Proline-catalyzed asymmetric formal α-alkylation of aldehydes via vinylogous iminium ion intermediates generated from arylsulfonyl indoles

Article abstract of DOI:10.1002/anie.200803947

(Chemical Equation Presented) Proline strikes again: The intermolecular enamine-catalyzed asymmetric formal a-alkylation of aldehydes is described. Alkylating reagent 1 generates a highly stabilized carbocation, which can readily intercept the enamine intermediate. L-Proline proved to be the best catalyst, providing an easy route to relevant 3-indolyl derivatives 2 with high diastereo-and enantiocontrol.

Full text of DOI:10.1002/anie.200803947

Angewandte
Chemie
DOI: 10.1002/anie.200803947
Asymmetric Organocatalysis (3)
Proline-Catalyzed Asymmetric Formal a-Alkylation of Aldehydes via
Vinylogous Iminium Ion Intermediates Generated from Arylsulfonyl
Indoles**
Rafik R. Shaikh, Andrea Mazzanti, Marino Petrini,* Giuseppe Bartoli, and Paolo Melchiorre*
Catalysis with chiral secondary amines (asymmetric amino-
catalysis) has become a well-established and powerful syn-
thetic tool for modern synthetic chemistry.[1] The impressive
level of scientific competition and high quality research
generated in this area have opened up new synthetic
opportunities that were considered inaccessible only a few
years ago. Even reactions that had been considered impos-
sible became a reality through aminocatalysis. One of the best
validations of this approach is the development of the
Herein, we report a new challenging strategy for the
asymmetric intermolecular enamine-catalyzed formal a-alky-
lation of aldehydes.[2] The novel approach is founded upon the
use of a reagent 1 (Scheme 1), which, because of the presence
catalytic, asymmetric direct a-alkylation of aldehydes.[2] This
[3]
À
highly challenging and valuable C C bond-forming strategy
was completely unknown before the advent of asymmetric
aminocatalysis.[4] In 2004, Vignola and List presented the first
catalytic asymmetric intramolecular a-alkylation of haloal-
dehydes under enamine catalysis.[5] They demonstrated the
ability of proline-derived catalysts to overcome the classical
drawbacks associated with the stoichiometric alkylation of
preformed aldehyde enolates, such as the tendency toward
aldol condensation and the Canizzaro or Tischenko reac-
tions.[6] However, extension of their aminocatalytic strategy to
an intermolecular version failed because of deactivation of
the amine catalyst by N-alkylation with the alkyl halide.[5a]
Thus, chemists started to search for different amino-
catalytic strategies to accomplish the challenging goal of an
intermolecular formal aldehyde a-alkylation.[7] In 2006,
Ibrahem and Córdova reported a non-asymmetric catalytic
intermolecular a-allylic alkylation of aldehydes by combina-
tion of transition-metal and enamine catalysis.[8] More
recently, MacMillan and co-workers exploited a new amino-
catalytic activation concept, based on radical intermediates,
to solve the synthetic problems of the catalytic asymmetric a-
allylation,[9a] arylation,[9a] enolation,[9b] and vinylation[9c] of
unmodified aldehydes.
Scheme 1. New approach for the intermolecular a-alkylation of alde-
hydes.
of a suitable leaving group, can generate a highly stabilized
carbocation that can readily intercept the enamine inter-
mediate.[10] l-Proline, a natural molecule that has played a
central role in the development of asymmetric aminocatal-
ysis,[11] proved to be the best catalyst for affording valuable
alkylation products with an indolic core in good yield and with
high level of stereoselectivity.
At the outset of our investigations, we identified the
nature of the alkylating agent 1 as the crucial point for the
development of an efficient formal alkylation strategy.
