An eco-friendly asymmetric organocatalytic conjugate addition of malonates to α,β-unsaturated aldehydes: Application on the synthesis of chiral indoles

Article abstract of DOI:10.1002/ejoc.201300431

The asymmetric Michael addition of malonates to α,β-unsaturated aldehydes using a modified Jorgensen-Hayashi organocatalyst in EtOH:brine solvent media is reported. The procedure proceeds smoothly to afford the corresponding Michael adducts in good yields with excellent enantioselectivities. The resulting Michael adducts represent excellent building blocks for the synthesis of chiral indoles. The asymmetric Michael reaction using a modified Jorgensen-Hayashi organocatalyst in EtOH:brine solvent media is reported. This procedure afforded the corresponding Michael adducts in good yields and with excellent enantioselectivities. The resulting adducts were further used as chiral building blocks for the synthesis of indoles. Copyright

Full text of DOI:10.1002/ejoc.201300431

Job/Unit: O30431
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Date: 25-07-13 17:03:44
Pages: 7
FULL PAPER
Asymmetric Michael Reactions
K. S. Feu, A. M. Deobald,
S. Narayanaperumal, A. G. Corrêa,
M. Weber Paixão* ............................ 1–7
An Eco-Friendly Asymmetric Organocata-
lytic Conjugate Addition of Malonates to
α,β-Unsaturated Aldehydes: Application
on the Synthesis of Chiral Indoles
Keywords: Synthetic methods / Organoca-
talysis / Michael addition / Green chemis-
try / Nitrogen heterocycles
The asymmetric Michael reaction using a
modified Jørgensen–Hayashi organocata-
lyst in EtOH:brine solvent media is re-
ported. This procedure afforded the corre-
sponding Michael adducts in good yields
and with excellent enantioselectivities. The
resulting adducts were further used as chi-
ral building blocks for the synthesis of
indoles.
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M. Weber Paixão et al.
FULL PAPER
DOI: 10.1002/ejoc.201300431
An Eco-Friendly Asymmetric Organocatalytic Conjugate Addition of
Malonates to α,β-Unsaturated Aldehydes: Application on the Synthesis of
Chiral Indoles
Karla Santos Feu,[a] Anna Maria Deobald,[a] Senthil Narayanaperumal,[a]
Arlene G. Corrêa,[a] and Márcio Weber Paixão*[a]
Keywords: Synthetic methods / Organocatalysis / Michael addition / Green chemistry / Nitrogen heterocycles
The asymmetric Michael addition of malonates to α,β-un-
saturated aldehydes using a modified Jørgensen–Hayashi or-
ganocatalyst in EtOH:brine solvent media is reported. The
procedure proceeds smoothly to afford the corresponding
Michael adducts in good yields with excellent enantio-
selectivities. The resulting Michael adducts represent excel-
lent building blocks for the synthesis of chiral indoles.
the E factor, and the volume productivity have become
similarly important.[10] Recently, aqueous solvent-mediated
organocatalytic processes have become an emerging field of
research.[11]
Introduction
Organocatalysis is represented by a set of broadly appli-
cable and efficient synthetic tools for the preparation of
many types of enantiomerically enriched and enantiomer-
ically pure molecules.[1] Chiral organic molecules used in
stereoselective reactions are usually nontoxic, highly ef-
ficient and selective and readily available.[2] In this regard,
l-proline and related derivatives[3] have risen to prominence
since List, Barbas and Lerner rediscovered that these small
molecules could stereoselectively catalyze reactions without
the requirement of transition metals.[4] In this context, the
asymmetric conjugate Michael addition[5] is one of the most
frequently used organocatalytic reactions for carbon-car-
bon and carbon-heteroatom bond formation,[6] as exem-
plified by the large number of publications in this field over
the last few years.[7] However, as with many other asymmet-
ric organocatalytic processes, volatile organic solvents are
used and a relatively high catalyst loading is required. These
characteristics of the method represent major drawbacks
for this type of Michael process.[8]
Currently, the synthetic community faces the need to ad-
dress growing environmental concerns. To lessen the envi-
ronmental impact of organic transformations, all conven-
tional synthetic methodologies, including asymmetric syn-
thetic protocols, should be reviewed and, if possible, re-
placed by new processes that continue to meet the needs of
efficiency, selectivity but that are environmentally benign.[9]
In this sense, although high yields remain imperative, al-
ternative parameters such as the “greenness” of a reaction,
Although great success has been achieved in the develop-
ment of water compatible organocatalyzed conjugation ad-
ditions through enamine chemistry,[12] the Michael addition
invoking formation of iminium ion species of α,β-unsatu-
rated aldehydes has been scarcely explored.[6c,13] This, no
doubt, is attributable to the instability of the intermediate
in aqueous solvent systems. Consequently, the development
of organocatalysts compatible with aqueous-solvent sys-
tems is gaining prominence from the perspective of green
synthetic methods.
