A modified and highly useful protocol for the Bronsted acid catalyzed, enantioselective, vinylogous Mannich reaction with aliphatic aldimines

Article abstract of DOI:10.1055/s-0031-1289303

Highly enantioselective as well as diastereoselective catalytic vinylogous Mannich reactions have been accomplished for the first time with aliphatic straight-chain aldimines and O,O-silylketene acetals and furnish valuable synthetic building blocks in hi

Full text of DOI:10.1055/s-0031-1289303

4050
PAPER
A Modified and Highly Useful Protocol for the Brønsted Acid Catalyzed,
Enantioselective, Vinylogous Mannich Reaction with Aliphatic Aldimines
Vinylogous
M
a
annich
R
ea
l
ctionw
k
ithAliphatic
o
Aldimines Abels, Christoph Schneider*
Institut für Organische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany
Fax +341(97)36599; E-mail: schneider@chemie.uni-leipzig.de
Received 18 August 2011; revised 20 September 2011
chain aldimines lacking a-substitution. For example, the
Abstract: Highly enantioselective as well as diastereoselective cat-
alytic vinylogous Mannich reactions have been accomplished for
the first time with aliphatic straight-chain aldimines and O,O-si-
lylketene acetals and furnish valuable synthetic building blocks in
high enantiomeric purity.
n-octanal-based aldimine was slowly converted into the
corresponding vinylogous Mannich product within three
days in 88% yield and only 70% ee.4 This appears to be a
general problem in VMR because there is currently only
one catalytic, enantioselective process, developed by
Snapper and Hoveyda,2c that readily tolerates aliphatic
aldimines, albeit with 2-silyloxy furans as nucleophiles.
Because we intended to employ our VMR in a range of
synthetic applications, we sought to devise an improved
protocol for the conversion of aliphatic aldimines.
Key words: vinylogous Mannich reaction, phosphoric acid, orga-
nocatalyis, contact ion pair, dienolate, BINOL
The asymmetric vinylogous Mannich reaction (VMR)
giving rise to enantiomerically enriched d-amino-a,b-un-
saturated carbonyl compounds is among the most impor-
tant tools in synthetic organic chemistry to construct
nitrogen-containing building blocks and natural prod-
ucts.1 Most prominent among the nucleophiles employed
for this reaction are 2-silyloxy furans, which furnish
amino-substituted g-butenolides and a,a-dicyanoalkenes
as products.2,3
By carefully monitoring the standard reaction of butanal-
based aldimine 1b with vinylketene O,O-silyl acetal 2a
through the use of HPLC analysis, it became clear that
enamine formation and self-aldolization processes involv-
ing the starting aldehyde decreased the active concentra-
tion of the aldimine, thus slowing down the entire reaction
and consuming material. To avoid such side reactions, the
protic solvent components were omitted and tetrahydrofu-
ran was screened as solvent alone in the condensation of
butanal and p-anisidine at –40 °C in the presence of chiral
phosphoric acid 3a (Scheme 2). Clean and quantitative
imine formation was observed within 30 minutes at
low temperature. Subsequent addition of dienolate 2a
(1 equiv) gave rise to an almost instantaneous reaction at
–40 °C and delivered vinylogous Mannich product 4b in
excellent yield and 74% ee within less than 15 minutes
(Table 1, entry 1).
Recently, we have documented the first catalytic, enantio-
selective Mukaiyama-type VMR of acyclic silyl dieno-
lates furnishing highly valuable, open-chain d-amino-a,b-
unsaturated carboxylic esters and amides in typically ex-
cellent yields and enantioselectivities.4 A specially opti-
mized, BINOL-based phosphoric acid of the type that
Akiyama and Terada have developed independently
mainly for imine addition reactions,5 was employed as
Brønsted acid catalyst to activate the imine and control the
enantioselectivity of the carbon–carbon bond-forming
event at the same time. A mixture of tetrahydrofuran, tert-
butanol, and 2-methyl-2-butanol with one equivalent of
water (TTM) proved to be the solvent of choice both in
terms of rate and enantioselectivity (Scheme 1).4
Ar
O
PO2H
O
Aliphatic aldimines were problematic substrates in this
process, however. Long reaction times and moderate
enantioselectivity were frequently observed under the
standard reaction conditions; in particular for straight-
Ar
PMP
PMP
OTBS
OEt
3 (10 mol%)
HN
N
O
+
THF (0.16 M)
–40 °C
C3H7
1b
H
C3H7
OEt
2a
4b
PMP
PMP
H
3b (5 mol%)
OTBS
OEt
HN
N
O
+
Scheme 2 VMR with aliphatic aldehydes; catalyst screening
TTM (0.16 M)
–50 °C
R
R
OEt
up to 97% yield
and 97% ee
Because the enantioselectivity was still only moderate, we
investigated some more chiral phosphoric acids (Table 1)
to evaluate their capacity for asymmetric induction. Not
surprisingly, our previously optimized chiral Brønsted
acid catalyst 3b, carrying 2,6-dimethyl-4-tert-butylphenyl
groups as 3,3¢-substituents in the BINOL-backbone, in-
creased the enantioselectivity to 77% ee. The optimal
Scheme 1 The Brønsted acid catalyzed enantioselective Mannich
reaction
SYNTHESIS 2011, No. 24, pp 4050–4058
Advanced online publication: 20.10.2011
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DOI: 10.1055/s-0031-1289303; Art ID: N81411SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Vinylogous Mannich Reaction with Aliphatic Aldimines
4051
Table 1 Catalyst Screening
Table 2 Substrate Scope of the VMR
Entry
3
Ar
Yield (%) ee (%)a
Entry 1/4
R
Time (min) Yield (%)a ee (%)b
1
2
3
4
5
3a
3b
3c
3d
3e
2,4,6-Me3C6H2
2,6-Me2-4-t-BuC6H2
2,6-Et2-4-t-BuC6H2
2,4,6-(i-Pr)3C6H2
Ph3Si
80
47
71
81
53
74
77
86
91
rac
1
2
a
b
c
d
e
f
Et
15
15
15
15
15
15
15
15
15
45
n.r.
n.r.
83
81
62
78
70
62
60
71
80
40
n.d.
n.d.
79
91
91
96
99
85
91
88
84
66
n.d.
n.d.
Pr
3
Hex
c
4
Me(CH2)8
d
5
EtO2C(CH2)2
Cl(CH2)5
a Determined by HPLC with a chiral stationary phase.
6
7
g
h
i
HC∫ C(CH2)9
i-Bu
chiral catalyst for this reaction, however, proved to be the
TRIP-catalyst 3d, developed by List et al.,6 which fur-
nished the product in excellent yield and 91% ee. The of-
ten reported switch in asymmetric induction when using
the triphenylsilyl group in the 3,3¢-position of the BINOL-
backbone was not observed here, instead, the product was
obtained as a racemic mixture (Table 1, entry 5).
8
9
i-Pr
10
11
12
j
c-Hex
k
l
t-Bu
4-EtC6H4
We next studied a broad range of aliphatic aldimines 1 in
the VMR with silyl dienolate 2a under the optimized re-
action conditions (Scheme 3 and Table 2). It turned out
that straight-chain aldimines were particularly good sub-
strates for our VMR process and delivered products with
typically good yields and excellent enantioselectivities
above 90% ee (Table 2, entries 2–5, and 7). Further func-
a Isolated yield.
b Determined by HPLC with a chiral stationary phase.
c Reaction was performed at –50 °C.
d Reaction was conducted in THF (0.1 M).
vorable steric interactions between the substrate and the
tional groups such as esters, halogens, and alkynes within catalyst that results in reduced enantioselectivities.
the alkyl chain were readily tolerated and the respective
With decanal as one of the best substrates, we briefly
Mannich products were formed with exceptional enantio-
checked the catalyst efficiency by varying the catalyst
selectivities (Table 2, entries 5–7).
loading from 10 mol% down to 0.5 mol% at –50 °C
(Scheme 4 and Table 3).
