Supporting Information
Wiley-VCH 2013
69451 Weinheim, Germany
Organocatalytic Asymmetric Conjugate Addition of Aldehydes to
Nitroolefins: Identification of Catalytic Intermediates and the Stereoselectivity-Determining Step by ESI-MS**
Florian Bchle, Jçrg Duschmal, Christian Ebner, Andreas Pfaltz,* and Helma Wennemers*
ange_201305338_sm_miscellaneous_information.pdf
Supporting Information
1.
2.
3.
4.
5.
6.
7.
8.
9.
General aspects and materials
Synthesis of catalysts 1a – c
Synthesis of catalysts 1d and 1e
Synthesis of the quasienantiomeric substrates 2 and ent-2’
Preparative catalytic reactions
Selectivity determination by ESI-MS screening of the back reaction
Supplemental ESI-MS spectra
Reversibility of conjugate addition reactions
References
S1
S1
S3
S4
S9
S16
S17
S22
S24
S1
1. General aspects and materials
Materials and reagents were of the highest commercially available grade and used
without further purification. Reactions were monitored by thin layer chromatography
using Merck silica gel 60 F254 plates. Compounds were visualized by UV, KMnO4 and
ninhydrin. Flash chromatography was performed using Merck silica gel 60, particle size
40 – 63 µm. 1H and 13C NMR spectra were recorded on a Bruker DPX 400, a VARIAN
Mercury 300 MHz or a Bruker Advance DRX 500 spectrometer. Chemical shifts are
reported in ppm using TMS or the residual solvent peak as a reference. HPLC analyses
were performed on an analytical HPLC with a diode array detector from Shimadzu.
2. Synthesis of catalysts 1a - c
Catalysts 1a, 1b and 1c were prepared by solid phase peptide synthesis using the
Fmoc/tBu protocol according to the general protocols outlined below:
a) Functionalization of Rink Amid polystyrene resin: The first amino acid was
coupled to a pre-swollen suspension of Rink Amid resin according to the
“General procedure for peptide couplings” described below.
b) Functionalization of PHB polystyrene (Wang) resin: To a pre-swollen
suspension of the resin in CH2Cl2, was added a solution of the Fmoc amino acid
(3 equiv.), N-methylimidazole (2.5 equiv.) and MSNT (3 equiv.) in CH2Cl2. The
reaction mixture was agitated at room temperature for 1 h, then washed with
DMF (3x) and CH2Cl2 (5x). Quantitative Fmoc tests were performed as spot
checks.
c) General procedure for peptide couplings: iPrNEt2 (9 eq as a 3M solution in
N-methylpyrrolidone) was added to a solution of Fmoc-Xxx-OH (3 eq) and
HCTU (3 eq) in DMF. The activated amino acid was added as a solution in
DMF (≈100 mM concentration) to the amino-functionalized resin, swollen in
DMF and the mixture was agitated for 1.5 h before washing with DMF (5x).
d) General procedure for Fmoc-deprotections: 40% piperidine in DMF was added
to the resin (preswollen in DMF) and the reaction mixture was agitated for 3 min,
drained and the piperidine treatment repeated for 10 min. Finally the resin was
washed with DMF (7x).
S2
e) General procedure for cleavage of peptides from the solid support: The solid
supported peptides were cleaved from the Rink Amide resin by stirring in a
mixture of TFA:CH2Cl2 2:1 for 1 h and a second time for 20 min. Pooling of
filtrates and removal of all volatiles under reduced pressure followed by
precipitation with Et2O afforded the peptides as their TFA salts.
f) General Protocol for the Ion-Exchange of Peptides: The TFA salt of the peptide
(50-100 mg) was dissolved in water (1.5 mL) and loaded on a VariPureTM IPE
tube (Varian, Inc.) which was previously rinsed with MeOH (2 mL). The tube
was washed with water or acetonitrile/water mixtures until the peptide was fully
eluted (TLC spots visualised with ninhydrin). Peptide containing fractions were
pooled and lyophilised. The desalted peptide was obtained as a white solid
(∼80%). The absence of TFA was confirmed by 19F-NMR analysis.