In connection with our ongoing research program into
the development and application of environmentally benign
solvent compatible organocatalysts, we recently reported an
eco-friendly synthesis of highly functionalized epoxides and
their incorporation into an organocatalytic multi-compo-
nent approach. To this end, a modified class of diaryl proli-
nol silyl ethers (Figure 1) was designed to enable high cata-
lytic activity in an aqueous solvent system.[14] Inspired by
these results, we further employed such a catalytic system
in the Michael addition of malonates to α,β-unsaturated
aldehydes in an environmentally benign approach.
[a] Department of Chemistry, Federal University of São Carlos
(UFSCar),
CEP:13.565-905, São Carlos, SP, Brazil
E-mail: mwpaixao@ufscar.br
Homepage: www.ufscar.br
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300431.
Figure 1. l-Proline based organocatalysts employed in this study.
2
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Chiral Indoles Synthesis
cally reduced yield and enantioselectivity. Catalysts 1a, 1b
and 2b afforded the desired products in good yield and ee
thus inspiring continued reaction optimization with par-
ticular emphasis on choices of solvent, reaction time and
catalyst loading required to promote this transformation.
As shown in Table 1, the use of solvents like brine and
water led to comparatively high ee as well as good yields,
Results and Discussion
We first examined the reaction of cinnamaldehyde 3 with
diethyl malonate 4 in EtOH as a model combination to
evaluate the activity of organocatalysts 1 and 2 (Figures 1
and 2). Figure 2 discloses that organocatalysts 1a and 2b
proved more effective for this reaction in terms of yield and
enantioselectivity. Although excellent enantioselectivities
were obtained with organocatalysts 1a, 1b, 1c, and 2b, the
chemical yields of Michael adducts revealed a small erosion
in activity relative to 2b (Figure 2, catalyst 1a vs. 2b).
Though a good ee was achieved when using 1c, the chemi-
cal efficiency was very low in this instance. Interestingly,
reactions involving organocatalyst 2a, suffered both drasti-
Table 1. Optimization of organocatalyst, solvent and reaction ti-
me.[a]
Entry Catalyst Solvent
Time [h]
Yield [%][b] ee [%][c]
1
2
3
4
1a
1b
2b
1a
1b
1b
1b
1b
1b
1b
brine
brine
brine
H2O
34
34
34
97
111
34
34
34
48
72
98
93
66
71
93
57
49
86
52
9
94
95
90
94
96
96
94
94
93
n.d.
5
H2O
6[d]
7[e]
8
brine
brine
EtOH
brine
brine
9[f]
10[g]
[a] Unless otherwise specified, all reactions were performed using
cinnamaldehyde (0.6 mmol), diethyl malonate (0.3 mmol), organo-
catalyst (0.03 mmol, 10 mol-%) and PhCO2H (10 mol-%) in appro-
priate solvent (0.15 mL). [b] Isolated yield. [c] The ee values were
determined by HPLC, after oxidation to the corresponding methyl
ester. [d] 5 mol-% of catalyst. [e] At room temperature. [f] Reaction
without PhCO2H. [g] Using 1 equiv. of aldehyde and 2 equiv. of
diethyl malonate.
Figure 2. Organocatalyst screening for the addition of diethyl mal-
onate to cinnamaldehyde.
Table 2. Reaction of diethyl and dibenzyl malonate with α,β-unsaturated aldehydes catalyzed by 1b.[a]
Entry
R1
R2
EtOH/brine[b]
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
7
8
9
o-OMePh
p-OMePh
p-MePh
o-MePh
o-NO2Ph
p-FPh
p-ClPh
Ph
Hep
Et
Et
Et
Et
Et
Et
Et
Bn
Et
1:1
2:1
1:1
4:1
3:1
2:1
1:1
1:1
1:1
66
59
54
65
71
63
69
63
45
92
90
94
94
97
94
94
96
90[e]
[a] All reactions were performed on a 0.3 mmol scale. [b] Proportion of EtOH/Brine was varied due to the solubility of aldehydes. [c] Iso-
lated yield. [d] Determined by chiral HPLC after oxidation to the corresponding methyl ester. [e] Determined by chiral GC.
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M. Weber Paixão et al.
FULL PAPER
although reaction times varied significantly (Table 1, En- and with high enantioselectivities (Table 2, Entries 1–7).
tries 1–5). Considering that the outcome of such reactions When using dibenzyl malonate as the Michael donor and
might ultimately serve as fragrances, agrochemicals, pig- cinnamaldehyde as corresponding acceptor, the reaction
ments, and materials catalyst 1b proved to be the best of readily furnished the anticipated product in 63% yield and
choice for further optimization (Table 1, Entry 2). This se- with 96% ee (Table 2, Entry 8). Conversely, decenal reacted
lection was driven, of course, also by the yields and ee af- in a Michael fashion with excellent ee but in poor yield
forded by the catalytic use of 1b. Reduction of 1b catalyst relative to other substrates; self-condensation of the ali-
loading from 10 to 5 mol-% led to a significant reduction
in yield although little change to the ee was noted (Table 1,
Entries 2 vs. 6). A similarly low yield was noted also when
the reaction was performed at room temperature (Table 1,
Entry 7).
