Microwave-assisted organocatalytic quadruple domino reactions of acetaldehyde and nitroalkenes

Article abstract of DOI:10.1055/s-0029-1217146

A microwave-assisted, organocatalytic domino Michael/Henry condensation/Michael/aldol condensation reaction has been developed. Employing acetaldehyde and nitroalkenes as substrates, this quadruple cascade allows an efficient asymmetric synthesis of trisubstituted cyclohexene carbaldehydes in moderate to good yields (25-45%) and high enantioselectivities (ee=89 to >99%). ESI-MS measurements were carried out to support the proposed complex catalytic cycle. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1217146

PAPER
567
Microwave-Assisted Organocatalytic Quadruple Domino Reactions of
Acetaldehyde and Nitroalkenes
Quadruple
D
omino
i
React
e
ions ter Enders,* Ralf Krüll, Wolfgang Bettray
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received 13 October 2009
In addition, we planned to undertake mechanistic investi-
gations to endorse the proposed mechanism.12
Abstract: A microwave-assisted, organocatalytic domino Michael/
Henry condensation/Michael/aldol condensation reaction has been
developed. Employing acetaldehyde and nitroalkenes as substrates,
this quadruple cascade allows an efficient asymmetric synthesis of
trisubstituted cyclohexene carbaldehydes in moderate to good
yields (25–45%) and high enantioselectivities (ee = 89 to >99%).
ESI-MS measurements were carried out to support the proposed
complex catalytic cycle.
At first we performed the reaction between acetaldehyde
(1) and nitrostyrene (2a) in dioxane at room temperature
using (S)-diphenylprolinol TMS-ether [(S)-4, 20 mol%]
as a catalyst. The reaction was completed in 14 days, af-
fording the aldehyde 3a with a moderate yield, high enan-
tioselectivity and a good diastereomeric ratio (96% ee, 4:1
dr, Table 1, entry 1). In the course of the optimization we
tested several other solvents (toluene, CH2Cl2, MeCN,
Et2O) or even neat acetaldehyde and additives (DABCO,
benzoic acid, TFA, p-nitrobenzoic acid, chloroacetic ac-
id). To our delight, the best result, with the most signifi-
cant acceleration of the reaction at room temperature,
occurred upon adding two equivalents of water (Table 1,
entry 7). To further improve the reaction we tried to apply
a modern technique and tested it in a microwave oven
(Table 1, entries 4, 5 and 9–12).
Key words: organocatalysis, cascade reaction, Michael addition,
aldol condensation, cyclohexene carbaldehydes
Over the last decade the area of organocatalysis has re-
ceived much attention, evolving from a narrow field of re-
search with fairly limited examples to one of the main
branches in asymmetric catalysis.1 Within this area, con-
siderable attention has been paid to the development of
highly stereoselective asymmetric domino reactions lead-
ing to complex molecular structures by convenient one-
pot protocols via a reaction cascade.2 A large number of
organocatalytic domino reactions have been developed
over the last few years.3,4 Our group, for example, pub-
lished a diphenylprolinol-TMS-ether catalyzed triple
domino reaction5–9 that forms tri- and tetrasubstituted cy-
clohexene carbaldehydes.4c,e–n As carbon–carbon bond
forming reactions with acetaldehyde provide access to
synthetically useful polyketides, many groups have tried
to integrate acetaldehyde into aldol, Michael or Mannich
reactions using enzymes,10a,h trimethyl siloxyethenes as a
synthetic equivalent10e–g or organocatalysis.10b–d The first
synthetically useful organocatalytic reactions with acetal-
dehyde were reported in 2008 by the groups of List and
Hayashi; these approaches involved secondary amine ca-
talysed Michael, (self-)aldol and Mannich reactions.10i–o
Following these protocols, we envisaged a quadruple
domino reaction of acetaldehyde with aromatic nitroalk-
enes, yielding trisubstituted cyclohexene carbaldehydes.