H-D-Pro-Pro-Glu-NH2 (1a): The peptide was prepared on Rink Amide PS resin
according to the general protocols for solid phase peptide synthesis. Spectroscopic data
are in agreement with published data.[1,2]
H-Pro-Pro-D-Glu-NH2 (1b): The peptide was prepared on Rink Amide PS resin
according to the general protocols for solid phase peptide synthesis. Spectroscopic data
are in agreement with published data.[3]
TFA·H-Pro-Pro-D-Gln-OH (1c): The peptide was prepared on polystyrene PHB
(Wang) resin according to the general protocols for solid phase peptide synthesis.
Spectroscopic data are in agreement with published data.[4]
3. Synthesis of catalysts 1d and 1e
Catalysts 1d and 1e were prepared by solution phase peptide synthesis as described
previously[5] according to the strategy outlined below. Spectroscopic data are in
agreement with published data.[5]
S3
4. Synthesis of the quasienantiomeric substrates 2 and ent-2’
The quasienantiomeric substrates 2 and ent-2’ were prepared as outlined below.[6]
S4
3-(4-Methylphenyl)propanal:
I
+
Me
O
OEt
H
OEt
Me
1-Iodo-4-methylbenzene (4.81 g, 22.0 mmol, 1.0 eq) was dissolved in 85 mL DMF.
Acrolein diethyl acetal (9.44 mL, 61.8 mmol, 2.8 eq), tetrabutylammonium acetate
(14.3 g, 47.4 mmol, 2.2 eq), potassium chloride (1.64 g, 22.0 mmol, 1.0 eq), potassium
carbonate (4.27 g, 30.9 mmol, 1.4 eq) and palladium(II) acetate (111 mg, 494 µmol,
2.0 mol%) were added and the mixture was stirred at 95 °C for 3 h. The black reaction
mixture was allowed to cool to room temperature and 100 mL 2m HCl solution was
added dropwise. After stirring for 10 min 300 mL of Et2O were added. The phases were
separated and the organic phase was washed with H2O (3x100 mL). After drying over
Na2SO4 the solvent was removed under reduced pressure. Purification by column
chromatography on silica gel (8 cm x 15 cm) eluting with a mixture of pentane and
EtOAc (10:1) afforded 2.65 g of a light yellow oil. The cinnamaldehyde derivative was
dissolved in 20 mL MeOH and 271 mg of Pd/C (10% w/w) was added. The resulting
mixture was stirred under a H2 atmosphere for 1.5 h. Filtration over Celite and
evaporation of the solvent under reduced pressure afforded a colorless oil that was
purified by column chromatography on silica gel (4 cm x 25 cm, pentane/EtOAc 10:1)
to provide 1.84 g (69 %) of a colorless oil.
1
H NMR (400 MHz, CDCl3) δ 9.83 (t, J = 1.5 Hz, 1H), 7.18 – 7.08 (m, 4H), 2.94 (t, J =
7.6 Hz, 2H), 2.77 (t, J = 8.0 Hz, 1H), 2.34 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 201.6,
137.1, 135.7, 129.2, 128.1, 45.3, 27.6, 20. 9.
Spectroscopic data are in agreement with published data.[7]
S5
3-(4-Ethylphenyl)propanal:
I
+
Et
O
OEt
H
OEt
Et
1-Iodo-4-methylbenzene (5.11 g, 22.0 mmol, 1.0 eq) was dissolved in 85 mL DMF.