By using EtOH as the solvent system, good enantio-
selectivity (94% ee) was obtained (Table 1, Entry 8) al-
though the conversion was reduced relative to the same re-
action carried out in brine (Table 1, Entry 2). In the absence
Figure 3. Product elaboration – Kpracho decarboxylation of 5a.
of additive (PhCO2H) but with an extended reaction time
52% yield and 93% ee were noted (Table 1, Entry 9).
Furthermore, the stoichiometry of the starting material was
also evaluated; in this case the desired product was obtained
with only low yield despite the use of a prolonged reaction
time (Table 1, Entry 10).
Next, a representative selection of α,β-unsaturated alde-
hydes and dibenzyl/diethyl malonates was evaluated as
Michael acceptors using the optimized reaction conditions
to demonstrate the scope of the Michael reaction.
With respect to the R1 substituent on the aromatic ring
of the α,β-unsaturated aldehydes, we found that the pres-
ence of either electron-donating groups, (e.g., methyl/meth-
oxyl) or electron-withdrawing groups, (e.g., chloro, fluoro
and nitro), had no significant influence on the reaction out-
come. In all cases products were obtained in similar yields heterocyclic indole framework.
Figure 4. Some biologically active important molecules containing
Figure 5. Fischer indole synthesis.
4
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Chiral Indoles Synthesis
Figure 6. Product elaboration – Kpracho decarboxylation of indole.
phatic unsaturated aldehyde likely accounts for the reduced alysts was that they all contained long alkyl chains in their
yield (Table 2, Entry 9).[13d]
structures, which might play an important role in bringing
A synthetically valuable feature of the present reaction is together the hydrophobic reactants in water and sequester-
that Michael adducts 5 can be easily manipulated under ing the transition state from water.[11b,13a,14,22] However,
Krapcho’s decarboxylation conditions to give correspond- substrate activation by hydrogen bonding in a biphasic me-
ing optically active 1,5-dicarbonyl compounds (Figure 3).
dia cannot be excluded.[23] Moreover, after aldehyde acti-
We next focused on validating the applicability of this vation, the iminium ion could be stabilized by chloride
method to the synthesis of indole compounds, as the indole anion, by lowering the LUMO energy and therefore, in-
ring is considered a privileged scaffold in a variety of re- creasing the reaction rate.[24] The reaction gives good results
search areas.[15] In addition, the indole moiety is one of the for a range of substrates furnishing products in good yield
most ubiquitous heterocyclic scaffolds found in natural and good to excellent enantioselectivities. In contrast to
products and pharmaceutical compounds (Figure 4).[16,17]
known methods, the reaction proceeds smoothly in a
As a consequence, many methods to access structurally shorter reaction time to afford the corresponding Michael
diverse indoles have been developed over the past few years. adducts with excellent enantioselectivities (up to 96% ee).
Among them, Fischer’s indole synthesis still remains the From an environmental point of view, the developed
most important and versatile approach for the synthesis of method could be readily scaled up and is practically com-
indole derivatives.[17,18] Although the Fischer approach is a patible with industrial processes. The synthesized adducts
well-established methodology for ketones – still there is a have been successfully applied to the synthesis of biolo-
strong demand for versatile, protecting-group-free ap- gically important substituted indole derivatives displaying
proaches for the synthesis of these heterocyclic scaffolds diverse functionalities with relevance to medicinal chemis-
starting from enolizable aldehydes. Hence, we focused our try.
attention on the synthesis of potentially important substi-
tuted indoles from synthesized Michael adducts 5a, 5b and
5f. Using cerium ammonium nitrate (CAN)[19] as the acid
Experimental Section
promoter under microwave irradiation (Figure 5) condi-
General: 1H and 13C NMR spectra were recorded with a Bruker
tions we found that almost all conjugate adducts afforded
ARX-400 (400 and 100 MHz respectively). All NMR spectra were
excellent ee values (91–98%) with moderate to good yields
obtained with CDCl3. HPLC chromatograms of Michael adduct
were obtained using a Shimadzu apparatus, LC-10AT Pump, SPD-
(44–51%).[20] The developed method clearly enables synthe-
sis of unprotected indoles with excellent ee thus illustrating
the effectiveness of our new Michael addition methodology.
