Synergistic stereoselective organocatalysis with indium(III) salts

Article abstract of DOI:10.1055/s-0033-1341022

The compatibility of indium(III) Lewis acids with water and amines allows their employment in synergistic and cooperative catalysis. Stereoselective organocatalytic S_N1-type reactions, in which carbenium ions are generated, are promoted by the presence of indium salts. The peculiar properties of indium salts can be exploited in organocatalysis for the design of water-compatible, benign, green processes. The development of such indium(III)-promoted organocatalytic procedures is the focus of our recent research, a summary of which is presented in this article. Georg Thieme Verlag Stuttgart.New York.

Full text of DOI:10.1055/s-0033-1341022

SPECIAL TOPIC
▌1321
special topic
Synergistic Stereoselective Organocatalysis with Indium(III) Salts
Organocatalysis with Indium(III) Salts
Andrea Gualandi,a Luca Mengozzi,a Claire Margaret Wilson,b Pier Giorgio Cozzi*a
a
Dipartimento di Chimica ‘G. Ciamician’, ALMA MATER STUDIORUM – Università di Bologna, Via Selmi 2, 40126 Bologna, Italy
Fax +39(051)2099456; E-mail: piergiorgio.cozzi@unibo.it
b
Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Dublin, Ireland
Received: 14.01.2014; Accepted after revision: 25.02.2014
The indium(III) chloride catalyzed Mukaiyama aldol re-
action has been investigated in detail by Juaristi, with at-
tempts made to achieve good reactivity in water-
containing solvents.6 In addition, enantioselective vari-
Abstract: The compatibility of indium(III) Lewis acids with water
and amines allows their employment in synergistic and cooperative
catalysis. Stereoselective organocatalytic SN1-type reactions, in
which carbenium ions are generated, are promoted by the presence
of indium salts. The peculiar properties of indium salts can be ex- ants of the reaction have been developed.7 The Lewis acid
ploited in organocatalysis for the design of water-compatible, be-
nign, green processes. The development of such indium(III)-
properties of indium salts in the presence of water (pro-
duced as a reaction by-product) makes it possible to use
promoted organocatalytic procedures is the focus of our recent re-
indium(III) in such multicomponent reactions.8 The
search, a summary of which is presented in this article.
Lewis acidity of indium(III) salts can also be modulated
by combination with silylating agents.9 The remarkable
Key words: organocatalysis, stereoselective, amine catalysis,
enamine-mediated catalysis, indium(III)
enhancement of the Lewis acidity of indium(III) chloride
by chlorosilanes can be seen in various reactions such as
the aza-Michael addition of carbamates to enones,10
Synergistic catalysis was recently defined as the synthetic
Friedel–Crafts alkylation, hydrosilylation, and reductive
allylation.11 In these processes the alcohol (secondary,
benzylic and tertiary) reactivity is quite remarkable, with
smooth generation of transient carbenium ions, catalyzed
by indium(III) chloride. From these processes a key les-
son can be learnt; the Lewis acidity of indium salts is com-
patible with water and with the generation of carbenium
ions. As previously mentioned, amines are also compati-
ble with indium salts. Amines and water are key compo-
nents in enamine catalysis, indicating the potential use of
indium salts in enamine-mediated organocatalytic pro-
cesses.
strategy wherein both the nucleophile and the electrophile
are activated simultaneously by two separate and distinct
catalysts to afford a single transformation.1 This new tool
has emerged as a powerful strategy for the development of
reaction methodologies. Synergistic interaction of two
catalytic cycles can be advantageously used to induce new
reactivity, improve existing reactions, and introduce ste-
reocontrol in existing transformations.
Due to their unusual properties, indium reagents and salts
have shown potential for use in synergistic systems. The
use of indium in organometallic chemistry has attracted
considerable attention since the discovery of indium-
mediated reactions in aqueous media.2 This remarkable
discovery was highlighted by several authors, who have
shown the compatibility of organometallic indium re-
agents with water and air.3 Moreover indium(III) Lewis
acids have shown similar properties, inspiring attempts to
use such Lewis acids in catalytic processes where water is
present.4 In addition to water compatibility, indium(III)
salts do not favorably form strong or irreversible com-
plexes with tertiary amines. This characteristic allows in-
dium(III) to act as a Lewis acid in the presence of strong
amines, as shown by the catalytic indium(III)–tertiary
amine reaction of alkynes with aldehydes.5 In the pres-
ence of indium(III) bromide (InBr3) (10 mol%) and N,N-
diisopropylethylamine (DIPEA) (20 mol%), aromatic al-
dehydes reacted smoothly with terminal alkynes. Spectro-
scopic studies showed dual activation of the terminal
alkyne and of the carbonyl group.
Stereoselective enamine-mediated catalysis has reached a
significant level of sophistication and can even be em-
ployed in the total synthesis of natural products.12 After
the publication of seminal works by MacMillan13 and
List,14 many researchers have entered the field, generating
more and more useful chemistry. However, the range of
electrophiles that can be used in enamine-mediated catal-
ysis is relatively limited. In fact, electrophiles are general-
ly Michael acceptors or electrophilic sources of
heteroatoms.15 Simple alkylating agents are still particu-
larly difficult substrates for enamine-mediated catalysis,
due to side reactions and deactivation of the amine cata-
lyst.16
It was thought that the scope of enamine-mediated cataly-
sis could be enhanced if an additive could be found that
was capable of forming the desired electrophile in situ,
thus avoiding unwanted side reactions and deactivation of
the catalyst (Scheme 1). In particular, the use of a metal in
synergistic cooperative catalysis could extend the range of
usable electrophiles.1 The synergistic use of metals could
also make the development of new, previously inaccessi-
ble chemical reactions possible. The use of transition met-
als, pioneered by Córdova in a Tsuji–Trost variant of
SYNTHESIS 2014, 46, 1321–1328
Advanced online publication: 25.03.2014
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1
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DOI: 10.1055/s-0033-1341022; Art ID: SS-2014-C0033-OP
© Georg Thieme Verlag Stuttgart · New York