Acrolein diethyl acetal (9.44 mL, 61.8 mmol, 2.8 eq), tetrabutylammonium acetate
(14.3 g, 47.4 mmol, 2.2 eq), potassium chloride (1.64 g, 22.1 mmol, 1.0 eq), potassium
carbonate (4.27 g, 30.9 mmol, 1.4 eq) and palladium(II) acetate (111 mg, 494 µmol,
2.0 mol%) were added and the mixture was stirred at 95 °C for 3 h. The black reaction
mixture was allowed to cool to room temperature and 100 mL 2m HCl solution was
added dropwise. After stirring for 10 min 300 mL of Et2O were added. The phases were
separated and the organic phase was washed with H2O (3x100 mL). After drying over
Na2SO4 the solvent was removed under reduced pressure. Purification by column
chromatography on silica gel (8 cm x 15 cm) eluting with a mixture of pentane and
EtOAc (10:1) afforded 3.20 g of a light yellow oil. The cinnamaldehyde derivative was
dissolved in 20 mL MeOH and 240 mg of Pd/C (10% w/w) was added. The resulting
mixture was stirred under a H2 atmosphere for 3 h. Filtration over Celite and
evaporation of the solvent under reduced pressure afforded a colorless oil that was
dissolved in 3 mL DMF and treated with 3 mL 4m HCl over night. 20 mL EtOAc were
added and washed with water (3x10 mL). Column chromatography on silica gel (4 cm x
15 cm, pentane/EtOAc 10:1) provided 2.57 g of a colorless liquid (72 %).
1
H NMR (400 MHz, CDCl3) δ 9.83 (t, J = 1.5 Hz, 1H), 7.22 – 7.10 (m, 4H), 2.96 (t, J =
7.6 Hz, 2H), 2.84 – 2.74 (m, 2H), 2.65 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ 201.6, 142.1, 137.4, 128.1, 128.0, 45.3, 28.3, 27.6, 15.5.
S6
(2S,3R)-2-(4-Methylbenzyl)-4-nitro-3-phenylbutanal (2):
To a solution of TFA·H-D-Pro-Pro-Glu-NH2 (33.6 mg, 73.9 µmol, 3 mol%) and
N-methylmorpholine (8.1 µL, 73.9 µmol, 3 mol%) in a 9:1 mixture of CHCl3 and iPrOH
(5 mL) was added 3-(4-methylphenyl)propanal (365 mg, 2.46 mmol, 1.0 eq) followed
by trans-β-nitrostyrene (551 mg, 3.69 mmol, 1.5 eq). The reaction mixture was agitated
at 5 °C for 24 h and then directly applied to column chromatography on silica gel (3 cm
x 10 cm) eluting with a mixture of cyclohexane and EtOAc (10:1).
(2S,3R)-2-(4-methylbenzyl)-4-nitro-3- phenyl butanal was obtained as a colorless solid
(608 mg, 83%, 97% ee).
1
H NMR (400 MHz, CDCl3) δ 9.71 (d, J = 2.3 Hz, 1H), 7.48 – 7.29 (m, 3H), 7.29 – 7.18
(m, 2H), 7.08 (d, J = 7.7 Hz, 2H), 6.92 (d, J = 8.1 Hz, 2H), 5.04 – 4.59 (m, 1H), 3.82 (td,
J = 8.6, 6.0 Hz, 1H), 2.87 – 2.65 (m, 2H), 2.31 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
203.1, 136.7, 136.5, 133.9, 129.4, 129.2, 128.6, 128.2, 128.0, 78.0, 55.3, 43.4, 33.8,
21.0; elemental analysis calcd (%) for C18H19NO3: C 72.71, H 6.44, N 4.71; found: C
72.54, H 6.47, N 4.92.
The enantiomeric excess was determined by HPLC using a Chiracel OD-H column
(n-hexane/i-PrOH 80:20, 25 °C) at 1.0 mL/min, UV detection at 254 nm: tR : (syn,
major) = 20.3 min, (syn, minor) = 23.5 min.
S7
(2R,3S)-2-(4-Ethylbenzyl)-4-nitro-3-phenylbutanal (ent-2’):
To a solution of TFA·H-Pro-D-Pro-D-Glu-NH2 (24.0 mg, 52.9 µmol, 3 mol%) and
N-methylmorpholine (5.8 µL, 52.9 µmol, 3 mol%) in a 9:1 mixture of CHCl3 and iPrOH
(5 mL) was added 3-(4-ethylphenyl)propanal (286 mg, 1.76 mmol, 1.0 eq) followed by
trans-β-nitrostyrene (394 mg, 2.64 mmol, 1.5 eq). The reaction mixture was agitated at
5° C for 24 h and then directly applied to column chromatography on silica gel (3 cm x
10 cm) eluting with a mixture of cyclohexane and EtOAc (10:1).
