Fiaud's Acid: A Br?nsted Acid Catalyst for Enantioselective Friedel-Crafts Alkylation of Indoles with 2-Alkene-1,4-diones

Article abstract of DOI:10.1021/acs.orglett.7b01383

Fiaud's acid (trans-1-hydroxy-2,5-diphenylphospholane 1-oxide), a phospholane-based phosphinic acid, is introduced as an efficient chiral Br?nsted acid catalyst that mediates the asymmetric Friedel-Crafts alkylation of indoles with 2-butene-1,4-diones. With a catalyst loading of 10 mol %, the reaction proceeded smoothly to afford 2-(indol-3-yl)butane-1,4-diones in high yield (up to 82%) and high enantioselectivity (up to 91% ee, one such product showed enhanced ee of 98% after recrystallization). The reaction conditions are sufficiently mild to tolerate sensitive functionality at room temperature and are therefore suitable for the synthesis of complex targets.

Full text of DOI:10.1021/acs.orglett.7b01383

Letter
pubs.acs.org/OrgLett
Fiaud’s Acid: A Brønsted Acid Catalyst for Enantioselective Friedel−
Crafts Alkylation of Indoles with 2‑Alkene-1,4-diones
Sourav Chatterjee,† Lukas Hintermann,‡ Madhumita Mandal,† Anushree Achari,† Sreya Gupta,†
and Parasuraman Jaisankar*,†
†Laboratory of Catalysis and Chemical Biology, Department of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical
Biology, 4 Raja S. C. Mullick Road, Kolkata 700 032, India
‡Department Chemie and TUM Catalysis Research Center, Technische Universitat Munchen, 80333 Munchen, Germany
̈
̈
̈
S
* Supporting Information
ABSTRACT: Fiaud’s acid (trans-1-hydroxy-2,5-diphenylphos-
pholane 1-oxide), a phospholane-based phosphinic acid, is
introduced as an efficient chiral Brønsted acid catalyst that
mediates the asymmetric Friedel−Crafts alkylation of indoles
with 2-butene-1,4-diones. With a catalyst loading of 10 mol %,
the reaction proceeded smoothly to afford 2-(indol-3-yl)butane-
1,4-diones in high yield (up to 82%) and high enantioselectivity
(up to 91% ee, one such product showed enhanced ee of 98%
after recrystallization). The reaction conditions are sufficiently
mild to tolerate sensitive functionality at room temperature and
are therefore suitable for the synthesis of complex targets.
nantioselective organic transformation by organocatalysts
1
Eis a thriving area of research throughout the world. The
advent of organocatalysis brought with it the prospects of ease
of operation, lower toxicity of the catalysts, inexpensive
operations, no sensitivity toward moisture and air, reductions
in chemical waste, and the potential for new lines of academic
thought and investigation.2 On the application of chiral
Brønsted acids of BINOL-phosphate type for a wide range of
asymmetric reactions,3 different groups have reported applica-
tions for various reactions such as Mannich-type,4 Friedel−
Crafts,5 hydrogenation,6 hetero-Diels−Alder,7 multicomponent
cascade reactions,8 and metal co-catalyzed reactions9 as well.
Considering the widespread usage of chiral Brønsted
phosphoric acids in asymmetric organic transformations, a
major limitation comes from the continuous use of the highly
successful BINOL-phosphoric acids, which are considered to be
privileged structures. However, structural modifications of the
backbones of the BINOL are fundamentally limited. It is
desirable to have a choice of other fundamental structural types
of chiral phosphoric acid with alternative backbones.
We have found Fiaud’s acid to be a potential structural type
that can be used in asymmetric catalysis (Figure 1). To the best
of our knowledge, this phosphinic acid (A), known as Fiaud’s
acid, has never been used as a chiral Brønsted acid catalyst.
Recently, Fiaud and co-workers reported the synthesis and
resolution of rac-2,5-diphenylphospholanic acid ( A), which is
a valuable building block for synthesizing 2,5-diphenylphos-
pholane-containing chiral ligands for asymmetric transition-
metal catalysis.10,11 It occurred to us that the C2-symmetric
phosphinic acid structure of this compound might also be
suited for applications as a chiral Brønsted acid catalyst where
Figure 1. Stereo and electronic properties of chiral Fiaud’s acid (R,R)-
(+)-A.
the steric and electronic properties of the 2,5-diarylphospholane
backbone could potentially be fine-tuned to accommodate the
specific requirements of the reaction and the substrate.10
Fiaud’s phosphine ligand has already proved successful in
various synthetic applications.11 One of us has recently
reported an asymmetric catalytic synthesis of Fiaud’s acid
from thiophene, which can potentially be extended to variable
2,5-diarylphospholane structures, and thus opens the way for
structural fine-tuning (Figure 2).12 However, the fundamental
ability of Fiaud’s acid to act as a chiral Brønsted acid catalyst
remains unproven. We now wish to report a proof of concept
study where we show that Fiaud’s acid is a new structural type
of chiral Brønsted acid that can catalyze the Friedel−Crafts
alkylation of indoles with 2-butene-1,4-dione acceptors in very
high (>90% ee) enantioselectivity.