1322
A. Gualandi et al.
SPECIAL TOPIC
enamine-mediated catalysis,17 has been explored by many Essentially, most organocatalytic reactions can be simply
researchers who have developed new methods for the al- described as the reaction of electrophiles with nucleo-
kylation of aldehydes [singly-occupied molecular orbital philes. Mayr has introduced the linear free-energy rela-
(SOMO) catalysis]18 using copper,19 gold,20 and other tionship, log k(20 °C) = sN(E + N),24 where electrophiles
metals.21 We have considered indium(III) salts as poten- are characterized by one parameter (E), and nucleophiles
tial Lewis acids for the promotion of enamine-mediated are characterized by the solvent-dependent nucleophilici-
alkylation. In such SN1-type reactions, an electrophilic ty (N) and sensitivity (sN) parameters. The Mayr equation
carbenium ion is generated in the presence of an organo- allows for simple prediction of organocatalytic reac-
catalyst, using a Lewis acid.22
tions.25a A simple rule introduced by Mayr states that a re-
action will proceed at 20 °C if (E+N) > –5.25b The solvent-
dependent nucleophilicity parameters of the enamines de-
rived from aldehydes and various organocatalysts were
determined by Mayr.25a For example, considering
the enamines derived from phenylacetaldehyde and
MacMillan’s imidazolidinones, it is possible to predict
that only strong electrophiles such as stabilized carbenium
ions (–8 < E < –2) would be suitable reaction partners. We
have successfully combined the Mayr scale26 with or-
ganocatalysis, using compatible carbenium ions that can
easily be generated during enamine-mediated catalysis
(Scheme 2). These carbenium ions are located precisely
on the Mayr scale between –1.5 and –7, and react rapidly
with the powerful enamine-nucleophile in the reaction
mixture. However, the scope of the reaction was limited
as many carbenium ions could not be generated under
such conditions. For example, when we investigated allyl-
ic alcohols27 as substrates for our methodology, only start-
ing materials and by-products (derived from the auto
condensation of the aldehyde) were isolated.
H2O
R
CHO
N
E
X
N
H
R
E
MLn
MLn
E+
X–
R
CHO
+ HX
X = leaving group
N+
X–
H2O
E
R
Scheme 1 Synergistic cooperation between an organocatalyst and a
metal complex (Lewis acid) in an alkylation reaction
Our small contribution to this field was inspired by the
limiting practical problems we encountered during our re-
search. In 2009, we described an organocatalytic stereose-
lective SN1-type reaction using alcohols as alkylating
agents (Scheme 2).23
Clearly this limitation was a consequence of the enhanced
electrophilicity of the carbenium ion, resulting in difficul-
ties in its generation under the reaction conditions. In an
effort to overcome this limitation, we drew inspiration
from simple chemistry; alcohols are known to react with
many electrophiles in SN1-type reactions carried out in the
presence of Lewis and Brønsted acids.28 We therefore
studied an organocatalytic alkylation reaction (with 1,3-
diphenylprop-2-en-1-ol and propanal in the presence of a
MacMillan catalyst) with many Lewis and Brønsted acids.
However, the peculiar properties of indium(III) salts at-
tracted our attention immediately. We discovered that the
allylation of aldehydes, with the allylic carbenium ions
generated in situ, occurred with good yield and stereose-
lectivity in the presence of these salts.29 In order to en-
hance the stereoselectivity we selected compound 5a as an
allylic alcohol model substrate (Scheme 3). It should be
noted that this substrate is completely unreactive in the
absence of indium(III) bromide.
Me
O
N
t-Bu
N
3a
H
Ph
R
CHO
Ar
OH
3a⋅TFA (20 mol%)
R
CHO
+
Et2O, 0 °C
Ar
Ar
1a–e
Ar
4a–e
2
30–95%, 60–92% ee
OH
OH
Me2N
NMe2
X
1a
1b X = S
1c X = O
OH
OH
The scope of the reaction was large, and included various-
ly substituted allylic alcohols that were easily prepared.
Unfortunately, with R = alkyl, we were unable to detect
the desired product, even in the presence of indium salts.
Again the stability of the carbenium ion dictates the reac-
tion outcome. Due to the presence of water and the high
electrophilicity of the generated carbenium ion, the reac-
tion was not successful. The products obtained in the ef-
fective indium(III)-mediated reactions were a mixture of
diastereoisomers, with a slight preference for the syn con-
Ph
Fe
HN
1e
1d
Scheme 2 Reaction of alcohols 1a–e with aliphatic aldehydes in the
presence of the MacMillan catalyst 3a
Synthesis 2014, 46, 1321–1328
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Organocatalysis with Indium(III) Salts
1323
mation. This observation precluded the possible roles
played by indium aggregates or complexes in determining
the stereochemical outcome of the reaction.
Ph
R
*
3a (20 mol%)
InBr3 (20 mol%)
CHO
Ph
OH
CHO
+
*
Ph
0 °C, CH2Cl2
Ph
R
n-C6H13
n-C6H13
The major role of indium(III) is determined by its Lewis
acidity, as shown by other simple experiments that were
carried out. When the reaction was performed with allylic
ethers 7a–c (Scheme 5), the results were all similar in
terms of the yield and stereoselectivity.