(2R,3S)-2-(4-ethylbenzyl)-4-nitro-3- phenyl butanal was obtained as a colorless solid
(393 mg, 72%, 97% ee).
1
H NMR (250 MHz, CDCl3) δ 9.71 (d, J = 2.3 Hz, 1H), 7.45 – 7.31 (m, 3H), 7.25 – 7.18
(m, 2H), 7.09 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 4.76 – 4.68 (m, 2H), 3.82
(ddd, J = 9.2, 8.1, 6.4 Hz, 1H), 3.10 (dddd, J = 9.2, 8.0, 6.4, 2.3 Hz, 1H), 2.80 – 2.69 (m,
2H), 2.60 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
203.2, 142.9, 136.7, 134.2, 129.2, 128.7, 128.2, 128.2, 128.0, 78.0, 55.3, 43.4, 33.8,
28.4, 15.5; elemental analysis calcd (%) for C19H21NO3: C 73.29, H 6.80, N 4.50;
found: C 73.15, H 6.81, N 4.50.
The enantiomeric excess was determined by HPLC using a Chiracel OD-H column
(n-hexane/i-PrOH 80:20, 25 °C) at 1.0 mL/min, UV detection at 254 nm: tR : (syn,
minor) = 16.6 min, (syn, major) = 20.8 min.
S8
5. Preparative catalytic reactions
General procedure for preparative catalytic reactions:
To a solution of the catalyst (22.0 µmol, 10 mol%) in the respective solvent (0.5 mL)
was added 3-phenylpropanal (330 µmol, 1.5 eq) followed by trans-β-nitrostyrene
(220 µmol, 1.0 eq). The reaction mixture was agitated at room temperature. EtOAc
(2 mL) and 0.1 M HCl were added and the phases were separated. The organic layer was
dried over Na2SO4. Evaporation of the solvent under reduced pressure followed by
silica gel chromatography (1.5 cm x 8 cm, cyclohexane:EtOAc 10:1) provided the
γ-nitroaldehyde as a colourless oil.
1
H NMR (300 MHz, CDCl3) δ 9.72 (d, J = 2.3 Hz, 1H), 7.43 – 7.10 (m, 8H), 7.07 – 7.00
(m, 2H), 4.76 – 4.67 (m, 2H), 3.83 (td, J = 8.5, 6.3 Hz, 1H), 3.17 – 3.03 (m, 1H), 2.82 –
2.70 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 202.9, 137.1, 136.7, 129.2, 128.8, 128.7,
128.3, 128.0, 126.9, 78.0, 55.3, 43.4, 34.2.
Spectroscopic data are in agreement with published data.[1]
The enantiomeric excess was determined by HPLC using a Chiracel OD-H column
(n-hexane/i-PrOH 80:20, 25°C) at 1.0 mL/min, UV detection at 254 nm: tR : (syn,
minor) = 27.5 min, (syn, major) = 30.9 min.
S9
S10
S11
S12
S13
S14
S15
6. Selectivity determination by ESI-MS screening of the back reaction
General remarks:
ESI-MS spectra were measured on a Varian 1200L Quadrupol MS/MS spectrometer
using mild desolvation conditions (39 psi nebulising gas, 4.9 kV spray voltage, 19 psi
drying gas at 200 °C, 1300 V detector voltage, 110 V capillary voltage for the peptide
catalysts 1a-e and 50 V capillary voltage for the Hayashi-Jørgensen catalyst 3). The
samples were diluted immediately with MeOH prior to their analysis and measured
using direct injection. The spectra were acquired in the centroid mode and the
selectivity was calculated from the ratios of the peak heights of the major isotopomers
of En and En’.
ESI-MS analysis of the forward-reaction:
10 µL of a 0.1 M solution of the organocatalyst 1a in a mixture of CHCl3/i-PrOH (9:1)
was mixed with 10 µL of a 1 M solution of 3-phenylpropanal and 10 µL of a 1 M
solution of trans-β-nitrostyrene in the same solvent. The mixture was shaken for 1 min
and then diluted with 1 mL of MeOH. This mixture was analyzed by ESI-MS under
mild desolvation conditions.