Nevertheless, the chemical efficiency of this new process
ranges only from moderate to good; the enolizable nature
of aldehydes likely enables side reactions that detract from
idealized yields.[21]
Furthermore, in an effort to realize our goal of generat-
ing synthetically useful products – the previously synthe-
sized indoles could be easily decarboxylated to afford useful
precursors for synthesis of biologically and pharmacologi-
cally active compounds (Figure 6).[15c]
10A UV/Vis Detector, SCL-10A System Controller, using a Chi-
ralpak AD-H (4.6 mmØϫ250 mmL, particle size 5 μm) or a Chi-
ralcel OD-H (4.6 mmØϫ250 mmL, particle size 5 μm). HPLC
chromatograms of indoles were obtained with a Shimadzu appara-
tus, LC-20AT Pump, SPD-M20A UV/Vis Detector, CBM-20A Sys-
tem Controller, using a Chiralcel OD-H (4.6 mmØϫ250 mmL,
particle size 5 μm). Chiral GC analyses were carried out with a
SHIMADZU 17A instrument with FID, equipped with a 30 m,
0.25 mm i.d., 0.25 μm, chiral capillary column heptakis (2,3-di-
methyl-6-pentyl)-γ-cyclodextrin. The column consisted of a mix-
ture of 20% of chiral phase and 80% of OV1701. The initial oven
temperature was 30 °C, increased at 2 °C/min to 220 °C, and then
held for 5 min. Nitrogen was the carrier gas at a flow rate of 3 mL/
min. The injector and detector (FID) temperatures were kept at
220 and 230 °C, respectively. Samples of 0.1 μL (50 ng in acetone)
were injected, with a 1:50 split ratio. Optical rotations were mea-
sured with a Perkin–Elmer Polarimeter, Mod. 241, at 589 nm, 25–
26 °C. High-resolution mass spectra were recorded using a Bruker –
AutoFlex Speed, MALDI-TOF/TOF MS (λ = 355 nm, f = 500 Hz,
matrix HCCA, calibration standard TPP, PEG 600). Column
Conclusions
In conclusion, we have developed an organocatalytic
conjugate Michael addition of malonates to various α,β-
unsaturated aldehydes in the presence of an organocatalyst
derived from proline in aqueous reaction media. The com-
mon feature of these modified diaryl prolinol silyl ether cat- chromatography was performed using Merck Silica Gel (230–
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FULL PAPER
2008, 120, 6232; Angew. Chem. Int. Ed. 2008, 47, 6138; i) X.
Yu, W. Wang, Chem. Asian J. 2008, 3, 516; j) S. Bertelsen, K. A.
Jørgensen, Chem. Soc. Rev. 2009, 38, 2178; k) P. M. Pihko, I.
Majander, A. Erkkilä, Top. Curr. Chem. 2010, 291, 29; l) R. C.
Wende, P. R. Schreiner, Green Chem. 2012, 14, 1821.
a) D. Enders, M. R. M. Hüttl, C. Grondal, G. Raabe, Nature
2006, 441, 861; b) J. Seayed, B. List, Org. Biomol. Chem. 2005,
3, 719; c) C. Grondal, M. Jeanty, D. Enders, Nature Chem.
2010, 2, 167; d) B. Westermann, C. Neuhaus, Angew. Chem.
2005, 117, 4145; Angew. Chem. Int. Ed. 2005, 44, 4077.
a) K. R. Nudsen, C. E. T. Mitchell, S. V. Ley, Chem. Commun.
2006, 66; b) R. A. Sheldon, I. Arenders, U. Hanefeld, Green
Chemistry and Catalysis; Wiley-VCH, Weinheim, Germany,
2007; c) K. L. Jensen, G. Dickmeiss, H. Jiang, Ł. Albrecht,
K. A. Jørgensen, Acc. Chem. Res. 2012, 45, 248; d) C. Palomo,
A. Mielgo, Angew. Chem. 2006, 118, 8042; Angew. Chem. Int.
Ed. 2006, 45, 7876; e) A. Quintard, A. Lefranc, A. Alexakis,
Org. Lett. 2011, 13, 1540; f) A. Quintard, A. Alexakis, Chem.
Commun. 2011, 47, 7212; g) M. Raj Vishnumaya, S. K. Gino-
tra, V. K. Singh, Org. Lett. 2006, 8, 4097; h) R. S. Schwab, F. Z.
Galetto, J. B. Azeredo, A. L. Braga, D. S. Lüdtke, M. W.
Paixão, Tetrahedron Lett. 2008, 49, 5094.
For seminal papers, see: a) B. List, C. F. Barbas III, R. Lerner,
J. Am. Chem. Soc. 2000, 122, 2295; b) K. Sakthivel, W. Notz,
T. Bui, C. F. Barbas III, J. Am. Chem. Soc. 2001, 123, 5260; c)
W. Notz, B. List, J. Am. Chem. Soc. 2000, 122, 7386; d) C.
Pidathala, L. Hoang, N. Vignola, B. List, Angew. Chem. 2003,
115, 2891; Angew. Chem. Int. Ed. 2003, 42, 2785; e) B. List,
Acc. Chem. Res. 2004, 37, 548; f) W. Notz, F. Tanaka, C. F.
Barbas III, Acc. Chem. Res. 2004, 37, 580; g) W. Notz, S.-I.