PMP
PMP
H
OTBS
OEt
3d (10 mol%)
HN
N
O
+
PMP
PMP
3d (X mol%)
OTBS
OEt
HN
N
THF (0.16 M)
–40 °C
O
R
R
OEt
+
1
2a
4
THF (0.16 M)
–50 °C
C9H19
H
C9H19
OEt
1d
2a
4d
Scheme 3 VMR with aliphatic aldehydes; substrate scope
Scheme 4 VMR with aliphatic aldehydes; catalyst loading
Table 3 Screening of the Catalyst Loading
Interestingly, gradually increasing the steric size of the
alkyl group within the imine resulted in a steady decrease
in enantioselectivity. For example, the 3-methylbutanal-
based imine 1h gave rise to 88% ee (Table 2, entry 8),
whereas moving the branching point from the b- to the a-
position, such as in isobutyraldehyde or cyclohexane car-
baldehyde, further lowered the selectivity to 84 and 66%
ee, respectively (Table 2, entries 9 and 10). More bulky or
aromatic aldimines did not react at all under these condi-
tions.
Entry
X
10
5
Time (h)
0.2
Yield (%)
ee (%)a
96
1
2
3
4
5
78
12
71
94
3
24
75
94
1
36
65
92
This reactivity and selectivity pattern is quite complemen-
tary to our previously optimized protocol, which gave ex-
cellent enantioselectivity in particular for sterically
demanding substrates.4 The TRIP catalyst, carrying ex-
tremely bulky 3,3¢-substituents within the BINOL back-
bone, apparently responds very sensitively to the steric
size within the imine component and provides excellent
enantioface differentiation only for unencumbered ald-
imines. With more bulky imines there may well be unfa-
0.5
36
<20 conv.
n.d.
a Determined by HPLC with a chiral stationary phase.
Reducing the amount of catalyst gradually increased the
reaction times from several minutes (10 mol%) to 24
hours (3 mol%). Isolated yields and enantioselectivities
were, however, only marginally different from the reac-
tion with 10 mol% catalyst, indicating that almost identi-
cal results can be obtained with significantly less catalyst
Synthesis 2011, No. 24, 4050–4058 © Thieme Stuttgart · New York

4052
F. Abels, C. Schneider
PAPER
PMP
PMP
(compare Table 3, entries 1 and 3). Even with as little as
1 mol% catalyst, a reasonable yield and excellent enantio-
selectivity was obtained (entry 4). Further reducing the
catalyst loading to below 1 mol% resulted in a sharp drop
in conversion.
3d (10 mol%)
OTBS
OEt
N
HN
O
+
THF (0.16 M)
–40 °C, 15 min
81%
C3H7
H
C3H7
OEt
1b
2a
4b 91% ee
H2, Pd/C (5 mol%)
EtOH (0.01 M)
r.t., 10 min
With this optimized protocol in hand, we investigated the
g-methyl-substituted silyl dienolate 2b as a vinylogous
nucleophile (Scheme 5). In previous studies we had found
that only the 3E-configured silyl dienolate gave rise to a
productive and highly diastereo- and enantioselective re-
action.4a Because of its lower reactivity, we had to typical-
ly employ 10 mol% catalyst for complete conversions
within 72 hours at –40 °C. Both enantio- as well as dia-
stereoselectivities were very good, whereas yields ranged
from moderate to excellent (Table 4).
99%
PMP
N
DIBAL-H (5.0 equiv)
NaBH4 (1.0 equiv)
PMP
C3H7
HN
O
C3H7
OEt
THF (0.01 M)
–78 °C to r.t., 1.5 h
75%
7
6
a) H5IO6 (1.0 equiv)
H2SO4 (1.0 equiv)
MeCN–H2O (1:1; 0.055 M)
reflux, 1 h
THF–AcOH (1:1)
reflux
6 h
99%
b) excess HCl•Et2O (1 M)
70%
Although straight-chain aldimines again displayed the
best results (entries 1–4), additional substitution in the
alkyl chain was detrimental to the reaction (entry 5) and,
in particular, a-substitution shut down the reactivity com-
pletely (entry 6).
PMP
H
C3H7
N
C3H7
N
O
HCl
(R)-coniine hydrochloride (8)
9
overall yield 42% and 91% ee
E/Z ~ 1:1
PMP
PMP
3d (10 mol%)
Scheme 6 Total synthesis of (R)-coniine hydrochloride
OTBS
HN
N
O
E
+
THF (0.16 M)
–40 °C, 72 h
OEt
R
H
R
OEt
Hydrogenation of the conjugate double bond with palladi-
um on charcoal, subsequent intramolecular reductive am-
ination with diisobutylaluminum hydride (DIBAL-H),
followed by mild PMP-oxidation with periodic acid, gave
rise to coniine hydrochloride (8) as colorless crystals in a
total of four steps within less than three hours and an over-
all yield of 42%. The R-configuration, which we assigned
by comparison of the optical rotation with literature val-
ues,9 is consistent with our previous findings on the sense
of asymmetric induction in the phosphoric acid catalyzed
VMR. In addition, it was possible to heat 6 to reflux in
acetic acid for six hours to obtain the corresponding lac-
tam 9 in quantitative yield. Lactams of this type are inter-
esting synthetic precursors for syntheses of other
piperidine alkaloids.
1
2b
5
Scheme 5 VMR with g-substituted silyl dienolates
Table 4 Substrate Scope; g-Substituted Dienolates
Entry 1, 5
R
Yield (%)a de (%)b ee (%)c
1
2
3
4
5
6
a
b
c
d
h
i
Et
63
61
96
40
48
n.r.
93
92
88
90
82
n.d.
90
88
88
87
72
n.d.
Pr
Me(CH2)5
Me(CH2)8
i-Bu
In conclusion, we have developed a modified and highly
useful protocol for the catalytic, enantioselective VMR of
acyclic silyl dienolates and aliphatic aldimines. Very short
reaction times, high functional group tolerance and high
diastereo- and enantioselectivities are the main features of
this reaction. In addition, we employed this novel protocol
in a rapid four-step synthesis of the alkaloid of (R)-coni-
ine, which was obtained in 42% overall yield and 91% ee.
i-Pr
a Isolated yield.
b Determined from 1H NMR analysis of the crude material.
c Determined by HPLC with a chiral stationary phase.
In order to document the synthetic potential of VMR with
aliphatic aldimines, a total synthesis of coniine was under-
taken, which we believe is the most efficient and rapid ap-
proach reported to date that is based on non-chiral starting
materials (Scheme 6).7 In analogy to our anabasine syn-
thesis,8 we envisioned a reduction–cyclization–oxidation
All reactions were performed in flame-dried glassware under an at-
mosphere of anhydrous nitrogen or argon. THF was dried over Na
and benzophenone. Abs. EtOH (>99.8) was purchased from VWR
sequence to arrive at the natural product within four steps, and used directly. All reactions were monitored by thin-layer chro-
matography (TLC) on precoated silica gel SIL G/UV254 plates
including our VMR. Following the newly developed pro-
(Machery, Nagel & Co.) or HPLC; spots were visualized by treat-
tocol, the vinylogous Mannich product and direct coniine
ment with a solution of molybdophosphoric acid (5 g) in EtOH (250
precursor 4b was obtained in a three-component reaction
at –40 °C within 15 minutes in 81% yield and 91% ee on
a multigram scale.
mL). Flash column chromatography was performed by using Merck
silica gel 60 (230–400 mesh). 1H and 13C NMR spectra were record-
ed with a VARIAN Gemini 300 (300 MHz) spectrometer or a
Synthesis 2011, No. 24, 4050–4058 © Thieme Stuttgart · New York

PAPER
Vinylogous Mannich Reaction with Aliphatic Aldimines
4053
Bruker Avance DRX 400 (400 MHz) spectrometer in CDCl3 at
25 °C with TMS as internal standard. IR spectra were obtained with
an FTIR spectrometer (Genesis ATI, Mattson/Unicam). UV spectra
were obtained with a Beckmann DU-650 spectrometer. Melting
points are uncorrected. Optical rotations were measured with a Po-
larotronic polarometer (Schmidt & Haensch). HPLC analyses were
performed with a JASCO MD-2010 plus instrument with a chiral
stationary phase column (Chiralcel ODH) purchased from Daicel
Co., Ltd. Mass spectra were measured at 70 eV (EI) with a Finnigan
MAT 95A spectrometer. High-resolution mass spectra (HRMS;
ESI/Na+) were measured with a Bruker Daltonics APEX II. GC/MS
measurements were performed with an AGILENT 5975B VL.MSD
(mass) combined with an AGILENT 6890N (GC) equipped with an
injector (7683B) and autosampler (7683) from AGILENT. Samples
were analyzed starting with an initial temperature of 100 °C (initial
time 1.0 min), which was increased by 50 °C/min to a final temper-
ature of 300 °C. Analytical data are presented as follows: retention
time (m/z with descending order in relative intensity). The nucleo-
philes 2 were prepared according to the literature.10–12 Aldehyde 1e
was prepared from commercially available pentenoic acid by ester-
ification and subsequent ozonolysis. Aldehydes 1f and 1g were ob-
tained by Swern oxidation of the corresponding commercially
available alcohols.