General procedure for the ESI-MS screening of the back-reaction without acid additive:
10 µL of a 0.1 M solution of the organocatalyst in the corresponding solvent was mixed
with
10 µL
of
a
1M
solution
of
an
equimolar
mixture
of
(2S,3R)-2-(4-Methylbenzyl)-4-nitro-3-phenylbutanal
2
(5 µmol)
and
(2R,3S)-2-(4-Ethylbenzyl)-4-nitro-3-phenylbutanal ent-2’ (5 µmol) in the same solvent.
The mixture was stirred for 10 min and then diluted with 1 mL of MeOH. This mixture
was analyzed by ESI-MS under mild desolvation conditions.
General procedure for the ESI-MS screening of the back-reaction with acid additive:
An equimolar mixture of (2S,3R)-2-(4-Methylbenzyl)-4-nitro-3-phenylbutanal 2
(5 µmol) and (2R,3S)-2-(4-Ethylbenzyl)-4-nitro-3-phenylbutanal ent-2’ (5 µmol) and
10 mol% or 100 mol% of the corresponding acid were dissolved in 10 µL DMSO.
10 µL of a 0.1 M solution of the organocatalyst 1d or 3 in DMSO was added and the
mixture was stirred for 2 min and then diluted with 1 mL of MeOH. This mixture was
analyzed by ESI-MS under mild desolvation conditions.
S16
7. Supplemental ESI-MS spectra
ESI-MS analysis of the forward reaction in CHCl3/iPrOH with tripeptide 1a:
O
H
N
N
O
NH 2
O
NH
OH
O
[1a+H]+
m/z = 341
100
Pro-Glu-NH 2
N
O
N+
Ph
Bn
rel. Int.
[1a+Na]+
m/z = 363
Ph
Pro-Glu-NH 2
O
NO 2
[1a2+H]+
+H+
m/z = 681
m/z = 457
+Na+
m/z = 479
m/z = 606
0
70
30
0
0
m/z
ESI-MS back reaction screening in CHCl3/iPrOH with tripeptide 1a:
N
O
NH 2
O
NH
100
O
H
N
O
[1a2+H]+
[1a+H]+
m/z = 681
m/z = 341
rel. Int.
OH
[1a-Im’]+
m/z = 634
[1a+Na]+
[1a2+Na]+
m/z = 703
m/z = 363
[1a-Im]+
m/z = 620
1
79
29
9
0
m/z
S17
Operator:Administrator Timebase:UltiMate3000 Sequence:JD127
19 pPE-dodecyl_DMSO
ODH
Sample Name:
pPE-dodecyl_DMSO
RE1
unknown
20%B_25°C_1mLmin_55min
line6-7
25.1.2013 18:24
55.00
Vial Number:
ESI-MS back reaction screening in DMSO with tripeptide
1e:
O
H
N
N
O
NH
N
H
O
1e
OMe
O
[1e-En+H]+
100
1 - 27.617
12.5
O
m/z = 653
10.0
Ph
NO 2
H
Bn
[1e+H]+
rel. Int.
JD127 #19 [modified by Administrator]
mAU
m/z = 802
[1e-En’+H]+
m/z = 531
16.0
[1e-Im’]+
m/z = 639
[1e+Na]+
Sample Type:
Control Program:
Quantif. Method:
C12H
25
Recording Time:
Run Time (min):
7.5
m/z = 509
Injection Volu
Channel:
Wavelength:
Bandwidth:
Dilution Facto
Sample Weig
Sample Amou
O
[1e-Im]+
Ph
NO 2
H
m/z = 788
Bn
2 - 31.425
5.0
2.5
3 - 40.550
4
0.0
1
[1e+K]+
99
40
0
0
m/z
m/z = 531
-2.0
20.0
Back reaction: 76 : 24 (En/En’)
25.0
30.0
Forward reaction: 75 : 25!
No.
1
2
3
4
Total:
Ret.Time
min
27.62
31.43
40.55
47.73
Peak Name
n.a.
n.a.
n.a.
n.a.
