Secondary amine-catalyzed asymmetric γ-alkylation of α-branched enals via dienamine activation

Article abstract of DOI:10.1002/hlca.201200412

The direct and enantioselective γ-alkylation of α-substituted α,β-unsaturated aldehydes proceeding under dienamine catalysis is described. We have found that the Seebach modification of the diphenyl-prolinol silyl ether catalyst in combination with saccha

Full text of DOI:10.1002/hlca.201200412

Helvetica Chimica Acta – Vol. 95 (2012)
1985
Secondary Amine-Catalyzed Asymmetric g-Alkylation of a-Branched Enals
via Dienamine Activation
by Mattia Silvia), Carlo Cassania), Antonio Morana), and Paolo Melchiorre*a)b)
a) ICIQ – Institute of Chemical Research of Catalonia, Avenida Paꢀsos Catalans 16 - ES-43007 Tarragona
(phone: þ 34977920807; e-mail: pmelchiorre@iciq.es)
b
´
) ICREA – Institucio Catalana de Recerca i Estudis AvanÅats, Passeig Lluꢁs Companys 23 – ES-08010
Barcelona
Dedicated to Dieter Seebach on the occasion of his 75th birthday
The direct and enantioselective g-alkylation of a-substituted a,b-unsaturated aldehydes proceeding
under dienamine catalysis is described. We have found that the Seebach modification of the diphenyl-
prolinol silyl ether catalyst in combination with saccharin as an acidic additive promotes an SN1 alkylation
pathway, while ensuring complete g-site selectivity and a high stereocontrol. Theoretical and
spectroscopic investigations have provided insights into the conformational behavior of the covalent
dienamine intermediate derived from the condensation of 2-methylpent-2-enal and the chiral amine.
Implications for the mechanism of stereoinduction are discussed.
Introduction. – Asymmetric amine catalysis has greatly expanded the chemistꢂs
ability to stereoselectively functionalize unmodified CO compounds1). Over the past
decade, enamine2), and iminium-ion3) activations have become reliable synthetic
platforms for generating stereogenic centers at the a- and b-positions of CO
compounds with very high fidelity. More recently, the chemistsꢂ interest has shifted
toward the use of amine catalysis for targeting ever more remote stereogenic centers4).
Moving along the chain of a CO substrate requires the propagation of the electronic
effects inherent to enamine and iminium-ion activations (i.e., the HOMO-raising and
the LUMO-lowering effect, resp.) through the conjugated p-system of poly-unsatu-
rated CO compounds5). The first success in the design of direct vinylogous processes6)
was achieved by means of dienamine activation of g-enolizable unsaturated CO
compounds. Introduced in 2006 by Jørgensen and co-workers [8] to promote the
1
)
For recent reviews on amine catalysis, see [1a][1b]. For insightful perspectives on amine catalysis
mediated by secondary amines, see [1c – 1e].
2
3
4
)
)
)
For the pioneering study, see [2a]. For a review on enamine activation: see [2b].
For the pioneering study, see [3a]. For a review on iminium-ion activation: see [3b].
For an overview, see [4a]. For a discussion on the mechanisms of amine catalysis by secondary
amines, see [4b].
Propagation of the HOMO-raising effect: for dienamine activation, see [5][6]. For trienamine
activation, see [7a][7b]. For our contribution, see [7c]. Propagation of the LUMO-lowering effect:
for vinylogous iminium-ion activation, see [7d].
5
)
)
6
Vinylogous reactivity is defined as the transmission of electronic effects through a conjugated p-
system [5a]. For a review on dienamine activation, see [5b].
ꢃ 2012 Verlag Helvetica Chimica Acta AG, Zꢄrich

1986
Helvetica Chimica Acta – Vol. 95 (2012)
enantioselective g-amination of a,b-unsaturated aldehydes under the catalysis of the
diaryl-prolinol silyl ether 1a [9], dienamine activation exploits the intrinsic vinylogous
nucleophilicity of the in situ generated dienamine intermediate. Surprisingly enough,
this activation mode has since found limited application in asymmetric synthesis [6]7),
probably because g-amination of enals under secondary-amine catalysis was originally
proposed to follow a particular [4 þ 2] cycloaddition path [8] instead of a more general
nucleophilic addition manifold.
We recently demonstrated that primary-amine catalysis, specifically the use of
cinchona-based amine of type 2 [10], can greatly expand the synthetic potential of
dienamine activation, promoting vinylogous nucleophilicity within Michael addition
patterns, upon selective activation of unmodified cyclic a,b-unsaturated ketones [11].
The logical extension to consolidating dienamine catalysis as a useful template for
the g-functionalization of unmodified CO compounds was its application to nucleo-
philic substitution reactions8). We found that 9-amino-6’-hydroxyquinidine 2a success-
fully catalyzed the direct asymmetric SN1-type g-alkylation [12] of a-substituted linear
a,b-unsaturated aldehydes 3 with bis[4-(dimethylamino)phenyl]methanol 4a9), which
can easily form in situ a stabilized benzhydryl carbocation under acidic conditions [14].
Achieving a high level of enantioselectivity in the g-alkylated compound 5 (up to 95%
ee) required the combination of the primary amine 2a with a chiral phosphoric acid in
order to integrate dienamine activation and Brønsted acid catalysis simultaneously
(Scheme 1,a) [15].
At the same time, an independent study by Christmann and co-workers established
the ability of secondary-amine catalyst, specifically the diphenylprolinol silyl ether 1b
(the JørgensenꢀHayashi catalyst) and its analog 1a, to promote the same SN1-type
alkylation of unsubstituted linear enals (Scheme 1,b). However, the catalytic system
provided moderate control over the site selectivity (competing a- vs. g-site alkylation)
and a high level of stereocontrol only for selected examples [16].
7
)
)
For selected examples using secondary-amine catalysis, see [6].
8
The alkylation of CO compounds is the archetypal nucleophilic substitution reaction. Recently, our
group [12] and others [13], independently, have established the possibility of intercepting in situ
generated stable carbocations with catalytic enamine intermediates, leading to the challenging
asymmetric a-alkylation of aldehydes via an SN1 pathway.
The in situ formation under acidic conditions of stabilized benzhydryl carbocation from 4 has been
used for the a-alkylation of aldehydes via enamine catalysis. For the pioneering work, see [13a]. For
related studies, see [13b]. For a recent highlight, see [13c].
9
)

Helvetica Chimica Acta – Vol. 95 (2012)
1987
Scheme 1. Vinylogous Substitution Reaction in the SN1-Type g-Alkylation of Enals via Dienamine
Activation. a) Primary-amine activation of a-branched enals: cooperative dual catalysis system between
dienamine and Brønsted acid catalysis [15]. b) Secondary-amine activation of linear enals [16]. c)
Secondary-amine activation of a-branched enals.

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Helvetica Chimica Acta – Vol. 95 (2012)
Herein, we report a novel, convenient, and effective catalytic system for the direct
asymmetric g-alkylation of a-branched enals 3 via an SN1 pathway (Scheme 1,c). We
have found that the amine 1c, the Seebach modification of the JørgensenꢀHayashi
catalyst [17a]10), in the presence of an achiral acid additive, induces perfect g-site
selectivity and very high enantioselectivity (up to 96% ee). Synthetically, the present
method outperforms the catalytic system previously reported by us [15], since a single
chiral entity is required. This study also offers the first evidence for the unanticipated
power of secondary-amine catalysis to induce vinylogous nucleophilicity through
dienamine activation of sterically hindered CO compounds, such as a,b-disubstituted
enals 3.
Results and Discussion. – As a model reaction, we chose the direct g-alkylation of
2-methylpent-2-enal (3a) with bis[4-(dimethylamino)phenyl]methanol (4a; Table 1).
The standard in terms of efficiency and enantioselectivity for this transformation has
been set during our previous investigations on cinchona-based primary-amine catalysis
[15]. The quinidine-derived amine 2a (15 mol-%) required the presence of a chiral
phosphoric acid co-catalyst (30 mol-%) to attain synthetically useful results, affording
Table 1. The Model Reaction for the Direct g-Alkylation of a-Branched Enals and the Catalysts Testeda)
Entry
Catalyst
Yield [%]b)
ee [%]c)
1d)
2
3
4
5
6
7
8
9
2a
1a
1b
1c
1d
1e
1f
1g
1h
98
3
10
18
13
3
n.r.
n.r.
n.r.
89 [15]
75
81
88
84
71
–
–
–
a) Reactions performed at 408 on a 0.1-mmol scale, with 2 equiv. of enal 3a with [4a]0 ¼ 0.5m in toluene,
without any precaution for excluding air. b) Determined by 1H-NMR analysis of the crude reaction
mixture using 1,3,5-trimethoxybenzene as the internal standard; n.r. ¼ no reaction. c) Determined by
HPLC analysis on a chiral stationary phase. d) Reaction conducted in CHCl3 at 508 and catalyzed by the
combination of 15 mol-% of the primary amine 2a and 30 mol-% of the chiral phosphoric acid. Result
taken from [15].
10
)
For an application of catalyst 1c in conjugate addition to enals under iminium ion activation, see
[17b].

