a
catalytic amount of phosphine, we observed the regioselective
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC),
Department of Chemistry, University of Leuven (KU Leuven),
Celestijnenlaan 200F, B-3001 Leuven, Belgium.
Email: usharma81@gmail.com; erik.vandereycken@kuleuven.be.
Center for Natural Products Research, Faculty of Chemistry, University
of Havana, Zapata y G, 10400 Havana, Cuba.
Prof. E. V. Van der Eycken
People’s Friendship University of Russia (RUDN University), Miklukho
-Maklaya street 6, RU-117198 Moscow, Russia.
[b]
[c]
Additional data related to this publication is available at the
https://doi.org/ data repository.
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Table 1: Optimization of spiroindolenines.a
concentration dependency up to 0.3 M and became almost
invariant at higher concentrations. A similar pattern was observed
for catalyst loading where yield remained identical past 20 mol%
of the catalyst.
Table 2: Substrate scope for spiroindolenine formation.a
Entry
1
2
3
4
5
6
7
8
Catalyst
PPh3
PPh3
PPh3
PPh3
Solvent
Toluene
Toluene
DCM
EtOAc
EtOH
EtOH
EtOAc
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
t (h)
5
5
5
3
3
3
2
1.2
3
3
3
3
3
4.5
8
12
3
T(°C)
30
80
30
80
80
80
80
80
80
80
80
80
80
80
80
80
80
Yieldb (%)
10
40
12
78
84
87C
<30
<30
10
50
-
PPh3
P(p-MeOPh)3
P(n-Bu)3
P(n-Bu)3
Me2PPh
(CF3Ph)3P
P(p-FC6H4)3
P(OPh)3
P(p-Tol)3
DMAP
9
10
11
12
13
14
15
16
17
-
trace
-
-
-
-
DBU
Quinuclidine
DABCO
EtOH
aReaction conditions: 1a (0.10 mmol), and catalyst (20 mol%), ethanol (0.3M).
bDetermined by 1HNMR using 1,3,5-trimethoxybenzaldehyde as an internal
standard. cIsolated yield.
formation of the six-membered spiroindolenine as the major
product. In view of recent reports on the phosphine-catalyzed
conjugate addition on electron-deficient acetylenes, we started
optimizing our reaction.[17] Various potential LB catalysts were
investigated under different reaction conditions using amide 1a as
substrate (Table 1).The initial investigation was carried out using
toluene as solvent with 20 mol% of triphenylphosphine at 30 °C
showing a slight conversion (Table 1, entry 1). On increasing the
temperature to 80 °C, we observed the formation of 2a with 40%
yield (entry 2). Considering the previous reports, the product yield
was increased to 78% (entry 4) by using the more polar ethyl
acetate as solvent. To further increase the yield of the desired
product 2a, we planned to use protic solvents like alcohols, as we
reasoned that they could increase the concentration of
intermediate II, via rapid proton transfer to intermediate I (Scheme
1d). This should favour the attack through the C-3 position of the
indole. To our delight 2a was obtained in 84% yield when EtOH
was used as solvent (entry 5). Ethanol has the potential to assist
[1,2]-proton shift in the intermediate III (Scheme 1d).[18] In
addition, we assumed that the rapid protonation of intermediate I
might avoid the chance of self-oligomerization.[14,19] In an attempt
to further enhance the yield we screened different phosphines.
With tris(4-methoxyphenyl)phosphine (p-MeOPh)3P under our
optimized reaction conditions, the yield increased to 87% (entry
6).[20] On the contrary, electron-rich PBu3 and PMe2Ph afforded
very low yields (entries 7-9). More electron deficient P(p-FC6H4)3
gave only 50% yield of the desired product 2a (entry 10), whereas
(CF3Ph)3P, P(OPh)3 and P(p-Tol)3 totally met with failure (entry
11-13). When various amine Lewis bases such as DMAP, DBU,
quinuclidine and DABCO were used, no desired product was
observed (entry 14-17).[21] Thereafter, we investigated the effect
of the reaction concentration as well as the amount of
aReaction conditions: 1a (0.40 mmol), and catalyst (20 mol%), ethanol (0.3M).
PClB
=
para-chlorobenzyl, PFB
=
para-fluorobenzyl, PMB
=
para-
methoxybenzyl. 2g-2j at 85°C for 6h; 2k at 90°C for 24h; 2h* P(p-MeOPh)3 (20
mol%) at 85°C for 4h; 3e at 85°C for 6h; 3g-3h at 80°C for 2h.
With the optimized conditions in hand, we explored the
substrate scope for the formation of 6-membered
spiroindolenines (Table 2). Substrates bearing different electron-
donating benzyl groups on the amide nitrogen successfully gave
the desired spiroindolenines with good product yields (2a-2d,
triphenylphosphine. The yield of the reaction showed
a
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Table 2). The methoxy- and alkyl substituted (2f; 5-OMe, 2o; 5-
Me) indolenines were each formed in high yields. Pleasingly,
halogen substitution in indole substrates (2e; 6-F, 2g; 6-Br, 2h; 5-
Br, 2i; 7-Cl and 2j; 6-Cl) showed only small influence on the
efficiency of the reaction (Table 2). The tryptophan-derived
propargylic amide as well as the substrate derived from
propargylic amine failed to give the desired products (2k, 2p,
Table 2).
cyclization. Formation of the ether instead of spiro-product might
be due to the rapid isomerization of intermediate 6a to form the
cyclic zwitterion 6b (Scheme 2). To favour intermediate 6a we
tried different types of phosphines such as DPPP (1,3-
bis(diphenylphosphino)propane) and P(NMe2)3 so as to decrease
the acidity of the proton.[24] However, all efforts failed to give the
desired spiro-product. To avoid the isomerization in the allenoate
product, we tried phenyl substituted propargylic amide in a range
of polar and non-polar solvent but unfortunately, we could not
achieve the desired spirocyclization (for detail see SI, Table S1).