Watanabe, N. S. Chowdari, G. Zhong, J. M. Betancort, F.
Tanaka, C. F. Barbas III, Adv. Synth. Catal. 2004, 346, 1131.
a) A. Perlmutter, Conjugative Additions in Organic Synthesis,
Pergamon Press: Oxford, 1992; b) M. Yamaguchi, Conjugate
Addition of Stabilized Carbanions, in: Comprehensive Asymmet-
ric Catalysis (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamo-
toEds.), Springer, Berlin, 1999, vol. 3; c) M. P. Sibi, S. Manyem,
Tetrahedron 2000, 56, 8033; d) N. Krause, A. Hoffmann-Röder,
Synthesis 2001, 171.
a) H. Pellissier, Tetrahedron 2007, 63, 9267; b) S. Brandau, A.
Landa, J. Franzen´, M. Marigo, K. A. Jørgensen, Angew. Chem.
2006, 118, 4411; Angew. Chem. Int. Ed. 2006, 45, 4305; c) C.
Palomo, A. Landa, A. Mielgo, M. Oiarbide, A. Puente, S. Vera,
Angew. Chem. 2007, 119, 8583; Angew. Chem. Int. Ed. 2007,
46, 8431; d) C. Bhanja, S. Jena, S. Nayak, S. Mohapatra, Be-
ilstein J. Org. Chem. 2012, 8, 1668; e) D. Almasi, D. A. Alonso,
D. Najera, Tetrahedron: Asymmetry 2007, 18, 299.
400 mesh). Thin layer chromatography (TLC) was performed using
Merck Silica Gel GF254, 0.25 mm thickness. For visualization,
TLC plates were either placed under ultraviolet light, or stained
with iodine vapor, or acidic vanillin. The following solvents were
dried and purified by distillation from the reagents indicated: tetra-
hydrofuran from sodium with a benzophenone as indicator; di-
chloromethane from calcium hydride. All other solvents were ACS
grade unless otherwise noted. Air- and moisture-sensitive reactions
were conducted in flame-dried or oven dried glassware equipped
with tightly fitted rubber septa and under a positive atmosphere of
dry argon. Reagents and solvents were handled using standard sy-
ringe techniques. Non-commercial aldehydes were prepared from
literature procedures.[25]
[2]
[3]
General Procedure for Asymmetric Organocatalytic Conjugate Ad-
dition of Malonates to α,β-Unsaturated Aldehydes: Malonate
(0.3 mmol) was added to organocatalyst 1 or 2 (0.03 mmol, 10 mol-
%), α,β-unsaturated aldehyde (0.6 mmol) and PhCO2H 10 mol-%
in appropriate proportions of EtOH/Brine (0.3 mL) at 0 °C. The
reaction mixture was allowed to stir for 34 h at 5 °C. After comple-
tion of the reaction (as monitored by TLC) the resultant mixture
was extracted using EtOAc and CH2Cl2, dried with MgSO4 and
purified by silica gel chromatography (EtOAc/Hexane) to afford the
corresponding Michael adducts. The ee was determined by HPLC
analysis using a chiral column after oxidation to the corresponding
methyl ester (see: Ref. 6b).
[4]
General Synthetic Procedure for Chiral Indoles: To a solution of
arylhydrazine hydrochloride (0.6 mmol) and Michael adduct
(0.3 mmol) in EtOH (1 mL) was added CAN (0.06 mmol, 20 mol-
%) and the mixture irradiated for 20 min in a CEM Discovery®
focused microwave oven at 80 °C. The reaction mixture was then
cooled to room temperature and poured into water (2.3 mL). The
crude product was extracted with EtOAc, and the combined or-
ganic phases washed with water, dried with MgSO4, and evaporated
under reduced pressure to provide a crude brown solid, that was
further purified by column chromatography.
[5]
[6]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details and characterization data for all com-
pounds.
Acknowledgments
[7]
a) T. Ooi, T. Miki, M. Taniguchi, M. Shiraishi, M. Takeuchi,
K. Maruoka, Angew. Chem. 2003, 115, 3926; Angew. Chem.
Int. Ed. 2003, 42, 3796; b) Y. Yamamoto, N. Momiyama, H.
Yamamoto, J. Am. Chem. Soc. 2004, 126, 5962; c) M. Marigo,
J. Franzén, T. B. Poulsen, W. Zhuang, K. A. Jørgensen, J. Am.
Chem. Soc. 2005, 127, 6964; d) R. Ballini, G. Bosica, D. Fio-
rini, A. Palmieri, M. Petrini, Chem. Rev. 2005, 105, 933; e) F.