Helvetica Chimica Acta – Vol. 95 (2012)
1989
the product 5a in almost quantitative yield and 89% of enantiomeric excess (ee;
Table 1, Entry 1). In this dual-catalyst system, the enantioselectivity was found to be
significantly higher, when a chiral phosphoric acid was used in place of an achiral co-
catalyst such as CF3COOH (TFA; 60% ee; results taken from [15]). This indicated that
the intrinsic potential of amine 2a to forge the g stereogenic center by means of
dienamine activation was moderate.
The quest for a more convenient g-alkylation protocol, based on the use of a single
chiral entity, prompted us to undertake an extensive catalyst screening, detailed in
Table 1. This study led to an unexpected observation: the commercially available
diphenylprolinol silyl ether 1b (JørgensenꢀHayashi catalyst) could indeed catalyze the
process [18]. The combination of 1b with 30 mol-% of 2,6-bis(trifluoromethyl)benzoic
acid11)12) led to compound 5a as the unique product with good enantiomeric control,
albeit with poor yield (Entry 3). This stands in contrast to the catalytic profiles of
secondary amines that are generally unable to efficiently activate sterically hindered
CO compounds, such as a,b-disubstituted enals [20]13). Despite the poor reactivity
initially achieved with catalyst 1b, we were encouraged by the unanticipated ability of
secondary-amine catalysis to direct the reaction manifold toward a g-site-selective
alkylation through dienamine activation of a-branched enals14).
Gratifyingly, both reactivity and stereocontrol were sensitive to catalyst structural
modifications, the bulkier silyl protective group of catalyst 1c leading to a significant
improvement (compare Entries 3 and 4). This catalyst was first reported by Seebach
et al. [17a], who predicted, based on the X-ray crystallographic analysis of the iminium-
ion structure, a more effective shielding of the chiral fragment over the pro-chiral face
of the reactive intermediate, in comparison with the standard Me3Si (TMS) group
within the catalyst 1b. Further increasing the steric hindrance of the pendant silyl group
did not provide higher stereoselectivity (Entry 5). Interestingly, other widely employed
chiral secondary amines (proline or the second-generation MacMillan catalyst15)) were
not able to promote this transformation.
Further optimization studies were carried out with amine 1c as the catalyst.
Examination of the reaction media, detailed in Table 2 (reactions performed at 258),
revealed the requirement for an apolar solvent in order to obtain high stereoselectivity.
11
)
)
The nucleophilic dienamine generated by activation of enal 3a undergoes the alkylation with the
benzhydryl carbocation derived from acid-catalyzed ionization of bis[4-(dimethylamino)phenyl]-
methanol 4a. In the absence of any acids, the model reaction does not proceed.
The SN1-type a-alkylation of aldehydes under enamine activation has been developed by using
different methods to induce the ionization of the carbocation precursors. For the use of Lewis acids,
see [19a]. For oxidative conditions, see [19b]. For preformed salts of the carbocation intermediate,
see [19c].
12
13
14
15
)
)
)
Chiral secondary amines have found limited applications only in the iminium ion activation of
hightly reactive a-branched acroleins, see, e.g., [21a – c]. For the sole examples dealing with the
iminium ion activation of a,b-disubstituted enals [21d][21e].
The activation of a,b-disubstituted enals generally requires chiral primary amines [20]. As far as we
know, there are no published examples of dienamine activation of a,b-disubstituted enals by
secondary-amine catalysis.
For excellent investigations on the relative reactivity of the covalent intermediates (enamines and
iminium ions) derived from diphenylprolinol trimethylsilyl ether and the MacMillan imidazolinone
catalysts, see [22].

1990
Helvetica Chimica Acta – Vol. 95 (2012)
Table 2. Solvent Screening for the Model Reactiona)
Entry
Solvent
Dielectric constant (e)b)
Yield [%]c)
ee [%]d)
1
2
3
4
5
6
Hexane
Toluene
Et2O
CHCl3
CH2Cl2
MeCN
2
2.4
4
5
9.1
36
5
5
11
10
18
46
87
94
77
81
81
78
a) Reactions performed at 258 on a 0.1-mmol scale over 16 h, with 20 mol-% of amine 1c, 30 mol-% of
2,6-bis(trifluoromethyl)benzoic acid, 2 equiv. of enal 3a with [4a]0 ¼ 0.5m in the specified solvent. b) Data
taken from [23]. c) Determined by 1H-NMR analysis of the crude reaction mixture with 1,3,5-
trimethoxybenzene as the internal standard. d) Determined by HPLC analysis on a chiral stationary
phase.
Solvents with a high dielectric constant strongly increased the reactivity but at the
expense of the enantioselectivity.
We then found that the nature of the acidic additives was also crucial for modulating
the catalyst efficiency, in particular in terms of reactivity. Upon investigation of a
variety of acid co-catalysts (Table 3; reaction performed in toluene as the solvent),
saccharin was identified as the most promising additive toward the design of an
effective amine 1c-based catalytic system (Entry 9).
Table 3. Acid Screening for the Model Reaction Carried Out in Toluenea)
Entry
Acid
Yield [%]b)
ee [%]c)
1
2
3
4
5
6
7
8d)
9
2,6-Bis(trifluoromethyl)benzoic acid
2,6-Difluorobenzoic acid
4-Nitrobenzoic acid
2-Nitrobenzoic acid
2,6-Dinitrobenzoic acid
Trifluoroacetic acid
p-Toluenesulfonic acid (TsOH)
Diphenyl phosphate
Saccharin
18
28
24
29
83
29
6
88
91
88
91
82
88
71
91
88
27
71
a) Reactions performed at 408 on a 0.1-mmol scale, with 20 mol-% of amine 1c, 30 mol-% of the acid,
2 equiv. of enal 3a with [4a]0 ¼ 0.5m in the specified solvent. Reaction time: 16 h. b) Determined by
1H-NMR analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as the internal standard.
c) Determined by HPLC analysis on a chiral stationary phase. d) Reaction carried out with 4 equiv. of 3a.
A second cycle of optimization with 20 mol-% of the catalyst 1c in toluene
established a 2 :1 saccharin/amine ratio as the most effective combination, while
revealing that the reagent concentration was also crucial for modulating the efficiency
(Table 4). Carrying out the reaction at 408 with an excess of enal 3a (4 equiv.) while
diluting the mixture ([4a]0 ¼ 0.25m) provided the product 5a with synthetically useful
results over a 24-h reaction time (Entry 8: 5a isolated in 88% yield and 93% ee). These
conditions were selected to evaluate the scope of the secondary-amine-catalyzed g-
alkylation of a-branched enals.