Next we employed this protocol to form 5-membered
spiroindolenines assuming that the exo-dig cyclization was also
preserved in this case. Propargylic amides bearing electronically
different substituents on the amide-nitrogen were successfully
transformed into the desired products (3a-3h, Table 2). An
additional halogen substituent on the indole (4-Br, 5-Br) resulted
in higher yields (3b and 3c, Table 2). The electron-donating 5-
OMe- substituent was behaving as in the higher analogous 2f (3d,
Table 2). Interestingly, the substrate bearing a strong electron-
withdrawing nitro-group gave 57% yield (3e, Table 2).[5] Notably,
when indole-based Ugi-adducts were treated with 20 mol% of
triphenylphosphine, they gave the tricyclic products (3g and 3h,
Table 2).[16e] These results inspired us to explore the methodology
on some phenol-containing propargylic amides to deliver
spirocarbocycles (Table 3). With the Ugi four-component reaction,
the free hydroxyl containing substrates (4a-d) were synthesized
conveniently. Here, the post-MCR reaction proceeded with an
ipso attack on the alkyne, followed by Michael addition to form
the tricyclic products (Table 3, 5a-5d) in moderate to good
yields.[22] As expected, the methoxy-substituted substrate did not
result in product formation (5e, Table 3).
Scheme 2. Remote C-H functionalization.
In order to develop a reusable catalytic-system we moved our
attention towards the application of polymer supported
triphenylphosphine. This resulted in a yield of 40% for 2a after 18h.
This encouraged us to employ continuous–flow technology[25] to
further improve the reaction efficiency under heterogeneous
conditions (Scheme 3). A 0.1M solution of 1a in a mixture of
toluene/ethanol (1:1) was passed through a 3 mm diameter
packed bed reactor with 120 mg of polymer bound catalyst
(loading 3 mmol/g, corresponding to 94 mg of triphenylphosphine)
at a flow rate of 0.025 mL/min. After optimization (for details see
SI Table S2) the reaction worked very efficiently, resulted in 88 %
of 2a (gram-scale reaction gave 79 % isolated yield).
Table 3: Substrate scope of ipso attack.a
Scheme 3: Spirocyclization of propargylamides under continuous-flow
conditions with
a
packed bed reactor using polymer supported
triphenylphosphine.
aReaction conditions: 4a (0.10 mmol), and catalyst (20 mol%), ethanol (0.3M).
4c: at 85 °C for 6 h. 4e: at 85 °C for 24 h.
A plausible mechanism is described in scheme 5. The catalytic
cycle starts with the Michael addition of PPh3 to propargylamide
1a to generate a phosphonium intermediate 1b, followed by
protonation, resulting in intermediate 1d. Thereafter, 1d
undergoes umpolung Michael addition at the -position, which is
induced by the electron withdrawing ability of the phosphonium
entity. The resultant ylide 1e undergoes proton transfer and
Encouraged by the above results, we evaluated the reaction
of a propargylic amide bearing a -proton (alkyl substituted
alkynes) under our optimized conditions. The ether appeared to
be the major product, resulting from nucleophilic attack of the
alcoholic solvent on the -position (Scheme 2).[23] Interestingly,
this could be regarded as a remote C-H functionalization. The
reaction required a longer time as compared to the spiro-
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elimination of phosphine from 1f, generating the final product 2a.
To gain more insight, we followed the 31P NMR spectrum in
ethanol for 2h (for detail see SI). Formation of closely associated
downfield peaks to triphenylphosphine might support the
formation of suitable intermediates during the catalytic cycle. In
addition, there was no decrease in the intensity of the
triphenylphosphine peak, which confirms the regeneration of the
catalyst.[26]
Leuven) and to Karel Duerinckx (KU Leuven) for the assistance
with NMR measurements.
Conflicts of interest
The authors declare no conflict of interest.
Keywords: Dearomatization • Spiroindolenine • Organocatalysis
• Indoles • Flow chemistry.
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In summary, we have developed a phosphine catalyzed “anti-
Michael addition” on alkynes to form the spiroindolines and
spiroindolenines in batch as well as continuous-flow
heterogeneous conditions. Over 28 examples of structurally and
functionally diverse products were successfully synthesized. This
nucleophilic catalysis enables a wide scope of six- and five-
membered spiroindolenines as well as ipso-cyclized products with
yields ranging from 56% to 98%. Moreover, triphenylphosphine
catalysed nucleophilic activation of alkynes allows us to form the
exo-product regioselectively. This new activation method should
enable the mild synthesis of these biologically relevant molecules
in a more sustainable manner.
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This project has received funding from the European Union’s
Horizon 2020 research and innovation Programme under the
Marie Skłodowska-Curie grant agreement No 721290. This
publication reflects only the author’s view, exempting the
Community from any liability. Project website: http://cosmic-
etn.eu/. PR is thankful to Marie–Curie action. GMO acknowledges
VLIR-UOS for financial support of a TEAM project (project code
CU2018TEA458A101) involving Flemish and Cuban institutions
and providing a doctoral scholarship. We acknowledge the
support of “RUDN University Program 5-100”. We are grateful to
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NMR spectrum with this of an authentic sample. For more details about
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10.1002/chem.201805945
Chemistry - A European Journal
COMMUNICATION
Prabhat Ranjan, Gerardo M. Ojeda, Dr.
Upendra K. Sharma,* Prof. Erik V. Van
der Eycken*
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Transition metal free
Ethanol as green solvent
Mild reaction conditions
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More than 25 examples
Packed-bed flow conditions
This article is protected by copyright. All rights reserved.