To investigate our hypothesis, the catalytic property of
Fiaud’s acid [(R,R)-A] was tested in the model alkylation
Received: May 8, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01383
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Organic Letters
Letter
preferred solvent, but other halogenated hydrocarbons were
equally well suited (entries 1−5). Polar solvents proved
unsatisfactory (entries 6−10). Prolonging the reaction time
over the standard 22 h did not increase the product yield (entry
2 vs 11, 12). Counterintuitively, increasing the concentration
reduced the conversion (entry 2 vs 13, 14), which appears to be
a consequence of the limited solubility of the catalyst that
effectively increases the substrate/catalyst ratio. Indeed, a
higher conversion was achieved under more dilute conditions
(entry 15). No improvement of enantioselectivity was attained
by lowering the reaction temperature to 0 °C (entry 16); the
yield of product dropped, which can be ascribed both to slower
kinetics and poor solubility of the catalyst. At room
temperature, a catalyst loading of 10 mol % gave the best
results with respect to yield and ee (entry 1 vs 17, 18).
Interestingly, when the reaction was carried out in daylight, a
fraction (2−5 mol %) of the starting material (E)-2a was
isomerized to (Z)-2a, which did not respond to alkylation.13 In
order to avoid this transformation, reactions were typically
performed in the dark. From the results of Table 1, the optimal
reaction conditions for the model transformation were
established to involve 10 mol % of (R,R)-(+)-A as catalyst in
dry dichloromethane at a concentration of 0.1 M at ambient
temperature (∼25 °C) over 22 h in the dark.14 To demonstrate
the advantage of the present catalytic system, the reaction was
carried out using well-known BINOL-derived phosphoric acid
catalysts like (R)-TRIP15 (B, entry 19) and 3,3′-BINOL-
phosphoric acid (C, entry 20). Both catalysts afforded the
desired product 3a in moderate yield and poor enantiopurity.
Thus, the present catalytic system has the advantage of
improved enantioselectivity.
Figure 2. Synthesis of 2,5-diarylphospholanes from 1,4-diaryl-1,3-
butadienes.
reaction of indole (1a) with (E)-1,4-diphenyl-2-butene-1,4-
dione (2a). Using 10 mol % of [(R,R)-A] in dry toluene (0.1
M) at room temperature afforded the corresponding alkylated
product 3a in satisfactory yield (67%) with moderate, but
notable, enantiopurity (Table 1, entry 1). The choice of solvent
proved to have an important influence on both the rate and
enantioselectivity of the reaction; dichloromethane was the
Table 1. Optimization of Asymmetric Friedel−Crafts
Alkylation by Using Fiaud’s Acid and Known BINOL-
a
phosphoric Acids as Catalysts
With these optimized reaction conditions in hand, the scope
of the reaction was explored by using various indole derivatives
(1a−l) and electrophiles 2a−e (Scheme 1). The alkylation
products 3a−e and 3h−o were obtained in high yields (67−
82%) with moderate-to-high enantioselectivity (39−91% ee).
The substituent at the C2 position of indole had an important
influence on the reaction efficacy; sterically demanding
substituents induced excellent enantioselectivity (up to 91%
ee) with a significant improvement in the yield of the
corresponding products (3a−e). Not unexpectedly, the
electron-deficient substrates 1f and 1g did not respond to
alkylation with 2a. The effect of indole C4, C5, and C6
substitution (substrates 1h−l) was found to not significantly
alter the ee, but it did lower the enantiomeric excess of the
respective reaction products 3h−l. Under optimized conditions,
(R)-TRIP (B) as catalyst instead of Fiaud’s acid for the reaction
of C2-substituted indole 1d with 2a afforded compound 3d in
comparable enantioselectivity (84% ee, Scheme 1) and yield.