Helvetica Chimica Acta – Vol. 95 (2012)
Table 4. Final Optimization Cyclea)
1991
Entry
Saccharin (x mol-%)
[4a]0 ¼ ym
0.5
0.5
0.5
t [h]
Yield [%]b)
ee [%]c)
1d)
2
3
4
5
6
7
8
30
30
20
40
40
75
40
40
16
16
16
16
16
16
16
25
71
83
45
93
44
54
81
88e)
88
92
95
91
96
95
94
93
0.5
0.15
0.15
0.25
0.25
a) Reactions performed at 408 on a 0.1-mmol scale, with 20 mol-% of amine 1c, a variable amount of
saccharin, 4 equiv. of enal 3a in toluene. b) Determined by 1H-NMR analysis of the crude reaction
mixture using 1,3,5-trimethoxybenzene as the internal standard. c) Determined by HPLC analysis on a
chiral stationary phase. d) Reaction carried out with 2 equiv. of 3a. e) Value refers to the yield of the
isolated compound 5a after chromatographic purification.
As shown in Table 5, different alkyl substituents, including a heteroatom-containing
moiety (Entry 6), can be accommodated at the enal g-position without affecting either
the site-selectivity or the enantioselectivity of the vinylogous SN1-type process (Entries
1 – 6). Remarkably, g-aryl-substituted enals are competent substrates for this catalytic
system (Entries 7 – 9). For these substrates, the g-alkylation protocol opens a direct
access to enantiomerically enriched benzylic stereogenic center, a valuable stereo-
chemical motif in medicinal chemistry due to its recurring presence among therapeutic
agents. Different aliphatic substituents in the a-position of the enals are well-tolerated,
enabling access to a broad variety of multifunctional molecules with complete g-site-
selectivity and moderate-to-high levels of enantioselectivity (Entries 10 and 11). As a
limitation of the system, 2-phenylpent-2-enal, bearing a Ph group at the a-position,
reacted smoothly providing the corresponding product 5l with a modest level of
stereocontrol (40% ee; Entry 12).
We also explored the possibility of extending chiral secondary-amine-induced
vinylogous nucleophilicity to cyclic a-branched enals. The protocol developed for the
linear substrates can be translated to cyclopent-1-ene-1-carboxaldehyde and cyclohex-

1992
Helvetica Chimica Acta – Vol. 95 (2012)
Table 5. The Scope of the Secondary-Amine-Catalyzed Asymmetric g-Alkylation of a-Branched Enalsa)
Entry
R1
R2
Product
t [h]
Yield [%]b)
ee [%]c)
1
2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
Et
iPr
Allyl
Bn
MeSCH2
Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
24
32
48
50
43
48
6
88
74
63
82
59
40
92
88
92
82
83
82
93
96
94
94
95
90
92
94
91
92
94
40
3d)
4
5
6
7
8
4-MeOꢀC6H4
6
9
4-ClꢀC6H4
5.5
78
48
26
10d)
11
12
Et
5j
5k
5l
Bn
Ph
Bn
Me
a) Reactions performed in toluene without any precaution for excluding air at 408 on a 0.1-mmol scale,
with 20 mol-% of amine 1c, 40 mol-% of saccharin, 4 equiv. of enal 3 with [4a]0 ¼ 0.25m. 1H-NMR
Analysis of the crude mixture indicated a highly g-site-selective alkylation pathway. b) Yield of the
isolated product 5 after chromatographic purification on SiO2. c) Determined by HPLC analysis on
chiral stationary phases. d) Reaction carried out in toluene with [4a]0 ¼ 0.5m.
1-ene-1-carboxaldehyde, maintaining a good level of reactivity but with moderate
stereoselectivity (Table 6). Notably, the five-membered substrate proved very reactive,
the reaction reaching completion within 4 h (Entry 1).
To further delineate the reaction scope, we tested other alcohols able to generate
stable carbocations through acid-catalyzed ionization. Xanthydrol (6a) and thioxant-
hydrol (6b) [13a] reacted smoothly under the reaction conditions, leading to the g-
alkylated products 7a and 7b, respectively, with synthetically meaningful results
(Table 7, Entries 1 and 2). (1H-Indol-3-yl)(phenyl)methanol (6c) [13a][18a] can be
used to easily access relevant indole-containing compounds in high ee, but with low
control of the diastereoselection (Entry 3).

Helvetica Chimica Acta – Vol. 95 (2012)
1993
Table 6. The Asymmetric g-Alkylation of Cyclic a-Branched Enalsa)
Entry
n
Product
t [h]
Yield [%]b)
ee [%]c)
1
2
1
2
5m
5n
4
32
76
86
68
63
a) Reactions performed in toluene without any precaution for excluding air at 408 on a 0.1-mmol scale,
with 20 mol-% of amine 1c, 40 mol-% of saccharin, 4 equiv. of enal 3 with [4a]0 ¼ 0.25m. 1H-NMR
Analysis of the crude mixture indicated a highly g-site-selective alkylation pathway. b) Yield of the
c
isolated product 5 after chromatographic purification on silica gel. ) Determined by HPLC analysis on
chiral stationary phases.
Table 7. Carbocation Precursor Scopea)
Entry
6
7
t [h]
Yield [%]b)
drc)
ee [%]d)
1e)
2f)
3
6a
6b
6c
7a
7b
7c
30
30
25
65
–
–
81
81
87/92
78
52g)
1.3 : 1
a) Reactions performed in toluene without any precaution for excluding air at 408 on a 0.1-mmol scale,
with 20 mol-% of amine 1c, 40 mol-% of saccharin, 4 equiv. of enal 3 with [6]0 ¼ 0.25m. 1H-NMR Analysis
of the crude mixture indicated a highly g-site-selective alkylation pathway. b) Yield of the isolated
c
product 7 after chromatographic purification on SiO2. ) Determined by 1H-NMR analysis of the crude
mixture. d) Determined by HPLC analysis on chiral stationary phases. e) Reaction performed in MeCN
f
with [6]0 ¼ 0.5m; 2,4-NO2ꢀC6H3CO2H was used as the acidic additive. ) Reaction performed in MeCN
with [6]0 ¼ 0.5m. g) Yield of the product obtained as a mixture of diastereoisomers.
The absolute configuration of compound 7b was unambiguously determined by
anomalous-dispersion X-ray crystallographic analysis: an (S) absolute configuration at
the newly formed g-stereogenic center was inferred (Fig. 1).
Mechanistic Investigations. – We decided to carry out preliminary mechanistic
investigations, by combining theoretical and spectroscopic approaches, to elucidate the
mechanism of catalysis and to understand the origin of the stereoselectivity. We used
NMR spectroscopic analyses to gain information on the conformational behavior of the

1994
Helvetica Chimica Acta – Vol. 95 (2012)
Fig. 1. X-Ray structure of the product 7b. Crystallographic data are available free of charge from the
Cambridge Crystallographic Data Centre, accession No. CCDC-894226.
covalent dienamine intermediate, which is actively involved in the configuration-
determining step16). An intimate appreciation of the interactions that allow the amine
catalyst to effectively control the molecular topology of the dienamine intermediate
may provide fundamental clues to understand and rationalize the origin of the
stereoselectivity. We investigated spectroscopically the dienamine intermediate
generated by direct condensation of 2-methylpent-2-enal 3a with the Jørgen-
senꢀHayashi catalyst 1b17), generated in the presence of 4-ꢅ molecular sieves as
detailed in the Exper. Part18).
In CDCl3, two different isomers A and B (shown in Scheme 2) were found in 3.5:1
ratio of abundance. Their conformational behavior was investigated by conventional
NMR techniques (Fig. 2), particularly vicinal coupling constant analysis and nuclear
Overhauser enhancement (NOE) spectroscopy.
Scheme 2. The Dienamine Intermediates Derived from Condensation of 2-Methylpent-2-enal 3a and
Amine 1b. MS, Molecular sieves.
16
)
)
For the characterization of covalent reactive intermediates involved in amine-catalytic processes,
see [24].
The dienamine intermediate derived from the catalyst 1c was too unstable for allowing an
exhaustive NMR analysis. We assume that the dienamine studied in the spectroscopic
investigations, derived from the parent amine 1b, should be structurally similar to the one obtained
from the bulkier catalyst 1c.
17
18
)
For the characterization of covalent reactive intermediates formed by condensation of
diarylprolinol silyl ether catalysts with aldehydes, see [25], and also [17a] and [26].