Recently, we introduced 3-(1-arylsulfonylalkyl)indoles as
suitable electrophilic precursors.[12] The sulfonyl moiety at
the benzylic position of 3-substituted indoles constitutes a
good leaving group, which under basic or acidic conditions
allows the generation of an electrophilic species that is able to
react with nucleophiles. With this in mind, and convinced of
the compatibility between a chiral secondary amine and a
stronger base, necessary for the in situ generation of the
actual alkylating intermediate, we sought to develop a simple
protocol for the aminocatalytic formal alkylation of alde-
hydes. For the exploratory studies, we selected the reaction
between propanal and the bench-stable sulfonylindole 1a,
leading to the 3-substituted indole 2a with two adjacent
stereocenters (Table 1).
[*] R. R. Shaikh, Prof. M. Petrini
Dipartimento di Scienze Chimiche, Università di Camerino
via S. Agostino 1, 62032 Camerino (Italy)
E-mail: marino.petrini@unicam.it
Dr. A. Mazzanti, Prof. G. Bartoli, Dr. P. Melchiorre
Dipartimento di Chimica Organica “A. Mangini”, Alma Mater
Studiorum, Università di Bologna
Viale Risorgimento 4, 40136 Bologna (Italy)
Fax: (+39)051-209-3654
E-mail: p.melchiorre@unibo.it
[**] D. Agostino is gratefully acknowledged for his help. This work was
supported by Bologna University and by MIUR National Project
“Stereoselezione in Sintesi Organica”.
Initial results revealed that, of the bases tested, whether
organic or inorganic, only KF supported on basic alumina was
able to promote the in situ formation of the electrophilic
compound from 1a. Surprisingly, in such a heterogeneous
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803947.
Angew. Chem. Int. Ed. 2008, 47, 8707 –8710
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8707

Communications
Table 1: Optimization studies.[a]
Table 2: Scope of the proline-catalyzed intermolecular a-alkylation of
aldehydes.[a]
Entry R1
R2
R3
2
Yield [%][b] d.r.[c] ee [%][d]
1
2
3
4
5
6
7
8
Me
Et
iPr
PhCH2
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
a
b
c
d
e
f
g
h
i
86
92
79
74
77
75
80
82
78
77
80
63
5:1
6.5:1
8:1
6:1
4.5:1
5:1
12:1
7:1
7:1
3:1
3:1
90
86
90
89
88
88
92
84
88
88
11
75
Entry Cat. Base
Solvent Yield [%][b] d.r.[c] ee [%][d]
1
2
3
4
5
6
7
8
9
A
A
A
K2CO3
DBU
CH2Cl2
CH2Cl2
0
–
–
3:1
–
–
–
86
–
<5
51
<5
MeSCH2 Ph
KF/alumina[e] CH2Cl2
allyl
iPr
iPr
iPr
iPr
iPr
Me
Ph
p-Br-C6H4
p-MeO-C6H4 Me
p-Me-C6H4
Ph
B–D KF/alumina[e] CH2Cl2
A
A
A
A
A
KF/alumina[e] toluene 45
2.5:1 74
KF/alumina[e] CHCl3
KF/alumina[e] THF
KF/alumina[e] acetone
KF/alumina[f] CH2Cl2
63
<10
0
3:1
–
–
75
–
–
9
Me
Ph
H
10
11
12
j
k
l
Ph
pentyl
86
5:1
90
Ph
1.5:1
[a] Reactions carried out on a 0.1 mmol scale using 3 equiv of propanal;
DCA=dichloroacetic acid; DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
[b] Yield of isolated product. [c] Determined by 1H NMR spectroscopy
of the crude mixture. [d] Determined by chiral HPLC analysis. [e] 80 mg
per 0.1 mmol. [f] 40 mg per 0.1 mmol.
[a] Reactions carried out on a 0.2 mmol scale using 3 equiv of aldehydes
and 80 mg of KF on alumina. [b] Yield of isolated product. [c] Determined
by 1H NMR spectroscopy of the crude mixture. [d] Determined by chiral
HPLC analysis.
system only l-proline provided catalytic activity, leading to
the formation of 2a in good yield and reasonable stereose-
lectivity (Table 1, entry 3). All the other chiral secondary
amines tested (B–D) failed in promoting the reaction
(Table 1, entry 4), highlighting the crucial function of the
carboxylic group of A. We also found a trend toward
increased rates and stereoselectivity as the polarity of the
solvent decreased (Table 1, entries 5–8). The best result in
terms of both yield and stereocontrol was achieved by
performing the proline-catalyzed reaction in CH2Cl2 and
adjusting the amount of the KF on alumina (Table 1, entry 9).