Wu, R. Hong, J. Khan, X. Liu, L. Deng, Angew. Chem. 2006,
118, 4407; Angew. Chem. Int. Ed. 2006, 45, 4301; f) Y. K. Chen,
M. Yoshida, D. W. C. MacMillan, J. Am. Chem. Soc. 2006, 128,
K. S. F. thanks Coordenação de Aperfeiçoamento de Pessoal de
Nível Superior (CAPES) for Master’s fellowship, while A. M. D.
and S. N. is a FAPESP fellowship holder for Ph.D. and Postdoc,
and cordially acknowledges their financial support. We are also
indebted to Conselho Nacional de Desenvolvimento Científico e
Tecnológico (CNPq) (INCT-Catálise and INBEQMeDI) and Fun-
dação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
(2009/07281-0) for financial support. The authors thank Prof. Dr.
Daniel G. Rivera for useful discussions.
9328; g) D. Almasi, D. A. Alonso, C. Nájera, Tetrahedron:
¸
Asymmetry 2007, 18, 299; h) H. Pellissier, Tetrahedron 2007,
63, 9267; i) G. Guillena, D. J. Ramón, M. Yus, Tetrahedron:
Asymmetry 2007, 18, 693; j) D. Enders, K. Lüttgen, A. A. Nar-
[1] For reviews on organocatalysis, see: a) P. I. Dalko, L. Moisan,
Angew. Chem. 2001, 113, 3840; Angew. Chem. Int. Ed. 2001,
40, 3726; b) P. I. Dalko, L. Moisan, Angew. Chem. 2004, 116,
5248; Angew. Chem. Int. Ed. 2004, 43, 5138; c) B. List, Chem.
Rev. 2007, 107, 5413; d) S. Mukherjee, J. W. Yang, S.
Hoffmann, B. List, Chem. Rev. 2007, 107, 5471; e) D. Enders,
C. Grondal, M. R. M. Hüttl, Angew. Chem. 2007, 119, 1590;
Angew. Chem. Int. Ed. 2007, 46, 1570; f) D. W. C. MacMillan,
Nature 2008, 455, 304; g) A. Dondoni, A. Massi, Angew. Chem.
2008, 120, 4716; Angew. Chem. Int. Ed. 2008, 47, 4638; h) P.
Melchiorre, M. Marigo, A. Carlone, G. Bartoli, Angew. Chem.
ine, Synthesis 2007, 959; k) D. Almasi, D. A. Alonso, E.
¸
Gómez-Bengoa, Y. Nagel, C. Nájera, Eur. J. Org. Chem. 2007,
2328; l) H. Pellissier, Tetrahedron 2007, 63, 9267; m) S. B. Tsog-
oeva, Eur. J. Org. Chem. 2007, 1701; n) J. L. Vicario, D. Badia,
L. Carrillo, Synthesis 2007, 2065; o) B. Tan, X. Zeng, Y. Lu,
P. J. Chua, G. Zhong, Org. Lett. 2009, 11, 1927; p) Y. Liu, B.
Sun, B. Wang, M. Wakem, L. Deng, J. Am. Chem. Soc. 2009,
131, 418; q) Y.-F. Sheng, Q. Gu, A.-J. Zhang, S.-L. You, J. Org.
Chem. 2009, 74, 6899; r) S. Chandrasekhar, K. Mallikarjum,
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Date: 25-07-13 17:03:44
Pages: 7
Chiral Indoles Synthesis
G. Pavankumarreddy, K. V. Rao, B. Jagadeesh, Chem. Com-
mun. 2009, 4985; s) S. Syu, T.-T. Kao, W. Lin, Tetrahedron
2010, 66, 891; t) G.-L. Zhao, A. Córdova, Tetrahedron Lett.
2007, 48, 5976; u) Y. Wang, P. Li, X. Liang, J. Ye, Adv. Synth.
Catal. 2008, 350, 1383; v) I. Fleischer, A. Pfaltz, Chem. Eur. J.
2010, 16, 95.
Yamamoto, Chem. Rev. 2004, 104, 2127; f) S. Cacchi, G. Fab-
rizi, Chem. Rev. 2005, 105, 2873; g) G. R. Humphrey, J. T. Kue-
the, Chem. Rev. 2006, 106, 2875; h) K. Kruger, A. Tillack, M.
Beller, Adv. Synth. Catal. 2008, 350, 2153; i) R. Vincente, Org.
Biomol. Chem. 2011, 9, 6469; j) D. F. Taber, P. K. Tirunahari,
Tetrahedron 2011, 67, 7195; k) S. Cacchi, G. Fabrizi, Chem.
Rev. 2011, 111, 215; l) M. Platon, R. Amardeil, L. Djakovitchb,
J.-C. Hierso, Chem. Soc. Rev. 2012, 41, 3929; m) M. Inman,
C. J. Moody, Chem. Sci. 2013, 4, 29. For biological application
of substituted indole, see: n) M. W. Robinson, J. H. Overmeyer,
A. M. Young, P. W. Erhart, W. A. Maltese, J. Med. Chem. 2012,
55, 1940; o) R. Álvarez, P. Puebla, J. F. Díaz, A. C. Bento, R.