(R,E)-Ethyl 5-(4-Methoxyphenylamino)oct-2-enoate (4b)
Prepared according to GP1 using p-anisidine (15 mg, 0.12 mmol),
butyric aldehyde (11 mL, 8.8 mg, 0.12 mmol), 3d (9.2 mg,
0.012 mmol) and 2a (28 mg, 0.12 mmol) in abs THF (0.8 mL). Re-
action time: 15 min. Purification was achieved by column chroma-
tography on silica gel (Et2O–hexanes, 1:3).
Yield: 28 mg (81%); yellow oil; 91% ee; Rf = 0.3 (EtOAc–hexanes,
1:2); [a]D +52.83 (c = 0.53, CHCl3).
IR (film): 3389, 2956, 2871, 2832, 1713, 1651, 1590, 1512, 1464,
1408, 1383, 1368, 1240, 1176, 1117, 1040, 983, 916, 866, 819, 759,
711, 597, 519 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.98 (dt, J = 15.5, 7.5 Hz, 1 H),
6.82–6.72 (m, 2 H), 6.61–6.54 (m, 2 H), 5.87 (dt, J = 15.5, 1.5 Hz,
1 H), 4.21 (q, J = 7.0 Hz, 2 H), 3.77 (s, 3 H), 3.47 (quint, J = 5.5 Hz,
1 H), 3.23 (s, 1 H), 2.44 (ddd, J = 7.0, 5.5, 1.5 Hz, 2 H), 1.60–1.35
(m, 4 H), 1.31 (t, J = 7.0 Hz, 3 H), 0.94 (t, J = 7.0 Hz, 3 H).
13C-{1H} NMR (100 MHz, CDCl3): d = 166.3, 152.0, 145.4, 141.4,
123.7, 115.0, 114.7, 60.26, 55.83, 52.97, 36.92, 36.74, 19.29, 14.27,
14.05.
HRMS (ESI): m/z [M + H]+ calcd for C17H26NO3: 292.1907; found:
292.1906.
HPLC (1b; Chiralcel-OD-H isocratic; hexane–i-PrOH, 70:30; flow
1.0 mL/min: l = 284 nm): tR = 6.20 min.
Brønsted Acid Catalyzed, Enantioselective VMR of Silyl Dieno-
late 2a with Aliphatic Aldehydes; General Procedure (GP 1)
In a reaction tube, p-anisidine (1.0 equiv) was dissolved in THF at
–40 °C to give a pale-yellow solution (0.16 M). Aliphatic aldehyde
(1.0 equiv) was added and imine (1) formation was monitored by
HPLC analysis until p-anisidine was completely consumed. Phos-
phoric acid 3d (10 mol%) followed by silyl dienolate 2a (1.0 equiv)
were added at –40 °C and the reaction mixture was stirred for the
indicated time until the reaction was judged complete by HPLC
analysis. The reaction mixture was subsequently allowed to warm
to r.t., concentrated in vacuo, subjected to a silica gel column puri-
fication and eluted with the solvent mixture indicated, to give the
purified vinylogous Mannich product 4.
HPLC (4b; Chiralcel-OD-H isocratic; hexane–i-PrOH, 98:2; flow
0.5 mL/min: l = 248 nm): tR = 34.05, 37.16 min.
GC/MS: 5.676 min (m/z 192, 305).
(R,E)-Ethyl 5-(4-Methoxyphenylamino)dodec-2-enoate (4c)
Prepared according to GP1 using p-anisidine (37 mg, 0.3 mmol),
heptanal (42 mL, 34 mg, 0.3 mmol), 3d (23 mg, 0.03 mmol) and 2a
(69 mg, 0.3 mmol) in abs THF (1.9 mL). Reaction time: 15 min. Pu-
rification was achieved by column chromatography on silica gel
(MTBE–hexanes, 1:9).
Yield: 62 mg (62%); yellow oil; 90% ee; Rf = 0.5 (MTBE–hexanes,
1:4); [a]D +37.6 (c = 0.98, CHCl3).
(R,E)-Ethyl 5-(4-Methoxyphenylamino)hept-2-enoate (4a)13,14
Prepared according to GP1 using p-anisidine (44 mg, 0.36 mmol),
propionic aldehyde (26 mL, 21 mg, 0.36 mmol), 3d (27 mg,
0.036 mmol) and 2a (82 mg, 0.36 mmol) in abs THF (2.3 mL). Re-
action time: 15 min. Purification was achieved by column chroma-
tography on silica gel (Et2O–hexanes, 1:5).
IR (film): 3389, 2953, 2929, 2856, 1717, 1652, 1618, 1465, 1442,
1368, 1318, 1236, 1178, 1121, 1095, 1041, 982, 819, 756, 725, 598,
517 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.97 (dd, J = 15.5, 7.5 Hz, 1 H),
6.81–6.72 (m, 2 H), 6.63–6.31 (m, 2 H), 5.85 (dt, J = 15.5, 1.5 Hz,
1 H), 4.18 (q, J = 7.0 Hz, 2 H), 3.74 (s, 3 H), 3.53–3.30 (m, 1 H),
3.21 (s, 1 H), 2.41 (ddd, J = 7.0, 5.5, 1.5 Hz, 2 H), 1.54–1.33 (m,
2 H), 1.28 (t, J = 7.0 Hz, 3 H), 1.34–1.23 (m, 8 H), 0.88 (t,
J = 7.0 Hz, 3 H).
13C-{1H} NMR (75 MHz, CDCl3): d = 166.4, 152.1, 145.6, 141.5,
123.7, 115.1, 114.8, 60.35, 55.89, 53.30, 37.02, 34.73, 31.87, 29.38,
26.15, 22.69, 14.36, 14.16.
HRMS (ESI): m/z [M + H]+ calcd for C20H32NO3: 334.2376; found:
334.2377.
Yield: 83 mg (83%); yellow oil; 78% ee; Rf = 0.5 (EtOAc–hexanes,
1:5); [a]D +52.1 (c = 1.44, CHCl3).
IR (film): 3389, 2961, 2932, 2831, 1713, 1651, 1619, 1511, 1440,
1384, 1368, 1235, 1176, 1094, 1041, 877, 819 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.99 (dt, J = 15.5, 7.5 Hz, 1 H),
6.84–6.76 (m, 2 H), 6.63–6.51 (m, 2 H), 5.94–5.84 (m, 1 H), 4.21
(q, J = 7.0 Hz, 2 H), 3.77 (s, 3 H), 3.60 (s, 1 H), 3.41 (quint, J =
6.0 Hz, 1 H), 2.45 (t, J = 7.0 Hz, 2 H), 1.70–1.46 (m, 2 H), 1.31 (t,
J = 7.0 Hz, 3 H), 0.99 (t, J = 7.0 Hz, 3 H).
13C-{1H} NMR (75 MHz, CDCl3): d = 166.3, 152.0, 145.5, 141.4,
123.6, 115.0, 114.8, 60.29, 55.81, 54.54, 36.46, 27.14, 14.28, 10.34.
HPLC (1c; Chiralcel-OD-H isocratic; hexane–i-PrOH, 60:40; flow
1.0 mL/min; l = 284 nm): tR = 5.08 min.
HRMS (ESI): m/z [M + H]+ calcd for C16H24NO3: 278.1751; found:
278.1750.
HPLC (4c; Chiralcel-OD-H isocratic; hexane–i-PrOH, 98:2; flow
0.5 mL/min; l = 248 nm): tR = 28.88, 31.44 min.
GC/MS: 6.241 min (m/z 220, 333).
HPLC (1a; Chiralcel-OD-H isocratic; hexane–i-PrOH, 70:30; flow
1.0 mL/min; l = 284 nm): tR = 6.97 min.
(R,E)-Ethyl 5-(4-Methoxyphenylamino)tetradec-2-enoate (4d)
Prepared according to GP1 using p-anisidine (36 mg, 0.3 mmol),
decanal (55 mL, 46 mg, 0.3 mmol), 3d (22 mg, 0.03 mmol) and 2a
(67 mg, 0.3 mmol) in abs THF (1.8 mL). Reaction time: 15 min. Pu-
rification was achieved by column chromatography on silica gel
(Et2O–hexanes, 1:3).