These catalytic conditions were selected for further explora-
tion aimed at expanding the scope of this transformation.
As portrayed in Table 2, the method proved to be
successful for a wide range of aliphatic aldehyde substituents,
including alkenyl and heterosubstituted groups (entries 1–6,
d.r. > 4.5:1, 86–90% ee).
Using isovaleraldehyde, structural variation in the alky-
lating reagent 1 was then briefly inspected (Table 2, entries 7–
11). Whereas the presence of different substituents R2 on the
aryl group had apparently little influence on the stereochem-
ical outcome of the reaction (Table 2, entries 7–9), the steric
nature of the indole core had a direct effect on the
stereoselectivity (Table 2, entries 10 and 11): that is, the lack
of a 2-substituent on the indolic scaffold drastically lowered
the stereoselectivity (Table 2, entry 11).[13] Finally, also sulfo-
nyl indole with an aliphatic R2 substituent can be employed,
although the a-alkylation product 2l was isolated with
moderate stereoselectivity (d.r. 1.5:1, 75% ee; Table 2,
entry 12).
Figure 1. X-ray crystal structure of compound 3.
At this point of our investigations, a detailed mechanistic
explanation of the stereodifferentiation appears premature.
However, all the experimental evidence supports the direct
involvement of the carboxylic group of proline.[15]
Although rationalization of the catalytic system is com-
plicated by the presence of a heterogeneous basic support, a
crucial role of the acid may be envisaged when considering
the likely formation of intermediate 4 after deprotonation
and loss of the leaving group of 1 (Scheme 2). Protonation of
this vinylogous imino derivative 4 by the carboxylic group of
the catalyst would strongly activate the system toward a
nucleophilic attack, resembling iminium ion activation.[16]
However, formation of the carbocation, which would pre-
serve the aromaticity of the indolic core, and its involvement
The relative and absolute configuration of compound 2d
was determined to be 2R,3S by anomalous dispersion X-ray
crystallography of the corresponding tosylated alcohol 3,
obtained by simple aldehyde reduction (Figure 1).[14]
Scheme 2.
8708 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 8707 –8710

Angewandte
Chemie
[10,17]
À
[8] I. Ibrahem, A. Córdova, Angew. Chem. 2006, 118, 1986; Angew.
in the C C bond-forming event may also be envisaged.
Chem. Int. Ed. 2006, 45, 1952.
Within this mechanistic framework, the derived proline
anionic enamine species might engage in electrostatic asso-
ciation through the pendant carboxylate group with the
positively charged intermediate.[18] This hypothesis is consis-
tent with the lack of reactivity of the secondary amines B–D
tested and the deleterious effect of polar reaction media on
both reactivity and stereoselectivity.[19]
In summary, we have discovered a novel strategy for the
enamine-catalyzed formal a-alkylation of aldehydes. The use
of l-proline allows easy access to relevant 3-indolyl deriva-
tives 2 with high diastereo- and enantiocontrol, affording an
easy alternative to the classical Friedel–Crafts route to these
compounds.[20] Further studies are focusing on the extension
of the method and on complete comprehension of the
mechanism involved. [21]
[9] a) T. D. Beeson, A. Mastracchio, J.-B. Hong, K. Ashton, D. W. C.
MacMillan, Science 2007, 316, 582; b) H.-Y. Jang, J.-B. Hong,
D. W. C. MacMillan, J. Am. Chem. Soc. 2007, 129, 7004; c) H.
Kim, D. W. C. MacMillan, J. Am. Chem. Soc. 2008, 130, 398.
