Direct enantioselective vinylogous Mannich-type reactions of acyclic enals: New experimental insights into the E/Z-dilemma

Article abstract of DOI:10.1002/chir.23077

The direct heterofunctionalization of acyclic α,β-unsaturated aldehydes with N-acylquinolinium ions contemplating the formation of two stereocentres is studied using dienamine catalysis. This work gives some new experimental insights on the remote stereocontrol in dienamine catalysis using unbiased aliphatic systems and large electrophiles, pointing to a (Z)-preference of the reactive configuration of the second double bond.

Full text of DOI:10.1002/chir.23077

Received: 20 March 2019
DOI: 10.1002/chir.23077
Revised: 9 April 2019
Accepted: 17 April 2019
R E G U L A R A R T I C L E
Direct enantioselective vinylogous Mannich‐type reactions
of acyclic enals: New experimental insights into the E/Z‐
dilemma
Michela Vargiu1 | Lucilla Favero1
| Andrea Menichetti1 | Valeria Di Bussolo2
|
Fabio Marchetti2
| Gennaro Pescitelli2 | Sebastiano Di Pietro1 | Mauro Pineschi1
1 Dipartimento di Farmacia, Sede di
Chimica Bioorganica e Biofarmacia,
Università di Pisa, Pisa, Italy
Abstract
The direct heterofunctionalization of acyclic α,β‐unsaturated aldehydes with
N‐acylquinolinium ions contemplating the formation of two stereocentres is
studied using dienamine catalysis. This work gives some new experimental
insights on the remote stereocontrol in dienamine catalysis using unbiased ali-
phatic systems and large electrophiles, pointing to a (Z)‐preference of the reac-
tive configuration of the second double bond.
2 Dipartimento di Chimica e Chimica
Industriale, Università di Pisa, Pisa, Italy
Correspondence
Mauro Pineschi, Dipartimento di
Farmacia, Sede di Chimica Bioorganica e
Biofarmacia, Università di Pisa, Via
Bonanno 33, 56126 Pisa, Italy.
Email: pineschi@farm.unipi.it
KEYWORDS
acyclic enals, dienamine catalysis, Mannich reactions, N,O‐acetals, vinylogous reactivity
Funding information
Università di Pisa, Grant/Award Number:
P.R.A. 2016_27
1 | INTRODUCTION
In principle, a vinylogous extension of recently
reported enantioselective α‐alkylations of aldehydes with
Remote‐stereocontrol still represents a challenging task
in the field of asymmetric catalysis.1 Despite the consoli-
dated use of preformed vinylogous nucleophiles in the
reaction with classical electrophiles such as carbonyl
groups and Michael acceptors,2 considerably less atten-
tion has been devoted to the exploitation of nucleophilic
γ‐reactivity using unmodified carbonyl compounds. In
particular, the γ‐nucleophilic character of dienamines
derived from α,β‐unsaturated aldehydes has been
reported for Michael reactions,3,4 aldol‐type reactions,5,6
SN1‐type alkylation,7-10 or in cocatalyzed allylation.11 As
regards nitrogen‐based electrophiles, besides the seminal
paper by Jørgensen in which the γ‐amination results from
a [4 + 2] cycloaddition process,12 only a very particular γ‐
selective Mannich‐initiated cascade reaction has been
described.13 However, a direct catalytic asymmetric γ‐
regioselective vinylogous Mannich reaction involving
acyclic enals to give δ‐amino‐α,β‐unsaturated aldehydes
has not been yet described.
N‐acyl quinolinium ions poses several reactivity and
selectivity issues.14-17 In fact, there are several regioselec-
tivity issues about the nucleophilic addition (α‐selectivity
vs γ‐selectivity) of the in situ formed dienamine to the
reactive positions of the N‐acylquinolinium ion (α′‐selec-
tivity vs γ′‐ selectivity) (Figure 1).18 Moreover, the influ-
ence and sense of the asymmetric induction imposed by
the chiral secondary amine catalyst in SN‐type γ‐
functionalizations are particularly intriguing given the
distance of the chiral centres of the organocatalyst from
the reactive remote γ‐position. In particular, the reactive
configuration of the second double bond in dienamine
catalysis (“E/Z‐dilemma”) using acyclic aldehydes is still
under dispute, and experimental insights useful for the
comprehension of this problem are very limited.
Recently, NMR and computational studies have been
reported by Gschwind et al using Michler's hydrol as a
model electrophile by dienamine activation of linear alde-
hydes with formation of one chiral centre.19
Chirality. 2019;1–12.
wileyonlinelibrary.com/journal/chir
© 2019 Wiley Periodicals, Inc.
1

2
VARGIU ET AL.
to 400 nm with the following conditions: scanning
speed, 100 nm min−1; step size, 0.1 nm; bandwidth,
2 nm, response time, 1 second; and accumulation of 24
scans. Melting points were determined on a Kofler appa-
ratus and are uncorrected. High‐resolution electrospray
ionization mass spectrometry (HRESIMS) was acquired
in positive ion mode with a Q‐TOF premier spectrometer
(Waters‐Milford). Analytical high performance liquid
chromatography (HPLC) was performed on a Waters
600E equipped with Varian Prostar 325 detector using
a Daicel Chiralpak AD‐H (250 × 4.6 mm) columns with
detection at 220 nm.
FIGURE
1
Different reactivity pathways of dienamine
intermediates with a N‐acylquinolinium ion
Computational Section (see Supporting Information
for details).
We now report the direct γ‐regioselective
functionalization of acyclic enals with in situ generated
N‐acyl quinolinium ions using dienamine catalysis with
formation of two stereocentres for each reaction pathway
(SN‐α′ and SN‐γ′).
2.2 | Optimized procedure for vinylogous
Mannich reaction
A 7‐mL oven‐dried pyrex vial was charged with 1.0
equivalent of the specified N,O‐acetal in dry toluene
(0.2 M). Subsequently, organocatalyst L3b (20 mol%),
the α,β‐unsaturated aldehyde (300 mol%), and H2O
(40 mol%) were added in this order. The reaction mix-
ture was cooled at 0°C, and In(OTf)3 (20 mol%) was
added. The reaction mixture was allowed to react at
room temperature until complete conversion of N,O‐
acetal (TLC detection). The reaction mixture was
quenched by the addition of H2O (3.0 mL) and the aque-
ous layer extracted with diethyl ether. The organic phase
was dried on MgSO4, filtered and concentrated in vac-
uum, and then purified by semi‐preparative TLC or flash
chromatography.
2 | MATERIALS AND METHODS
2.1 | General
All reagents were purchased from commercially avail-
able sources. Compounds 1a,b and have been prepared
by known procedures.14-16 For the preparation of other
N,O‐acetals, see ESI. Tetrahydrofuran (THF) and toluene
were distilled on sodium/benzophenone ketyl. Solvents
for extraction and chromatography were distilled before
use. Analytical thin layer chromatography (TLC) was
performed on silica gel on TLC Al foils (Sigma‐Aldrich)
with detection by exposure to ultraviolet light (254 nm)
and/or by immersion in an acidic staining solution of
p‐anisaldehyde in EtOH. Merck silica gel 60 (230‐400
2.3 | Methyl (E)(2R*)‐2‐((4R)1‐oxohex‐2‐
en‐4‐yl)quinoline‐1(2H)‐carboxylate (2a‐syn,
anti) (Entry 10, Table 1)
mesh)
was
used
for
flash
chromatography.
Semipreparative TLC was performed on Merck PLC sil-
ica gel 60. Proton nuclear magnetic resonance (1H‐
NMR) spectra were recorded on a Bruker Avance II
250 MHz spectrometer. Chemical shifts are reported in
ppm downfield from tetramethylsilane with the solvent
resonance as the internal standard (chloroform‐d: δ
7.26). Signal patterns are indicated as follows: br s, broad
singlet; s, singlet; d, doublet; t, triplet; q, quartet; and m,
multiplet. Coupling constants (J) are given in hertz (Hz).
Carbon‐13 nuclear magnetic resonance (13C‐NMR) spec-
tra were recorded at 62.5 MHz with complete proton
decoupling. Chemical shifts are reported in ppm down-
field from tetramethylsilane with the solvent resonance
as the internal standard (chloroform‐d: δ 77.16). Elec-
tronic circular dichroism (ECD) spectra were recorded
on a Jasco J‐715 spectropolarimeter with 0.01‐cm cells
on acetonitrile solutions ca. 3.8 mM in the range 200
According to the general procedure, methyl‐2‐
methoxyquinoline‐1(2H)‐carboxylate
(35.0
mg,
0.15 mmol), trans‐2‐hexenal (45.0 mg, 0.45 mmol, 98%),
L3b (18.5 mg, 0.03 mmol, 97%), In (OTf)3 (16.9 mg,
0.03 mmol), H2O (1.1 μL, 0.06 mmol), and toluene
(0.6 mL) were allowed to react for 2 hours. Subsequent
flash chromatography (hexanes/Et2O 7:3, Rf = 0.13)
afforded 16 mg (36% yield) of the title compound as a
colourless oil. 1H‐NMR (250 MHz, CDCl3) δ: 9.34 (d,
J = 8.0 Hz, 0.4H, CHO anti); 9.20 (d, J = 7.9 Hz, 0.6H,
CHO syn); 8.48 to 7.40 (m, 1H, Ar―H); 7.25 to 7.03 (m,
3H, Ar―H); 6.57 (d, J = 9.6 Hz, 1H, H4); 6.46 (dd,
J = 15.7, 9.7 Hz, 1H, H3′); 6.11 (dd, J = 9.5, 6.0 Hz,
0.5H, H3); 6.01 to 5.81 (m, 1.5H, H3, H2′); 5.10 (t,
J = 6.9 Hz, 1H, H2); 5.10 (t, J = 6.9 Hz, 1.8H,