Helvetica Chimica Acta – Vol. 95 (2012)
1995
Fig. 2. 1H-NMR of the crude from the condensation of amine 1b and 2-methylpent-2-enal 3a in CDCl3 at
298 K. Inset: the most diagnostic signals.
Several topological elements have the same geometry in the major and the minor
isomers A and B, respectively. The presence of strong NOESY cross-peak between the
HꢀC(2) and HꢀC(a) indicates a s-trans-conformation of the single bond connecting
N(1)ꢀC(2) (Fig. 3). Additionally, the 15.5- and 15.3-Hz coupling constants between
HꢀC(4) and HꢀC(5) for the intermediates A and B, respectively, are evidence of an
(E)-configured C(4)¼C(5) bond. Finally, the NOE cross-peak between HꢀC(3’) and
HꢀC(5) (H-atom signal overlap for the major and the minor species) suggests an s-
trans-conformation around the C(3)ꢀC(4) bond.
The two dienamine conformers differ in the configuration of the C(2)¼C(3) bond.
The major isomer A has an (E)-configured C¼C bond, assigned on the basis of the two
NOESY cross-peaks between HꢀC(3’) and HꢀC(d), and HꢀC(4) and HꢀC(2) (Fig. 3).
In contrast, the minor isomer B has a (Z)-configured C¼C bond, as assigned on the
basis of the two diagnostic NOESY signals HꢀC(3’)/HꢀC(2) and HꢀC(4)/HꢀC(d).
Overall, these studies establish the (E)-s-trans-(E) as the most populated ground-state
conformation of the major isomer, while the minor isomer has a (Z)-s-trans-(E)
topology.
We then carried out conformational studies in (D8)toluene, the deuterated analog
of the reaction medium. Two isomers, having the same topological arrangement as in
CDCl3, were detected. However, the major (E)-s-trans-(E) dienamine of type A was
formed in a much higher relative abundance (A/B 10 :1; Figs. 4 and 5).

1996
Helvetica Chimica Acta – Vol. 95 (2012)
Fig. 3. NOESY Spectra in CDCl3 at 298 K
These findings provoke interesting mechanistic considerations when compared with
the spectroscopic studies carried out by Jørgensen and co-workers [8] on the dienamine
adduct derived by condensation of a similar catalyst (amine 1a) with a linear
unsubstituted a,b-unsaturated aldehyde (see Scheme 3). For this system, two possible
conformers were detected in a C6D6 solution, differing in the geometry of the second
C¼C bond, more distant from the N-atom. The major isomer showed a (Z)-
configuration of this topological element.
Remarkably, both detected dienamines derived from the a-branched enal 3a show
an exclusive (E)-geometry at the remote C¼C bond. There thus arises the interesting
prospect that the a-branched enals, which are generally difficult substrates for enamine
and iminium ion catalysis, have the structural properties (namely the a-substituent) to
bias the dienamine geometry, a necessary requirement for forging a stereogenic center
at the g-position with high fidelity.
To gain more insights into the conformational preferences of the dienamine
structures derived from a-branched enals, we performed a computational analysis by
means of the hybrid functional B3LYP with the 6-31G(d) basis. This level of theory has

Helvetica Chimica Acta – Vol. 95 (2012)
1997
Fig. 4. 1H-NMR of the crude from the condensation of amine 1b and 2-methylpent-2-enal 3a in
(D8)toluene at 298 K
been previously used for accurate geometry optimizations of similar compounds [26].
Single-point energy calculations were performed with M06-2X/6-311 þþ G(d,p) on
B3LYP/6-31G(d) geometries to reproduce the dispersion effect [27]. Fig. 6 shows the
five energy minima found after optimization of several isomers of the dienamine.
The optimized geometries have relative energies in agreement with the spectro-
scopic results. This level of theory suggests that the (E)-s-trans-(E) dienamine of type
A is the most stable isomer, as experimentally observed in solution. The minor (Z)-s-
trans-(E) isomer B is by 0.4 kcal/mol less stable, a difference in energy which
corresponds to a 2 :1 ratio of A to B in the gas phase at 298 K. This ratio is similar to the
3.5 :1 ratio spectroscopically observed in CHCl3.
The other isomers are much higher in energy, but their analysis can provide
interesting insights. Intermediate C, characterized by a s-cis-conformation around the
N(1)ꢀC(2) bond, is greatly destabilized by the steric clash between the methyl a-
branched substituent and the diphenyl silyl ether fragment. Isomer D, with a s-cis-
conformation of the C(3)ꢀC(4) bond, is by 2.8 kcal/mol less stable than A, an energy
penalty that somehow reflects the 2.4-kcal/mol difference reported between the s-trans/
s-cis conformations of 2,4-dimethylbuta-1,3-diene [28]. Finally, the 1,3-allylic strain
between the two Me groups greatly destabilizes the conformer E, having a (Z)-
configured C(4)¼C(5) bond. As previously commented (Scheme 3), the adduct E is the
analog of the major conformer detected in solution for a dienamine derived from a-
unsubtituted linear enals [8].

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Helvetica Chimica Acta – Vol. 95 (2012)
Fig. 5. NOESY Spectra in (D8)toluene at 298 K
Our mechanistic studies have identified the (E)-s-trans-(E) isomer A as the
thermodynamically more stable dienamine in solution. Based on these findings, we can
propose a model for rationalizing the stereoselectivity of the g-alkylation of a-
branched enals. The classical ꢆsteric control approachꢂ [9c] generally invoked to
rationalize the stereochemical outcome of a process catalyzed by the Jørgen-
senꢀHayashi-type catalyst is consistent with the sense of asymmetric induction
observed. Indeed, the efficient shielding by the chiral fragment in 1c determines the
selective engagement of the in situ generated carbocation with the Si-face of the more
stable dienamine intermediate (Fig. 7)19).
19
)
Another striking difference between a-branched and linear enals can be envisaged when
considering the stereochemical outcome of the SN1-type g-alkylation chemistry catalyzed by the
JørgensenꢀHayashi-type catalyst. Indeed, on the basis of the data reported by Christmann and co-
workers [16], the sense of stereoinduction when using linear enals [16] and a-branched enals (this
work), but the same catalyst enantiomer and alcohol 4a, is opposite.

Helvetica Chimica Acta – Vol. 95 (2012)
1999
Scheme 3. Comparison of the Conformational Behavior of the Dienamines Formed by Condensation of
a-Branched and Linear Enals with Diaryl-prolinol Silyl Ether Derivatives
Fig. 6. Optimized geometries and relative energies (in kcal/mol in parenthesis) at M06-2X/6-311 þþ
G(d,p)// B3LYP/6-31G(d) level of the more stable dienamine conformers

2000
Helvetica Chimica Acta – Vol. 95 (2012)
Fig. 7. Stereochemical model for the g-alkylation of a-branched enals catalyzed by (S)-diphenylpyrro-
lidine-2-methanol methyl(diphenyl)silyl ether 1c
Conclusions. – We have reported an effective catalytic system for the direct g-site-
selective alkylation of a-branched enals proceeding through an SN1 pathway. Key to the
development of the chemistry was the ability of chiral secondary-amine catalysis to
activate a-substituted a,b-unsaturated aldehydes toward vinylogous nucleophilicity.
We expect this unexpected reactivity will rapidly find application in the design of other
asymmetric direct g-functionalizations of sterically hindered CO compounds.
Research support from the ICIQ Foundation, MICINN (grant CTQ2010-15513), and the European
Research Council (ERC Starting Grant ORGA-NAUT to P. M. ) is gratefully acknowledged. C. C. and
A. M. are grateful to MICINN for a FPI predoctoral fellowship and a JdC postdoctoral fellowship,
´
respectively. The authors thank Elena Arceo for her contribution, and Eduardo Escudero-Adan for X-ray
crystallographic analysis.
Experimental Part
General. All the reactions were set up under air and using freshly dist. solvents, without any
precautions to exclude moisture, unless otherwise noted. All the yields reported in the optimization
1
studies are obtained through H-NMR analysis using 1,3,5-trimethoxybenzene as the internal standard
(3.75 (s, 3 MeO); 6.08 (s, 3 arom. H)) and comparing these signals with those of the aldehyde H-atom of
the product 5a. Chromatographic purification of products was accomplished by force-flow chromatog-
raphy (FC) on silica gel (SiO2; 35 – 70 mesh). For TLC analysis, Merck precoated TLC plates (silica gel
60 GF254, 0.25 mm) were used, using UV light as the visualizing agent and an acidic mixture of ceric
ammonium molybdate or basic aq. KMnO4, and heat as developing agents. HPLC Analysis on chiral
stationary phase was performed on an Agilent 1200 series instrumentation. Daicel Chiralpak IA, IC, IA-3,
i
or IC-3 columns with PrOH/hexane as the eluent were used. HPLC Traces were compared to racemic
samples prepared by performing the reactions in the presence of a catalytic amount of an equimolar
mixture of (R)- and (S)-diphenylprolinol trimethylsilyl ether 1b. Optical rotations are reported as [a]Dr:t:
(c in g/100 ml, solvent). The 1H- and 13C-NMR spectra were recorded at 400 or 500 MHz for 1H, and at
1
100 and 125 MHz for 13C; the chemical shifts (d) for H and 13C are given in ppm relative to residual
signals of the solvents (CHCl3 at 7.26 (1H-NMR) and 77.0 ppm (13C-NMR)); coupling constants, J, are
given in Hz. C-Atom types were determined from DEPT 13C-NMR experiments. High-resolution mass
spectra (HR-MS): ICIQ unit on LCT-Premier time-of-flight (TOF) mass spectrometer by direct infusion
with ESI. X-Ray data were obtained from the ICIQ X-Ray unit using a Bruker-Nonius diffractometer
equipped with an APPEX 2 4K CCD area detector.
Catalysts 1a and 1b are commercially available. Catalyst 1c was prepared starting from commercially
available (S)-a,a-diphenylprolinol according to the procedure described in [17a]. The aldehydes 3 were
purchased from commercial suppliers and used without further purification; otherwise, they were
synthesized according to the procedure described in [15]. Aldehyde 3k has been obtained from