Considering the synthetic versatility of the resulting adducts,
our next attempt was focused on expanding the reaction scope
toward other prochiral electrophiles (2b−e). The reaction
proceeded well with diaryl as well as alkylaryl enediones. The
unsymmetrical (E)-1-phenylpent-2-ene-1,4-dione (2c) reacted
with 2-phenylindole (1c) regioselectively, providing the
alkylated product 3n in moderate yield (67%) and
enantioselectivity (65% ee). Even the less activated acceptor
methyl (E)-4-oxo-4-phenylbutenoate (2d) reacted with 2-
phenyl indole (1c) to regioselectively afford 3o. On the other
hand, the dialkyl enedione 1,2-diacetylethylene (2e), in which
the trans-alkene unit is flanked by two acetyl groups, proved
inactive under the above reaction conditions. In contrast to
indoles, carbazoles proved unreactive as nucleophiles. The
e
f
entry cat. (mol %)
solvent (M)
time (h) yield (%) ee (%)
1
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
5
toluene (0.1)
DCM (0.1)
CHCl3 (0.1)
PhCl (0.1)
24
22
24
24
24
24
24
24
24
24
36
42
22
22
22
22
22
22
22
22
67
72
51
59
2
3
63
22
4
64
47
5
1,2-DCE (0.1)
CH3OH (0.1)
dioxane (0.1)
CH3CN (0.1)
THF (0.1)
66
48
6
22
12
7
NR
NR
NR
NR
75
ND
ND
ND
ND
57
8
9
10
11
12
13
14
15
16
17
18
19
20
DMF (0.1)
DCM (0.1)
DCM (0.1)
DCM (0.2)
DCM (0.5)
DCM (0.05)
DCM (0.1)
DCM (0.1)
DCM (0.1)
DCM (0.1)
DCM (0.1)
75
56
45
58
39
47
70
58
b
39
60
44
57
20
10
10
74
60
c
60
32
d
48
04
a
Reactions were carried out with 1a (0.1 mmol), 2a (0.1 mmol), and
catalyst (R,R)-A in the given solvent at the indicated concentration at
room temperature (∼25 °C) in the dark. Reaction temperature 0 °C.
(R)-TRIP (B) was used as a chiral Brønsted acid catalyst. (R)-
b
c
d
BINOL-phosphoric acid (C) was used as a chiral Brønsted acid
e
catalyst. Yields were determined by 1H NMR analysis using 1,2-
f
dichloroethane as internal standard. NR= no reaction. Determined
from chiral HPLC analysis. ND = not determined.
B
DOI: 10.1021/acs.orglett.7b01383
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Scheme 1. Fiaud’s Acid (R,R)-(+)-A-Catalyzed Asymmetric
Friedel−Crafts Alkylation of Substituted Indoles with trans-
Scheme 2. Fiaud’s Acid Catalyzed Asymmetric Friedel−
Crafts Alkylation of Substituted Pyrroles 4a−c with trans-
a,b
Enediones
Enedione 2a
and while the expected reaction products (3r and 3s) were
obtained, they were found to be racemic (Scheme 3), strongly
suggesting that free indole N−H is essential for enantiocontrol
in this transformation.
Scheme 3. Friedel−Crafts Alkylation of N-Methylindoles
1m,n
The good ee’s of the products in Scheme 1 indicate the
preferential approach of indole to the Re face of the enedione
(E)-double bond if (R,R)-A is the catalyst. On the basis of the
investigation of the reaction conditions and the substrate
diversity, we postulate a mechanism for this enantioselective
transformation (Figure 3). The nucleophilicity of the indole
a
b
Isolated yields are given. Enantiomeric excess determined by chiral
c
d
HPLC. 98% ee after recrystallization. (R)-TRIP (B) was used as
catalyst. 94% ee after recrystallization.
e
combinations of β-nitrostyrene with 2-phenyl indole gave the
expected product (3q), but as a racemic mixture (see the
Supporting Information). The major enantiomers of all isolated
products were found to have the (S)-configuration with a
positive sign for the optical rotation and positive CD (λmax
=
345 nm).16,17 The relative configuration, optical rotation, and
sign of the CD spectra were further compared with the
literature report.16
Figure 3. Suggested mechanism for the Fiaud’s acid catalyzed Friedel−
Crafts alkylation of 2-tert-butylindole (1c) with (E)-1,4-diphenyl-2-
butene-1,4-dione (2a).
In another extension of the asymmetric catalytic Friedel−
Crafts alkylation with Fiaud’s acid as catalyst, pyrroles 4a−c
were reacted with trans-1,2-dibenzoylethylene (2a) under the
reaction conditions already used for indoles (Scheme 2).
Although the reactions proceeded smoothly to give the
alkylated pyrroles 5a−c in >70% yield, unexpectedly, these
products were obtained as racemic mixtures.