[10] Both the carbocation and the vinylogous iminium ion inter-
mediate depicted in Scheme 2 are contributing resonance
structures. One referee suggested that the presented process be
considered as a “simple” conjugate addition, in which the
catalytically generated enamine intercepts the vinylogous imi-
nium ion intermediate. However, an SN1-type reaction involving
the carbocation, leading to a “formal” a-alkylation, may also be
possible (see Ref. [17]). Considering the unconventional nature
of the electrophilic system, the presented process surely escapes
classical definitions.
[11] For reviews, see: a) B. List, Tetrahedron 2002, 58, 5573; b) M.
Movassaghi, E. N. Jacobsen, Science 2002, 298, 1904.
[12] a) R. Ballini, A. Palmieri, M. Petrini, R. R. Shaikh, Adv. Synth.
Catal. 2008, 350, 129; b) A. Palmieri, M. Petrini, J. Org. Chem.
2007, 72, 1863; c) R. Ballini, A. Palmieri, M. Petrini, E.
Torregiani, Org. Lett. 2006, 8, 4093.
Received: August 9, 2008
Published online: October 7, 2008
[13] Also the use of 5-chloro-(2H)-sulfonyl indole derivative
afforded poor results in terms of stereoselectivity (88% yield,
d.r. 3:1, 17% ee). This result is likely due to a steric rather than
an electronic effect.
[14] CCDC 700758 (3) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
Keywords: aldehydes · alkylation · indoles · organocatalysis ·
proline
.
[1] For recent reviews on aminocatalysis, see: a) C. F. Barbas III,
Angew. Chem. 2008, 120, 44; Angew. Chem. Int. Ed. 2008, 47, 42;
b) P. Melchiorre, M. Marigo, A. Carlone, G. Bartoli, Angew.
Chem. 2008, 120, 6232; Angew. Chem. Int. Ed. 2008, 47, 6138;
c) S. Mukherjee, J. W. Yang, S. Hoffmann, B. List, Chem. Rev.
2007, 107, 5471; d) G. Lelais, D. W. C. MacMillan, Aldrichimica
Acta 2006, 39, 79.
[15] O-Methylation of the carboxylic group of proline had
a
deleterious effect on both the reactivity and selectivity of the
process (25 mol% of hydrochloric salt of proline methyl ester,
less than 30% conversion, d.r. 1.1:1 and < 10% ee under the
optimal reaction conditions).
[2] The conventional a-alkylation of carbonyl compounds is con-
sidered to be an SN2 addition to alkyl halides and generally
utilizes stoichiometric amounts of metal enolates.
[16] Adding silica gel (100 mg per 0.1 mmol) to the reaction mixture
had a beneficial effect on the reactivity, which supports the
mechanistic requirement for the protonation of 4. Even catalysts
that proved to be inactive under the reported conditions led to
product formation: for example, catalyst B (25 mol%) in the
reaction of propanal with 1a afforded 2a in 45% yield with high
enantioselectivity (85% ee) but poor diastereoselectivity
(d.r.1.1:1).
[17] The formation of such a carbocation has been recently proposed
by Enders; see: a) D. Enders, A. A. Narine, F. Toulgoat, T.
Bisschops, Angew. Chem. 2008, 120, 5744; Angew. Chem. Int. Ed.
2008, 47, 5661. For related papers, see: b) F. Colombo, G.
Cravotto, G. Palmisano, A. Penoni, M. Sisti, Eur. J. Org. Chem.
2008, 2801; c) B. Ke, Y. Qin, Q. He, Z. Huang, F. Wang,
Tetrahedron Lett. 2005, 46, 1751.
[18] The proposed mechanism closely resembles the direct electro-
static activation (DEA) concept advanced by MacMillan to
rationalize the mechanism of the aminocatalytic asymmetric
cyclopropanation of enals; see: a) R. K. Kunz, D. W. C. Mac-
Millan, J. Am. Chem. Soc. 2005, 127, 3240. It should be also
noted that proline is typically a poor catalyst for enamine-
activated aldehyde additions to Michael acceptors: b) B. List, P.