HPLC (4a; Chiralcel-OD-H isocratic; hexane–i-PrOH, 80:20; flow
1.0 mL/min; l = 248 nm): tR = 6.53, 8.00 min.
GC/MS: 5.54 min (m/z 164, 277).
Synthesis 2011, No. 24, 4050–4058 © Thieme Stuttgart · New York

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F. Abels, C. Schneider
PAPER
Yield: 88 mg (78%); yellow oil; 96% ee; Rf = 0.2 (MTBE–hexanes,
1:9); [a]D +37.5 (c = 1.49, CHCl3).
1H NMR (300 MHz, CDCl3): d = 6.96 (dd, J = 15.5, 7.5 Hz, 1 H),
6.83–6.70 (m, 2 H), 6.61–6.48 (m, 2 H), 5.85 (dt, J = 15.5, 1.0 Hz,
1 H), 4.18 (q, J = 7.0 Hz, 2 H), 3.74 (s, 3 H), 3.51 (t, J = 7.0 Hz,
3 H), 3.47–3.39 (m, 1 H), 3.18 (s, 1 H), 2.42 (dd, J = 10.0, 4.0 Hz,
2 H), 1.86–1.69 (m, 2 H), 1.62–1.36 (m, 6 H), 1.28 (t, J = 7.0 Hz,
3 H).
13C-{1H} NMR (75 MHz, CDCl3): d = 166.3, 152.2, 145.3, 141.3,
123.9, 115.1, 114.9, 60.40, 55.91, 53.25, 45.05, 37.09, 34.61, 32.58,
26.95, 25.54, 14.37.
IR (film): 3390, 2926, 2854, 1718, 1651, 1619, 1511, 1465, 1442,
1408, 1383, 1368, 1318, 1238, 1178, 1123, 1096, 1042, 981, 872,
819, 757, 721, 598, 518, 458 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.99 (dt, J = 15.5, 7.5 Hz, 1 H),
6.86–6.75 (m, 2 H), 6.63–6.52 (m, 2 H), 5.88 (dt, J = 15.5, 1.5 Hz,
1 H), 4.22 (q, J = 7.0 Hz, 2 H), 3.78 (s, 3 H), 3.51–3.40 (m, 1 H),
3.22 (s, 1 H), 2.45 (ddd, J = 7.0, 6.0, 1.0 Hz, 2 H), 1.58–1.41 (m,
2 H), 1.38–1.24 (m, 17 H), 0.91 (t, J = 7.0 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C19H29ClNO3: 354.1830;
found: 354.1829.
13C-{1H} NMR (75 MHz, CDCl3): d = 166.3, 152.0, 145.5, 141.4,
123.7, 115.0, 114.7, 60.28, 55.83, 53.20, 36.91, 34.63, 31.89, 29.63,
29.59, 29.57–29.54 (4 Signals), 29.31, 26.10, 22.69, 14.28, 14.13.
HPLC (1f; Chiralcel-OD-H isocratic; hexane–i-PrOH, 70:30; flow
1.0 mL/min; l = 284 nm): tR = 7.64 min.
HRMS (ESI): m/z [M + H]+ calcd for C23H38NO3: 376.2846; found:
376.2843.
HPLC (4f; Chiralcel-OD-H isocratic; hexane–i-PrOH, 98:2; flow
0.5 mL/min; l = 248 nm): tR = 74.78, 83.41 min.
HPLC (1d; Chiralcel-OD-H isocratic; hexane–i-PrOH, 70:30; flow
1.0 mL/min; l = 284 nm): tR = 5.35 min.
GC/MS: 6.904 min (m/z 240, 353).
(R,E)-Ethyl 5-(4-Methoxyphenylamino)pentadec-2-en-14-
ynoate (4g)
Prepared according to GP1 using p-anisidine (32 mg, 0.26 mmol),
10-undecynal (43 mg, 0.26 mmol), 3d (20 mg, 0.026 mmol) and 2a
(59 mg, 0.26 mmol) in abs THF (1.6 mL). Reaction time: 15 min.
Purification was achieved by column chromatography on silica gel
(MTBE–hexanes, 1:10).
HPLC (4d; Chiralcel-OD-H isocratic; hexane–i-PrOH, 98:2; flow
0.5 mL/min; l = 248 nm): tR = 25.96, 28.33 min.
GC/MS: 7.164 min (m/z 262, 375).
(R,E)-Diethyl 5-(4-Methoxyphenylamino)oct-2-enedioate (4e)14
Prepared according to GP1 using p-anisidine (28 mg, 0.23 mmol),
1e-derived aldehyde (30 mg, 0.23 mmol), 3d (17 mg, 0.023 mmol)
and 2a (53 mg, 0.23 mmol) in abs THF (1.4 mL). Reaction time: 15
min. Purification was achieved by column chromatography on silica
gel (Et2O–hexanes, 1:5).
Yield: 60 mg (60%); yellow oil; 91% ee; Rf = 0.24 (MTBE–hex-
anes, 1:4); [a]D +33.27 (c = 1.35, CHCl3).
IR (film): 3390, 3293, 2930, 2855, 2359, 1716, 1651, 1618, 1511,
1464, 1442, 1408, 1384, 1368, 1319, 1237, 1178, 1112, 1041, 982,
819, 754, 721, 637, 518 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.95 (dt, J = 15.5, 7.5 Hz, 1 H),
6.81–6.72 (m, 2 H), 6.61–6.49 (m, 2 H), 5.85 (dt, J = 15.5, 1.5 Hz,
1 H), 4.18 (q, J = 7.0 Hz, 2 H), 3.74 (s, 3 H), 3.47–3.37 (m, 1 H),
3.22 (s, 1 H), 2.44–2.38 (m, 2 H), 2.17 (td, J = 7.0, 2.5 Hz, 2 H),
1.93 (t, J = 2.5 Hz, 1 H), 1.58–1.32 (m, 2 H), 1.31–1.20 (m, 15 H).
13C-{1H} NMR (100 MHz, CDCl3): d = 166.3, 152.1, 145.5, 141.5,
123.8, 115.1, 114.8, 84.83, 68.21, 60.36, 55.90, 53.29, 37.03, 34.71,
29.62, 29.49, 29.09, 28.78, 28.54, 26.14, 18.48, 14.37.
HRMS (ESI): m/z [M + H]+ calcd for C24H36NO3: 386.2689; found:
386.2690.
Yield: 56 mg (70%); yellow oil; 99% ee; Rf = 0.4 (E/hexanes, 2:1);
[a]D +13.2 (c = 1.22, CHCl3).
IR (film): 3389, 2982, 2936, 2833, 1719, 1653, 1619, 1513, 1465,
1445, 1369, 1319, 1239, 1180, 1096, 1039, 983, 822, 756, 602, 519
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.04–6.82 (m, 1 H), 6.77 (m, 2 H),
6.54 (m, 2 H), 5.86 (dt, J = 15.5, 1.5 Hz, 1 H), 4.15 (2 × q, J =
7.0 Hz, J = 7.0 Hz, 4 H), 3.74 (s, 3 H), 3.57–3.37 (m, 1 H), 3.20
(br s, 1 H), 2.51–2.30 (m, 4 H), 1.99–1.84 (m, 1 H), 1.84–1.65 (m,
1 H), 1.28 (t, J = 7.0 Hz, 3 H), 1.23 (t, J = 7.0 Hz, 3 H).
13C-{1H} NMR (100 MHz, CDCl3): d = 173.6, 166.3, 152.3, 144.8,
141.2, 124.2, 115.2, 114.9, 60.59, 60.41, 55.90, 53.07, 37.37, 31.29,
29.81, 14.37, 14.31.
HPLC (1g; Chiralcel-OD-H isocratic; hexane–i-PrOH, 70:30; flow
1.0 mL/min; l = 284 nm): tR = 6.52 min.
HRMS (ESI): m/z [M + H]+calcd for C19H27NO5: 350.1962; found:
350.1963.
HPLC (4g; Chiralcel-OD-H isocratic; hexane–i-PrOH, 98:2; flow
0.5 mL/min; l = 248 nm): tR = 49.79, 55.79 min.
HPLC (1e; Chiralcel-OD-H isocratic; hexane–i-PrOH, 80:20; flow
1.0 mL/min; l = 284 nm): tR = 9.41 min.
GC/MS: 7.734 min (m/z 272, 385).