Helvetica Chimica Acta – Vol. 95 (2012)
2001
autocondensation of hydrocinnamaldehyde following the procedure reported by Erkkilꢀ and Pihko [29].
Bis[4-(dimethylamino)phenyl]methanol (4a) and xanthydrol (¼ 9H-xanthen-9-ol; 4b) are commercially
available. (1H-Indol-2-yl)(phenyl)methanol (4d) [30] and thioxanthydrol (¼ 9H-thioxanthen-9-ol; 4c)
were synthesized according to known procedures [31].
General Procedure (GP) for the g-Alkylation of a-Branched Enals. All the reactions were carried out
in toluene (synthesis grade, > 99%) without any precaution for excluding air and moisture. An ordinary
1-ml vial equipped with a Teflon-coated stir bar and a plastic screw cap was charged with 0.1 mmol of the
alcohol 4, 0.02 mmol of (ꢀ)-(S)-a,a-diphenylpyrrolidine-2-methanol methyl(diphenyl)silyl ether (1c)
and 0.4 mmol of the enal 3 in 400 ml of toluene ([4]0 ¼ 0.25m). Then, 0.04 mmol of saccharin was added.
The vial was sealed and immerged in a H2O bath (thermostated at 408), and stirring was continued for the
time specified in the Tables. The mixture assumes a green color that disappears upon complete
consumption of the alcohol 4 (generally 24 – 36 h). Upon completion of the reaction (as verified by
TLC), the mixture is directly charged on SiO2 and subjected to chromatographic purification with
hexane/Et2O or toluene/Et2O. All the products are stable if conserved in sealed vials flushed with Ar and
stored at 08 in the absence of any trace of acids (for spectroscopic analysis, basified CHCl3 pre-treated
with K2CO3 was employed).
Known and previously unreported compounds were fully characterized. The absolute configuration
of the g-alkylated products 5 was assigned by comparison of the optical rotation to those of known
compounds [15], while the absolute configuration for compound 7b was unambiguously determined by
anomalous-dispersion X-ray crystallographic analysis20).
(2E,4S)-5,5-Bis[4-(dimethylamino)phenyl]-2,4-dimethylpent-2-enal (5a). The reaction was carried
out according to GP. After 24 h, the title compound was isolated by FC (eluent hexane/Et2O 4 :1) as a
colorless oil (31 mg, 0.088 mmol, 88%). ee 93% (by HPLC, Daicel Chiralpak IA; hexane/iPrOH 95 :5;
flow rate, 1.00 ml/min, l 254 nm: tR(major), 8.4, tR(minor), 9.6 min). [a]2D6 ¼ þ30.4 (c ¼ 0.73, CHCl3).
1H-NMR (500 MHz, CDCl3): 9.24 (s, 1 H); 7.17 – 7.10 (m, 2 H); 7.07 – 7.00 (m, 2 H); 6.72 – 6.63 (m, 2 H);
6.61 – 6.54 (m, 2 H); 6.32 (dq, J ¼ 9.9, 1.4, 1 H); 3.62 (d, J ¼ 10.5, 1 H); 3.50 – 3.40 (m, 1 H); 2.86 (s, 6 H);
2.90 (s, 6 H); 1.74 (d, J ¼ 1.4, 3 H); 1.01 (d, J ¼ 6.6, 3 H). 13C-NMR (125 MHz, CDCl3): 195.6; 160.1; 149.1;
149.0; 137.6; 132.1; 132.0; 128.6; 128.3; 112.8; 112.6; 56.2; 40.7; 40.6; 38.2; 19.0; 9.3.
(2E,4S)-4-{Bis[4-(dimethylamino)phenyl]methyl}-2-methylhex-2-enal (5b). The reaction was carried
out according to GP. After 32 h, 5b was isolated by FC (eluent hexane/Et2O 5 :1) as a white solid (27 mg,
0.074 mmol, 74%). ee 96% (by HPLC, Daicel Chiralpak IA; hexane/iPrOH 95 :5; flow rate, 1.00 ml/min;
l 254 nm: tR(major) 8.4 min, tR(minor) 9.5 min). [a]2D5 ¼ þ7.1 (c ¼ 1.24, CHCl3, 96% ee). 1H-NMR
(500 MHz, CDCl3): 9.27 (s, 1 H); 7.20 – 7.11 (m, 2 H); 7.09 – 6.92 (m, 2 H); 6.76 – 6.63 (m, 2 H); 6.63 – 6.52
(m, 2 H); 6.23 (dq, J ¼ 10.3, 1.3, 1 H); 3.69 (d, J ¼ 10.3, 1 H); 3.30 (qd, J ¼ 10.3, 3.2, 1 H); 2.90 (s, 6 H);
2.85 (s, 6 H); 1.74 (d, J ¼ 1.3, 3 H); 1.71 – 1.65 (m, 1 H); 1.26 – 1.20 (m, 1 H); 0.80 (t, J ¼ 7.4, 3 H).
13C-NMR (125 MHz, CDCl3): 195.5; 158.9; 149.1; 148.9; 139.4; 132.1; 132.1; 128.5; 128.3; 112.8; 112.6;
54.8; 45.3; 40.7; 40.6; 26.5; 11.5; 9.9. HR-MS: 365.2596 ([M þ H]þ, C24H33ON2þ ; calc. 365.2593).
(2E,4S)-4-{Bis[4-(dimethylamino)phenyl]methyl}-2,5-dimethylhex-2-enal (5c). The reaction was
carried out according to GP, but with [4a]0 ¼ 0.5m. After 48 h, 5c was isolated by FC (eluent hexane/
Et2O 4 :1) as a white solid (24 mg, 0.063 mmol, 63%). ee 94% (by HPLC, Daicel Chiralpak IA; hexane/
iPrOH 80 :20; flow rate, 1.00 ml/min; l 254 nm: tR(major) 4.7, tR(minor) 5.8 min). [a]2D6 ¼ ꢀ12.5 (c ¼ 0.70,
CHCl3). 1H-NMR (500 MHz, CDCl3): 9.25 (s, 1 H); 7.22 – 7.15 (m, 2 H); 7.06 – 7.00 (m, 2 H); 6.70 – 6.66
(m, 2 H); 6.55 – 6.51 (m, 2 H); 6.30 (dq, J ¼ 11.1, 1.3, 1 H); 3.85 (d, J ¼ 11.1, 1 H); 3.38 (td, J ¼ 11.1, 3.1,
1 H); 2.90 (s, 6 H); 2.84 (s, 6 H); 1.92 (sept.d, J ¼ 7.0, 3.1, 1 H); 1.71 (d, J ¼ 1.3, 3 H); 0.89 (d, J ¼ 7.0, 3 H);
0.83 (d, J ¼ 7.0, 3 H). 13C-NMR (125 MHz, CDCl3): 195.5; 156.2; 149.1; 148.9; 140.5; 132.3; 132.0; 128.3;
128.1; 112.9; 112.6; 52.7; 48.6; 40.7; 40.6; 29.8; 22.1; 15.7; 10.1.
(2E,4S)-4-{Bis[4-(dimethylamino)phenyl]methyl}-2-methylhepta-2,6-dienal (5d). The reaction was
carried out according to GP. After 50 h, 5d was isolated by FC (hexane/Et2O 4 :1 to 3 :1) as a white solid
(31 mg, 0.082 mmol, 82%). ee 94% (by HPLC, Daicel Chiralpak IA; hexane/iPrOH 94 :6; flow rate,
1.00 ml/min; l 254 nm: tR(major) 8.2, tR(minor) 8.9 min). [a]2D7 ¼ ꢀ12.9 (c ¼ 1.00, CHCl3). 1H-NMR
20
)
CCDC-894226 contains the supplementary crystallographic data for this article. These data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/data_request/cif.