35.0
40.0
45.0
Height
Area
Rel.Area
mAU
mAU*min
%
12.949
12.201
61.83
4.105
3.968
20.11
1.790
2.368
12.00
0.819
1.197
6.06
19.664
19.734 100.00
A
For the tripeptide 1e, the corresponding enamine signals 1e-En and 1e-En’ were
observed in a poor signal-to-noise ratio. Nevertheless, the intermediate ratios
1e-En/1e-En’ were well reproducible.
[1e-En+H]+
m/z = 639
[1e-En+H]+
[1e-En’+H]+
m/z = 639
[1e-En’+H]+
m/z = 653
m/z = 653
Chr
Version 6
DEFAULT/Integration
77:23
75:25
S18
ESI-MS back reaction screening in DMSO with tripeptide ent-1b:
H
N
N
O
NH
O
NH 2
O
OH
ent-1b O
[ent-1b+H]+
100
m/z = 341
[ent-1b-En+H]+
O
m/z = 471
O
Ph
NO 2
H
[ent-1b-En’+H]+
Ph
NO 2
H
Bn
Bn
rel. Int.
m/z = 485
[ent-1b-Im]+
m/z = 620
[ent-1b-Im’]+
m/z = 634
0
0
0
79
30
m/z
Back reaction: 65 : 35 (En/En’) (ent-1b)
Operator:Administrator Timebase:Shimadzu Sequence:JD196
Forward reaction: 35 : 65 (1b)!
3
JD196_O_1
Sample Name:
JD196_O_1
Quantif. Method:
Recording Time:
Run Time (min):
line6-7
7.6.2013 17:46
60.00
Injection Volu
Channel:
Wavelength:
Bandwidth:
Dilution Facto
Sample Weig
Sample Amou
ESI-MS back reaction screening in 2,2,2-trifluoroethanol
Vial Number: with 22Hayashi-Jørgensen
Sample Type:
unknown
catalyst 3:
Control Program:
40%B_1,0mL_25C_60min_OD-H
OTMS
N
H Ph Ph
3
100
300
JD196 #3 [modified by Administrator]
mAU
JD196_O_1
2 - 31.558
[3+H]+
250
m/z = 326
O
200
Ph
NO 2
H
Bn
rel. Int.
150
[3-En’+H]+
m/z = 470
[3-En+H]+
m/z = 456
[3-Im]+
100
O
[3-Im’]+
m/z 605 m/z = 619
Ph
NO 2
H
50
Bn
3 - 40.108
1 - 27.800
0
Back reaction: 35 : 65 (En/En’)
0
m/z
79
30
0
0
-50
20.0
25.0
30.0
Forward
reaction:
2 : 98!
No.
1
2
3
4
Total:
Ret.Time
min
27.80
31.56
40.11
48.16
Peak Name
n.a.
n.a.
n.a.
n.a.
35.0
40.0
45.0
Height
Area
Rel.Area
mAU
mAU*min
%
6.809
6.600
1.81
264.150
S19 273.131 74.91
16.700
21.128
5.79
42.486
63.745
17.48
330.145 364.604 100.00
A
Operator:Administrator Timebase:Shimadzu Sequence:JD196
2
JD196_M_1
Sample Name:
JD196_M_1
ESI-MS back reaction screening in DMSO with Hayashi-Jørgensen
catalyst 3 and
Vial Number:
21
Sample Type:
unknown
p-nitrophenol (10 mol%):
Control Program:
40%B_1,0mL_25C_60min_OD-H
OTMS
+
N
H Ph Ph
O 2N
3
100
Quantif.
OH Method:
Recording Time:
Run Time (min):
(10 mol%)
300
[3+H]+
line6-7
7.6.2013 16:45
60.00
JD196 #2 [modified by Administrator]
mAU
250
m/z = 326
O
rel. Int.
Bn
150
100
[3-En+H]+
m/z = 456
NO 2
m/z = 619
m/z 605
JD196_M_1
2 - 31.533
Ph
H
+
200
[3-Im’]
[3-Im]+
Injection Volu
Channel:
Wavelength:
Bandwidth:
Dilution Facto
Sample Weig
Sample Amou
O
3 - 39.983
Ph
NO 2
H
[3-En’+H]+
Bn
50
m/z = 470
1 - 27.575
0
0
Operator:Administrator Timebase:Shimadzu Sequence:JD196
0
79
30
0
m/z
-50
Back reaction: 67 : 33 (En/En’)
20.0 reaction:
25.0 11 : 30.0
Forward
89!