HPLC (4e; Chiralcel-OD-H isocratic; hexane–i-PrOH, 70:30; flow
0.5 mL/min; l = 239 nm): tR = 13.25, 19.96 min.
(R,E)-Ethyl 5-(4-Methoxyphenylamino)-7-methyloc-2-enoate
(4h)14
Prepared according to GP1 using p-anisidine (40 mg, 0.33 mmol),
3-methylbutyric aldehyde (35 mL, 28 mg, 0.33 mmol), 3d (25 mg,
0.033 mmol) and 2a (75 mg, 0.33 mmol) in abs THF (2.0 mL). Re-
action time: 15 min. Purification was achieved by column chroma-
tography on silica gel (Et2O–hexanes, 1:5).
GC/MS: 6.459 min (m/z 236, 190, 349).
(R,E)-Ethyl10-Chloro-5-(4-methoxyphenylamino)dec-2-enoate
(4f)
Prepared according to GP1 using p-anisidine (35 mg, 0.28 mmol),
6-chlorohexanal (38 mL, 0.28 mmol), 3d (21 mg, 0.028 mmol) and
2a (65 mg, 0.28 mmol) in abs THF (1.8 mL). Reaction time: 15
min. Purification was achieved by column chromatography on silica
gel (MTBE–hexanes, 1:5).
Yield: 71 mg (71%); yellow oil; 88% ee; Rf = 0.5 (EtOAc–hexanes,
1:5); [a]D +57.9 (c = 1.31, CHCl3).
IR (film): 3386, 2954, 2932, 2869, 2831, 1715, 1651, 1718, 1511,
1465, 1442, 1408, 1384, 1368, 1317, 1241, 1209, 1177, 1124, 1111,
1095, 1041, 981, 959, 819, 754, 714, 597, 518 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.98 (dt, J = 15.5, 7.5 Hz, 1 H),
6.83–6.74 (m, 2 H), 6.61–6.54 (m, 2 H), 5.86 (dt, J = 15.5, 1.5 Hz,
1 H), 4.21 (q, J = 7.0 Hz, 2 H), 3.76 (s, 3 H), 3.60–3.48 (m, 1 H),
3.17 (s, 1 H), 2.52–2.30 (m, 2 H), 1.81 (mc, 1 H), 1.46–1.34 (m,
Yield: 62 mg (62%); yellow oil; 85% ee; Rf = 0.12 (MTBE–hex-
anes, 1:6); [a]D = 30.3 (c = 0.76, CHCl3).
IR (film): 3389, 2935, 2857, 1715, 1651, 1618, 1511, 1463, 1443,
1408, 1384, 1368, 1318, 1239, 1178, 1097, 1041, 981, 820, 730,
648 cm–1.
Synthesis 2011, No. 24, 4050–4058 © Thieme Stuttgart · New York

PAPER
Vinylogous Mannich Reaction with Aliphatic Aldimines
4055
2 H), 1.31 (t, J = 7.0 Hz, 3 H), 0.96 (d, J = 7.0 Hz, 3 H), 0.91 (d,
J = 7.0 Hz, 3 H).
HPLC (4j; Chiralcel-OD-H isocratic; hexane–i-PrOH, 80:20; flow
1.0 mL/min; l = 248 nm): tR = 6.44, 7.57 min.
13C-{1H} NMR (100 MHz, CDCl3): d = 166.3, 151.9, 145.4, 141.4,
123.7, 115.0, 114.6, 60.28, 55.80, 51.10, 44.14, 37.20, 24.90, 23.05,
22.38, 14.29.
HRMS (ESI): m/z [M + H]+ calcd for C18H28NO3: 306.2064; found:
306.2063.
Brønsted Acid Catalyzed, Enantioselective VMR of g-Methyl
Silyl Dienolate 2b with Aliphatic Aldehydes; General Proce-
dure (GP2)
In a reaction tube, p-anisidine (1.0 equiv) was dissolved in THF at
–40 °C to give a pale-yellow solution (0.16 M). The aliphatic alde-
hyde (1.0 equiv) was added and imine (1) formation was monitored
by HPLC analysis until p-anisidine was completely consumed.
Phosphoric acid 3d (10 mol%), followed by silyl dienolate 2b
(1.0 equiv) were added at –40 °C and the reaction mixture was
stirred for 72 h. The reaction mixture was subsequently allowed to
warm to r.t., concentrated in vacuo, subjected to a silica gel column
and eluted with the solvent mixture indicated, to give the purified
vinylogous Mannich product 5.
HPLC (1h; Chiralcel-OD-H isocratic; hexane–i-PrOH, 70:30; flow
1.0 mL/min; l = 284 nm): tR = 5.65 min.
HPLC (4h; Chiralcel-OD-H isocratic; hexane–i-PrOH, 90:10; flow
1.0 mL/min; l = 248 nm): tR = 9.27, 12.11 min.
GC/MS: 5.73 min (m/z 192, 305).
(R,E)-Ethyl 5-(4-Methoxyphenylamino)-6-methylept-2-enoate
(4i)4,13,14
Prepared according to GP1 using p-anisidine (42 mg, 0.34 mmol),
2-methylpropanal (37 mL, 30 mg, 0.34 mmol), 3d (26 mg,
0.034 mmol) and 2a (78 mg, 0.34 mmol) in abs THF (2.1 mL). Re-
action time: 15 min. Purification was achieved by column chroma-
tography on silica gel (Et2O–hexanes, 1:5).
(4S,5R,E)-Ethyl 5-(4-Methoxyphenylamino)-4-methylhept-2-
enoate (5a)15
Prepared according to GP2 using p-anisidine (42 mg, 0.34 mmol),
propanal (25 mL, 20 mg, 0.34 mmol), 3d (26 mg, 0.034 mmol) and
2b (83 mg, 0.34 mmol) in abs THF (2.1 mL). Purification was
achieved by column chromatography on silica gel (Et2O–hexanes,
1:9).
Yield: 80 mg (80%); yellow oil; 84% ee; Rf = 0.5 (EtOAc–hexanes,
1:5); [a]D +69.7 (c = 2.79, CHCl3).
Yield: 63 mg (63%); yellow oil; 93% de; 90% ee; Rf = 0.3 (EtOAc–
hexanes, 1:5); [a]D –22.7 (c = 1.14, CHCl3).
IR (film): 3391, 2958, 2831, 1714, 1651, 1619, 1512, 1441, 1386,
1235, 1177, 1095, 1041, 981, 819, 755, 712, 586, 520 cm–1.
IR (film): 3391, 2929, 2872, 2856, 1715, 1649, 1621, 1511, 1465,
1369, 1235, 1180, 1041, 986, 819, 738, 522 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.99 (dt, J = 15.5, 7.5 Hz, 1 H),
6.82–6.74 (m, 2 H), 6.61–6.51 (m, 2 H), 5.88 (dt, J = 15.5, 1.5 Hz,
1 H), 4.19 (q, J = 7.0 Hz, 2 H), 3.76 (s, 3 H), 3.34–3.26 (m, 2 H),
2.51–2.28 (m, 2 H), 1.90 (mc, 1 H), 1.30 (t, J = 7.0 Hz, 3 H), 0.99
(d, J = 7.0 Hz, 3 H), 0.97 (d, J = 7.0 Hz, 3 H).
13C-{1H} NMR (100 MHz, CDCl3): d = 166.3, 151.8, 146.2, 141.8,
123.3, 115.0, 114.6, 60.26, 58.66, 55.82, 34.05, 30.69, 18.73, 18.39,
14.29.
1H NMR (300 MHz, DMSO-d6): d = 6.99 (dd, J = 15.5, 7.5 Hz, 1
H), 6.76–6.64 (m, 2 H), 6.62–6.54 (m, 2 H), 5.85 (dd, J = 15.5, 1.5
Hz, 1 H), 4.98 (d, J = 9.5 Hz, 1 H), 4.10 (q, J = 7.0 Hz, 2 H), 3.62
(s, 3 H), 3.24 (ddd, J = 13.0, 9.0, 4.5 Hz, 1 H), 2.69–2.55 (m, 1 H),
1.48–1.26 (m, 2 H), 1.20 (t, J = 7.0 Hz, 3 H), 0.97 (d, J = 7.0 Hz, 3
H), 0.85 (t, J = 7.5 Hz, 3 H).
13C-{1H} NMR (75 MHz, CDCl3): d = 166.6, 151.9, 151.3, 142.2,
121.6, 115.1, 114.5, 60.39, 59.66, 55.90, 39.09, 24.88, 14.47, 14.37,
11.09.