5a R = Ph
5b R = 3,5-Me2C6H3
5c R = 2-MeO-1-naphthyl
6a, 70%, dr 2:1 (syn/anti),
90% ee syn
6b, 53%, dr 2:1 (syn/anti),
85% ee syn
6c, 71%, dr 3:1 (syn/anti),
91% ee syn
O
Me
O
Me
Ph
*
3a (20 mol%)
N
N
CHO
OR
InBr3 (20 mol%)
CHO
Ph
Ph
+
Ph
*
Ph
t-Bu
t-Bu
N
0 °C, CH2Cl2
N
Ph
Ph
n-C6H13
H
H
Ph
n-C6H13
H
H
+
+
8, 60–70% dr 1:1,
80–81% ee syn
Ph
7a R = H
Ph
Ar
Ar
Ph
R
7b R = Me
7c R = allyl
R
O
Ph
anti (minor)
syn (major)
Ph
Ph
Scheme 3 Reaction of allylic alcohols promoted by the presence of
InBr3 in the reaction mixture
7d
Scheme 5 Reactions of allylic ethers 7a–c with octanal and the or-
ganocatalyst 3a (20 mol%)
figured product. A steric model (Scheme 3) suggested a
possible explanation for the selectivity observed. The
model has some flaws, such as not taking into account the
role of the indium in this chemistry. The generated carbe-
nium ion is not thought to be free in solution, with the al-
cohol activated by indium, as suggested in many cases
reported in the literature.8–10 In addition, NMR experi-
ments clearly demonstrated the complexation of the
MacMillan amine catalyst with indium. To shed light on
the process and to understand the role of indium, simple
experiments were carried out.
In addition, when allylic alcohol 7a was reacted in the
presence of catalytic quantities of an indium(III) salt, we
immediately observed the formation of the corresponding
ether 7d as a mixture of stereoisomers. We can conclude
that the role of indium in this methodology is to aid the
slow and reversible formation of the allylic carbenium
ion, which is able to react with the chiral enamine ob-
tained in situ. The Lewis acidity of indium(III) precludes
the use of the more nucleophilic chiral enamines derived
from the Hayashi–Jørgensen catalyst,31,32 as this catalyst
is not stable in the presence of indium salts.
A study of the ‘nonlinear effect’30 (Scheme 4) clearly sup-
ported the hypothesis that only one MacMillan catalyst
was involved in the transmission of stereochemical infor-
We have also explored the possibility of increasing the
range of the benzhydrylic and benzylic alcohols that can
be employed in the SN1-type reaction with synergistic use
of indium(III) salts. A limited number of examples of
benzhydrylic alcohols were examined in our first paper.33
In this study, we found that as the carbenium ions gener-
ated from the alcohols were above or near zero on the
Mayr scale, no reactivity was observed without the use of
indium(III) salts (Scheme 6). The presence of a dimethyl-
amino group on the aromatic ring was necessary to
achieve the desired reactivity. Although a methoxy group
at the para-position of one aryl group is sufficient to acti-
vate the substrate 9d, with this and other benzhydrylic al-
cohols, the reaction was quite sluggish and gave moderate
to low yields. For alcohols 9a–c, the presence of indi-
um(III) was required to produce the desired reactivity.
With this type of alcohol, the combination of indium(III)
triflate [In(OTf)3] with n-hexane as the reaction solvent
gave excellent results in terms of the enantiomeric excess.
A further advantage of the dimethylamino group was the
possibility of further functionalization by various cross-
coupling reactions.34
100
80
60
40
40
60
80
100
Ph
ee 3a (%)
Ph
*
3a (20 mol%)
InBr3 (20 mol%)
CHO
Ph
OH
CHO
+
*
Ph
0 °C, CH2Cl2
Ph
Ph
n-C6H13
n-C6H13
6a
5a
Scheme 4 Absence of a nonlinear effect in the indium-mediated al-
kylation reaction
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1321–1328

1324
A. Gualandi et al.
SPECIAL TOPIC
EtCHO
3b, 20 mol %
In(OTf)3, 20 mol%
EtCHO
3c (20 mol%)
In(OTf)3 (20 mol%)
CHO
*
CHO
OH
*
*
OH
Ar
R
*
R
Ar
0 °C, n-hexane (0.5 M)
0°C, n-hexane (0.5 M)
NMe2
Me2N
Me2N
NMe2
Me
9f R = CH2CH2OTBS
9g R = CH2CH2CH2NPhBoc
O
N
10a, 85% dr 2:1 (anti/syn),
95% ee anti
9a Ar = 4-MeOC6H4
9b Ar = Ph
9c Ar = 3-thiophenyl
10f, 85%, dr 6:1 (anti/syn),
99% ee anti
10g, 92%, dr 4.5:1 (anti/syn),
95% ee anti
Me
10b, 85% dr 2:1 (anti/syn),
89% ee anti
O
N
N
OH
10c, 84% dr 2:1 (anti/syn),
93% ee anti
H
3b
Ph
N
H
Ph
OMe
3c
9d
Scheme 8 Organocatalytic indium-mediated reactions of functional-
ized benzylic alcohols
Scheme 6 Organocatalytic alkylation of propanal with benzhydrylic
alcohols promoted by indium
As previously mentioned, the dimethylamino group is not
only an activating group capable of stabilizing the carbe-
nium ion, it can also be advantageous for further synthetic
transformations using nickel- or palladium-catalyzed
cross-coupling reactions.34a,b After reduction and protec-
tion of the primary alcohol group with tert-butyldimethyl-
silyl chloride, the key transformation involves preparation
of the corresponding ammonium triflate by treatment with
methyl triflate. The ammonium salts are good starting ma-
terials for cross-coupling reactions and their formation
proceeds without racemization.