4
JD196_N_1
No.
Ret.Time
min
1 Name:
27.58
Sample
2
31.53
Vial Number:
3
39.98
Sample Type:
4
48.15
Control Program:
Total:
Quantif.
Method:
OH
Recording Time:
Run Time (min):
35.0
40.0
45.0
Peak Name
Height
Area
Rel.Area A
mAU
mAU*min
%
n.a.
28.920
28.869 Injection
6.61Volum
JD196_N_1
n.a.
234.906 242.787 Channel:
55.63
23
n.a.
92.142 123.213
28.23
Wavelength:
unknown
n.a.
27.013
41.575
9.53
Bandwidth:
40%B_1,0mL_25C_60min_OD-H
382.981 436.443 100.00
Dilution Factor
line6-7
Sample Weigh
7.6.2013 18:48
Sample Amou
60.00
ESI-MS back reaction screening in DMSO with Hayashi-Jørgensen catalyst 3 and
p-nitrophenol (100 mol%):
OTMS
+
N
H Ph Ph
O 2N
3
100
(100 mol%)
600
[3+H]+
JD196 #4 [modified by Administrator]
mAU
2 - 31.650
500
m/z = 326
[3-Im’]+
O
Ph
400
[3-Im]+
m/z = 619
jd/Integration
rel. Int.
m/z 605
JD196_N_1
Chr
Version 6
NO 2
H
Bn
300
200
O
[3-En+H]+ [3-En’+H]+
m/z = 456
m/z = 470
Ph
NO 2
H
100
3 - 40.008
Bn
1 - 27.592
0
Back reaction: 57 : 43 (En/En’)
0
m/z
79
30
0
0
-100
20.0
25.0
Forward
reaction:
3 :30.0
97!
No.
1
2
3
4
Total:
Ret.Time
min
27.59
31.65
40.01
48.18
Peak Name
n.a.
n.a.
n.a.
n.a.
35.0
40.0
45.0
Height
Area
Rel.Area
mAU
mAU*min
%
19.751
17.540
2.35
500.942 523.799
70.14
106.006 138.037
18.48
44.861
67.431
9.03
S20
671.560 746.807 100.00
Am
Operator:Administrator Timebase:Shimadzu Sequence:JD196
1
JD196_L_1
ESI-MS back reaction screening in DMSO with Hayashi-Jørgensen catalyst 3 and
Sample Name:
JD196_L_1
Vial Number:
20
acetic acid (10 mol%):
OTMS
N
H Ph Ph
Sample Type:
Control Program:
Quantif. Method:
Recording Time:
Run Time (min):
O
+
OH
unknown
40%B_1,0mL_25C_60min_OD-H
line6-7
7.6.2013 15:43
60.00
(10 mol%)
3
220
Injection Volum
Channel:
Wavelength:
Bandwidth:
Dilution Factor:
Sample Weight
Sample Amoun
JD196 #1 [modified by Administrator]
mAU
100
JD196_L_1
2 - 31.500
[3+H]+
O
m/z = 326
Ph
NO 2
H
[3-Im’]+
Bn
150
m/z = 619
rel. Int.
[3-Im]+
m/z 605
3 - 39.975
100
O
[3-En+H]+
m/z = 456
Ph
NO 2
H
Bn
[3-En’+H]+
50
1 - 27.542
m/z = 470
4-
Operator:Administrator Timebase:Shimadzu Sequence:JD196
0
0
0
79
30
m/z
-20
20.0
Back reaction: 73 : 27 (En/En’)
25.0
30.0
Forward
14 : 86!
8 reaction:
JD196_P_1
No.
Ret.Time
min
1
27.54
2 Name:
31.50
Sample
39.98
Vial 3Number:
4 Type:
48.08
Sample
Total: Program:
Control
Peak Name
n.a.
n.a.
JD196_P_1
n.a.