2002
Helvetica Chimica Acta – Vol. 95 (2012)
(500 MHz, CDCl3): 9.26 (s, 1 H); 7.21 – 7.13 (m, 2 H); 7.08 – 6.99 (m, 2 H); 6.73 – 6.66 (m, 2 H); 6.61 – 6.53
(m, 2 H); 6.25 (dq, J ¼ 10.4, 1.3, 1 H); 5.66 (ddt, J ¼ 17.3, 10.2, 7.2, 1 H); 5.00 – 4.89 (m, 2 H); 3.74 (d, J ¼
10.4, 1 H); 3.55 – 3.41 (m, 1 H); 2.91 (s, 6 H); 2.85 (s, 6 H); 2.42 – 2.32 (m, 1 H); 2.10 – 1.98 (m, 1 H); 1.70
(d, J ¼ 1.3, 3 H). 13C-NMR (125 MHz, CDCl3): 195.4; 158.0; 149.2; 149.0; 139.2; 135.4; 131.7 (ꢁ2); 128.6;
128.3; 116.8; 112.9; 112.6; 54.4; 43.6; 40.7; 40.6; 37.8; 9.9.
(2E,4S)-4-Benzyl-5,5-bis[4-(dimethylamino)phenyl]-2-methylpent-2-enal (5e). The reaction was
carried out according to GP. After 43 h, 5e was isolated by FC (eluent hexane/Et2O 4 :1) as a white
solid (25 mg, 0.059 mmol, 59%). ee 95% (by HPLC, Daicel Chiralpak IC; hexane/iPrOH 85 :15; flow
rate, 1.00 ml/min, l 254 nm: tR(major) 19.4 min, tR(minor) 21.0 min). [a]2D6 ¼ þ5.2 (c ¼ 0.94, CHCl3).
1H-NMR (500 MHz, CDCl3): 9.20 (s, 1 H); 7.29 – 7.21 (m, 2 H); 7.21 – 7.09 (m, 3 H); 7.07 – 6.96 (m, 4 H);
6.77 – 6.71 (m, 2 H); 6.61 – 6.52 (m, 2 H); 6.22 (dq, J ¼ 10.3, 1.3, 1 H); 3.79 (d, J ¼ 10.3, 1 H); 3.63 (qd, J ¼
10.3, 3.2, 1 H); 3.02 (dd, J ¼ 13.4, 3.2, 1 H); 2.93 (s, 6 H); 2.85 (s, 6 H); 2.42 (dd, J ¼ 13.4, 10.3, 1 H); 1.19
(d, J ¼ 1.3, 3 H). 13C-NMR (125 MHz, CDCl3): 195.3; 157.3; 149.2; 149.0; 139.8; 139.6; 131.8; 131.7; 129.1;
128.6; 128.2; 128.1; 126.0; 113.1; 112.6; 54.9; 46.4; 40.7; 40.6; 39.8; 9.1.
(2E,4S)-5,5-Bis[4-(dimethylamino)phenyl]-2-methyl-4-[(methylsulfanyl)methyl]pent-2-enal (5f).
The reaction was carried out according to GP. After 48 h, 5f was isolated by FC (hexane/Et2O 5 :1 –
4 :1) as a yellowish solid (16 mg, 0.040 mmol, 40%). ee 90% (by HPLC, Daicel Chiralpak IA-3;
hexane/iPrOH 97:3; flow rate, 0.80 ml/min; l 254 nm: tR(major) 14.0, tR(minor) 15.0 min. [a]2D5 ¼ þ19.7
1
(c ¼ 1.07, CHCl3). H-NMR (500 MHz, CDCl3): 9.29 (s, 1 H); 7.20 – 7.14 (m, 2 H); 7.06 – 7.01 (m, 2 H);
6.72 – 6.66 (m, 2 H); 6.61 – 6.54 (m, 2 H); 6.31 (dq, J ¼ 10.3, 1.4, 1 H); 3.89 (d, J ¼ 10.3, 1 H); 3.64 (tdd, J ¼
10.3, 8.7, 3.6, 1 H); 2.91 (s, 6 H); 2.86 (s, 6 H); 2.73 (dd, J ¼ 12.8, 3.6, 1 H); 2.48 (dd, J ¼ 12.8, 8.7, 1 H); 2.02
(s, 3 H); 1.74 (d, J ¼ 1.4, 3 H). 13C-NMR (125 MHz, CDCl3): 195.3; 156.6; 149.2; 149.0; 140.1; 131.1 (2ꢁ);
128.5; 128.4; 113.0; 112.6; 53.9; 43.6; 40.7; 40.6; 38.6; 16.7; 10.0. HR-MS: 397.2333 ([M þ H]þ,
C24H33N2OSþ; calc. 397.2314).
(2E,4S)-5,5-Bis[4-(dimethylamino)phenyl]-2-methyl-4-phenylpent-2-enal (5g). The reaction was
carried out according to GP. After 6 h, 5g was isolated by FC (hexane/Et2O 4 :1) as a white solid
(38 mg, 0.092 mmol, 92%). ee 92% (by HPLC, Daicel Chiralpak IA; hexane/iPrOH 93 :7; flow rate,
1.00 ml/min; l 254 nm: tR(major) 8.3, tR(minor) 9.2 min). [a]2D6 ¼ þ6.9 (c ¼ 1.05, CHCl3). 1H-NMR
(400 MHz CDCl3): 9.25 (s, 1 H); 7.23 – 7.17 (m, 2 H); 7.17 – 7.09 (m, 5 H); 6.96 – 6.91 (m, 2 H); 6.65 – 6.59
(m, 3 H); 6.54 – 6.45 (m, 2 H); 4.50 (t, J ¼ 10.9, 1 H); 4.26 (d, J ¼ 10.9, 1 H); 2.89 (s, 6 H); 2.83 (s, 6 H);
1.70 (s, 3 H). 13C-NMR (100 MHz, CDCl3): 195.3; 157.0; 149.1; 148.7; 141.7; 137.9; 131.2; 131.1; 128.7
(2ꢁ); 128.5; 128.3; 126.5; 112.6; 112.5; 55.4; 50.3; 40.6 (2ꢁ); 9.5.
(2E,4S)-5,5-Bis[4-(dimethylamino)phenyl]-4-(4-methoxyphenyl)-2-methylpent-2-enal (5h). The re-
action was carried out according to GP. After 5.5 h, 5h was isolated by FC (eluent hexane/Et2O 2 :1) as a
white solid (39 mg, 0.088 mmol, 88%). ee 94% (by HPLC, Daicel Chiralpak IC-3; hexane/iPrOH 80 :20;
flow rate, 0.80 ml/min; l 254 nm: tR(major) 25.9, tR(minor) 30.8 min). [a]2D6 ¼ ꢀ2.1 (c ¼ 1.00, CHCl3).
1H-NMR (500 MHz, CDCl3): 9.25 (s, 1 H); 7.14 – 7.03 (m, 4 H); 6.99 – 6.92 (m, 2 H); 6.79 – 6.72 (m, 2 H);
6.66 – 6.57 (m, 3 H); 6.55 – 6.47 (m, 2 H); 4.47 (dd, J ¼ 11.1, 9.9, 1 H); 4.21 (d, J ¼ 11.1, 1 H); 3.74 (s, 3 H);
2.89 (s, 6 H); 2.83 (s, 6 H); 1.70 (d, J ¼ 1.3, 3 H). 13C-NMR (125 MHz, CDCl3): 195.4; 158.0; 157.4; 149.1;
148.7; 137.6; 133.8; 131.4; 131.2; 129.2; 128.7 (2ꢁ); 113.9; 112.6; 112.5; 55.5; 55.1; 49.4; 40.6 (2ꢁ); 9.4.
(2E,4S)-4-(4-Chlorophenyl)-5,5-bis[4-(dimethylamino)phenyl]-2-methylpent-2-enal (5i). The reac-
tion was carried out according to GP. After 6 h, 5i was isolated by FC (hexane/Et2O 3 :1) as a white solid
(41 mg, 0.092 mmol, 92%). ee 91% (by HPLC, Daicel Chiralpak IA-3; hexane/iPrOH 90 :10; flow rate,
1
0.80 ml/min; l 254 nm: tR(minor) 10.1, tR(major) 10.9 min). [a]2D6 ¼ þ12.4 (c ¼ 1.00, CHCl3). H-NMR
(400 MHz, CDCl3): 9.25 (s, 1 H); 7.20 – 7.14 (m, 2 H); 7.12 – 7.03 (m, 4 H); 6.95 – 6.89 (m, 2 H); 6.64 – 6.55
(m, 3 H); 6.53 – 6.48 (m, 2 H); 4.47 (dd, J ¼ 11.1, 9.7, 1 H); 4.18 (d, J ¼ 11.1, 1 H); 2.89 (s, 6 H); 2.83 (s,
6 H); 1.67 (d, J ¼ 1.3, 3 H). 13C-NMR (100, MHz, CDCl3): 195.1; 156.1; 149.2; 148.8; 140.4; 138.4; 132.1;
130.8; 130.7; 129.6; 128.7; 128.6; 128.6; 112.6; 112.5; 55.5; 49.7; 40.6 (2ꢁ); 9.5.
(2E,4S)-4-{Bis[4-(dimethylamino)phenyl]methyl}-2-ethylhex-2-enal (5j). The reaction was carried
out according to GP but with [4a]0 ¼ 0.5m. After 78 h, 5j was isolated by FC (hexane/Et2O 4 :1) as a white
solid (31 mg, 0.082 mmol, 82%). ee 92% (by HPLC, Daicel Chiralpak IC; hexane/iPrOH 90 :10; flow
rate, 1.00 ml/min; l 254 nm: tR(major) 15.7, tR(minor) 18.4 min). [a]2D7 ¼ ꢀ16.7 (c ¼ 0.85, CHCl3, 92%).
1H-NMR (400 MHz, CDCl3): 9.23 (s, 1 H); 7.19 – 7.13 (m, 2 H); 7.06 – 7.00 (m, 2 H); 6.71 – 6.65 (m, 2 H);