To the best of our knowledge, only two amine-catalyzed
quadruple domino reactions have been reported so far;
these involved an oxa-Michael reaction followed by a
Michael addition to a nitroalkene, a consecutive Michael
addition of the resulting nitroalkane to an a,b-unsaturated
aldehyde followed by an intramolecular aldol reaction.11
Ph
Ph
O
N
H
OTMS
O
(S)-4 (20 mol%)
NO2
+
R
conditions
R
1
2
NO2
(10 equiv)
(1 equiv)
3
Scheme 1 Asymmetric synthesis of cyclohexene carbaldehydes 3
from acetaldehyde (1) and nitroalkenes 2
In the absence of water, formation of the aldehyde 3a was
not observed. However, in the presence of at least two
equivalents of water, the reaction went to completion
within five hours in high yield (45%), excellent enantiose-
lectivity and with a diastereomeric ratio of 3.5:1 (Table 1,
entry 9). Adding more than two equivalents of water
(Table 1, entries 10 and 11) or performing the reaction at
a higher temperature (Table 1, entry 12) did not lead to
any further improvements.
Based on these results, we investigated the scope of the re-
action by varying the substituents of the aromatic nitroalk-
ene 2. In all cases, the cyclohexene carbaldehydes 3 were
synthesized at 60 °C in good yields (25–45%), excellent
enantioselectivities (89 to >99%) but, unfortunately, low
diastereomeric ratios (1.4:1 to 3.5:1, Table 2). The diaste-
reomers were separated by flash chromatography (>96%
de, Table 2). The electronic features and the position of
the substituent on the aromatic ring had significant influ-
SYNTHESIS 2010, No. 4, pp 0567–0572
x
x
.
x
x
.2
0
1
0
Advanced online publication: 27.11.2009
DOI: 10.1055/s-0029-1217146; Art ID: Z21809SS
© Georg Thieme Verlag Stuttgart · New York

568
D. Enders et al.
PAPER
the epimer at the carbon atom bearing the nitro group with
4S,5R,6R configuration.
Table 1 Optimization of the Organocatalytic Quadruple Domino
Reaction
A plausible catalytic cycle is shown in Scheme 2. The re-
action starts with enamine activation of acetaldehyde 1 by
the amine catalyst (S)-4 and Michael addition to the ni-
troalkene 2. In the next step, the resulting nitroalkane 5
performs a Henry reaction with a second acetaldehyde fol-
lowed by a condensation, which leads to the newly formed
nitroalkene 6. Enamine activation of a third acetaldehyde
and Michael addition of this to the nitroalkene 6 affords
the dialdehyde 7. After an enamine activated intramolec-
ular aldol condensation reaction followed by hydrolysis,
the final product 3 is formed and (S)-4 is regenerated for
the next catalytic cycle. The result of the Henry condensa-
tion step can be explained either by a direct reaction of the
iminium nitronate form of 5 with 1 or by the reaction of
the nitronate anion of 5 with 1 under iminium activation
of 1 and direct elimination of the catalyst.
Entry Solvent
Temp H2O
(°C) (equiv) (h)
Time Yield ee
(%)a (%)b
drc
1
2
dioxane
r.t.
40
r.t.
70
60
r.t.
r.t.
r.t.
60
60
60
0
0
2
0
2
0
2
4
2
4
6
2
14 d
23 d
7 d
8
29
20
20
0
96
97
4:1
dioxane
2.5:1
2.5:1
–
3
dioxane
>99
–
4d
5d
6
dioxane
dioxane
4.5
14 d
7 d
7 d
5
30
0
>99
–
2.5:1
–
anhyd THF
anhyd THF
anhyd THF
anhyd THF
anhyd THF
anhyd THF
7
25
20
45
31
30
0
>99
>99
>99
98
3.5:1
3.5:1
3.5:1
3.5:1
3.5:1
1:1
8
d
9
10d
11d
12d
4.5
4.5
0.8
To support the proposed mechanism and to show that all
steps are catalyzed, we conducted additional experiments
as well as performing ESI-MS measurements. Both List et
al. and Hayashi et al. reported that the Michael addition of
acetaldehyde to nitroalkenes proceeded with high enantio-
selectivities, and therefore this first step can be seen as be-
ing catalyzed by the diphenylprolinol (S)-4.10i,k
>99
–
anhyd THF 100
a Yield of the two isolated diastereomers.