13
n.a.
unknown
35.0
40.0
45.0
Height
Area
Rel.Area Am
mAU
mAU*min
%
29.500
30.191
7.88
182.543 187.755
49.02
Injection V
97.847 133.109
34.75
Channel:
20.791
31.938
8.34
Waveleng
330.681 382.993 100.00
Bandwidth
ESI-MS back reaction screening in DMSO with Hayashi-Jørgensen catalyst 3 and
acetic acid (100 mol%):
20%D_1,0mL_25C_60min_OD-H
OTMS
N
H Ph Ph
+
OH
700
JD196 #8 [modified by Administrator]
mAU
O
[3-Im’]+ jd/Integration
500
m/z = 456
JD196_P_1
2 - 29.992
Ph
Chrom
Version 6.8
NO 2
H
Bn
m/z = 619
[3-En+H]+
Dilution Fa
Sample W
Sample Am
line6-7
18.6.2013 10:55
60.00
600
[3+H]+
m/z = 326
rel. Int.
Quantif. Method:
Recording Time:
Run Time (min):
(100 mol%)
3
100
O
400
[3-En’+H]+
m/z = 470
[3-Im]+
m/z 605
300
O
200
3 - 39.217
Ph
NO 2
H
Bn
100
4 - 44.29
0
0
m/z
79
30
0
0
1 - 26.908
-100
Back reaction: 61 : 39 (En/En’)
25.0
30.0
Forward20.0reaction:
10 : 90!
No.
1
2
3
4
Total:
Ret.Time
min
26.91
29.99
39.22
44.29
Peak Name
n.a.
n.a.
n.a.
n.a.
35.0
40.0
45.0
Height
Area
Rel.Area
mAU
mAU*min
%
65.102
62.277
6.01
561.716 567.245
54.72
241.292 317.700
30.65
64.653
89.414
8.63
S21
932.763 1036.635 100.00
8. Reversibility of conjugate addition reactions
The reversibility of of the conjugate addition reaction was confirmed by a cross-over
1
experiment
using
H-NMR
spectroscopy.
The
γ-nitroaldehyde
2-ethyl-3-(4-methoxyphenyl)-4-nitrobutanal, resulting from the conjugate addition
reaction of butanal to trans-4-methoxy nitrostyrene was mixed with an equimolar
amount of nitrostyrene in the presence of 2 mol% of the catalyst 1a in a 9:1 mixture of
CDCl3:iPrOH d-9 and the reaction was followed by 1H-NMR spectroscopy. If the
reverse reaction takes place, the enamine resulting after C-C bond cleavage is expected
to preferentially react with nitrostyrene rather than the liberated 4-methoxy nitrostyrene,
because the former is not only present in a much higher concentration but also more
electrophilic than the latter.[8] Thus, it should be possible to monitor the back reaction
by the formation of free 4-methoxy nitrostyrene even if it only occurs to a small extent.
Indeed in this experiment the back reaction occurred and after an extended reaction time
of two weeks approximately 20 % conversion to the cross-over product and the free
4-methoxy nitrostyrene was observed together with epimerization of the γ-nitroaldehyde.
However, the back reaction was found to be a slow process since on the time scale of
the catalytic reaction (up to 48 h) the release of 4-methoxy nitrostyrene was determined
to be less than 5 %.
S22
S23
9. References
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
M. Wiesner, M. Neuburger, H. Wennemers, Chem. Eur. J. 2009, 15,
10103–10109.
M. Wiesner, H. Wennemers, Synthesis 2010, 2010, 1568–1571.
J. D. Revell, H. Wennemers, Adv. Synth. Catal. 2008, 350, 1046–1052.
J. Duschmalé, H. Wennemers, Chem. Eur. J. 2012, 18, 1111–1120.
H. Wennemers, J. Duschmale, M. Wiesner, J. Wiest, Chem. Sci. 2013, 4,
1312–1318.
C. A. Müller, A. Pfaltz, Angew. Chem. Int. Ed. 2008, 47, 3363–3366.
G. Satyanarayana, M. E. Maier, Tetrahedron 2012, 68, 1745–1749.
I. Zenz, H. Mayr, J. Org. Chem. 2011, 76, 9370–9378.
S24