We were also able to establish the absolute configuration
of the products by employing an SN1-type reaction as de-
scribed by Evans et al. (Scheme 7).35 Based on the finding
from this and previous studies, the model for the stereose-
lective induction considered the approach of the carbeni-
um ion from the less hindered face of the enamine. Using
this model, starting with the (S)-MacMillan catalyst, we
expected to form the (R)-configured stereocenter at the α-
position of the aldehyde (Scheme 7).
OMe
In continuation of our efforts to expand the repertoire of
organocatalytic SN1-type reactions, we have also consid-
ered propargylic alcohols as substrates. The direct use of
propargylic alcohols in organocatalytic SN1-type reac-
tions did not provide the desired results. Again, this is due
to the stability of the resulting carbenium ion, which could
not be generated under our reaction conditions. While we
were publishing the synergistic use of indium with allylic
alcohols, Nishibayashi reported two complementary
methods for the enantioselective α-propargylation of alde-
hydes. This methodology combines enamine-mediated
catalysis and transition-metal catalysis, with propargylic
alcohols36a,b and propargylic benzoates36c as substrates.
Interestingly, the stabilization of the cationic propargylic
intermediates was possible through the formation of the
corresponding metal–allenylidene complexes with copper
and ruthenium. However, the reaction was limited to ter-
minal alkynes, as the key metal–allenylidene intermedi-
ates could not be formed with internal alkynes. We
considered using indium(III) salts with this type of sub-
strate and embarked on the optimization of this process.
Preliminary results were obtained in 2010, and consider-
able efforts and studies were devoted to improving the ste-
reoselectivity and enantiomeric excess. We found that
when the reaction was performed using water as the sol-
vent, the formation of the ether (generated by attack of the
propargylic alcohol on the incipient propargylic cation)
was minimized. The scope of the reaction was investigat-
ed, and naturally the stabilization of the propargylic cation
was required for the reaction to proceed. Although gener-
ally the 4-methoxyphenyl group was sufficient to stabilize
O
O
O
O
i) TiCl4, DIPEA, 0 °C
O
N
R
O
N
ii)
OH
S
S
Ph
Ph
11
S
MeO
9e
super-hydride
0 °C to r.t.
i) 3b (20 mol%)
In(OTf)3 (20 mol%)
OH
R
CHO
0 °C, n-hexane (0.5 M)
9e
+
ii) NaBH4, MeOH
S
OMe
12
Scheme 7 Determination of absolute configuration using Evans’
auxiliary chemistry
Benzylic carbenium ions were not previously studied in
our SN1-type reaction, due to their high electrophilicity.
Again, in order to consider the corresponding alcohol as a
substrate, we introduced a dimethylamino group on the ar-
omatic moiety to improve the stability of the carbenium
ion. Various substituents at the benzylic position showed
tolerance to the reaction conditions employed (Scheme 8).
Other benzylic substrates bearing different aromatic
groups were also applicable and successful in this reac-
tion.
Synthesis 2014, 46, 1321–1328
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Organocatalysis with Indium(III) Salts
1325
the carbenium ion, the use of water as the reaction solvent In conclusion, indium(III) salts can be used in synergistic
limited the possible use of such substitution (Scheme 9).37 processes in which carbenium ions are generated. Allylic,
benzylic, benzhydrylic and propargylic alcohols are suit-
able substrates for this chemistry. The Hayashi–Jørgensen
nC6H13
CHO
OH
C7H15CHO
*
catalyst (normally a good catalyst for the α-functionaliza-
tion of aldehydes) could not be employed in these pro-
cesses.31a,b Studies on this topic are ongoing in our
research group, using indium(III) salts in order to generate
carbenium ions in the presence of various organocatalysts.
We will disclose more general and efficient SN1-type or-
ganocatalytic reactions in the near future.
3c (20 mol%)
*
In(OTf)3 (20
mol%)
H2O, 0 °C
R
R
Me2N
Me2N
13a R = CH(OEt)2
14a, 97%, dr 2.6:1 (anti/syn),
97% ee anti
14b, 94%, dr 2.5:1(anti/syn),
98% ee anti
13b R = CH2CH2OTBS
Scheme 9 Addition of aldehydes under synergistic cooperative ca-
talysis using indium(III) salts, with water as the reaction medium
Chromatographic purification was performed with Merck KGaA
SiO2 (240–400 mesh). Determination of diastereomeric ratios (dr)
and enantiomeric excesses (ee) was accomplished with an Agilent
Technologies 1200 instrument equipped with a variable wavelength
UV detector (reference 420 nm), using Daicel Chiralpak® columns
(0.46 cm ID × 25 cm) and HPLC grade i-PrOH and n-hexane as
eluting solvents. 1H and 13C NMR spectra were recorded on Varian
Gemini 200 and Varian Mercury 400 spectrometers. Chemical
shifts are reported in ppm relative to TMS, with the residual solvent
resonance as the internal standard [δ = 7.27 (1H), δ = 77.0 (13C)
ppm]. 1H NMR data are reported as follows: chemical shift, multi-
plicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet
of doublets, dt = doublet of triplets, tt = triplet of triplets, br
s = broad singlet, m = multiplet), coupling constant(s) (Hz). GC–
MS spectra were recorded by EI ionization at 70 eV on a Hewlett-
Packard 5971 instrument with GC injection. LC-electrospray ion-
ization mass spectra (ESI-MS) were obtained using an Agilent
Technologies MSD1100 single-quadrupole mass spectrometer.