b Determined by HPLC analysis on a chiral stationary phase.
c Determined by GC.
d Carried out in a microwave oven at the temperature and the time giv-
en.
O
O
ence on the reaction time required (from 5 hours up to 12
hours) and the diastereoselectivity obtained (from 3.5:1
down to 1.4:1 dr) but had no influence on the enantiose-
lectivity.
+
NO2
R
R
Ph
Ph
OTMS
NO2
3
1
2
N
aldol
Michael
H
In the case of 3a, the absolute configuration of the major
diastereomer was determined to be 4S,5S,6R (Scheme 1)
by NMR measurements and based on previous assign-
ments, whereas the minor diastereomer was shown to be
(S)-4
En
En
(S)-4
H2O
O
O
O
5
R
R
7
Table 2 Yield and Stereoselectivity of the Organocatalytic Domino
NO2
NO2
O
Reactiona
O
+ [(S)-4]
Im
En
+ H O
(S)-4
2
3
R
Time
(h)
Yield
(%)b
drc
ee
de
1
(%)d (%)e
R
Michael
Henry
NO2
6
H2O
O
a
b
c
Ph
5
8
45
33
40
31
25
3.5:1
1.7:1
1.4:1
1.5:1
1.5:1
>99
89
>96
>96
>96
>96
>96
[(S)-4]
+
(S)-4
o-ClC6H4
p-ClC6H4
Naph
1
8
97
Scheme 2 Proposed catalytic cycle of the quadruple cascade reac-
tion
d
e
8
>99
>99
p-MeC6H4
12
For the second step – the Henry reaction of nitroalkane 5
with acetaldehyde – we isolated the 4-nitroaldehyde 5 and
tried to apply it as a starting point for our domino reaction
under the following conditions: (a) without any additive
or catalyst; (b) with triethylamine as an additive and (c)
with the diphenylprolinol TMS-ether catalyst. Only in
case (c) was the formation of 3a observed. In the case of
the third step – the formation of dialdehyde 7 – we made
a Reaction conditions: 1 (10 mmol), nitroalkene 2 (1 mmol), (S)-4 (20
mol%, 0.2 equiv), THF (2 mL), H2O (2 mmol, 2 equiv), MW (Ramp-
time: 1 min, 60 W, 60 °C, PowerMax: Off).
b Yield of the two isolated diastereomers.
c Determined by GC.
d Determined by HPLC analysis on a chiral stationary phase.
e Major diastereomer obtained after flash chromatography, deter-
mined by NMR spectroscopy.
Synthesis 2010, No. 4, 567–572 © Thieme Stuttgart · New York

PAPER
Quadruple Domino Reactions
569
the observation that when the enantiopure catalyst (S)-4
was used, only two diastereomers were formed as the ma-
jor products; the other two diastereomers were formed in
only trace amounts that were detectable only by GC-MS.
Applying the racemic catalyst rac-4, all four diastereo-
mers could be detected via GC-MS in the particular dia-
stereomeric ratio given in Table 2. We concluded that this
is caused by attack of one enamine-activated acetaldehyde
bearing either the (S)- or the (R)-prolinol 4 on a nitroalk-
ene formed by either (S)- or (R)-prolinol. This would lead
to the formation of all four possible diastereomers and
proves that the catalyst controls the stereochemical out-
come of this step.