VARGIU ET AL.
3
TABLE 1 Screening of organocatalysts and reaction conditions in the model reactiona
Entrya
L
Solv
t[h]
2/3/Qb
drb Anti/Syn
ee[%]c
1d
L1a
L2
THF
2
2
Q > 95
Nd
Nd
2d
THF
Q > 85
Nd
Nd
3d
L3a
L3b
L2
Toluene
Toluene
THF
18
18
1
Q > 95
Nd
Nd
4d
Q > 85
Nd
Nd
5e
6f
70/23/7
12/11/77
27/16/57
22/11/67
10/5/85
56/36/8
56/36/8
50/35/15
52/34/14
57/33/10
38/62
31/69
38/62
35/65
Nd
2/8
L2
THF
1
4/6
7e
L1a
L1b
L3a
L3b
L3b
L3b
L3b
L3b
THF
12
12
18
2
10/20
12/32
Nd
8e
THF
9e
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
10e
11e,g
12g,h
13g,i
14g,j
60/40
57/43
58/42
56/44
60/40
65/6
72/23
79/12
77/35
83/26
2
3
48
3
aUnless stated otherwise, all reactions were carried out at 0°C using 0.20 mmol of 1a, In(OTf)3 (0.04 mmol), organocatalyst (0.04 mmol), 2‐hexenal (0.6 mmol),
solvent (0.4 mL) up to complete conversion (TLC analysis).
bDetermined by 1H NMR of the crude mixture on compounds of type 2.
cEnantioselectivity of diastereoisomers of α,α′ adducts determined by HPLC on a chiral stationary phase.
dReaction carried out in strictly anhydrous conditions.
eReaction carried out with 100 mol% of H2O.
fReaction carried out with 0.2 mL of H2O.
gReaction carried out with 1b.
hBA = 20 mol% of TsOH‐H2O.
iBA = anhydrous TsOH.
jReaction carried out with 20 mol% of In (OTf)3 and 40 mol% of H2O.
NCOOCH3syn); 3.75 (s, 1.2H, NCOOCH3anti); 2.50 to
2.27 (m, 1H, H4′); 1.77 to 1.34 (m, 2H, H5′); 0.88 to 0.77
(m, 3H, H6′). 13C‐NMR (63 MHz, CDCl3) δ: 193.7, 193.6,
158.4, 134.8, 134.5, 129.1, 128.4, 127.9, 127.1, 126.9,
125.2, 125.0, 122.1, 121.9, 111.6, 110.0, 53.5, 52.7, 52.1,
42.9, 42.5, 24.1, 23.9, 12.3, 12.2. HRMS (ESI) m/z
[M + Na+] Calcd for C17H19NO3Na 308.1257, found
308.1255. The ee's were determined by Daicel Chiralcel
AD‐H column (heptane–i‐PrOH, 92:8) flow rate 1.0 ml/
min; 220 nm: syn: tr (major): 15.28 min, tr (minor):
15.68 min; anti: tr (major): 18.10 min, tr (minor):
18.84 min.
2.4 | Benzyl (E)(2S)‐2‐((4R)1‐oxohex‐2‐en‐
4‐yl)quinoline‐1(2H)‐carboxylate (2b‐syn)
(Entry 14, Table 1)
According to the general procedure, benzyl‐2‐
methoxyquinoline‐1(2H)‐carboxylate
(35.0
mg,