Helvetica Chimica Acta – Vol. 95 (2012)
2003
6.59 – 6.53 (m, 2 H); 6.16 (d, J ¼ 10.6, 1 H); 3.70 (d, J ¼ 10.2, 1 H); 3.35 – 3.23 (m, 1 H); 2.90 (s, 6 H); 2.84
(s, 6 H); 2.22 (q, J ¼ 7.5, 2 H); 1.73 – 1.62 (m, 1 H); 1.26 – 1.20 (m, 1 H); 0.91 (t, J ¼ 7.5, 3 H); 0.80 (t, J ¼
7.5, 3 H). 13C-NMR (100 MHz, CDCl3): 195.6; 158.5; 149.1; 149.0; 144.9; 132.1; 131.8; 128.6; 128.4; 112.8;
112.6; 54.8; 45.0; 40.7; 40.7; 26.5; 18.2; 12.8; 11.6.
(2E,4S)-2,4-Dibenzyl-5,5-bis[4-(dimethylamino)phenyl]pent-2-enal (5k). The reaction was carried
out according to GP. After 48 h, 5k was isolated by FC (toluene/Et2O 97:3 to 95 :5) as a white solid
(42 mg, 0.083 mmol, 83% yield). ee 94% (by HPLC, Daicel Chiralpak IA; hexane/iPrOH 96 :4; flow rate.
1
1.00 ml/min; l 254 nm: tR(minor) 11.8, tR(major) 12.5 min). [a]2D6 ¼ ꢀ33.6 (c ¼ 1.00, CHCl3). H-NMR
(500 MHz, CDCl3): 9.29 (s, 1 H); 7.24 – 7.19 (m, 5 H); 7.15 – 7.12 (m, 3 H); 7.03 – 7.00 (m, 2 H); 6.88 – 6.82
(m, 2 H); 6.76 – 6.72 (m, 4 H); 6.49 – 6.44 (m, 2 H); 6.38 (d, J ¼ 10.2, 1 H); 3.77 (d, J ¼ 10.3, 1 H); 3.70 –
3.63 (m, 1 H); 3.12 (d, J ¼ 15.1, 1 H); 3.01 (dd, J ¼ 13.4, 3.2, 1 H); 2.93 (s, 6 H); 2.85 (s, 6 H); 2.69 (d, J ¼
15.1, 1 H); 2.46 (dd, J ¼ 13.4, 9.4, 1 H). 13C-NMR (125 MHz, CDCl3): 194.8; 158.8; 149.2; 148.9; 142.3;
139.3; 138.8; 131.4; 131.4; 129.4; 128.7; 128.5; 128.5; 128.3; 128.1; 126.2; 125.7; 113.0; 112.6; 54.9; 46.4;
40.7; 40.6; 39.8; 29.3.
(2E,4S)-5,5-Bis[4-(dimethylamino)phenyl]-4-methyl-2-phenylpent-2-enal (5l). The reaction was
carried out according to GP. After 26 h 5l was isolated by FC (hexane/Et2O 4 :1) as a yellowish oil
(34 mg, 0.082 mmol, 82%). ee 40% (by HPLC, Daicel Chiralpak IA; hexane/iPrOH 95 :5; flow rate,
1.00 ml/min; l 254 nm: tR(major) 9.9, tR(minor) 12.8 min). [a]2D5 ¼ þ38.9 (c ¼ 1.30, CHCl3). 1H-NMR
(400 MHz, CDCl3): 9.44 (s, 1 H); 7.48 – 7.39 (m, 3 H); 7.08 – 6.98 (m, 4 H); 6.92 – 6.87 (m, 2 H); 6.65 – 6.60
(m, 2 H); 6.59 – 6.51 (m, 3 H); 3.63 (d, J ¼ 10.5, 1 H); 3.41 – 3.28 (m, 1 H); 2.88 (s, 6 H); 2.87 (s, 6 H); 1.07
(d, J ¼ 6.5, 3 H). 13C-NMR (100 MHz, CDCl3): 193.9; 161.4; 149.1 (2ꢁ); 142.8; 133.1; 132.0; 131.6; 129.3;
128.5 (ꢁ2); 128.2; 127.8; 112.8; 112.6; 56.5; 40.7 (2ꢁ); 38.5; 19.7.
3-{Bis[4-(dimethylamino)phenyl]methyl}cyclopent-1-ene-1-carbaldehyde (5m). The reaction was
carried out according to GP. After 4 h, 5m was isolated by FC (toluene/Et2O from 96 :4 to 95 :5) as a
yellowish oil (26 mg, 0.076 mmol, 76%). ee 68% (by HPLC, Daicel Chiralpak IA; hexane/iPrOH 90 :10;
flow rate, 1.00 ml/min, l 254 nm: tR(major) 11.2, tR(minor) 12.2 min). [a]2D7 ¼ þ76.2 (c ¼ 1.00, CHCl3).
1H-NMR (500 MHz, CDCl3): 9.69 (s, 1 H); 7.18 – 7.10 (m, 4 H); 6.72 – 6.64 (m, 5 H); 3.77 – 3.68 (m, 1 H);
3.60 (d, J ¼ 11.2, 1 H); 2.91 (s, 6 H); 2.90 (s, 6 H); 2.62 – 2.51 (m, 1 H); 2.50 – 2.40 (m, 1 H); 2.17 – 2.06 (m,
1 H); 1.71 – 1.60 (m, 1 H). 13C-NMR (125 MHz, CDCl3): 190.4; 156.3; 149.1; 149.1; 147.0; 132.6; 132.1;
128.4; 128.3; 112.9; 112.8; 55.0; 51.8; 40.7; 29.3; 27.8. HR-MS: 349.2263 ([M þ H]þ, C23H28N2Oþ; calc.
349.2280).
3-[Bis[4-(dimethylamino)phenyl]methyl}cyclohex-1-ene-1-carbaldehyde (5n). The reaction was
carried out according to GP. After 32 h, 5n was isolated by FC (toluene/Et2O 5 :1) as a yellowish solid
(31 mg, 0.086 mmol, 86%). ee 63% (by HPLC, Daicel Chiralpak IA; hexane/iPrOH 90 :10; flow rate,
1.00 ml/min; l 254 nm: tR(major) 8.5, tR(minor) 9.9 min). [a]2D6 ¼ þ8.7 (c ¼ 1.00, CHCl3). 1H-NMR
(500 MHz, CDCl3): 9.28 (s, 1 H); 7.20 – 7.11 (m, 4 H); 6.73 – 6.65 (m, 4 H); 6.65 – 6.61 (m, 1 H); 3.56 (d,
J ¼ 11.2, 1 H); 3.20 – 3.09 (m, 1 H); 2.92 (s, 6 H); 2.90 (s, 6 H); 2.33 – 2.25 (m, 1 H); 2.11 – 2.03 (m, 1 H);
1.87 – 1.76 (m, 1 H); 1.77 – 1.70 (m, 1 H); 1.56 – 1.47 (m, 1 H); 1.27 – 1.19 (m, 1 H). 13C-NMR (125 MHz,
CDCl3): 194.9; 154.6; 149.1; 149.1; 141.5; 132.0; 131.4; 128.6; 128.3; 113.0; 112.9; 54.9; 41.0; 40.7; 40.7;
28.0; 21.7; 20.6.
(2E,4S)-2-Methyl-4-(9H-xanthen-9-yl)pent-2-enal (7a). The reaction was carried out according to
GP, but with [6a]0 ¼ 0.5m and 2,4-dinitrobenzoic acid as the acidic additive (40% mol) in MeCN. After
30 h, the mixture was subjected to FC (hexane/Et2O 95 :5) to afford a mixture of the product and
xanthone (this compound shows fluorescence at 354 nm). This mixture was finally purified on prep. TLC
(CH2Cl2; Rf(product) 0.6) to afford 7a as a white solid (18 mg, 0.065 mmol, 65%). ee 81% (by HPLC,
Daicel Chiralpak IA; hexane/iPrOH 95 :5; flow rate, 1.00 ml/min; l 254 nm: tR(minor) 5.6, tR(major)
5.8 min). [a]2D6 ¼ þ13.8 (c ¼ 1.00, CHCl3, 81% ee). HR-MS: 301.1210 ([M þ Na]þ, C19H18NaOþ2 ; calc.
301.1204). 1H-NMR (500 MHz, CDCl3): 9.30 (s, 1 H); 7.29 – 7.22 (m, 2 H); 7.22 – 7.14 (m, 2 H); 7.13 – 7.04
(m, 4 H); 6.11 (dq, J ¼ 10.3, 1.4, 1 H); 3.98 (d, J ¼ 5.0, 1 H); 3.00 (dqd, J ¼ 10.3, 6.8, 5.0, 1 H); 1.36 (d, J ¼
1.4, 3 H); 1.03 (d, J ¼ 6.8, 3 H). 13C-NMR (125 MHz, CDCl3): 195.2; 155.8; 153.0; 152.9; 139.4; 129.2;
129.0; 128.1; 123.3; 123.2; 123.0; 122.7; 116.5; 116.4; 45.0; 42.4; 16.7; 8.8.
(2E,4S)-2-Methyl-4-(9H-thioxanthen-9-yl)pent-2-enal (7b). The reaction was carried out according
to GP, but with [6b]0 ¼ 0.5m and MeCN as the solvent. After 30 h, 7b was isolated by FC (hexane/Et2O