Table 3 HRMS (ESI) Analysis of Detected Intermediates Leading
to 3b
Species Mass
(calcd)
Mass
Formula
Error
(ppm)
(measured)a
8
236.14338
236.14301 C17H18N
–0.4
–0.4
0.3
[4 + H]+ 326.19347
326.19305 C20H28ONSi
535.21753 C30H36O3N2ClSi
561.23297 C32H38O3N2ClSi
605.25928 C34H42O4N2ClSi
587.24933 C34H40O3N2ClSi
649.28583 C36H46O5N2ClSi
693.31207 C38H50O6N2ClSi
9
10
11
12
13
14
535.21782
561.23347
605.259689
587.24913
649.28590
693.31212
0.5
0.4
0.3
We then performed ESI-MS measurements of the reaction
mixture to find evidence of the proposed intermediates.
We were glad to see that all of the corresponding iminium
ions of product 3b and all the intermediates given in
Scheme 2 could be observed (Figure 1). We also detected
two further intermediates (13 and 14), which indicate side
reactions of acetaldehyde with the other intermediates.
The measured and calculated high resolution masses of
the intermediates are given in Table 3. The results of the
experiments and the ESI-MS measurements support the
proposed mechanism.
0.1
–0.1
a Calibration using internal standard (MRFA).
selectivities (89 to >99% ee). The practically pure major
diastereomer (de >96%) could be obtained after flash
chromatography. The proposed mechanism of the catalyt-
ic cycle was supported by additional experiments and
ESI-MS measurements.
In summary, we have developed a quadruple domino re-
action based on a Michael addition – Henry condensation
– Michael addition – aldol condensation sequence of acet-
aldehyde and aromatic nitroalkenes 2. This process is ef-
ficiently catalyzed by (S)-diphenylprolinol TMS-ether to
afford trisubstituted functionalised cyclohexene carbalde-
hydes with three stereogenic centres in moderate to good
All solvents were dried by conventional methods. THF was freshly
distilled from Na/molecular sieve (Solvona pellets) under argon.
Acetaldehyde was freshly distilled before use with a drop of con-
centrated sulfuric acid at 60 °C oil bath temperature. The nitroalk-
enes were prepared according to literature procedures. Preparative
column chromatography used Merck silica gel 60, particle size
0.040–0.064 mm (230–240 mesh; flash). Silica gel 60, F254 plates
yields (25–45%; 70–85% per step) and excellent enantio- from Merck, Darmstadt were used for analytical TLC. IR spectra
Figure 1 ESI-MS spectrum (positive mode) of the cascade reaction for the synthesis of cyclohexene carbaldehydes, five minutes after the
start of the reaction
Synthesis 2010, No. 4, 567–572 © Thieme Stuttgart · New York

570
D. Enders et al.
PAPER
1
were taken on a Perkin–Elmer FT-IR 1760 spectrophotometer. H
and 13C NMR spectra were recorded on Varian Gemini 300, Mercu-
ry 300 or Inova 400 spectrometers and all measurements were per-
formed with TMS as internal standard. HRMS (EI) were acquired
on a Finnigan MAT 95 spectrometer. Microanalyses were obtained
with a Vario EL elemental analyzer. ESI-MS measurements were
made on a LTQ Orbitrap XL, Fa. ThermoFisher Scientific instru-
ment equipped with an ESI source. The microwave oven used was
a CEM Discover BenchMate.
MS (EI, 70 eV): m/z (%) = 75 (11), 76 (11), 77 (18), 82 (12), 83
(15), 88 (11), 91 (13), 114 (16), 125 (100), 126 (25), 127 (29), 128
(12), 138 (26), 140 (20), 151 (28), 152 (32), 153 (11), 164 (19), 167
(19), 168 (13), 189 (18), 197 (13), 203 (53), 204 (11), 205 (23), 217
(32), 231 (20), 232 (13), 233 (10), 279 (7) [M]+.
HRMS (ESI): m/z [M + H]+ calcd for C14H14NO3Cl: 279.0662;
found: 279.0657.