4
VARGIU ET AL.
0.15 mmol), trans‐2‐hexenal (45.0 mg, 0.45 mmol, 98%),
L3b (18.5 mg, 0.03 mmol, 97%), In(OTf)3 (16.9 mg,
0.03 mmol), H2O (1.1 μL, 0.06 mmol), and toluene
(0.6 mL) were allowed to react for 3 hours. Subsequent
semipreparative TLC (hexanes/Et2O 6:4, 3 runs, Rf = 0.40)
afforded 8.1 mg (15% yield) of the title compound as a
colourless oil. 1H‐NMR (250 MHz, CDCl3) δ: 9.10 (d,
J = 7.6 Hz, 1H, CHO); 7.33 (d, J = 8.0 Hz, 1H, Ar―H);
7.29 to 6.94 (m, 8H, Ar―H); 6.51 (d, J = 9.6 Hz, 1H,
H4); 6.41 (dd, J = 15.6, 9.6 Hz, 1H, H3′); 6.09 (dd,
J = 9.6, 6.0 Hz, 1H, H3); 5.68 (dd, J = 15.6, 7.6 Hz, 1H,
H2′); 5.10 (d, J = 3.3 Hz, 2H, NCOOCH3Ar); 5.06 to 4.96
(m, 1H, H2); 2.29 to 2.14 (m, 1H, H4′); 1.66 to 1.30 (m,
2H, H5′); 0.73 (t, J = 7.4 Hz, 3H6′). 13C‐NMR (63 MHz,
CDCl3) δ: 194.4, 159.0, 135.2, 128.9, 128.6, 128.3, 128.2,
126.8, 126.5, 125.0, 68.4, 55.4, 50.2, 23.51, 12.0. HRMS
(ESI) m/z [M + Na+] Calcd for C23H23NO3Na 384.1570,
found 384.1571. The ee was determined with Daicel
Chiralcel AD‐H column (heptane–i‐PrOH, 92:8) flow rate
1.0 mL/min; 220 nm: tr (minor): 12.61 minutes, tr (major):
13.06 minutes.
L3b (18.5 mg, 0.03 mmol, 97%), In(OTf)3 (16.9 mg,
0.03 mmol), H2O (1.1 μL, 0.06 mmol), and toluene
(0.6 mL) were allowed to react for 5 hours. Subsequent
semipreparative TLC (hexanes/Et2O 6:4, 4 runs, Rf = 0.58)
afforded 4.7 mg (9% yield) of the title compound as an
amorphous solid. 1H‐NMR (250 MHz, CDCl3) δ: 9.21
(bs, 1H,CHO), 7.38 to 7.32 (m, 7H, Ar―H), 7.10 to 7.06
(m, 2H, Ar―H), 6.59 (d, J = 9.5 Hz, 1H, H4) 6.71 to
6.50 (m, 1H, H3′), 6.10 (dd, J = 9.5, 6.0 Hz, 1H, H3),
5.85 (dd, J = 15.6, 7.9, 1H, H2′), 5.25 (d, J = 13.8 Hz,
2H, NCOOCH2Ar), 4.99 (t, J = 7.7 Hz, 1H, H2), 2.62 to
2.45 (m, 1H, H4′), 1.11 (d, J = 6.7 Hz, 3H, H5′). 13C‐
NMR (63 MHz, CDCl3) δ ppm: δ 193.9, 159.1, 158.4,
136.1, 134.5, 133.5, 133.1, 128.8, 128.5, 128.2, 128.1,
127.5, 126.6, 126.4, 125.1, 124.9, 68.1, 55.9, 41.5, 15.5.
HRMS (ESI) m/z [M + Na+] Calcd for C22H21NO3Na
370.1414, found 370.1415. The ee (23%) was determined
with Daicel Chiralcel AD‐H column (heptane–i‐PrOH,
95:5) flow rate 0.8 mL/min; 220 nm: tr (minor):
15.61 minutes, tr (major): 22.81 minutes.
2.7 | Benzyl (E)(3R)‐2‐((4R)6‐oxopent‐2‐
en‐4‐yl)quinoline‐1(2H)‐carboxylate (2c‐
anti)
2.5 | Benzyl (E)(2R)‐2‐((4R)1‐oxohex‐2‐en‐
4‐yl)quinoline‐1(2H)‐carboxylate (2b‐anti)
(Entry 14, Table 1)
The faster eluting fractions (hexanes/Et2O 6:4, 4 runs,
Rf = 0.65) afforded 6.3 mg (12% yield) of the title com-
pound as a white solid. Mp: 99°C to 102°C. 1H‐NMR
(250 MHz, CDCl3) δ: 9.27 (d, J = 7.8 Hz, 1H, CHO);
7.56 to 7.47 (m, 1H, Ar―H); 7.41 to 7.31 (m, 5H,
Ar―H); 7.24 to 7.15 (m, 1H, Ar―H); 7.11 to 7.06 (m,
2H, Ar―H); 6.65 (dd, J = 15.6, 8.3, 1H, H3′); 6.58 (d,
J = 10.3 Hz, 1H, H4); 6.06 to 5.92 (m, 2H, H2′ + H3);
5.26 (ABq, J = 12.3 Hz, 2H, NCOOCH2Ph); 5.03 (t,
J = 7.0 Hz, 1H, H2); 2.68 to 2.51 (m, 1H, H4′); 1.07 (d,
J = 6.8 Hz, 3H, H5′). 13C‐NMR (63 MHz, CDCl3) δ:
193.6, 158.3, 133.3, 128.6, 128.3, 128.0, 127.9, 126.5,
126.3, 124.7, 68.0, 55.7, 41.9, 30.9, 15.3. HRMS (ESI) m/z
[M + Na+] Calcd for C22H21NO3Na 370.1414, found
370.1414.The ee (72%) was determined with Daicel
Chiralcel AD‐H column (heptane–i‐PrOH, 95:5) flow rate
0.8 mL/min; 220 nm: 17.96 minutes, tr (major):
19.47 minutes.
The faster eluting fractions of the above chromatography
(hexanes/Et2O 6:4, 3 runs, Rf = 0.50) afforded 13.3 mg
(27% yield) of the title compound as a colourless oil. H‐
1
NMR (250 MHz, CDCl3) δ: 9.18 (d, J = 7.8 Hz, 1H,
CHO); 7.52 to 7.43 (m, 1H, Ar―H); 7.39 to 7.31 (m, 5H,
Ar―H); 7.21 to 7.12 (m, 1H, Ar―H); 7.08 to 7.03 (m,
2H, Ar―H); 6.57 (d, J = 9.6 Hz, 1H, H4); 6.45 (dd,
J = 15.6, 9.7 Hz, 1H, H3′); 6.00 to 5.88 (m, 2H, H3, H2′);
5.26 (ABq, J = 12.4 Hz, 2H, NCOOCH2Ph); 5.12 (t,
J = 6.6 Hz, 1H, H2); 2.46 to 2.31 (m, 1H, H4′); 1.75 to
1.57 (m, 1H, H5′); 1.45 to 1.31 (m, 1H, H5′); 0.79 (t,
J = 7.4 Hz, 3H, H6′). 13C‐NMR (63 MHz, CDCl3) δ:
193.3, 157.1, 135.9, 135.0, 128.6, 128.3, 128.0, 127.9,
127.3, 126.5, 126.2, 124.7, 68.0, 54.9, 49.7, 22.9, 11.5.
HRMS (ESI) m/z [M + Na+] Calcd for C23H23NO3Na
384.1570, found 384.1569. The ee was determined with
Daicel Chiralcel AD‐H column (heptane–i‐PrOH, 92:8)
flow rate 1.0 mL/min; 220 nm: tr (minor): 14.27 minutes,
tr (major): 17.37 minutes.
2.8 | Methyl (E)(3R*)‐2‐((4R)1‐ oxodec‐2‐
en‐4‐yl)quinoline‐1(2H)‐carboxylate (2d‐
syn,anti)
2.6 | Benzyl (E)(3S)‐2‐((4R)6‐oxopent‐2‐en‐
4‐yl)quinoline‐1(2H)‐carboxylate (2c‐syn)
According to the general procedure, methyl‐2‐
According to the general procedure, benzyl‐2‐
methoxyquinoline‐1(2H)‐carboxylate
(35.0
mg,
methoxyquinoline‐1(2H)‐carboxylate
0.15 mmol), trans‐2‐pentenal (39.8 mg, 0.45 mmol, 95%),
(35.0
mg,
0.15 mmol), trans‐2‐decenal (73.1 mg, 0.45 mmol, 95%),
L3b (18.5 mg, 0.03 mmol, 97%), In (OTf)3 (16.9 mg,