HPLC (1i; Chiralcel-OD-H isocratic; hexane–i-PrOH, 70:30; flow
1.0 mL/min; l = 284 nm): tR = 5.03 min.
HPLC (4i; Chiralcel-OD-H isocratic; hexane–i-PrOH, 80:20; flow
1.0 mL/min; l = 248 nm): tR = 6.57, 7.72 min.
HRMS (ESI): m/z [2 M + Na]+ calcd for C34H50N2O6: 605.3561;
found: 605.3562.
GC/MS: 5.619 min (m/z 178, 291).
HPLC (1a; Chiralcel-OD-H isocratic; hexane–i-PrOH, 70:30; flow
1.0 mL/min; l = 284 nm): tR = 6.97 min.
(S,E)-Ethyl 5-Cyclohexyl-5-(4-methoxyphenylamino)pent-2-
enoate (4j)4,13,14
Prepared according to GP1 using p-anisidine (37 mg, 0.3 mmol),
cyclohexanal (36 mL, 34 mg, 0.3 mmol), 3d (23 mg, 0.03 mmol)
and 2a (69 mg, 0.3 mmol) in abs THF (1.9 mL). Reaction time: 45
min. Purification was achieved by column chromatography on silica
gel (Et2O–hexanes, 1:5).
HPLC (5a; Chiralcel-OD-H isocratic; hexane–i-PrOH, 95:5; flow
1.0 mL/min; l = 228 nm): tR = 29.23, 56.91 min.
GC/MS: 5.51 min (m/z 164, 293).
(4S,5R,E)-Ethyl 5-(4-Methoxyphenylamino)-4-methylhept-2-
enoate (5b)15
Yield: 40 mg (40%); yellow oil; 66% ee; Rf = 0.5 (EtOAc–hexanes,
1:5); [a]D +31.5 (c = 2.09, CHCl3).
Prepared according to GP2 using p-anisidine (42 mg, 0.34 mmol),
butyric aldehyde (31 mL, 25 mg, 0.34 mmol), 3d (26 mg,
0.034 mmol) and 2b (83 mg, 0.34 mmol) in abs THF (2.1 mL). Pu-
rification was achieved by column chromatography on silica gel
(Et2O–hexanes, 1:9).
IR (film): 3392, 2980, 2926, 2851, 1715, 1651, 1618, 1511, 1448,
1367, 1317, 1237, 1179, 1113, 1096, 1042, 978, 892, 818, 754,
520 cm–1.
Yield: 63 mg (61%); yellow oil; 92% de; 88% ee; Rf = 0.3 (Et2O–
hexanes, 1:5); [a]D –27.3 (c = 0.91, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.04–6.92 (m, 1 H), 6.81–6.75 (m,
2 H), 6.60–6.52 (m, 2 H), 5.86 (dt, J = 15.5, 1.5 Hz, 1 H), 4.19 (q, J
= 7.0 Hz, 2 H), 3.76 (s, 3 H), 3.29 (dd, J = 12.0, 5.5 Hz, 1 H), 2.53–
2.43 (m, 1 H), 2.43–2.33 (m, 1 H), 1.92–1.60 (m, 6 H), 1.58–1.43
(m, 2 H), 1.30 (t, J = 7.0 Hz, 3 H), 1.29–0.99 (m, 7 H).
IR (film): 3391, 2959, 2933, 2872, 2832, 1714, 1649, 1619, 1511,
1464, 1408, 1368, 1241, 1181, 1157, 1040, 989, 932, 864, 819, 761,
737, 599, 521 cm–1.
13C-{1H} NMR (100 MHz, CDCl3): d = 166.4, 151.8, 146.2, 141.9,
123.3, 115.0, 114.5, 60.28, 58.16, 55.84, 41.05, 34.23, 29.44, 29.07,
26.53, 26.32, 26.30, 14.29.
1H NMR (300 MHz, CDCl3): d = 7.01 (dd, J = 16.0, 7.0 Hz, 1 H),
6.81–6.71 (m, 2 H), 6.61–6.41 (m, 2 H), 5.87 (dd, J = 16.0, 1.5 Hz,
1 H), 4.21 (q, J = 7.0 Hz, 2 H), 3.74 (s, 3 H), 3.45–3.27 (m, 1 H),
3.18 (s, 1 H), 2.83–2.64 (m, 1 H), 1.53–1.39 (m, 4 H), 1.31 (t, J =
7.0 Hz, 3 H), 1.05 (d, J = 7.0 Hz, 3 H), 0.89 (t, J = 6.0 Hz, 3 H).
HPLC (1j; Chiralcel-OD-H isocratic; hexane–i-PrOH, 70:30; flow
1.0 mL/min; l = 284 nm): tR = 4.83 min.
Synthesis 2011, No. 24, 4050–4058 © Thieme Stuttgart · New York

4056
F. Abels, C. Schneider
PAPER
13C-{1H} NMR (75 MHz, CDCl3): d = 166.7, 151.9, 151.3, 142.2,
121.6, 115.1, 114.4, 60.41, 57.83, 55.92, 39.31, 34.41, 19.89, 14.39,
14.23, 14.19.
13C-{1H} NMR (75 MHz, CDCl3): d = 166.72, 151.89, 151.33,
142.11, 121.68, 115.19, 114.36, 60.41, 55.93, 55.76, 41.39, 39.29,
25.02, 23.59, 22.14, 14.40, 13.91.
HRMS (ESI): m/z [M + H]+ calcd for C24H40NO3: 412.2822; found:
412.2824.
HPLC (1d; Chiralcel-OD-H isocratic; hexane–i-PrOH, 70:30; flow
1.0 mL/min; l = 284 nm): tR = 5.35 min.
HPLC (5d; Chiralcel-OD-H isocratic; hexane–i-PrOH, 95:5; flow
1.0 mL/min; l = 228 nm): tR = 15.12, 36.41 min.
HRMS (ESI): m/z [M + H]+ calcd for C18H28NO3: 328.1883; found:
328.1882.
GC/MS: 7.21 min (m/z 262, 389).
HPLC (1b; Chiralcel-OD-H isocratic; hexane–i-PrOH, 70:30; flow
1.0 mL/min; l = 284 nm): tR = 6.20 min.
(4S,5R,E)-Ethyl 5-(4-Methoxyphenylamino)-4,7-dimethyloct-2-
enoate (5h)15
Prepared according to GP2 using p-anisidine (42 mg, 0.34 mmol),
3-methylbutyric aldehyde (38 mL, 30 mg, 0.34 mmol), 3d (26 mg,
0.034 mmol) and 2b (83 mg, 0.33 mmol) in abs THF (2.1 mL). Pu-
rification was achieved by column chromatography on silica gel
(Et2O–hexanes; 1:9).
HPLC (5b; Chiralcel-OD-H isocratic; hexane–i-PrOH, 95:5; flow
1.0 mL/min; l = 228 nm): tR = 24.66, 60.79 min.
GC/MS: 5.69 min (m/z 178, 305).
(4S,5R,E)-Ethyl 5-(4-Methoxyphenylamino)-4-methyloct-2-
enoate (5c)15
Prepared according to GP2 using p-anisidine (40 mg, 0.33 mmol),
heptanal (47 mL, 37 mg, 0.33 mmol), 3d (25 mg, 0.033 mmol) and
2b (79 mg, 0.33 mmol) in abs THF (2.0 mL). Purification was
achieved by column chromatography on silica gel (Et2O–hexanes,
1:9).
Yield: 50 mg (48%); yellow oil; 82% de; 72% ee; Rf = 0.3 (Et2O–
hexanes, 1:5); [a]D –24.0 (c = 0.76, CHCl3).
IR (film): 3391, 2956, 2870, 2832, 1715, 1649, 1619, 1511, 1465,
1409, 1368, 1242, 1182, 1111, 1096, 1039, 985, 933, 864, 819, 755,
733, 601, 521 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 6.98 (dd, J = 15.7, 7.1 Hz,
1 H), 6.81–6.65 (m, 2 H), 6.65–6.47 (m, 2 H), 5.84 (dd, J = 15.7,
1.4 Hz, 1 H), 4.99 (d, J = 9.4 Hz, 1 H), 4.11 (q, J = 7.1 Hz, 2 H),
3.62 (s, 3 H), 3.49–3.34 (m, 1 H), 2.62 (dd, J = 9.4, 7.0 Hz, 1 H),
1.78–1.57 (m, 1 H), 1.38–1.24 (m, 1 H), 1.21 (t, J = 7.1 Hz, 3 H),
1.11–0.99 (m, 1 H), 0.96 (d, J = 6.8 Hz, 3 H), 0.86 (d, J = 6.7 Hz,
3 H), 0.78 (d, J = 6.5 Hz, 3 H).
13C-{1H} NMR (75 MHz, CDCl3): d = 166.72, 151.89, 151.33,
142.11, 121.68, 115.19, 114.36, 60.41, 55.93, 55.76, 41.39, 39.29,
25.02, 23.59, 22.14, 14.40, 13.91.