García-Navas, J. de la Iglesia-Vicente, F. Mollinedo, J. M. And-
reu, M. Medarde, R. Pelaéz, J. Med. Chem. 2013, 56, 2813; p)
A. J. Liedtke, A. O. Adeniji, M. Chen, M. C. Byrns, Y. Jin,
D. W. Christianson, L. J. Marnett, T. M. Penning, J. Med.
Chem. 2013, 56, 2429.
[8] a) J. G. Hernández, E. Juaristi, Chem. Commun. 2012, 48, 5396;
b) Y.-F. Wang, R.-X. Chem, K. Wang, B.-B. Zhang, Z.-B. Li,
D.-Q. Xu, Green Chem. 2012, 14, 893; c) W. Zhang, Green
Chem. 2009, 11, 911; d) B. Ni, Q. Zhang, A. D. Headley, Green
Chem. 2007, 9, 737; e) M. Jörres, S. Mersmann, G. Raabe, C.
Bolm, Green Chem. 2013, 15, 612.
[9] a) P. T. Anastas, T. C. Williamson, Green Chemistry: Frontiers
in Benign Chemical Syntheses and Processes, Oxford Science
Publications, New York, 1998; b) J. M. DeSimone, Science
2002, 297, 799; c) P. J. Walsh, H. Li, C. Anaya de Parrodi,
Chem. Rev. 2007, 107, 2503; d) S. Narayanaperumal, R. C.
Silva, K. S. Feu, A. F. Torre, A. G. Corrêa, M. W. Paixão, Ul-
trason. Sonochem. 2013, 20, 793.
[17] G. W. Gribble, J. Chem. Soc. Perkin Trans. 1 2000, 1045.
[18] For selected recent references on Fischer’s indole synthesis
using ketones as electrophiles, see: a) H.-S. Mun, W.-H. Ham,
J.-H. Jeong, J. Comb. Chem. 2005, 7, 130; b) H. Chen, L. S.
Eberlin, M. Nefliu, R. Augusti, R. G. Cooks, Angew. Chem.
2008, 120, 3470; Angew. Chem. Int. Ed. 2008, 47, 3422; c) D.
McAusland, S. Seo, D. G. Pintori, J. Finlayson, M. F. Greaney,
Org. Lett. 2011, 13, 3667. Using aldehydes as electrophiles, see:
d) P. Linnepe (née Köhling), A. M. Schmidt, P. Eilbracht, Org.
Biomol. Chem. 2006, 4, 302; e) A. Porcheddu, M. G. Mura,
L. D. Luca, M. Pizzetti, M. Taddei, Org. Lett. 2012, 14, 6112.
For representative modifications on Fischer’s indole Synthesis
see: f) S. Wagaw, B. H. Yang, S. L. Buchwald, J. Am. Chem.
Soc. 1998, 120, 6621; g) I.-K. Park, S.-E. Suh, B.-Y. Lim, C.-
G. Cho, Org. Lett. 2009, 11, 5454; h) B. A. Haag, Z.-G. Zhang,
J.-S. Li, P. Knochel, Angew. Chem. 2010, 122, 9703; Angew.
Chem. Int. Ed. 2010, 49, 9513; i) N. T. Patil, A. Konala, Eur. J.
Org. Chem. 2010, 6831; j) M. Inman, C. J. Moody, Chem. Com-
mun. 2011, 47, 788; k) D. McAusland, S. Seo, D. G. Pintori, J.
Finlayson, M. F. Greaney, Org. Lett. 2011, 13, 3667; l) I.-K.
Park, J. Park, C.-G. Cho, Angew. Chem. 2012, 124, 2546; An-
gew. Chem. Int. Ed. 2012, 51, 2496; m) S. Gore, S. Baskaran,
B. König, Org. Lett. 2012, 14, 4568; n) F. Zhan, G. Liang,
Angew. Chem. Int. Ed. 2013, 52, 1266.
[19] For a review of CAN and its uses, see: V. Sridharan, J. C.
Menendez, Chem. Rev. 2010, 110, 3805.
[20] See ESI for optimization and synthetic procedures for unpro-
tected indoles.
[21] a) P. Köhling, A. M. Schmidt, P. Eilbracht, Org. Lett. 2003,
5, 3213; b) V. Khedkar, A. Tillack, M. Michalik, M. Beller,
Tetrahedron 2005, 61, 7622; c) N. Çelebi-Ölçüm, B. W. Boal,
A. D. Huters, N. K. Crag, K. N. Houk, J. Am. Chem. Soc.
2011, 133, 5752.
[22] N. Mase, Y. Nakai, N. Ohara, H. Yoda, K. Takabe, F. Tanaka,
C. F. Barbas III, J. Am. Chem. Soc. 2006, 128, 734.
[10] a) R. A. Sheldon, Chem. & Ind. 1992, 903; b) E. N. Jacobsen,
N. S. Finney, Chem. Biol. 1994, 1, 85.
[11] a) S. Toma, R. Sebesta, M. Meciarova, Curr. Org. Chem. 2011,
15, 2257; b) N. Mase, C. F. Barbas III, Org. Biomol. Chem.