VARGIU ET AL.
5
0.03 mmol), H2O (1.1 μL, 0.06 mmol), and toluene
(0.6 mL) were allowed to react for 5 hours. Subsequent
semipreparative TLC (hexanes/AcOEt 9:1, four runs
Rf = 0.32) afforded 20.2 mg (45% yield) of the title com-
322.1411.The ee was determined with Daicel Chiralcel
AD‐H column (heptane–i‐PrOH, 96:4) flow rate 1.0 mL/
min; 220 nm: diastereoisomer 1: 25%, tr (minor):
9.84 minutes, tr (major): 10.26 minutes; diastereoisomer
2: 84%, tr (minor): 11.13 minutes, tr (major):
12.05 minutes.
1
pound as a colourless oil. H‐NMR (250 MHz, CDCl3) δ:
9.33 (d, J = 7.9 Hz, 0.55H, CHO anti); 9.17 (dd, J = 7.8,
2.1 Hz, 0.45H, CHO syn); 7.47 to 7.32 (m, 1H, Ar―H);
7.25 to 7.14 (m, 1H, Ar―H); 7.11 to 7.03 (m, 2H,
Ar―H); 6.56 (d, J = 9.7, 2.8 Hz, 1H, H4); 6.53 to 6.39
(m, 1H,),6.11 (dd, J = 9.5, 6.0 Hz, 0.57H anti), 6.01 to
5.79 (m, 1.5H), 5.13 to 4.99 (m, 1H, H2), 3.82 (s, 1.35H,
NCOOCH3 syn), 3.75 (s, 1.65H, NCOOCH3 anti), 2.52 to
2.31 (m, 1H, H4′), 1.59 to 1.12 (m, 10H, H5′, H6′, H7′,
H8′, H9′), 0.86 (q, J = 7.0 Hz, 3H, H10′). 13C‐NMR
(63 MHz, CDCl3) δ: 193.8, 193.4, 158.4, 157.5, 155.2,
135.0, 134.6, 128.1, 128.0, 127.7, 127.4, 126.7, 126.4,
126.3, 125.2, 124.9, 124.8, 55.2, 54.9, 53.3, 48.2, 48.0,
32.0, 31.7, 30.2, 30.0, 29.8, 29.4, 29.2, 27.5, 27.0, 22.7,
2.10 | Ethyl (E)(3R*)‐2‐((4R)1‐oxohept‐2‐
en‐4‐yl)6‐methylquinoline‐1(2H)‐
carboxylate (2f‐syn,anti)
According to the general procedure, ethyl‐2‐ethoxy‐6‐
methylquinoline‐1(2H)‐carboxylate (38.9 mg, 0.15 mmol),
trans‐2‐heptenal (52.03 mg, 0.45 mmol, 97%), L3b
(18.5 mg, 0.03 mmol, 97%), In(OTf)3 (16.9 mg, 0.03 mmol),
H2O (1.1 μL, 0.06 mmol), and toluene (0.6 mL) reacted for
5 hours. Subsequent semipreparative TLC (hexanes/
AcOEt 8:2, two runs, Rf = 0.46) afforded 26.4 mg (54%
yield) of the title compounds as a colourless oil. 1H‐
NMR (250 MHz, CDCl3) δ: 9.35 (d, J = 7.9 Hz, 0.5H,
CHO), 9.20 (d, J = 7.9 Hz, 0.5H, CHO), 7.40 to 7.28 (m,
1H, Ar―H), 7.07 to 6.95 (m, 1H, Ar―H) 6.92 to 6.83
(m, 1H, Ar―H), 6.66 to 6.41 (m, 1.5H), 6.16 to 6.02 (m,
0.5H), 6.00 to 5.79 (m, 1H), 5.05 (dd, J = 13.8, 7.3 Hz,
1H, H2), 4.38 to 4.06 (m, 2H, NCOOCH2CH3), 2.57 to
2.18 (m, 4H, H4′, Ar‐CH3), 1.83 to 1.00 (m, 7H, H5′, H6′,
NCOOCH2CH3), 0.96 to 0.81 (m, 3H, H7′).13C‐NMR
(63 MHz, CDCl3) δ: 193.9, 193.6, 159.7, 158.8, 157.8,
134.8, 134.5, 134.3, 134.2, 132.6, 128.7, 127.4, 127.2,
126.8, 126.8, 126.7, 126.5, 125.0, 124.7, 62.4, 62.3, 55.0,
54.7, 47.8, 47.8, 45.7, 45.5, 36.5, 33.7, 32.4, 32.1, 29.8,
29.3, 22.9, 21.0, 20.9, 20.7, 20.2, 14.6, 14.2, 14.0. HRMS
(ESI) m/z [M + Na+] Calcd for C20H25NO3Na 350.1727,
found 350.1729. The ee determined with Daicel Chiralcel
AD‐H column (heptane–i‐PrOH, 92:8) flow rate 0.5 mL/
min; 220 nm: one diastereoisomer tr (minor):
13.9 minutes, tr (major): 14.6 minutes; the enantiomers
of the other diastereoisomer gave a single peak at
13.3 minutes.
14.2. HRMS (ESI) m/z [M
+
Na+] Calcd for
C21H27NO3Na 364.1883, found 364.1880. The ee's were
determined with Daicel Chiralcel AD‐H column (hep-
tane–i‐PrOH, 96:4) flow rate 0.8 mL/min; 220 nm; syn:
tr (minor): 7.70 minutes, tr (major): 8.24 minutes; anti: tr
(minor): 8.87 minutes, tr (major): 10.97 minutes.
2.9 | Methyl (E)(3R*)‐2‐((4R)1‐oxohept‐2‐
en‐4‐yl)quinoline‐1(2H)‐carboxylate (2e‐
syn,anti)
According to the general procedure, methyl‐2‐
methoxyquinoline‐1(2H)‐carboxylate
(35.0
mg,
0.15 mmol), trans‐2‐heptenal (52.03 mg, 0.45 mmol,
97%), L3b (18.5 mg, 0.03 mmol, 97%), In(OTf)3
(16.9 mg, 0.03 mmol), H2O (1.1 μL, 0.06 mmol), and tolu-
ene (0.6 mL) reacted for
3
hours. Subsequent
semipreparative TLC (hexanes/AcOAt 9:1, three runs
Rf = 0.21) afforded 18 mg (40% yield) of the title com-
1
pounds as a colourless oil. H‐NMR (250 MHz, CDCl3)
δ: 9.32 (d, J = 7.9 Hz, 0.55H CHO anti); 9.16 (d,
J = 7.9 Hz, 0.45H CHO syn); 7.45 to 7.34 (m, 1H,
Ar―H); 7.24 to 7.13 (m, 1, Ar―H); 7.11 to 7.03 (m, 2H,
Ar―H); 6.56 (d, J = 9.6 Hz, 1H, H4); 6.45 (dd, J = 15.9,
9.8 Hz, 1H3′); 6.11 (dd, J = 9.5, 6.0 Hz, 0.5H, H3); 6.01
to 5.79 (m, 1.5H, H3, H2′); 5.07 (dd, J = 12.2, 6.2 Hz,
1H, H2); 3.81 (s, 1.45H, NCOOCH3 syn), 3.75 (s, 1.55H,
NCOOCH3 anti), 2.44 (dd, J = 9.6, 4.4 Hz, 1H, H4′), 1.39
to 0.93 (m, 4H, H5′, H6′), 0.89 to 0.80 (m, 3H, H7′). 13C‐
NMR (63 MHz, CDCl3) δ: 193.7, 193.4, 158.3, 157.4,
134.8, 134.4, 128.0, 127.9, 127.6, 127.3, 126.5, 126.3,
126.2, 125.0, 124.8, 124.7, 55.0, 54.7, 53.3, 53.2, 47.8,
47.6, 32.2, 32.0, 20.6, 20.1, 14.0, 13.9. HRMS (ESI) m/z
[M + Na+] Calcd for C18H21NO3Na 322.1414, found
2.11 | Methyl (E)(3R*)‐2‐((4R)1‐oxohept‐2‐
en‐4‐yl)6‐bromoquinoline‐1(2H)‐
carboxylate (2g‐syn,anti)
According to the general procedure, methyl‐2‐methoxy‐6‐
bromoquinoline‐1(2H)‐carboxylate (44.5 mg, 0.15 mmol),
trans‐2‐heptenal (52.03 mg, 0.45 mmol, 97%), L3b
(18.5 mg, 0.03 mmol, 97%), In(OTf)3 (16.9 mg, 0.03 mmol),
H2O (1.1 μL, 0.06 mmol), and toluene (0.6 mL) reacted for
5.5 hours. Subsequent semipreparative TLC (hexanes/
AcOEt 7:3, two runs, Rf = 0.58) afforded 42.4 mg (75%
yield) of the title compounds as an amorphous solid.