(4S,5S,6R)-4-(4-Chlorophenyl)-6-methyl-5-nitrocyclohex-1-
enecarbaldehyde (3c)
Microwave-Assisted Organocatalytic Quadruple Domino Reac-
tion; General Procedure
Yield: 105 mg (40%); pale-yellow oil; ee >97% (Daicel Chiralpak
22
AD; heptane–i-PrOH, 9:1); dr = 1.4:1 (GC); [a]D +65.1 (c 1.00,
In a 10-mL microwave vial, diphenylprolinol TMS-ether (S)-4 (65
mg, 0.2 mmol), the aromatic nitroalkene 2 (1 mmol) and distilled
H2O (36 mg, 2 mmol) were dissolved in anhydrous THF (2 mL). Af-
ter addition of freshly distilled acetaldehyde (0.53 mL, 10 mmol),
the vial was closed and heated under microwave irradiation for the
time given in Table 2 (1 min Ramptime, 60 W, 60 °C, PowerMax:
off). The reaction mixture was then concentrated and directly puri-
fied by flash column chromatography (n-pentane–Et2O, 10:1→2:1).
CHCl3); Rf = 0.3 (pentane–Et2O, 2:1).
IR (KBr): 3436, 3021, 2920, 2851, 1723, 1685, 1649, 1547, 1493,
1455, 1417, 1372, 1337, 1256, 1216, 1165, 1141, 1094, 1014, 883,
822, 757, 665, 525 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.55 (d, J = 7.2 Hz, 3 H, CH3),
2.95 (dt, J = 5.7, 20.0 Hz, 1 H, CHH), 3.24–3.34 (m, 1 H, CHH),
3.51–3.61 (m, 2 H, CHCH3, CHAr), 5.11 (dd, J = 2.7, 9.7 Hz, 1 H,
CHNO2), 7.17 (dd, J = 2.0, 4.7 Hz, 1 H, HC=C), 7.28–7.35 (m, 2 H,
ArH), 7.45–7.56 (m, 2 H, ArH), 9.70 (s, 1 H, CHO).
Preparation of ESI-MS Samples
Samples were taken after 5 min of microwave irradiation. After
evaporation of the solvent the residue was dissolved in MeCN (1
mL). For measurements with an internal standard the tetrapeptide
Met-Arg-Phe-Ala (MRFA) was added.
13C NMR (100 MHz, CDCl3): d = 19.6, 27.8, 32.3, 37.5, 90.8, 128.7,
128.9, 128.9, 129.2, 133.9, 136.7, 141.3, 148.5, 192.5.
MS (EI, 70 eV): m/z (%) = 77 (12), 91 (13), 115 (15), 125 (73), 127
(36), 128 (22), 139 (20), 141 (18), 149 (10), 151 (11), 152 (31), 153
(35), 154 (17), 165 (23), 167 (11), 168 (11), 179 (11), 189 (30), 191
(14), 197 (13), 199 (18), 203 (21), 205 (10), 217 (55), 219 (19), 231
(12), 232 (100), 233 (65), 234 (42), 235 (22), 279 (20) [M]+.
HRMS (ESI): m/z [M + H]+ calcd for C14H14NO3Cl: 279.0662;
found: 279.0657.
(4S,5S,6R)-6-Methyl-5-nitro-4-phenylcyclohex-1-enecarbalde-
hyde (3a)
Yield: 110 mg (45%); pale-yellow oil; ee >99% (Daicel Chiralpak
AD; heptane–i-PrOH, 9:1); dr = 3.5:1 (GC); [a]D22 +177.1 (c 1.00,
CHCl3); Rf = 0.3 (pentane–Et2O, 2:1).