2010, 8, 4043; c) M. Raj, V. K. Singh, Chem. Commun. 2009,
44, 6687; d) M. Gruttadauria, F. Giacalone, R. Noto, Adv.
Synth. Catal. 2009, 351, 33; e) A. P. Brogan, T. J. Dickerson,
K. D. Janda, Angew. Chem. 2006, 118, 8278; Angew. Chem. Int.
Ed. 2006, 45, 8100; f) Y. Hayashi, Angew. Chem. 2006, 118,
8281; Angew. Chem. Int. Ed. 2006, 45, 8103; g) S. Duce, A.
Mateo, I. Alonso, J. L. G. Ruano, M. B. Cid, Chem. Commun.
2012, 48, 5184.
[12] For selected examples of Michael reactions in aqueous media
proceeding through an enamine mechanism, see: a) N. Mase,
K. Watanabe, H. Yoda, K. Takabe, F. Tanaka, C. F. Barbas III,
J. Am. Chem. Soc. 2006, 128, 4966; b) S. Luo, X. Mi, S. Liu,
H. Xu, J. P. Cheng, Chem. Commun. 2006, 3687; c) L. Zu, J.
Wang, H. Li, W. Wang, Org. Lett. 2006, 8, 3077; d) A. Carlone,
M. Marigo, C. North, A. Landa, K. A. Jørgensen, Chem. Com-
mun. 2006, 4928; e) V. Singh, V. K. Singh, Org. Lett. 2007, 9,
1117; f) S. Zhu, S. Yu, D. Ma, Angew. Chem. 2008, 120, 555;
Angew. Chem. Int. Ed. 2008, 47, 545; g) S. Belot, A. Massaro,
A. Tenti, A. Mordini, A. Alexakis, Org. Lett. 2008, 10, 4557;
h) J. Wang, F. Yu, X. Zhang, D. Ma, Org. Lett. 2008, 10, 2561;
i) J. Wu, B. Ni, A. D. Headley, Org. Lett. 2009, 11, 3354.
[13] For examples of Michael additions in aqueous media proceed-
ing through an iminium mechanism, see: a) A. Ma, S. Zhu, D.
Ma, Tetrahedron Lett. 2008, 49, 3075; b) Z. Mao, Y. Jia, W. Li,
R. Wang, J. Org. Chem. 2010, 75, 7428; c) S. K. Ghosh, K.
Dhungana, A. D. Headley, B. Ni, Org. Biomol. Chem. 2012, 10,
8322; d) B. J. Bench, C. Liu, C. R. Evett, C. M. H. Watanabe,
J. Org. Chem. 2006, 71, 9458.
[14] General procedure for the synthesis of catalyst 1 and 2 details
and characterization, see: A. M. Deobald, A. G. Corrêa, D. G.
Rivera, M. W. Paixão, Org. Biomol. Chem. 2012, 10, 7681.
[15] a) R. J. Sundberg, in: The Chemistry of Indoles, Academic
Press, New York, 1970; b) R. K. Brown, in: Indoles (Ed.: W. J.
Houlihan), Wiley-Interscience, New York, 1972; c) H. Johans-
son, T. B. Jørgensen, D. E. Gloriam, H. Bräuner-Osborne,
D. S. Pedersen, RSC Adv. 2013, 3, 945.
[16] For reviews on indole syntheses, see: a) B. Robinson, Chem.
Rev. 1963, 63, 373; b) B. Robinson, Chem. Rev. 1969, 69, 227;
c) M. Bandini, A. Eichholzer, Angew. Chem. 2009, 121, 9786;
Angew. Chem. Int. Ed. 2009, 48, 9608; d) F. Alonso, I. P. Belets-
kaya, M. Yus, Chem. Rev. 2004, 104, 3079; e) I. Nakamura, Y.
[23] Y. Yung, R. A. Marcus, J. Am. Chem. Soc. 2007, 129, 5492.
[24] a) S. Lakhdar, H. Mayr, Chem. Commun. 2011, 47, 1866; b) D.
Marcoux, P. Bindschädler, A. W. H. Speed, A. Chiu, J. E. Pero,
G. A. Borg, D. A. Evans, Org. Lett. 2011, 13, 3758; c) S. Duce,
A. Mateo, I. Alonso, J. L. G. Ruano, M. B. Cid, Chem. Com-
mun. 2012, 48, 5184.
[25] a) L. Zu, S. Zhang, H. Xie, W. Wang, Org. Lett. 2009, 11, 1627;
b) J. Kang, G. J. Lim, S. K. Yoon, M. Y. Kim, J. Org. Chem.
1996, 60, 564; c) M. Avi, R. Gaisberger, S. Feichtenhofer, H.
Griengl, Tetrahedron 2009, 65, 5418.
Received: March 23, 2013
Published Online: ᭿
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