6
VARGIU ET AL.
1H‐NMR (250 MHz, CDCl3) δ: 9.39 (d, J = 7.9 Hz, 0.5H,
CHO anti), 9.26 (d, J = 7.8 Hz, 0.5H, CHO syn), 7.38 to
7.14 (m, 3H, Ar―H), 6.61 to 6.40 (m, 2H, H4, H3′), 6.17
(dd, J = 9.6, 6.0 Hz, 0.5H, H3), 6.06 to 5.90 (m, 1H, H3,
H2′), 5.85 (dd, J = 15.6, 8.0 Hz, 0.5H, H2′), 5.12 to 4.97
(m, 1H, H2), 3.82 (s, 1.5H, NCOOCH3), 3.75 (s, 1.5H,
NCOOCH3), 2.53 to 2.29 (m, 1H, H4′), 1.73 to 1.06 (m,
4H, H5′, H6′), 0.85 (t, J = 7.28 Hz, 1.5H, H7′), 0.84 (t,
J = 7.42 Hz, 1.5H, H7′).13C‐NMR (63 MHz, CDCl3) δ:
193.6, 193.3, 158.0, 156.9, 135.2, 134.8, 134.0, 133.4,
130.8, 129.4, 129.2, 129.0, 129.0, 128.2, 126.7, 126.4,
125.5, 125.4, 117.6, 55.2, 54.8, 53.6, 53.5, 47.8, 47.8, 32.2,
32.1, 29.8, 29.5, 22.8, 20.7, 20.2, 14.1, 14.0. HRMS (ESI)
m/z [M + Na+] Calcd for C18H20BrNO3Na 400.0519,
found 400.0517. The ee's were determined with Daicel
Chiralcel AD‐H column (heptane–i‐PrOH, 96:4) flow rate
1.0 mL/min; 220 nm; diastereomer 1: 42% ee tr (minor):
10.94 minutes, tr (major): 10.26 minutes; diastereomer 2:
33% ee, tr (minor): 10.83 minutes, tr (major):
12.00 minutes.
2.13 | Methyl (E)(3R*)‐2‐((4R)1‐oxohept‐2‐
en‐4‐yl)4,7‐dichloroquinoline‐1(2H)‐
carboxylate (2i‐syn,anti)
According to the general procedure, methyl‐4,7‐dichloro‐
2‐ethoxyquinoline‐1(2H)‐carboxylate
(45.1
mg,
0.15 mmol), trans‐2‐heptenal (52.03 mg, 0.45 mmol, 97%),
L3b (18.5 mg, 0.03 mmol, 97%), In(OTf)3 (16.9 mg,
0.03 mmol), H2O (1.1 μL, 0.06 mmol), and toluene
(0.6 mL) reacted for 28 hours. Subsequent semipreparative
TLC (hexanes/AcOEt 8:2, three runs, Rf = 0.4) afforded
17.4 mg (32% yield) of the title compounds as a colourless
1
oil. H‐NMR (250 MHz, CDCl3) δ: 9.38 (d, J = 7.8 Hz,
0.40H, CHO anti), 9.26 (d, J = 7.7 Hz, 0.60H, CHO syn),
7.57 to 7.37 (m, 2H), 7.21 to 7.11 (m, 1H), 6.47 (dd,
J = 15.6, 6.5 Hz, 1H, H3′), 6.24 (d, J = 6.7 Hz, 0.40H, H3
anti), 6.11 (d, J = 6.6 Hz, 0.60H, H3 syn), 5.98 (dd,
J = 14.3, 6.4 Hz, 0.60H, H2′ syn), 5.89 (dd, J = 15.38,
8.4 Hz, 0.40 H, H2′ anti), 5.17 to 5.08 (m, 1H, H2), 3.85 (s,
1.80H, NCOOCH3 syn), 3.79 (s, 1.20H, NCOOCH3 anti),
2.53 to 2.28 (m, 1H, H4′), 1.27 to 1.24 (bs, 4H, H5′, H6′),
0.89 to 0.83 (m, 3H, H7′).13C‐NMR (63 MHz, CDCl3) δ:
193.4, 193.0, 157.1, 155.9, 154.5, 135.4, 135.1, 134.9, 125.8,
125.7, 125.3, 125.2, 125.0, 124.8, 124.5, 124.1, 56.3, 56.0,
53.9, 47.8, 47.6, 45.7, 32.2, 32.1, 29.8, 22.8, 20.6, 20.1, 14.1,
2.12 | Ethyl (E)(3R*)‐2‐((4R)1‐oxohept‐2‐
en‐4‐yl)6‐methoxyquinoline‐1(2H)‐
carboxylate (2h‐syn,anti)
14.0. HRMS (ESI) m/z [M
+
Na+] Calcd for
C20H25Cl2NO3Na 390.0634, found 390.0629. The ee was
determined with Daicel Chiralcel AD‐H column (hep-
tane–i‐PrOH, 92:8) flow rate 0.5 mL/min; 220 nm; one dia-
stereoisomer: tr (minor): 8.7 minutes, tr (major):
9.0 minutes.
According to the general procedure, ethyl‐2,6‐
dimethoxyquinoline‐1(2H)‐carboxylate
(39.5
mg,
0.15 mmol), trans‐2‐heptenal (52.03 mg, 0.45 mmol, 97%),
L3b (18.5 mg, 0.03 mmol, 97%), In(OTf)3 (16.9 mg,
0.03 mmol), H2O (1.1 μL, 0.06 mmol), and toluene
(0.6 mL) reacted for 4 hours. Subsequent semipreparative
TLC (hexanes/AcOEt 7:3, one run, Rf = 0.28) afforded
25.5 mg (50% yield) of the title compounds as a colourless
2.14 | Methyl (E)(3S)‐2‐((4R)1‐oxohept‐2‐
en‐4‐yl)4‐bromoquinoline‐1(2H)‐
carboxylate (2j‐syn)
1
oil. H‐NMR (250 MHz, CDCl3) δ: 9.34 (d, J = 7.9 Hz,
0.6H, CHO anti), 9.23 (d, J = 7.9 Hz, 0.4H, CHO syn),
8.04 to 7.74 (m, 3H, Ar―H), 6.52 (d, J = 9.5 Hz, 1H, H4),
6.65 to 6.42 (m, 2H, olefinic protons), 6.02 to 5.79 (m, 1H,
olefinic proton), 5.12 to 4.93 (m, 1H, H2); 4.35 to 4.06 (m,
2H, NCOOCH2CH3), 3.79 (s, 3H, Ar―OCH3); 2.54 to 2.27
(m, 1H, H4′), 1.68 to 1.04 (m, 4H, H5′, H6′), 0.85 (t,
J = 7.38, 0.6H, H7′ anti), 0.84 (t, J = 7.38, 0.4H, H7′
syn).13C‐NMR (63 MHz, CDCl3) δ: 193.9, 193.6, 162.9,
158.6, 157.8, 156.5, 156.5, 134.8, 134.5, 129.3, 129.1, 128.6,
128.4, 128.2, 126.6, 126.5, 126.0, 113.6, 113.5, 111.0, 111.0,
62.4, 62.3, 55.6, 55.0, 54.7, 47.7, 44.4, 32.4, 32.2, 29.8, 27.5,
20.7, 20.2, 14.6, 14.1, 14.0. HRMS (ESI) m/z [M + Na+]
Calcd for C20H25NO4Na 366.1676, found 366.1780. The
ee's were determined with Daicel Chiralcel AD‐H column
(heptane–i‐PrOH, 96:4) flow rate 1.0 mL/min; 220 nm;
syn 11% ee, tr (minor): 10.00 minutes, tr (major):
12.24 minutes; anti: 40% ee, tr (minor): 13.57 minutes, tr
(major): 15.72 minutes.
According to the general procedure, methyl‐4‐bromo‐2‐
methoxyquinoline‐1(2H)‐carboxylate
(74.5
mg,
0.25 mmol), trans‐2‐heptenal (115.7 mg, 0.75 mmol,
95%), L3b (29.9 mg, 0.05 mmol, 97%), In(OTf)3
(28.1 mg, 0.05 mmol), H2O (1.8 μL, 0.10 mmol), and tol-
uene (1.0 mL) reacted for
2 hours. Subsequent
semipreparative TLC (hexanes/AcOEt 8:2, three runs,
Rf = 0.46) afforded 20 mg (21% yield) of the title com-
1
pound as a colourless oil. H‐NMR (250 MHz, CDCl3)
δ: 9.18 (d, J = 7.8 Hz, 1H, CHO); 7.55 (d, J = 7.7 Hz,
1H, Ar―H); 7.46 to 7.11 (m, 3H, Ar―H); 6.47 to 6.34
(m, 2H, H3′ + H3); 5.94 (dd, J = 15.5, 7.9 Hz, 1H, H2);
5.08 (t, J = 6.9 Hz, 1H, H2); 3.82 (s, 3H, NCOOCH3);
2.57 to 2.39 (m, 1H, H4′); 1.63 to 1.25 (m, 4H,
H5′ + H6′); 0.84 (t, J = 6.69 Hz, 3H, H7′).13C‐NMR
(63 MHz, CDCl3) δ: 193.1, 156.2, 135.0, 130.6, 129.4,