Pojarliev, J. Martin, Org. Lett. 2001, 3, 2423..
[19] The sense of asymmetric induction is opposite to that observed
in other proline-catalyzed asymmetric a-functionalization of
aldehydes believed to proceed by a hydrogen-bond-directing
approach of the electrophiles. The observed stereochemical
outcome is consistent with the proposed electrostatic activation
mode when assuming the syn-E-enamine of proline as the
reactive intermediate, because of the closer proximity with the
vinylogous iminium ion intermediate; see Ref. [18a] for similar
[3] a) Modern Carbonyl Chemistry (Ed.: J. Otera), Wiley-VCH,
Weinheim, 2000; b) S. Carrettin, J. Guzman, A. Corma, Angew.
Chem. 2005, 117, 2282; Angew. Chem. Int. Ed. 2005, 44, 2242.
[4] For phase-transfer catalytic asymmetric a-alkylation of glycine
derivatives, see: a) T. Ooi, K. Maruoka, Angew. Chem. 2007, 119,
4300; Angew. Chem. Int. Ed. 2007, 46, 4222 and references
therein. For catalytic asymmetric alkylations of preformed
lithium enolates with oligoamine catalysts, see: b) M. Imai, A.
Hagihara, H. Kawasaki, K. Manabe, K. Koga, J. Am. Chem. Soc.
1994, 116, 8829. For metal-catalyzed asymmetric alkylations of
preformed tin enolates, see: c) A. G. Doyle, E. N. Jacobsen, J.
Am. Chem. Soc. 2005, 127, 62.
[5] a) N. Vignola, B. List, J. Am. Chem. Soc. 2004, 126, 450; b) A. Fu,
B. List, W. Thiel, J. Org. Chem. 2006, 71, 320. This reaction was
the first nucleophilic substitution proceeding under enamine
catalysis and opened up unexplored routes for asymmetric
aminocatalysis.
[6] a) H. O. House, W. C. Liang, P. D. Weeks, J. Org. Chem. 1974, 39,
3102; b) G. Stork, A. Brizzolara, H. Landesman, J. Szmuszko-
vicz, R. Terrell, J. Am. Chem. Soc. 1963, 85, 8829.
[7] For organocatalytic asymmetric domino reactions consisting of
Michael addition followed by intramolecular a-alkylation of
aldehydes, leading to cyclic compounds, see: a) H. Xie, L. Zu, H.
Li, J. Wang, W. Wang, J. Am. Chem. Soc. 2007, 129, 10886; b) R.
Rios, H. SundØn, J. Vesely, G.-L. Zhao, P. Dziedzic, A. Córdova,
Adv. Synth. Catal. 2007, 349, 1028; c) R. Rios, J. Vesely, H.
SundØn, I. Ibrahem, G.-L. Zhao, A. Córdova, Tetrahedron Lett.
2007, 48, 5835; d) D. Enders, C. Wang, J. W. Bats, Angew. Chem.
2008, 120, 7649; Angew. Chem. Int. Ed. 2008, 47, 7539.
Angew. Chem. Int. Ed. 2008, 47, 8707 –8710
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 8709

Communications
considerations. Theoretical studies are underway to shed more
light on the mechanistic path.
[21] Note added in proof: After acceptance of this manuscript, the
asymmetric intermolecular a-alkylation of aldehydes with
activated alkyl halides has been accomplished, exploiting the
combination of photoredox catalysis with emamine catalysis:
D. A. Nicewicz, D. W. C. MacMillan, Science 2008, DOI:10.1126/
science.1161976.
[20] A stereoselective Friedel–Crafts approach to 2 should be based
upon an asymmetric addition to a,b-disubstituted unsaturated
aldehydes, a challenging yet elusive transformation. For a
different organocatalytic entry to 2, see: Y. Chi, S. T. Scroggins,
J. M. J. FrØchet, J. Am. Chem. Soc. 2008, 130, 6322.
8710
www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 8707 –8710