We anticipated that the indole NH unit, which is capable of
hydrogen bonding to a phosphoryl oxygen (PO) of the
catalyst, plays a key role in defining the enantioselectivity of the
Friedel−Crafts alkylation. To test this hypothesis, the standard
reaction was repeated with two N-methylated indoles (1m,n),
derivative is fostered through hydrogen bonding between
indole-NH and phosphoryl oxygen (PO) of the phosphinic
acid (A). Simultaneously, the Brønsted acidic hydroxyl group
(P−OH) of A increases the electrophilicity of the enedione
acceptor via hydrogen bonding to a carbonyl group. Both
substrates are thus involved in a spatially defined interaction
with the catalyst in the transition state. The lack of hydrogen
bonding of N-methylated indoles 3r,s to the phosphoryl oxygen
C
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Organic Letters
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(3) For initial reports on the chiral Brønsted acid catalysts of the
BINOL-phosphoric acid type, see: (a) Akiyama, T.; Itoh, J.; Yokota,
K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43, 1566. (b) Uraguchi,
D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356.
(4) For a few examples of Mannich-type reactions, see: (a) Akiyama,
T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43,
1566. (b) Guo, Q. X.; Liu, H.; Guo, C.; Luo, S. W.; Gu, Y.; Gong, L. Z.
J. Am. Chem. Soc. 2007, 129, 3790. (c) Itoh, J.; Fuchibe, K.; Akiyama,
T. Synthesis 2008, 2008, 1319.
(5) For selected examples of asymmetric Friedel−Crafts reactions,
see: (a) Terada, M.; Yokoyama, S.; Sorimachi, K.; Uraguchi, D. Adv.
Synth. Catal. 2007, 349, 1863. (b) Itoh, J.; Fuchibe, K.; Akiyama, T.
Angew. Chem., Int. Ed. 2008, 47, 4016.
(6) For selected examples of organocatalytic asymmetric-transfer
hydrogenation reactions, see: (a) Rueping, M.; Antonchick, A. P.
Angew. Chem., Int. Ed. 2007, 46, 4562. (b) Li, G.; Liang, Y.; Antilla, J.
C. J. Am. Chem. Soc. 2007, 129, 5830.
of A disrupts this cyclic transition state, and consequently,
racemic products are obtained.
In summary, we have reported for the first time the
successful use of Fiaud’s phosphinic acid as a new structural
type of chiral Brønsted acid catalyst in an asymmetric Friedel−
Crafts alkylation of indoles with 2-ene-1,4-diones to deliver
products in good yield (up to 82%) and high enentioselectiv-
ities (up to 91% ee, which could be improved to 98% ee after
recrystallization). The enantiomerically enriched indoles
synthesized by the process are potential intermediates for
natural product synthesis and for the synthesis of biologically
active compounds. Further applications of 2,5-diaryl-substituted
phospholane-based phosphinic acids for various asymmetric
transformations are currently being pursued in this laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
(7) For selected examples of asymmetric hetero-Diels−Alder
reactions, see: (a) Akiyama, T.; Morita, H.; Fuchibe, K. J. Am.
Chem. Soc. 2006, 128, 13070. (b) Gioia, C.; Hauville, A.; Bernardi, L.;
Fini, F.; Ricci, A. Angew. Chem., Int. Ed. 2008, 47, 9236.
S
Representative experimental procedures, spectroscopic data, 1H
and 13C NMR spectra, and chiral HPLC profiles for all
synthesized molecules, crystallographic data for 3b, (R,R)-
(+)-A, and (S,S)-(−)-A are provided. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.orglett.7b01383.
(8) For selected examples of asymmetric multicomponent, cascade
reactions, see: (a) Li, N.; Chen, X. H.; Song, J.; Luo, S. W.; Fan, W.;
Gong, L. Z. J. Am. Chem. Soc. 2009, 131, 15301. (b) Akiyama, T.;
Katoh, T.; Mori, K. Angew. Chem., Int. Ed. 2009, 48, 4226.
(9) For selected examples of metal cocatalyzed enantioselective
reactions, see: (a) Mukherjee, S.; List, B. J. Am. Chem. Soc. 2007, 129,
11336. (b) Hu, W. H.; Xu, X. F.; Zhou, J.; Liu, W. J.; Huang, H. X.;
Hu, J.; Yang, L. P.; Gong, L. Z. J. Am. Chem. Soc. 2008, 130, 7782.