VARGIU ET AL.
7
128.3, 126.8, 126.4, 125.0, 124.8, 119.8, 56.9, 53.5, 47.5,
32.0, 29.7, 20.0, 13.8. HRMS (ESI) m/z [M + Na+] Calcd
for C18H20BrNO3Na 400.0519, found 400.0518. The ee
(68%) was determined with Daicel Chiralcel AD‐H
column (heptane–i‐PrOH, 95:5) flow rate 0.8 mL/min;
220 nm: tr (minor): 9.57 minutes, tr (major):
11.67 minutes.
to 0.82 (m, 3H, H7′).13C‐NMR (63 MHz, CDCl3) δ: 193.5,
157.7, 152.0, 149.7, 145.0, 134.8, 129.5, 128.8, 127.1,
125.2, 68.3, 58.7, 56.6, 47.3, 32.3, 29.8, 20.6, 14.1. HRMS
(ESI) m/z [M + Na+] Calcd C24H24BrNO3Na 476.0832,
found 476.0834. The ee (50%) was determined with Daicel
Chiralcel AD‐H column (heptane–i‐PrOH, 95:5) flow rate
0.8 mL/min; 220 nm: 13.12 minutes, tr (major):
14.36 minutes.
2.15 | Methyl (E)(3R)‐2‐((4R)1‐oxohept‐2‐
en‐4‐yl)4‐bromoquinoline‐1(2H)‐
carboxylate (2j‐anti)
2.17 | Benzyl (E)(3R)‐2‐((4R)1‐oxohept‐2‐
en‐4‐yl)4‐bromoquinoline‐1(2H)‐
carboxylate (2k‐anti)
The slower eluting fractions of the above
semipreparative TLC (hexanes/AcOEt 8:2,
3
runs,
The slower eluting fractions of the above
semipreparative TLC (hexanes/Et2O 8:2, 4 runs, Rf = 0.36)
afforded 6.8 mg (6% yield) of the title compound as
unstable colourless oil. 1H‐NMR (250 MHz, CDCl3) δ:
9.16 (d, J = 7.8, Hz, 1H, CHO); 7.54 (dd, J = 7.7,
1.8 Hz, 1H, Ar―H); 7.39 to 7.33 (m, 7H, Ar―H); 7.15
(d, J = 7.4 Hz, 1H, Ar―H); 6.47 to 6.28 (m, 2H,
H3′ + H3); 5.92 (dd, J = 15.6, 7.9 Hz, 1H, H2′), 5.34 to
5.18 (m, 2H, NCOOCH2Ar); 5.10 (t, J = 7.0 Hz, 1H,
H2); 2.44 to 2.37 (m, 1H, H4′); 1.68 to 1.10 (m, 4H, H5′,
H6′);0.80 (t, J = 8.1 Hz, 3H, H7′). 13C‐NMR (63 MHz,
CDCl3) δ: 201.9, 193.6, 193.1, 159.9, 156.2, 154.0, 135.0,
134.3, 129.4, 128.6, 128.4, 128.1, 126.8, 126.4, 125.0,
124.8, 119.8, 68.3, 56.9, 47.5, 32.0, 20.0, 14.0, 13.8. HRMS
(ESI) m/z [M + Na+] Calcd C24H24BrNO3Na 476.0832,
found 476.0831. The ee (66%) was determined with
Daicel Chiralcel AD‐H column (heptane–i‐PrOH, 95:5)
flow rate 0.8 mL/min; 220 nm: tr (minor): 16.45 minutes,
tr (major): 20.40 minutes.
Rf = 0.40), afforded 17.2 mg (18% yield) of the title com-
1
pound as a colourless oil. H‐NMR (250 MHz, CDCl3) δ:
9.36 (d, J = 7.9 Hz, 1H, CHO); 7.56 (d, J = 7.7 Hz, 1H,
Ar―H); 7.33 to 7.29 (m, 2H, Ar―H); 7.20 (d,
J = 8.1 Hz, 1H, Ar―H); 6.49 (dd, J = 15.33, 5.99 Hz,
1H, H3′); 6.51 (d, J = 6.6 Hz, 1H, H3); 5.84 (dd,
J = 15.5, 7.8 Hz, 1H, H2′); 5.07 to 4.97 (m, 1H, H2);
3.76 (s, 3H, NCOOCH3); 2.42 (dd, J = 9.6, 3.8 Hz, 1H,
H4′); 1.43 to 1.10 (m, 4H, H5′, H6′); 0.86 (t, J = 7.2 Hz,
3H, H7′).13C‐NMR (63 MHz, CDCl3) δ: 13C NMR
(75 MHz, CDCl3) δ 194.4, 144.5, 135.8, 130.4, 127.9,
127.5, 126.3, 59.5, 57.3, 54.3, 48.3, 33.3, 30.8, 21.6, 19.6,
14.9. HRMS (ESI) m/z [M
+
Na+] Calcd for
C18H20BrNO3Na 400.0519, found 400.0519. The ee
(45%) was determined with Daicel Chiralcel AD‐H col-
umn (heptane–i‐PrOH, 95:5) flow rate 0.8 mL/min;
220 nm: tr (minor): 8.08 minutes, tr (major):
8.98 minutes.
2.16 | Benzyl (E)(3S)‐2‐((4R)1‐oxohept‐2‐
en‐4‐yl)4‐bromoquinoline‐1(2H)‐
carboxylate (2k‐syn)
2.18 | Methyl (Z)‐2‐(1‐(2‐oxoethylidene)‐
1,2,3,4‐tetrahydronaphthalen‐2‐yl)
quinoline‐1(2H)‐carboxylate (2l)
According to the general procedure, benzyl‐4‐bromo‐2‐
According to the general procedure, methyl‐2‐
methoxyquinoline‐1(2H)‐carboxylate
(93.5
mg,
methoxyquinoline‐1(2H)‐carboxylate
(35.0
mg,
0.25 mmol), trans‐2‐heptenal (115.7 mg, 0.75 mmol,
95%), L3b (29.9 mg, 0.05 mmol, 97%), In(OTf)3
(28.1 mg, 0.05 mmol), H2O (1.8 μL, 0.10 mmol), and tolu-
ene (1.0 mL) reacted for 2.5 hours. Subsequent
semipreparative TLC (hexanes/Et2O 8:2, 4 runs, Rf = 0.41)
afforded 5.1 mg (4.5% yield) of the title compound as
0.15 mmol), (E)‐2‐(3,4‐dihydronaphthalen‐1(2H)‐yidene)
acetaldehyde (77.5 mg, 0.45 mmol), L3b (18.5 mg,
0.03 mmol, 97%), In(OTf)3 (16.9 mg, 0.03 mmol), H2O
(1.1 μL, 0.06 mmol), and toluene (0.6 mL) reacted for
3.5 hours. Subsequent semipreparative TLC (hexanes/
EAcOEt 8:2, two runs, Rf = 0.23) afforded 12.8 mg
(22% yield) of the title compound as a colourless oil.
1H‐NMR (250 MHz, CDCl3) δ: 9.41 (d, J = 8.1 Hz, 1H,
CHO); 7.59 (d, J = 7.8 Hz, 1H, Ar―H); 7.41 to 7.09
(m, 8H); 6.63 (d, J = 9.6 Hz, 1H); 6.46 (d, J = 8.1 Hz,
1H); 6.15 (dd, J = 9.6, 6.1 Hz, 1H), 5.11 (bs, 1H); 3.43
(s, 3H); 3.70 (dd, J = 10.2, 3.7 Hz, 1H); 3.20 to 2.86
(m, 2H); 2.47 to 1.75 (m, 3H). 13C‐NMR (63 MHz,
1
unstable colourless oil. H‐NMR (250 MHz, CDCl3) δ:
9.28 (bs, 1H, CHO); 7.56 (d, J = 7.8 Hz, 1H, Ar―H);
7.39 to 7.28 (m, 7H, Ar―H); 7.19 (d, J = 7.9 Hz, 1H,
Ar―H); 6.69 to 6.34 (m, 1H, H3′); 6.50 (d, J = 6.7 Hz,
1H, H3); 5.79 (dd, J = 15.5, 7.8 Hz, 1H, H3′); 5.31 to 5.14
(m, 2H, NCOOCH3Ar); 5.08 to 4.99 (m, 1H, H2); 2.46 to
2.34 (m, 1H, H4′); 1.71 to 1.20 (m, 4H, H5′ + H6′); 0.90

8
VARGIU ET AL.
CDCl3) δ: 192.1, 157.3, 155.9,131.7, 130.5, 128.5,128.2,
127.3, 127.2, 126.3, 126.3, 126.0, 54.0, 51.3 (C5), 36.5,
25.1, 24.5.HRMS (ESI) m/z [M + Na+] Calcd for
C24H23NO3Na 396.1570, found 396.1570. The ee (81%)
was determined with Daicel Chiralcel AD‐H column
(heptane–i‐PrOH, 95:5) flow rate 0.8 ml/min; 220 nm:
tr (minor): tr (minor): 41.77 minutes, tr (major):
46.14 minutes.
7.8 Hz, 0.5H, H2′); 5.83 (dd, J = 15.7, 7.8 Hz, 0.5H,H2′).
13C‐NMR (63 MHz, CDCl3) δ: 193.5, 193.4, 158.3, 158.1,
152.1, 135.7, 128.8, 126.0, 128.3, 127.7, 126.8, 126.7,
126.4, 125.1, 124.8, 121.8, 121.7, 111.3, 110.0, 68.2, 52.5,
52.0, 42.7, 42.1, 24.0, 23.5, 12.1, 12.0. HRMS (ESI) m/z
[M + Na+] Calcd for C23H23NO3Na 384.1570, found
384.1573.
3 | RESULTS AND DISCUSSION
2.19 | Methyl (E)(4R*)‐4‐((4R)1‐oxohex‐2‐
en‐4‐yl)quinoline‐1(4H)‐carboxylate (3a‐
syn,anti)
At the outset, in order to explore the regioselectivity and
stereoselectivity of the reaction of in situ formed
dienamines with N‐acylquinolinium ions, trans‐2‐
hexenal was allowed to react with N,O‐acetal 1a in the
presence of catalytic amounts (20 mol%) of MacMillan
(L1a,L2) or Hayashi‐Jørgensen (L3a,b) organocatalysts,
and In(OTf)3 in anhydrous THF or toluene, respectively
(Scheme Table 1). This choice of solvents proved to be
optimal in terms of yield and enantioselectivity for related
α‐alkylations.14 After complete conversion of 1a, only
trace amounts of regioisomeric addition products 2a
(γ,α′) and 3a (γ,γ′) were detected in the crude mixture,
with quinoline (Q) found as the major decomposition
product (>85%, entries 1‐4, Table 1). Much to our delight,
we found that the reaction carried out in the presence of
stoichiometric amounts (100 mol%) of water dramatically
reduced the extent of decomposition to quinoline and
delivered good yields of addition products 2a and 3a,
albeit in a racemic fashion, in a very short reaction time
(entry 5). On the other hand, the use of a large excess of
water afforded compounds 2a and 3a with a lower effi-
ciency (entry 6). The use of first generation MacMillan
catalysts L1a,b gave a much slower reaction with a
slightly improved enantioselectivity, but a consistent
amount of quinoline was found (entries 7,8).
Regioisomeric compounds of type 2 (γ,α′‐addition) and
of type 3 (γ,γ′‐addition) turned out to be separable by sil-
ica gel chromatography (Table 1).
According
to
the
general
procedure,
2‐
methoxyquinoline‐1(2H)‐carboxylate (35 mg, 0.15 mmol),
trans‐2‐hexenal (45.0 mg, 0.45 mmol, 98%), L3b
(18.5 mg, 0.03 mmol, 97%), In(OTf)3 (16.9 mg,
0.03 mmol), H2O (1.1 μL, 0.06 mmol), and toluene
(0.6 mL) reacted for 2 hours. Subsequent flash chroma-
tography (hexanes/Et2O 7:3, Rf = 0.25) afforded 10 mg
(23% yield) of the title compounds as a colourless oil.
1H‐NMR (250 MHz, CDCl3) δ: 9.33 (d, J = 7.8 Hz, 0.5
H, CHO), 9.30 (d, J = 7.8 Hz, 0.5 H, CHO), 7.87 (dd,
J = 12.9, 8.2 Hz, 1H, H2), 7.19 (m, 4H, Ar―H), 6.44
(dd, 1H, J = 15.7, 9.4 Hz, H3′), 5.93 (m, 1H, H2′), 5.33
(dd, 1H J = 7.8, 6.2 Hz, H3), 3.82 (s, 1.5H, COOCH3),
3.86 (s, 1.5H, COOCH3), 3.55 (m, 1H, H4), 2.38 (dd,
J = 14.0, 9.5 Hz, 1H, H4′), 1.73 to 1.45 (m, 1H, H5′),
0.85 (t, J = 7.4 Hz, 1.5H), 0.90 (t, J = 7.3 Hz, 1.5H).
13C‐NMR (63 MHz, CDCl3) δ: 193.7, 193.6, 153.0, 158.4,
134.8, 134.5, 129.1, 128.4, 127.9, 127.1, 122.1, 121.9,
111.6, 110.0, 53.6, 52.7, 52.1, 42.9, 42.5, 24.1, 23.9, 12.3,
12.2. HRMS (ESI) m/z [M
+
Na+] Calcd for
C23H23NO3Na 308.1257, found 308.12576.
2.20 | Benzyl (E)(4R*)‐4‐((4R)1‐oxohex‐2‐
en‐4‐yl)quinoline‐1(4H)‐carboxylate (3b‐
syn,anti)
The high reactivity of organocatalyst L2 in this
vinylogous reaction was quite surprising considering
that MacMillan imidazolidinones have a very weak pref-
erence for dienamine formation.20 Interestingly, whilst
prolinol aminocatalyst L3a afforded mainly the decom-
position product (entry 9), the use of catalyst L3b gave
a lower amount of quinoline with an increase of the
enantioselectivity (entry 10). We then concentrated our
optimization efforts on Cbz‐protected quinoline N,O‐
acetal 1b. In fact, with this substrate, the syn,anti‐
diastereoisomers of corresponding γ,α′‐nucleophilic enal
addition product 2b turned out to be separable by silica
gel chromatography (entries 11‐14). The use of a strong
Brønsted acid (BA) such as TsOH‐H2O was found
According to the general procedure, benzyl‐2‐
methoxyquinoline‐1(2H)‐carboxylate (35 mg, 0.15 mmol),
trans‐2‐hexenal (45.0 mg, 0.45 mmol, 98%), L3b (18.5 mg,
0.03 mmol, 97%), In(OTf)3 (16.9 mg, 0.03 mmol), H2O
(1.1 μL, 0.06 mmol), and toluene (0.6 mL) reacted for
3 hours. Subsequent semipreparative TLC (hexanes/
Et2O 6:4, 3 runs, Rf = 0.60) afforded 8.9 mg (12.4% yield)
of the title compound as a colourless oil. 1H‐NMR
(250 MHz, CDCl3) δ: 9.33 (d, J = 7.8 Hz, 0.5H, CHO);
9.20 (d, J = 7.8 Hz, 0.5H, CHO); 7.93 (d, J = 8.3 Hz,
0.5H, H2); 7.88 (d, J = 8.3 Hz, 0.5H, H2) 7.44 to 7.02 (m,
9H, Ar―H); 6.56 (dd, J = 15.1, 9.3 Hz, 1H, 0.5 H, H3′);
6.38 (dd, J = 15.5, 9.6 Hz, 0.5H, H3′); 6.03 (dd, J = 15.6,