Quite remarkably, the reaction tolerated a range of func-
tional groups including thio, amides, silyl ether, and even
acetals on the alkyne moiety. Different functionalized al-
dehydes were also used, and the corresponding products
were isolated in good yield as mixtures of two diastereo-
isomers, each with high stereoselectivity. The relative and
absolute configurations of the products were determined
for this class of substrate, and the selective functionaliza-
tion of the obtained products was also described. More-
over, the absolute and relative configurations of the
reaction products were in agreement with the proposed
model, which seems capable of predicting the stereo-
chemical outcome of these reactions (Figure 1).
Organocatalytic Enantioselective α-Allylation of Aldehydes;
General Procedure A
O
O
Me
Me
N
N
To a solution of compound 5 or 7 (0.1 mmol, 1 equiv) in CH2Cl2 (1
mL), MacMillan catalyst 3a (0.02 mmol, 20 mol%) and an aldehyde
(0.3 mmol, 3 equiv) were added at 0 °C. The mixture was stirred for
5 min at the same temperature and then InBr3 solution (20 mol%,
0.33 M in MeCN) was slowly added. The mixture was stirred at the
same temperature until no further conversion took place (monitored
by TLC). The reaction was then quenched with H2O (3 mL). The or-
ganic layer was separated and the aq layer extracted with Et2O (2 ×
20 mL). The combined organic layers were washed with H2O (10
mL), dried over Na2SO4 and concentrated in vacuo. The residue was
purified by flash chromatography.
Bn
Bn
N
N
H
H
H
H
+
+
Ar
Ar
R
R
TMS
TMS
syn (minor)
anti (major)
Ar = 4-Me2NC6H4
R = C6H13
Figure 1 Stereochemical model for the indium(III)-mediated alkyl-
ation of propargylic alcohols
Enantioselective α-Alkylation of an Aldehyde with Benzylic and
Benzhydrylic Alcohols; General Procedure B
Alcohol 9a–g (0.1 mmol, 1 equiv), catalyst 3b or 3c (20 mol%, 0.02
mmol), and an aldehyde (0.3 mmol, 3 equiv) were placed in a vial
containing anhydrous n-hexane (0.5 M) at 0 °C. The mixture was
stirred and a solution of In(OTf)3 (20 mol%, 0.33 M in MeCN) was
added. The solution was stirred for 8 h at 0 °C. The reaction was
quenched with H2O (5 mL). The organic layer was separated and the
aq layer extracted with Et2O (2 × 20 mL). The combined organic
layers were dried over Na2SO4 and concentrated in vacuo. The res-
idue was purified by flash chromatography.
The possibility of performing the synergistic SN1-type re-
action in water with a suitable Lewis acid is quite interest-
ing. We have investigated if the formation of the
propargylic ether is determined by the presence of the
Lewis acid, and if the propargylic carbenium ion is
formed reversibly under the reaction conditions. When the
reaction was performed in an organic solvent, ether for-
mation occurred as a side reaction affecting the yield of
the desired product. It seems that in the case of propargyl-
ic substrates, when the ether is formed, the carbenium ion
is not easily regenerated, even in the presence of indi-
um(III) salts. When the reaction is performed in water,
formation of the by-product propargylic ether is mini-
mized.
Enantioselective α-Alkylation of Aldehydes with Propargylic
Alcohols; General Procedure C
The catalyst 3c (0.02 mmol, 20 mol%), propargylic alcohol 13a,b
(0.1 mmol, 1 equiv) and H2O (0.5 mL) were added to a vial. The
suspension was cooled to 0 °C, and then octanal (0.3 mmol, 3 equiv)
and a solution of In(OTf)3 (20 mol%, 0.33 M in MeCN) were added.
The mixture was stirred for 24 h and then diluted with Et2O (3 mL).
The organic phase was separated and the aq layer extracted with
Et2O (3 × 10 mL). The organic phases were combined, washed with
brine (5 mL), dried over Na2SO4 and evaporated in vacuo. The
crude product was reduced with NaBH4 (0.4 mmol, 4 equiv) in
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1321–1328

1326
A. Gualandi et al.
SPECIAL TOPIC
MeOH (1 mL) a 0 °C. After 1 h, the reaction was quenched with
H2O (2 mL) and diluted with Et2O (10 mL). The organic layer was
separated and the aq layer extracted with Et2O (2 × 20 mL). The
combined organic layers were washed with H2O (10 mL), dried
over Na2SO4, and concentrated in vacuo. The residue was purified
by flash chromatography.
Yield: 0.041 g (92%); orange oil; dr 4.5:1 (anti/syn) (determined by
integration of the RCHO H NMR signals); ee (anti) = 95%, ee
1
(syn) = 97% [ees were determined by chiral HPLC (Daicel Chiral-
cel OD-H column: n-hexane–i-PrOH, 99:1 to 90:10 over 30 min,
flow rate = 0.50 mL/min, 30 °C, λ = 214, 254 nm)]; tR (anti) = 21.3
min (minor), 22.1 min (minor), tR (syn) = 25.0 min (major), 27.8
min (minor).
1H NMR (400 MHz, CDCl3): δ (anti) = 0.86 (d, J = 7.1 Hz, 3 H),
1.39 (s, 9 H), 1.54–1.77 (m, 4 H), 2.27–2.38 (m, 1 H), 2.73–2.81 (m,
1 H), 2.93 (s, 6 H), 3.58–3.70 (m, 2 H), 6.67 (d, J = 8.7 Hz, 2 H),
6.95 (d, J = 9.1 Hz, 2 H), 7.08 (br d, J = 7.5 Hz, 2 H), 7.17 (tt,
J = 5.9 Hz, J = 7.1 Hz, J = 8.3 Hz, 1 H), 7.30 (d, J = 4.5 Hz, 2 H),
9.61 (d, J = 3.5 Hz, 1 H).