IR (KBr): 2969, 2918, 2852, 1677, 1648, 1540, 1495, 1454, 1408,
1374, 1338, 1278, 1251, 1163, 1140, 1077, 1006, 903, 881, 835,
762, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.35 (d, J = 7.1 Hz, 3 H, CH3),
2.75 (ddd, J = 20.3, 4.9, 4.9 Hz, 1 H, CHH), 3.10–3.22 (m, 1 H,
CHH), 3.33 (br q, J = 7.1 Hz, 1 H, CHCH3), 3.43 (m, 1 H, CHPh),
4.81 (m, 1 H, CHNO2), 7.01 (dd, J = 2.7, 4.7 Hz, 1 H, HC=C),
7.18–7.38 (m, 5 H, PhH), 9.51 (s, 1 H, CHO).
(4S,5S,6R)-6-Methyl-4-(naphthalene-2-yl)-5-nitrocyclohex-1-
enecarbaldehyde (3d)
Yield: 91 mg (31%); pale-yellow oil; ee >99% (Daicel Chiralpak
23
AS; heptane–i-PrOH, 8:2); dr = 1.5:1 (GC); [a]D +53.7 (c 1.00,
CHCl3); Rf = 0.2 (pentane–Et2O, 2:1).
IR (CHCl3): 3387, 3056, 3018, 2919, 2851, 1684, 1649, 1547, 1453,
1418, 1375, 1334, 1217, 1142, 963, 894, 860, 820, 754, 668, 478
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.59 (d, J = 7.2 Hz, 3 H, CH3),
3.04 (ddd, J = 20.0, 5.4, 5.4 Hz, 1 H, CHH), 3.43–3.50 (m, 1 H,
CHH), 3.52–3.60 (m, 1 H, CHCH3), 3.73–3.83 (m, 1 H, CHNaph),
5.15 (dd, J = 3.2, 1.2 Hz, 1 H, CHNO2), 7.24 (dd, J = 4.9, 2.5 Hz,
1 H, HC=C), 7.49–7.72 (m, 3 H, Naph), 7.92–8.07 (m, 3 H, Naph),
9.73 (s, 1 H, CHO).
13C NMR (100 MHz, CDCl3): d = 19.6, 27.8, 31.3, 37.9, 90.7, 126.9
(2 × C), 127.9 (2 × C), 128.8, 137.9, 141.1, 148.9, 192.4.
MS (EI, 70 eV): m/z (%) = 51 (11), 65 (12), 77 (24), 91 (100), 105
(24), 115 (29), 127 (13), 128 (23), 192 (23), 141 (18), 152 (13), 153
(17), 154 (18), 155 (44), 165 (11), 169 (58), 170 (12), 171 (13), 181
(12), 183 (47), 197 (17), 198 (34), 199 (14), 245 (16) [M]+.
Anal. Calcd for C14H15NO3: C, 68.56; H, 6.16; N, 5.71. Found: C,
68.25; H, 6.22; N, 5.39.
13C NMR (75 MHz, CDCl3): d = 19.7, 27.9, 32.8, 38.1, 90.4, 125.2,
126.1, 126.2, 126.3, 126.5, 127.6, 127.9, 132.9, 133.4, 135.5, 141.4,
192.7.
(4S,5S,6R)-4-(2-Chlorophenyl)-6-methyl-5-nitrocyclohex-1-
enecarbaldehyde (3b)
MS (EI, 70 eV): m/z (%) = 77 (17), 91 (11), 93 (14), 101 (11), 115
(16), 127 (12), 128 (19), 141 (72), 152 (17), 155 (22), 165 (40), 166
(11), 178 (42), 179 (34), 189 (19), 190 (13), 191 (22), 192 (11), 202
(30), 203 (28), 204 (20), 205 (52), 206 (12), 215 (34), 216 (14), 219
(30), 220 (11), 231 (34), 232 (12), 233 (25), 247 (30), 248 (88), 249
(39), 295 (100) [M]+, 296 (20) [M + H]+.