VARGIU ET AL.
9
suitable to promote the reaction (entry 12). However,
differently from the enantioselective α‐alkylations of
aldehydes,14 anhydrous TsOH prolonged the reaction
time (entry 13). The use of 20 mol% of In(OTf)3 in the
presence of 40 mol% of H2O gave the best compromise
between reactivity and enantioselectivity (entry 14).
Even if the beneficial effect of measured amounts of
water in our case has not been fully rationalized, its
effect is likely related to an improvement in catalyst
turnover during the hydrolysis of the final iminium
ion (Scheme 1).21,22
conditions. The use of substituted dihydroquinolines was
tolerated, but a drop in yields and enantioselectivity was
generally observed (compounds 2f‐k). The use of substit-
uent at the 4‐position of the quinoline‐N,O‐acetal clearly
avoided the formation of the regioisomeric γγ′‐adduct
but also caused a depletion of isolated yields (compounds
2j‐k). The highest enantioselectivity (96% ee for the major
anti‐diastereoisomer of 2d) was obtained with 2‐decenal.
It should be noted that similar embedment of α,β‐
unsaturated linear aldehydes at the 2‐position of a
tetrahydroquinoline has been previously obtained only
After these preliminary results, we then applied the
optimized reaction conditions making use of Hayashi‐
Jørgensen L3b to a broader range of enals and N‐
acylquinolinium ions, and the results are summarized in
Scheme 1. It should be noted that the use of quinoline
N,O‐acetals containing more hindered protecting group
(PG = COOiPr, COOtBu) in order to get an improved
diastereoselectivity and or enantioselectivity was totally
uneffective.23 In general, the formation of two
stereocenters was accomplished with moderate regiose-
lectivity (γα′‐γγ∋), low diastereoselectivity for both
regioisomeric
adducts,
and
good
to
high
enantioselectivity at least for one diastereoisomer that is
usually the anti one. α−Substituted and α,β‐disubstituted
acyclic aldehydes were found not reactive in our reaction
FIGURE 2 Molecular structure of 2c‐anti. Thermal ellipsoids are
at 50% probability
SCHEME 1 Scope of the vinylogous
Mannich reaction with prolinol catalyst
L3b

10
VARGIU ET AL.
after very long synthetic procedures and in racemic form
en route to compounds of pharmaceutical interest.24 The
only cyclic α,β‐unsaturated aldehyde used with our proto-
col afforded the corresponding functionalized 1,2‐
dihydroquinoline 2l with a high level of regioselectivity,
diastereoselectivity, and enantioselectivity, albeit with a
low isolated yield.
The determination of the relative and absolute config-
urations of 1,2‐dihydroquinolines 2a‐k derived from acy-
clic enals was realized by the combination of several
techniques. In particular, the relative configuration was
determined on compound 2c‐anti by X‐ray analysis
(Figure 2).25
The diastereoisomeric nature of 2c‐syn was then con-
firmed by NMR. The absolute configuration of the
endocyclic stereocentre was established as (S) for com-
pound 2c‐syn and (R) for 2c‐anti by ECD.
Using a combined experimental and computational
procedure, the ECD spectra of 2c‐syn and 2c‐anti were
recorded in acetonitrile and compared with those calcu-
lated by density functional theory (DFT) on a truncated
model of 2c (benzyl of Cbz replaced by methyl).26,27 As
SCHEME 2 Stereochemical models for
main facial selectivity observed
FIGURE 3 Transition states leading to (R,R) and (S,S)‐anti diastereoisomers