1H NMR (400 MHz, CDCl3): δ (syn) = 0.88 (d, J = 7.1 Hz, 3 H),
1.39 (s, 9 H), 1.54–1.77 (m, 4 H), 2.44–2.56 (m, 1 H), 2.73–2.81 (m,
1 H), 2.93 (s, 6 H), 3.58–3.70 (m, 2 H), 6.67 (d, J = 8.7 Hz, 2 H),
6.98 (d, J = 8.7 Hz, 2 H), 7.08 (d, J = 7.5 Hz, 2 H), 7.17 (tt, J = 5.9
Hz, J = 7.1 Hz, J = 8.3 Hz, 1 H), 7.30 (d, J = 4.5 Hz, 2 H), 9.51 (d,
J = 2.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ (anti) = 12.1, 14.1, 22.7, 28.3 (3 C),
31.2, 40.7 (2 C), 45.1, 52.4, 77.2, 80.0, 112.7 (2 C), 125.9 (2 C),
128.6 (2 C), 128.8, 129.0 (2 C), 142.4, 149.4, 154.7, 205.4.
(S)-2-[(R/S)-1,3,3-Triphenylallyl]octanal (6a)
The title product was prepared according to the general procedure
A. The residue was purified by flash chromatography (cyclohex-
ane–Et2O, 7:3).
Yield: 0.036 g (90%); yellow oil; dr = 2:1 (syn/anti) (determined by
1
integration of the RCHO H NMR signals); ee (syn) = 90%, ee
(anti) = 75% [ees were determined by chiral HPLC after reduction
of the product with NaBH4 in MeOH (Daicel Chiralcel column IC:
n-hexane–i-PrOH, 99:1, flow rate = 0.50 mL/min, 30 °C, λ = 210,
254 nm)]; tR (syn) = 23.6 min (major), 19.2 min (minor), tR
(anti) = 17.2 min (major), 20.6 min (minor).
1H NMR (200 MHz, CDCl3): δ (syn) = 0.89 (t, J = 6.2 Hz, 3 H),
1.13–1.26 (m, 8 H), 1.62–1.65 (m, 2 H), 2.73–2.75 (m, 1 H), 3.75 (t,
J = 9.6 Hz, 1 H), 6.14 (d, J = 10.6 Hz, 1 H), 7.16–7.46 (m, 15 H),
9.34 (d, J = 4.0 Hz, 1 H).
1H NMR (200 MHz, CDCl3): δ (anti) = 0.89 (t, J = 6.2 Hz, 3 H),
1.13–1.26 (m, 8 H), 1.62–1.65 (m, 2 H), 2.73–2.75 (m, 1 H), 3.64 (t,
J = 9.6 Hz, 1 H), 6.26 (d, J = 11.2 Hz, 1 H), 7.16–7.46 (m, 15 H),
9.43 (d, J = 4.8 Hz, 1 H).
13C NMR (50 MHz, CDCl3): δ (syn/anti) = 14.0, 22.5, 26.9, 27.1,
27.4, 27.5, 28.9, 29.3, 31.4, 31.6, 45.9 (syn), 46.1 (anti), 57.8 (syn),
58.5 (anti), 126.7 (2 C), 127.2 (3 C), 127.4 (5 C), 127.8 (2 C), 127.9
(2 C), 128.1, 128.2 (3 C), 128.3 (4 C), 128.8 (4 C), 129.0, 129.3,
129.7 (4 C), 139.5 (2 C), 141.8 (4 C), 141.9 (2 C), 204.2 (syn), 204.5
(anti).
13C NMR (100 MHz, CDCl3): δ (syn) = 12.1, 14.1, 22.7, 28.3 (3 C),
31.2, 40.7 (2 C), 45.1, 52.4, 77.2, 80.0, 112.7 (2 C), 125.9 (2 C),
128.6 (2 C), 128.8, 129.0 (2 C), 142.4, 149.4, 154.7, 205.4.
ESI-MS: m/z (%) = 447.2 (100) [M + Na]+, 871.4 (18) [2 M + Na]+.
(R)-2-{(R/S)-1-[4-(Dimethylamino)phenyl]-4,4-diethoxybut-2-
yn-1-yl}octanal (14a)
The title product was prepared according to the general procedure
C. The product was isolated as the corresponding alcohol after re-
duction with NaBH4 (see Supporting Information for details). The
residue was purified by flash chromatography (cyclohexane–Et2O,
8:2).
HRMS: m/z [M]+ calcd for C29H32O: 396.24531; found: 396.24588.
(2R/S,3S)-3-[4-(Dimethylamino)phenyl]-2-methyl-3-(thiophen-
3-yl)propanal (10c)
The title product was prepared according to the general procedure
B. The residue was purified by flash chromatography (cyclohex-
ane–Et2O, 7:3).
Yield: 0.038 g (97%); yellow oil; dr = 2.6:1 (anti/syn) (determined
by integration of the RCHO 1H NMR signals); ee (anti) = 97%, ee
(syn) = 94% [ees were determined by chiral HPLC (Daicel Chiral-
cel column IC: hexane–i-PrOH, 95:5, flow rate = 0.50 mL/min,
40 °C, λ = 210, 254 nm)]; tR (anti) = 29.2 min (major), 23.9 min
(minor), tR (syn) = 30.5 min (major), 56.8 min (minor).