2004
Helvetica Chimica Acta – Vol. 95 (2012)
10 :1) as a white solid (23 mg, 0.078 mmol, 78%). ee 81% (by HPLC, Daicel Chiralpak IA; hexane/iPrOH
90 :10; flow rate, 1.00 ml/min; l 254 nm: tR(minor) 6.2, tR(major) 8.4 min). [a]2D6 ¼ ꢀ106.7 (c ¼ 0.85,
1
CHCl3). H-NMR (500 MHz, CDCl3): 9.31 (s, 1 H); 7.54 – 7.45 (m, 1 H); 7.44 – 7.33 (m, 1 H); 7.35 – 7.24
(m, 3 H); 7.21 – 7.03 (m, 3 H); 6.28 (dq, J ¼ 10.5, 1.3, 1 H); 3.84 (d, J ¼ 9.8, 1 H); 3.52 – 3.37 (m, 1 H); 1.18
(d, J ¼ 1.3, 3 H); 0.94 (d, J ¼ 6.6, 3 H). 13C-NMR (125 MHz, CDCl3): 195.2; 157.1; 139.7; 136.2; 135.7;
132.7; 132.5; 130.3; 129.8; 127.2; 126.9; 126.8; 126.7; 126.2; 126.0; 55.0; 33.2; 18.6; 8.5. HR-MS: 317.0961
([M þ Na]þ, C19H18NaOSþ; calc. 317.0976).
(2E)-5-(1H-Indol-3-yl)-2,4-dimethyl-5-phenylpent-2-enal (7c). The reaction was carried out accord-
ing to GP. After 25 h, 7c was isolated by FC (toluene/Et2O 98 :2 to 95 :5) as a white solid (16 mg,
0.052 mmol, 52%) as a mixture of diastereoisomers in a ratio of 1.3 :1 (checked by 1H-NMR on the crude
mixture) with an ee of 87 and 92%, resp. (by HPLC, Daicel Chiralpak IA; hexane/iPrOH 80 :20; flow
rate, 1.00 ml/min; l 254 nm: major diastereoisomer, tR(minor) 6.5 min, tR(major) 14.5 min; minor
diastereoisomer, tR(minor) 5.7 min, tR(major) 7.5 min). 1H-NMR (400 MHz, C6D6): 9.17 (s, 1 H); 7.63 (d,
J ¼ 7.6, 1 H); 7.23 – 6.89 (m, 10 H); 6.59 – 6.50 (m, 1 H); 6.01 (d, J ¼ 9.9, 1 H); 3.98 (d, J ¼ 9.0, 1 H); 3.41 –
3.31 (m, 1 H); 1.62 (d, J ¼ 1.4, 3 H); 0.92 (d, J ¼ 6.7, 3 H). 13C-NMR (100 MHz, C6D6): 195.1; 158.5; 144.4;
139.2; 138.7; 137.4; 129.4; 129.2; 127.4; 123.2; 122.2; 120.6; 120.4; 118.9; 112.3; 49.8; 39.5; 19.9; 10.2. HR-
MS: 326.1522 ([M þ Na]þ, C21H21NNaOþ; calc. 326.1521).
Procedure for Preparing the Dienamine Intermediate. The reaction was conducted under Ar using
Schlenk technique. 2-Methylpent-2-enal (3a; 19.6 mg, 0.2 mmol) was added to a dry deuterated solvent
(200 ml) containing freshly activated molecular sieves. (S)-a,a-Diphenylpyrrolidine-2-methanol trime-
thylsilyl ether (65 mg, 0.2 mmol, 1m) was added, and the mixture was stirred over 16 h at ambient temp.
Then, the mixture was filtered under Ar through a 0.2-mm PTFE filter directly into a dry NMR tube.
After dilution (until ca. 0.1 – 0.2m) with the same deuterated solvent (previously anhydrified on activated
molecular sieves in pellets), the sample was analyzed by NMR spectroscopy (500 MHz).
Theoretical Calculations of Structures. The different structures of the dienamine intermediate were
fully optimized at the B3LYP/6-31G(d) level [32]. For each structure, a frequency calculation has been
performed to verify that it is an energy minimum, i.e., having no imaginary frequency. Energy evaluations
of the B3LYP/6-31G(d)-optimized structures were carried out at the M06-2X [33] levels using a larger
basis set, 6-311 þþ G(d,p) [34]. The B3LYP calculations do not reproduce dispersion effects, but the
M06 – 2X calculations do consider them, at least in part [27]. The Gaussian 09 program [35] was used for
all theoretical calculations.
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Received August 3, 2012