HRMS (ESI): m/z [M + H]+ calcd for C19H30NO3: 342.2039; found:
342.2039.
Yield: 113 mg (96%); yellow oil; 88% de; 88% ee; Rf = 0.3 (Et2O–
hexanes, 1:5); [a]D –35.6 (c = 1.66, CHCl3).
IR (film): 3391, 2929, 2856, 1715, 1649, 1621, 1511, 1465, 1369,
1235, 1180, 1039, 986, 819, 526 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 6.99 (dd, J = 15.7, 7.2 Hz,
1 H), 6.73–6.64 (m, 2 H), 6.62–6.52 (m, 2 H), 5.84 (dd, J = 15.7,
1.3 Hz, 1 H), 4.98 (d, J = 9.4 Hz, 1 H), 4.11 (q, J = 7.1 Hz, 2 H),
3.62 (s, 3 H), 2.67–2.55 (m, 1 H), 1.38–1.17 (m, 14 H), 0.96 (d,
J = 6.8 Hz, 3 H), 0.82 (t, J = 6.7 Hz, 3 H).
13C-{1H} NMR (75 MHz, CDCl3): d = 166.73, 151.93, 151.42,
142.20, 121.66, 115.16, 114.52, 60.43, 58.11, 55.95, 39.27, 32.18,
31.89, 29.45, 26.68, 22.72, 14.40, 14.25, 14.17.
HPLC (1h; Chiralcel-OD-H isocratic; hexane–i-PrOH, 70:30; flow
1.0 mL/min; l = 284 nm): tR = 5.65 min.
HRMS (ESI): m/z [M + Na]+ calcd for C21H34NO3: 370.2353;
found: 370.2351.
HPLC (5h; Chiralcel-OD-H isocratic; hexane–i-PrOH, 95:5; flow
1.0 mL/min; l = 228 nm): tR = 20.81, 40.71 min.
HPLC (1c; Chiralcel-OD-H isocratic; hexane–i-PrOH, 60:40; flow
1.0 mL/min; l = 284 nm): tR = 5.08 min.
GC/MS: 5.72 min (m/z 192, 319).
HPLC (5c; Chiralcel-OD-H isocratic; hexane–i-PrOH, 95:5; flow
1.0 mL/min; l = 228 nm): tR = 17.78, 44.46 min.
(R)-Ethyl 5-(4-Methoxyphenylamino)octanoate (6)
To a stirred solution of 4b (513 mg, 1.76 mmol, 1.0 equiv) in abs
EtOH (35 mL) was added palladium on charcoal (9.4 mg,
0.088 mmol, 0.05 equiv, 10 wt% Pd) and the reaction vessel was
charged with hydrogen. The progress of the reaction was followed
by GC/MS analysis and, after full conversion (10 min), the crude
black suspension was filtered through a pad of Celite, and concen-
trated in vacuo.
GC/MS: 6.27 min (m/z 220, 347).
(4S,5R,E)-Ethyl 5-(4-Methoxyphenylamino)-4-methyltetradec-
2-enoate (5d)15
Prepared according to GP2 using p-anisidine (40 mg, 0.33 mmol),
decanal (62 mL, 51 mg, 0.33 mmol), 3d (25 mg, 0.033 mmol) and
2b (79 mg, 0.33 mmol) in abs THF (2.0 mL). Purification was
achieved by column chromatography on silica gel (Et2O–hexanes,
1:9).
Yield: 511 mg (99%); colorless oil; Rf = 0.3 (EtOAc–hexanes, 1:2);
[a]D +3.7 (c = 0.53, CHCl3).
IR (film): 3393, 2956, 2933, 2870, 2831, 2359, 1732, 1645, 1617,
1511, 1563, 1409, 1374, 1296, 1239, 1177, 1111, 1040, 819, 756,
639, 593, 518 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.77–6.62 (m, 2 H), 6.52–6.40 (m,
2 H), 4.04 (q, J = 7.1 Hz, 2 H), 3.66 (s, 3 H), 3.19 (quint,
J = 5.9 Hz, 1 H), 3.06 (s, 1 H), 2.22 (t, J = 7.3 Hz, 2 H), 1.75–1.22
(m, 8 H), 1.17 (t, J = 7.1 Hz, 3 H), 0.83 (t, J = 7.1 Hz, 3 H).
13C-{1H} NMR (75 MHz, CDCl3): d = 173.6, 151.7, 142.3, 115.1,
114.3, 60.34, 55.96, 53.51, 37.26, 34.43, 34.30, 21.45, 19.21, 14.34,
14.29.
Yield: 51 mg (40%); yellow oil; 90% de; 87% ee; Rf = 0.3 (Et2O–
hexanes, 1:5); [a]D –26.0 (c = 0.66, CHCl3).
IR (film): 3367, 2960, 2925, 2853, 1715, 1648, 1510, 1455, 1412,
1368, 1259, 1108, 1040, 819, 700 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 6.99 (dd, J = 15.7, 7.2 Hz,
1 H), 6.71–6.65 (m, 2 H), 6.61–6.53 (m, 2 H), 5.84 (dd, J = 15.7,
1.3 Hz, 1 H), 4.98 (d, J = 9.4 Hz, 1 H), 4.10 (q, J = 7.1 Hz, 2 H),
3.62 (s, 3 H), 2.67–2.56 (m, 1 H), 1.38–1.15 (m, 20 H), 0.96 (d,
J = 6.8 Hz, 3 H), 0.84 (t, J = 6.7 Hz, 3 H).
13C-{1H} NMR (75 MHz, CDCl3): d = 166.74, 151.94, 151.43,
142.20, 121.67, 115.16, 114.52, 60.43, 58.12, 55.95, 39.28, 32.19,
32.00, 29.79, 29.70, 29.67, 29.41, 26.72, 22.80, 14.41, 14.28, 14.23.
HRMS (ESI): m/z [M + H]+ calcd for C17H28NO3: 294.2063; found:
294.2063.
GC/MS: 5.545 min (m/z 178, 250, 293).
Synthesis 2011, No. 24, 4050–4058 © Thieme Stuttgart · New York

PAPER
Vinylogous Mannich Reaction with Aliphatic Aldimines
4057
(R)-1-(4-Methoxyphenyl)-2-propylpiperidine (7)
separated, the organic layer washed with NaHCO3 (3 × 25 mL) and
the combined aqueous layers were extracted with MTBE (3 × 25
mL). The recombined organic layers were dried over Na2SO4, fil-
tered, and concentrated in vacuo to give the crude product.
To a stirred solution of 6 (173 mg, 0.59 mmol, 1.0 equiv) in abs
THF (5.9 mL) was added DIBAL-H (1 M in hexane, 2.9 mL,
2.95 mmol, 5.0 equiv) at –78 °C. The crude mixture was subse-
quently allowed to warm slowly to ambient temperature while stir-
ring and, after 80 min, the reaction mixture was treated with NaBH4
(22 mg, 0.59 mmol, 1.0 equiv) and one drop of acetic acid. The
mixture was stirred for 10 min at r.t., then treated with Rochelle salt
(5 mL) and further diluted with dist. H2O (2 mL) and MTBE
(2 mL). After 30 min, the layers were separated, the organic layer
was washed with H2O (3 × 25 mL) and the combined aqueous lay-
ers were extracted with MTBE (25 mL). The recombined organic
layers were dried over Na2SO4, filtered, and concentrated in vacuo
to give a pale-yellow oil. Purification was achieved by column chro-
matography on silica gel (MTBE–hexanes, 1:19).
Yield: 245 mg (99%); colorless oil; Rf = 0.2 (MTBE); [a]D –25.9
(c = 0.46, CHCl3).