1H NMR (400 MHz, CDCl3): δ (anti) = 0.88 (t, J = 6.6 Hz, 3 H),
1.21–1.34 (m, 16 H), 1.83 (m, 1 H), 2.94 (s, 6 H), 3.57–3.66 (m, 3
H), 3.69–3.79 (m, 3 H), 3.82 (d, J = 5.7 Hz, 1 H), 5.33 (d, J = 1.6
Hz, 1 H), 6.69–6.71 (m, 2 H), 7.20–7.23 (m, 2 H), 9.69 (d, J = 3.4
Hz, 1 H).
Yield: 0.023 g (84%); colorless oil; dr = 2:1 (anti/syn) (determined
by integration of the RCHO 1H NMR signals); ee (anti) = 93%, ee
(syn) = 90% [ees were determined by chiral HPLC (Daicel Chiral-
cel column IA: n-hexane–i-PrOH, 99:1 to 90:10 over 30 min, flow
rate = 0.50 mL/min, 30 °C, λ = 210, 254 nm)]; tR (anti) = 21.7 min
(major), 24.3 min (minor), tR (syn) = 23.1 min (minor), 28.7 min
(major).
1H NMR (400 MHz, CDCl3): δ (syn) = 0.85 (t, J = 7.0 Hz, 3 H),
1.21–1.34 (m, 16 H), 1.83 (m, 1 H), 2.94 (s, 6 H), 3.57–3.66 (m, 3
H), 3.69–3.79 (m, 3 H), 3.93 (d, J = 6.3 Hz, 1 H), 5.34 (d, J = 1.6
Hz, 1 H), 6.69–6.71 (m, 2 H), 7.20–7.23 (m, 2 H), 9.65 (d, J = 3.1
Hz, 1 H).
13C NMR (50 MHz, CDCl3): δ (anti) = 14.1, 15.1 (2 C), 22.6, 27.2,
29.2, 29.5, 31.8, 38.4, 40.6 (2 C), 47.1, 60.7 (2 C), 63.3 (2 C), 86.7,
91.5, 112.6 (2 C), 127.2, 128.7 (2 C), 149.6.
1H NMR (400 MHz, CDCl3): δ (anti) = 1.02 (d, J = 6.8 Hz, 3 H),
2.94 (s, 6 H), 3.08–3.19 (m, 1 H), 4.32 (d, J = 10.2 Hz, 1 H), 6.66–
6.70 (m, 2 H), 6.89–6.96 (m, 2 H), 7.13 (d, J = 8.3 Hz, 1 H), 7.00–
7.18 (m, 2 H), 9.67 (d, J = 3.0 Hz, 1 H).
1H NMR (400 MHz, CDCl3): δ (syn) = 1.12 (d, J = 6.8 Hz, 3 H),
2.92 (s, 6 H), 3.08–3.19 (m, 1 H), 4.31 (d, J = 9.9 Hz, 1 H), 6.66–
6.70 (m, 2 H), 6.92–6.89 (m, 2 H), 7.06–7.18 (m, 3 H), 9.57 (d,
J = 2.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ (syn/anti) = 13.4 (anti), 13.5 (syn),
40.4 (2 C), 40.5 (2 C), 47.2, 48.0, 51.9 (syn), 52.0 (anti), 112.4,
112.6 (2 C), 112.7, 124.0 (2 C), 124.2, 126.5, 126.6, 128.6, 128.7 (2
C), 129.2 (anti), 129.3, 129.4 (syn), 132.7 (syn), 146.8 (syn), 147.1
(anti), 149.2 (syn), 149.5 (anti), 204.0 (syn), 204.1 (anti).
13C NMR (50 MHz, CDCl3): δ (syn) = 14.1, 15.1 (2 C), 22.6, 27.2,
29.2, 29.5, 31.8, 38.4, 40.6 (2 C), 47.1, 60.8 (2 C), 63.3 (2 C), 86.7,
91.5, 112.6 (2 C), 127.2, 128.7 (2 C), 149.6.
ESI-MS: m/z (%) = 390.2 (100) [M + H]+, 412.3 (21) [M + Na]+.
(R)-2-{(R/S)-5-[(tert-Butyldimethylsilyl)oxy]-1-[4-(dimethyl-
amino)phenyl]pent-2-yn-1-yl}octanal (14b)
ESI-MS: m/z (%) = 274.2 (100) [M + H]+.
The title product was prepared according to the general procedure
C. The residue was purified by flash chromatography (cyclohex-
ane–Et2O, 8:2).
tert-Butyl {(4S/R,5R)-4-[4-(Dimethylamino)phenyl]-5-methyl-
6-oxohexyl}(phenyl)carbamate (10g)
The title product was prepared according to the general procedure
B. The residue was purified by flash chromatography (cyclohex-
ane–Et2O, 8:2).
Yield: 0.042 g (94%); yellow oil; dr = 2.5:1 (anti/syn) (determined
by integration of the RCHO 1H NMR signals); ee (anti) = 98%, ee
Synthesis 2014, 46, 1321–1328
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Organocatalysis with Indium(III) Salts
1327
(syn) = 92% [ees were determined by chiral HPLC (Daicel Chiral-
cel column IA: n-hexane–i-PrOH, 99.5:0.5, flow rate = 0.50
mL/min, 30 °C, λ = 210, 254 nm)]; tR (anti) = 12.3 min (major),
15.1 min (minor), tR (syn) = 14.1 min (major), 11.8 min (minor).