Yield: 92 mg (33%); pale-yellow oil; ee >89% (Daicel Chiralpak
22
IA; heptane–i-PrOH, 8:2); dr = 1.7:1 (GC); [a]D +225.4 (c 1.00,
CHCl3); Rf = 0.4 (pentane–EtOAc, 6:1).
IR (KBr): 2929, 2827, 1677, 1645, 1593, 1543, 1475, 1439, 1417,
1404, 1369, 1335, 1265, 1191, 1166, 1127, 1102, 1035, 1015, 906,
885, 844, 762, 700, 673 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C18H17NO3: 295.1208; found:
295.1203.
1H NMR (400 MHz, CDCl3): d = 1.35 (d, J = 7.9 Hz, 3 H, CH3),
2.65 (ddd, J = 19.8, 5.5, 5.5 Hz, 1 H, CHH), 3.12–3.22 (m, 1 H,
CHH), 3.43 (br q, J = 7.9 Hz, 1 H, CHCH3), 4.03 (m, 1 H, CHAr),
4.94 (m, 1 H, CHNO2), 7.15 (dd, J = 2.7, 4.9 Hz, 1 H, HC=C),
7.18–7.38 (m, 4 H, ArH), 9.53 (s, 1 H, CHO).
13C NMR (100 MHz, CDCl3): d = 19.2, 29.7, 32.7, 34.3, 87.9, 127.3,
127.9, 129.1, 129.9, 141.4, 148.2, 192.3.
(4S,5S,6R)-6-Methyl-5-nitro-4-p-tolylcyclohex-1-enecarbalde-
hyde (3e)
Yield: 65 mg (25%); pale-yellow oil; ee >99% (Daicel Chiralpak
IA; heptane–i-PrOH, 8:2); dr = 1.7:1 (GC); [a]D +55.4 (c 1.00,
CHCl3); Rf = 0.3 (pentane–Et2O, 1:1).
23
Synthesis 2010, No. 4, 567–572 © Thieme Stuttgart · New York

PAPER
Quadruple Domino Reactions
571
IR (KBr): 2929, 2851, 1685, 1648, 1547, 1515, 1451, 1418, 1372,
1337, 1265, 1165, 1145, 1080, 1045, 884, 839, 814, 737, 704, 547
cm–1.
1H NMR (400 MHz, CDCl3): d = 1.25 (d, J = 7.1 Hz, 3 H, CH3),
2.47 (s, 3 H, ArCH3), 2.87 (ddd, J = 20.1, 5.5, 5.5 Hz, 1 H, CHH),
3.21–3.31 (m, 1 H, CHH), 3.43 (dq, J = 1.0, 7.1 Hz, 1 H, CHCH3),
3.48–3.52 (m, 1 H, CHAr), 4.91 (dd, 1 H, J = 1.4, 3.0 Hz, CHNO2),
7.11–7.14 (m, 1 H, HC=C), 7.20–7.30 (m, 4 H, ArH), 9.64 (s, 1 H,
CHO).
(4) For selected examples of organocatalytic domino reactions,
see: (a) Yang, J. W.; Fonseca, M. T. H.; List, B. J. Am.
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13C NMR (100 MHz, CDCl3): d = 19.7, 21.2, 28.1, 32.8, 37.8, 90.7,
127.3, 127.8 (2 × C), 129.4, 129.7, 141.3, 149.1, 192.5.
MS (EI, 70 eV): m/z (%) = 77 (13), 91 (21), 93 (12), 105 (100), 115
(18), 119 (17), 138 (18), 129 (16), 141 (11), 143 (14), 145 (12), 153
(10), 169 (43), 183 (32), 184 (38), 185 (16), 195 (12), 197 (32), 212
(22), 213 (13), 259 (24) [M]+.
HRMS (ESI): m/z [M + H]+ calcd for C15H17NO3: 259.1208; found:
259.1203.
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
(priority program Organocatalysis) and the Fonds der Chemischen
Industrie. We thank the former Degussa AG and BASF AG for the
donation of chemicals.
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