IR (film): 3451, 3040, 2956, 2871, 2836, 1730, 1649, 1606, 1587,
1510, 1443, 1409, 1382, 1355, 1331, 1294, 1168, 1148, 1105, 1032,
830 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.10–7.01 (m, 2 H), 6.95–6.84 (m,
2 H), 3.79 (s, 3 H), 3.73–3.61 (m, 1 H), 2.50 (t, J = 6.5 Hz, 2 H),
2.10–1.87 (m, 2 H), 1.85–1.72 (m, 2 H), 1.60–0.99 (m, 4 H), 0.77 (t,
J = 7.0 Hz, 3 H).
13C-{1H} NMR (75 MHz, CDCl3): d = 170.6, 158.2, 134.4, 129.0,
114.3, 60.20, 55.42, 35.36, 32.80, 27.05, 18.89, 18.11, 13.94.
HRMS (ESI): m/z [M + H]+ calcd for C15H22NO2: 248.1645; found:
248.1644.
Yield: 110 mg (80%); colorless oil; Rf = 0.3 (MTBE–hexanes, 1:8);
[a]D +34.9 (c = 1.20, CHCl3).
IR (film): 2932, 2859, 2360, 2073, 1729, 1652, 1608, 1579, 1509,
1457, 1441, 1383, 1348, 1289, 1241, 1178, 1041, 824, 793, 600 cm–1.
GC/MS: 5.545 min (m/z 204, 247).
1H NMR (400 MHz, CDCl3): d = 6.97–6.90 (m, 2 H), 6.88–6.81 (m,
2 H), 3.80 (s, 3 H), 3.45–3.37 (m, 1 H), 3.09–2.94 (m, 2 H), 1.91–
1.78 (m, 1 H), 1.77–1.58 (m, 4 H), 1.57–1.47 (m, 1 H), 1.47–1.23 Acknowledgment
(m, 3 H), 1.23–1.07 (m, 1 H), 0.83 (t, J = 7.1 Hz, 3 H).
13C-{1H} NMR (100 MHz, CDCl3): d = 153.6, 145.9, 120.5, 114.3,
57.97, 55.63, 48.12, 30.62, 28.93, 26.13, 20.72, 19.97, 14.38.
We are grateful to the Deutsche Forschungsgemeinschaft (SPP
Organocatalysis) and the Evonik-Stiftung (graduate fellowship to
F.A.) for generous financial support of this work.
HRMS (ESI): m/z [M + H]+ calcd for C15H24NO: 234.1852; found:
234.1854.
References
GC/MS: 6.599 min (m/z 190, 233).
(1) (a) Martin, S. F. Acc. Chem. Res. 2002, 35, 895. (b) Bur, S.
K.; Martin, S. F. Tetrahedron 2001, 57, 3221.
(R)-Coniine Hydrochloride (8)
(2) (a) Martin, S. F.; Lopez, O. D. Tetrahedron Lett. 1999, 40,
8949. (b) Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H.
Angew. Chem. Int. Ed. 2006, 45, 7230. (c) Mandai, H.;
Mandai, K.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem.
Soc. 2008, 130, 17961. (d) Akiyama, T.; Honma, Y.; Itoh,
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1620. (c) For a review, see: Cui, H.-L.; Chen, Y.-C. Chem.
Commun. 2009, 4479.
To a stirred solution of 7 (257 mg, 1.1 mmol, 1.0 equiv) in a mixture
of MeCN–H2O (1:1, 20 mL, 0.055 M] and H2SO4 (0.55 mL,
1.1 mmol, 1 equiv, 2 M), was added H5IO6 (253 mg, 1.1 mmol, 1.0
equiv) at r.t. The crude mixture was heated to reflux for 60 min, then
allowed to cool to ambient temperature and washed with CH2Cl2
(3 × 25 mL). The aqueous layer was then basified (pH 12–14) by
adding an excess of NaOH (5 M) and subsequently extracted with
EtOAc (5 × 50 mL). The combined organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo. The crude pale-yellow
solid was dissolved in Et2O (20 mL) and treated with an excess of
HCl·Et2O (1 M). The crude solution was concentrated in vacuo
and the resulting solid was recrystallized from a mixture of MTBE–
i-PrOH (10:1) to give 8.
(4) (a) Sickert, M.; Abels, F.; Lang, M.; Sieler, J.; Birkemeyer,
C.; Schneider, C. Chem. Eur. J. 2010, 16, 2806. (b) Sickert,
M.; Schneider, C. Angew. Chem. Int. Ed. 2008, 47, 3631.
(c) Giera, D. S.; Sickert, M.; Schneider, C. Org. Lett. 2008,
10, 4259.
Yield: 128 mg (71%); colorless needles; mp 213–216 °C (Lit.9 217–
218 °C); [a]D –7.8 (c = 0.53, EtOH) (Lit.9 –6.3; c = 0.62, EtOH).
IR (film): 3417, 2954, 2869, 2845, 2803, 2733, 1633, 1583, 1455,
1435, 1392, 1035, 1009 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.28 (s, 2 H), 3.50–3.36 (m, 1 H),
2.99–2.88 (m, 1 H), 2.81 (td, J = 12.5, 3.0 Hz, 1 H), 2.03–1.77 (m,
5 H), 1.75–1.54 (m, 2 H), 1.51–1.36 (m, 3 H), 0.93 (t, J = 7.5 Hz,
3 H).
13C-{1H} NMR (100 MHz, CDCl3): d = 57.31, 44.89, 35.49, 28.30,
22.56, 22.35, 18.72, 13.87.
HRMS (ESI): m/z [M + H – HCl]+ calcd for C8H18N: 128.1433;
found: 128.1433; m/z [M + M (–Cl)]+ calcd for C16H36N2Cl:
291.2651; found: 291.2559.
(5) For excellent reviews, see: (a) Akiyama, T. Chem. Rev.
2007, 107, 5744. (b) Terada, M. Chem. Commun. 2008,
4097. (c) Terada, M. Synthesis 2010, 1929.
(6) (a) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem. Int.
Ed. 2005, 44, 7424. (b) Adair, G.; Mukherjee, S.; List, B.
Aldrichimica Acta 2008, 41, 31.
(7) (a) Fernandez-Ibanez, M. A.; Marcia, B.; Pizzuti, M. G.;
Minnaard, A. J.; Feringa, B. L. Angew. Chem. Int. Ed. 2009,
48, 9339. (b) Hande, S. M.; Kawai, N.; Ueniishi, J. J. Org.
Chem. 2009, 74, 244. (c) Adriaenssens, L. V.; Austin, C. A.;
Gibson, M.; Smith, D.; Hartley, R. C. Eur. J. Org. Chem.
2006, 4998. (d) Sanchez-Sancho, F.; Herradon, B.
Tetrahedron: Asymmetry 1998, 9, 1951. (e) Al-awar, R. S.;
Joseph, S. P.; Comins, D. L. J. Org. Chem. 1993, 58, 7732.
(8) Giera, D.; Sickert, M.; Schneider, C. Synthesis 2009, 3797.
(9) Enders, D.; Tiebes, J. Liebigs Ann. Chem. 1993, 173.
(R)-1-(4-Methoxyphenyl)-6-propylpiperidin-2-one (9)
A stirred solution of 6 (293 mg, 1.0 mmol, 1.0 equiv) in a mixture
of THF–AcOH (1:1, 10 mL) was heated to reflux for 6 h. When
complete conversion was determined by GC/MS analysis, the crude
mixture was allowed to cool to ambient temperature and neutralized
with sat. NaHCO3 and diluted with MTBE (5 mL). The layers were
Synthesis 2011, No. 24, 4050–4058 © Thieme Stuttgart · New York

4058
F. Abels, C. Schneider
PAPER
(13) Sickert, M. Dissertation; Universität Leipzig: Germany,
(10) Denmark, S. E.; Beutner, G. L. J. Am. Chem. Soc. 2003, 125,
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2010.
(11) Hassfeld, J.; Christmann, M.; Kalesse, M. Org. Lett. 2001, 3,
3561.
(12) Bazán-Tejeda, B.; Bluet, G.; Broustal, G.; Campagne, J.-M.
Chem. Eur. J. 2006, 12, 8358.
(14) Enantiomeric excess was determined after reduction to the
corresponding allylic alcohol with DIBAL-H (0.1 M in
THF, 5 equiv) at –78 °C to r.t.
(15) Enantiomeric excess was determined after hydrogenation
and lactamization according to the synthesis of 9.
Synthesis 2011, No. 24, 4050–4058 © Thieme Stuttgart · New York