(11) Onishi, Y.; Ito, T.; Yasuda, M.; Baba, A. Tetrahedron 2002,
58, 8227.
(12) Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D.
W. C. Nature 2011, 475, 183.
1H NMR (400 MHz, CDCl3): δ (anti) = 0.07 (s, 6 H), 0.84–0.86 (m,
3 H), 0.89 (s, 9 H), 1.24–1.35 (m, 8 H), 1.60–1.89 (m, 2 H), 2.34 (t,
J = 7.3 Hz, 2 H), 2.43–2.46 (m, 1 H), 2.93 (s, 6 H), 3.71 (t, J = 7.1
Hz, 2 H), 3.95 (d, J = 5.4 Hz, 1 H), 6.70 (d, J = 8.9 Hz, 2 H), 7.19
(d, J = 8.9 Hz, 2 H), 9.68 (d, J = 3.5 Hz, 1 H).
1H NMR (400 MHz, CDCl3): δ (syn) = 0.08 (s, 6 H), 0.84–0.86 (m,
3 H), 0.91 (s, 9 H), 1.24–1.35 (m, 8 H), 1.60–1.89 (m, 2 H), 2.34 (t,
J = 7.3 Hz, 2 H), 2.48–2.51 (m, 1 H), 2.92 (s, 6 H), 3.73 (t, J = 7.3
Hz, 2 H), 3.95 (dt, J = 2.1 Hz, J = 6.4 Hz, 1 H), 6.69 (d, J = 8.9 Hz,
2 H), 7.18 (d, J = 8.8 Hz, 2 H), 9.66 (d, J = 3.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ (anti) = –5.3 (2 C), 14.1, 18.3, 22.6,
23.8, 25.9 (3 C), 27.0, 28.9, 29.0, 31.6, 34.0, 37.9, 40.7 (2 C), 62.1,
80.1, 82.1, 112.8 (2 C), 126.9, 128.6 (2 C), 149.7, 204.8.
13C NMR (100 MHz, CDCl3): δ (syn) = –5.3 (2 C), 14.0, 18.3, 22.5,
23.9, 25.9 (3 C), 26.9, 29.2, 29.3, 34.4, 37.2, 40.7 (2 C), 62.2, 81.7,
85.8, 112.7 (2 C), 126.8, 129.7 (2 C), 149.7, 204.9.
(13) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2000, 122, 4243.
(14) List, B.; Lerner, R. A.; Barbas, C. F. III J. Am. Chem. Soc.
2000, 122, 2395.
(15) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38,
2178.
(16) For a recent breakthrough in α-alkylation, see: List, B.;
Corić, I.; Grygorenko, O. O.; Kaib, P. S. J.; Komarov, I.;
Lee, A.; Leutzsch, M.; Pan, S. C.; Tymtsunik, A. V.; van
Gemmeren, M. Angew. Chem. Int. Ed. 2014, 53, 282.
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P.; Córdova, A. Chem. Eur. J. 2012, 18, 2972.
(18) For reviews on enantioselective organo-SOMO catalysis,
see: (a) MacMillan, D. W. C.; Rendler, S. In Asymmetric
Synthesis II; Christmann, M.; Bräse, S., Eds.; Wiley-VCH:
Weinheim, 2012, 8. (b) MacMillan, D. W. C. In Science of
Synthesis: Asymmetric Organocatalysis; Vol. 1; List, B.;
Maruoka, K., Eds.; Thieme: Stuttgart, 2012, 271.
(19) Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2011,
133, 4260.
(20) Chiarucci, M.; di Lillo, M.; Romaniello, A.; Cozzi, P. G.;
Cera, G.; Bandini, M. Chem. Sci. 2012, 3, 2859.
(21) For a recent review of methodology combining transition-
metal catalysis with organocatalysis, see: Du, Z.; Shao, Z.
Chem. Soc. Rev. 2013, 42, 1337.
(22) (a) Gualandi, A.; Cozzi, P. G. Synlett 2013, 281.
(b) Gualandi, A.; Petruzziello, D.; Emer, E.; Cozzi, P. G. In
Comprehensive Enantioselective Organocatalysis:
Catalysts, Reactions, and Applications; Dalko, P. I., Ed.;
Wiley–VCH: Weinheim, 2013, 729. (c) Tak-Tak, L.;
Dhimane, H.; Dalko, P. I. Angew. Chem. Int. Ed. 2011, 50,
12146.
ESI-MS: m/z (%) = 444.3 (100) [M + H]+, 466.2 (24) [M + Na]+.
Acknowledgment
Financial support for A. Gualandi and L. Mengozzi came from Bo-
logna University, PRIN (Rome) and from the European Projects:
IBAAC, LigBANK, BioHEMLig, MolarNet, and in particular, the
organocatalytic CATAFLUO.OR project. Issue number 7 of Chem-
CatChem, 2012, is dedicated to this project and has special contri-
butions from many outstanding scientists. Special gratitude for
financial support is due to STMicroelectronics. C. M. Wilson is gra-
teful for the award of an Irish Research Council (IRC) Enterprise
Partnership Scheme Postgraduate Scholarship in collaboration with
Eli Lilly.
(23) (a) Cozzi, P. G.; Benfatti, F.; Zoli, L. Angew. Chem. Int. Ed.
2009, 48, 1313. (b) Benfatti, F.; Benedetto, E.; Cozzi, P. G.
Chem. Asian J. 2010, 5, 2047.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
(24) Mayr, H.; Patz, M. Angew. Chem., Int. Ed. Engl. 1994, 33,
938.
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Synthesis 2014, 46, 1321–1328
© Georg Thieme Verlag Stuttgart · New York