VARGIU ET AL.
11
recently observed for other 1,2‐dihydroquinoline deriva-
tives,28 the ECD spectra of 2c is dominated by the config-
uration of the endocyclic stereocentre. The configuration
of the endocyclic stereocentre depends on the attack of
the dienamine with either Re or Si face of the N‐acyl
quinolinium ion (Scheme 2). What is relevant for this
work is the (R)‐absolute configuration of the exocyclic
stereocentre present in the major enantiomer of both
compounds 2c‐anti (72% ee) and 2c‐syn (23% ee). As only
one face is shielded by the substituent, the (R)‐absolute
configuration of the exocyclic stereocentre derives neces-
sarily by the ul and lk addition, respectively, of the Re face
of the second double bond of the corresponding
dienamine in its (E)‐s‐trans‐(Z) form, to the N‐acyl
quinolinium ion (Scheme 2).
The experimental data obtained throughout this work
in which the (R,R)‐anti diastereoisomer is the prevailing
enantiomer are also supported by theoretical calculations
(B3LYP‐D3/def2‐SVP).27 These data have shown that TS1
leading to (R,R)‐anti‐diastereoisomeric adduct starting
from a (Z)‐configuration of the remote double bond is
by 5.1 kJ/mol more favoured as compared with the TS2
leading to (S,S)‐anti‐diastereoisomer starting from E‐
configuration of the remote double bond (Figure 3).
These results are in agreement with computational
results obtained by Gschwind and coworkers where a
kinetic preference for Z configuration of the second dou-
ble bond was evidenced.19 The facial selectivity of the
only one chiral centre formed was rationalized by the
authors in terms of advantageous CH‐π interactions
between (E)‐s‐trans‐(Z)‐dienamine and the electrophile.
via a kinetic preference for the (Z)‐form of the second
double bond.
ACKNOWLEDGMENTS
We gratefully acknowledge the University of Pisa for
financial support (P.R.A. 2016_27). G.P. acknowledges
the CINECA award under the ISCRA initiative, for the
availability of high performance computing resources
and support. We also acknowledge Enrico Mazzoni and
Giuseppe Terreni (INFN Sezione di Pisa) for the availabil-
ity of additional computing resources.
ORCID
Lucilla Favero https://orcid.org/0000-0003-3178-7566
Valeria Di Bussolo https://orcid.org/0000-0001-6126-9984
Fabio Marchetti https://orcid.org/0000-0002-3683-8708
Gennaro Pescitelli https://orcid.org/0000-0002-0869-5076
Sebastiano Di Pietro
https://orcid.org/0000-0003-3585-
6573
Mauro Pineschi https://orcid.org/0000-0001-6063-2198
REFERENCES AND NOTES
1. Arceo E, Melchiorre P. Extending the aminocatalytic HOMO‐
raising activation strategy: where is the limit? Angew Chem Int
Ed. 2012;51(22):5290‐5291.
2. Casiraghi G, Zanardi F, Battistini L, Rassu G. Advances in
exploring heterocyclic dienoxysilane nucleophiles in asymmetric
synthesis. Synlett.2009;(10):1525‐1542.
3. Gu Y, Wang Y, Yu TY, Liang YM, Xu PF. Rationally designed
multifunctional supramolecular iminium catalysis: direct
vinylogous Michael addition of unmodified linear dienol. Angew
Chem Int Ed. 2014;53(53):14128‐14131.
4. Donslund BS, Halskov KS, Leth LA, Matos Paz B, Jørgensen
KA. Organocatalytic asymmetric strategies to carbocyclic struc-
tures by γ‐alkylation‐annulation sequences. Chem Commun.
2014;50(89):13676‐13679.
4 | CONCLUSIONS
In conclusion, we have studied the direct
functionalization of acyclic enals with in situ generated
N‐acyl quinolinium ions using dienamine catalysis with
formation of two stereocentres. The activation of the enal
proved to be completely γ‐regioselective, but complex
mixtures of products were generally obtained. MacMillan
imidazolidinone L2 showed to be unexpectedly reactive
in the activation of enals by dienamine formation even
if the corresponding products were obtained with a poor
enantioselectivity. Several chiral nonracemic γ‐
dihydroquinolyl‐substituted‐α,β‐unsaturated aldehydes
have been obtained with moderate to good
5. deFigueiredo RM, Fröhlich R, Christmann M. Amine‐catalyzed
cyclizations of tethered α,β‐unsaturated carbonyl compounds.
Angew Chem Int Ed. 2008;47(8):1450‐1453.
6. Volz N, Bröhmer MC, Nieger M, Bräse S. Thieme chemistry
journal awardees—where are they now? An asymmetric
organocatalytic
tetrahydroxanthones:
sequence
formal
towards
synthesis
4a‐methyl
of 4‐
dehydroxydiversonol. Synlett. 2009;4:550‐553.
7. Stiller J, Marqués‐López E, Herrera RP, Fröhlich R, Strohmann
C, Christmann M. Enantioselective α‐ and γ‐alkylation of α,β‐
unsaturated aldehydes using dienamine activation. Org Lett.
2011;13(13):70‐73.
enantioselectivities, albeit with
a
generally poor
8. Bergonzini G, Vera S, Melchiorre P. Cooperative organocatalysis
for the asymmetric γ alkylation of α‐branched enals. Angew
Chem Int Ed. 2010;49(50):9685‐9688.
diastereocontrol, using prolinol organocatalyst L3b. Our
experimental and theoretical data corroborate the
hypothesis according to which the remote SN‐type reac-
tions of dienamines with large electrophiles occur mainly
9. Silvi M, Cassani C, Moran A, Melchiorre P. Secondary
amine‐catalyzed asymmetric γ‐alkylation of α‐branched

12
VARGIU ET AL.
enals via dienamine activation. Helv Chim Acta.
2012;95(10):1985‐2006.
21. Giacalone F, Gruttadauria M. Water in organocatalytic reac-
tions. In: Dalko PI, ed. Comprehensive Enantioselective
Organocatalysis. Vol.II Wiley‐VCH; 2013:673‐717. https://doi.
org/10.1002/9783527658862.ch24
10. Kutwal MS, Appayee C. Highly regio‐ and enantioselective γ‐
alkylation of linear α,β‐unsaturated aldehydes. Eur J Org
Chem.2017;(29):4230‐4234.
22. For combinations of indium salts and water, see:Sinisi R, Vita
MV, Gualandi A, Emer E, Cozzi PG. SN1‐Type Reactions in
the Presence of Water: Indium (III)‐Promoted Highly
Enantioselective Organocatalytic Propargylation of Alde-
hydes. Chem A Eur J. 2011;17:7404‐7408. and references
cited therein
11. Næsborg L, Halskov KS, Tur F, Mønsted SMN, Jørgensen KA.
Asymmetric γ‐allylation of α,β‐unsaturated aldehydes by com-
bined organocatalysis and transition‐metal catalysis. Angew
Chem Int Ed. 2015;54(35):10193‐10197.
12. Bertelsen S, Marigo M, Brandes S, Dinér P, Jørgensen KA.
23. It was not possible to obtain the quinoline N,O‐acetal with Boc‐
protection. The quinoline N,O‐acetal with PG = COOiPr was
prepared but it was found totally unreactive in our reaction
conditions.
Dienamine catalysis: organocatalytic asymmetric γ‐amination
of
α,β‐unsaturated
aldehydes.
J
Am
Chem
Soc.
2006;128(39):12973‐12980.
13. Ransborg LK, Overgaard M, Hejmanowska J, Barfüsser S,
Jørgensen KA, Albrecht L. Asymmetric formation of bridged
benzoxazocines through an organocatalytic multicomponent
dienamine‐mediated one‐pot cascade. Org Lett. 2014;16(16):
4182‐4185.
24. Scott JD, Miller MW, Li SW, et al. Tetrahydroquinoline sulfon-
amides as vasopressin 1b receptor antagonists. Biorg Med
Chem Lett. 2009;19(21):6018‐6022.
25. CCDC 1874936 contains the supplementary crystallographic
data for compound 2c‐anti. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
14. Berti F, Malossi F, Marchetti F, Pineschi M. Highly
enantioselective Mannich reaction of aldehydes with cyclic N‐
acyliminium ions by synergistic catalysis. Chem Commun.
2015;51(71):13694‐13696.
26. Pescitelli G, Bruhn T. Good computational practice in the
assignment of absolute configurations by TDDFT calculations
of ECD spectra. Chirality. 2016;28(6):466‐474.
15. Volla CMR, Fava E, Atodiresei I, Rueping M. Dual metal and
Lewis base catalysis approach for asymmetric synthesis of
dihydroquinolines and the α‐arylation of aldehydes via N‐
acyliminium ions. Chem Commun. 2015;51(87):15788‐15791.
27. See Supporting Information for details.
28. Menichetti A, Berti F, Guazzelli L, et al. Organocatalytic alkyl-
16. Sun S, Mao Y, Lou H, Liu L. Copper (II)/amine synergistically
catalyzed enantioselective alkylation of cyclic N‐acyl
hemiaminals with aldehydes. Chem Commun. 2015;51(53):
10691‐10694.
ation
of
carbohydrate‐containing
aldehydes
with
dihydroquinoline N,O‐acetals: absolute configuration of 1,2‐
dihydroquinolines. Chirality. 2019;31(2):127‐137.
17. For a review on the use of N,O‐acetals in asymmetric synthesis,
see:Huang YY, Cai C, Yang X, Lv ZC, Schneider U. Catalytic
asymmetric reactions with N,O‐aminals. ACS Catalysis.
2016;6:5747‐5763.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
18. For a recent review about dienamine activation with enals, see:
Marcos V, Alemán J. Old tricks, new dogs: organocatalytic
dienamine activation of α,β‐unsaturated aldehydes. Chem Soc
Rev. 2016;45:6812‐6832.
19. Seegerer A, Hioe J, Hammer MM, Morana F, Fuchs PJW,
Gschwind RM. Remote‐stereocontrol in dienamine catalysis: Z‐
dienamine preferences and electrophile–catalyst interaction
revealed by NMR and computational studies. J Am Chem Soc.
2016;138(31):9864‐9873.
How to cite this article: Vargiu M, Favero L,
Menichetti A, et al. Direct enantioselective
vinylogous Mannich‐type reactions of acyclic enals:
New experimental insights into the E/Z‐dilemma.
Chirality. 2019;1–12. https://doi.org/10.1002/
chir.23077
1
20. For a very recent H NMR study of dienamine formation, see:
Lagiewka B, Albrecht L. Studies on the formation of dienamine
and trienamine intermediates by 1H NMR spectroscopy. Asian J
Org Chem. 2017;6:516‐519.