(10) Synthesis of 2, 5-diphenylphospholane: Guillen, F.; Rivard, M.;
Toffano, M.; Legros, J. Y.; Daran, J. C.; Fiaud, J. C. Tetrahedron 2002,
58, 5895.
(11) For development of phospholane ligands and their application
in asymmetric synthesis, see: (a) Dobrota, C.; Duraud, A.; Toffano,
M.; Fiaud, J. C. Eur. J. Org. Chem. 2008, 2008, 2439. (b) Galland, A.;
Paris, J. M.; Schlama, T.; Guillot, R.; Fiaud, J. C.; Toffano, M. Eur. J.
Org. Chem. 2007, 2007, 863. (c) Galland, A.; Dobrota, C.; Toffano,
M.; Fiaud, J. C. Tetrahedron: Asymmetry 2006, 17, 2354. (d) Toffano,
M.; Dobrota, C.; Fiaud, J. C. Eur. J. Org. Chem. 2006, 2006, 650.
(e) Dobrota, C.; Toffano, M.; Fiaud, J. C. Tetrahedron Lett. 2004, 45,
8153. (f) Rivard, M.; Guillen, F.; Fiaud, J. C.; Aroulanda, C.; Lesot, P.
Tetrahedron: Asymmetry 2003, 14, 1141.
(12) For organocatalytic isomerization of meso phospholenes, see:
(a) Hintermann, L.; Schmitz, M. Adv. Synth. Catal. 2008, 350, 1469.
(b) Hintermann, L.; Schmitz, M. Adv. Synth. Catal. 2010, 352, 2411.
(c) Hintermann, L.; Schmitz, M.; Maltsev, O. V.; Naumov, P. Synthesis
2013, 45, 308.
(13) In order to confirm the unreactivity of (Z)-2a in the Friedel−
Crafts alkylation with indoles, a test reaction was performed with (Z)-
2a and 2-tert-butylindole (1c) following the optimized reaction
conditions. After 24 h, only 5% of desired 3c was obtained
(determined by crude NMR analysis using toluene as an internal
standard), and the remaining mixture was found to be unreactive
starting materials. For detailed NMR analysis, see the Supporting
Information.
Representative experimental procedures, spectroscopic
data, 1H and 13C NMR spectra, and chiral HPLC profiles
for all synthesized molecules; crystallographic data for
3b, (R,R)-(+)-A, and (S,S)-(−)-A (PDF)
X-ray crystallographic data for compound 3b (CIF)
X-ray crystallographic data for compound (R,R)-(+)-A
(CIF)
X-ray crystallographic data for compound (S,S)-(−)-A
(CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jaisankar@iicb.res.in.
ORCID
Parasuraman Jaisankar: 0000-0003-0583-4920
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project was funded by SERB, New Delhi, India (EEQ/
2016/000605). P.J. thankfully acknowledges DAAD, Bonn,
Germany, for the award of a DAAD fellowship under the
reinvitation program-2013 for a visit to the laboratory of L.H.
S.C. thankfully acknowledges UGC, New Delhi, India, for the
award of research fellowships. We thank Mr. Sandip Kundu for
data collection and Dr. Ramalingam Natarajan for his help in
determination of structures (X-ray single-crystal), Dr. Tapas
Sarkar (NMR), and Mr. Diptendu Bhattacharya (HRMS) for
instrumental analysis.
(14) A significant difference in enantiomeric excess (ee dropped to
9%) was found when commercially available nondried DCM was used
instead of dry DCM.
(15) For chiral TRIP-catalyzed Friedel−Crafts reaction of indoles,
see: (a) Mori, K.; Wakazawa, M.; Akiyama, T. Chem. Sci. 2014, 5,
1799. (b) Terada, M.; Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 292.
(16) The relative configuration was determined by comparison with
the literature report; see: Blay, G.; Fernandez, I.; Monleon, A.; Munoz,
M. C.; Pedro, J. R.; Vila, C. Adv. Synth. Catal. 2009, 351, 2433.
(17) CCDC 1544517 (3b), CCDC 919165 [(R,R)-A], and CCDC
919163 [(S,S)-A]; see the Supporting Information for details.
REFERENCES
■
(1) For reviews on organocatalysts, see: (a) Mukherjee, S.; Yang, J.
W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471. (b) List, B.
Chem. Rev. 2007, 107, 5413. (c) List, B. Asymmetric Organocatalysis;
Springer-Verlag: Berlin, 2010.
(2) For the advent and development of organocatalysis, see:
MacMillan, D. W. C. Nature 2008, 455, 304.
D
DOI: 10.1021/acs.orglett.7b01383
Org. Lett. XXXX, XXX, XXX−XXX