Chiral 1,1′-bi(tetrahydroisoquinoline)-type diamines as efficient ligands for nickel-catalysed enantioselective Michael addition to nitroalkenes

Article abstract of DOI:10.1002/ejoc.201100488

A chiral C₂-symmetric 1,2-diamine based on a 1,1′-bi(tetrahydroisoquinoline) scaffold was found to be an efficient ligand for the enantioselective Ni^II-catalysed Michael addition of malonic esters to conjugated nitroalkenes. The reac

Full text of DOI:10.1002/ejoc.201100488

FULL PAPER
DOI: 10.1002/ejoc.201100488
Chiral 1,1Ј-Bi(tetrahydroisoquinoline)-Type Diamines as Efficient Ligands for
Nickel-Catalysed Enantioselective Michael Addition to Nitroalkenes
Kristina Wilckens,[a] Marcel-Antoine Duhs,[a] Dieter Lentz,[a][‡] and Constantin Czekelius*[a]
Keywords: Asymmetric catalysis / Michael addition / Nitroalkenes / N ligands / Noncovalent interactions
A chiral C2-symmetric 1,2-diamine based on a 1,1Ј-bi(tetra- even at elevated temperatures. The solid-state structure of
hydroisoquinoline) scaffold was found to be an efficient li-
gand for the enantioselective NiII-catalysed Michael addition
of malonic esters to conjugated nitroalkenes. The reactions
proceed with 92–99% yield and 91–99% enantioselectivity
the catalyst precursor revealed intramolecular π–π stacking
as well as supramolecular halogen···halogen bonding inter-
actions.
gands.[8c] In recent publications, the potential of 1,1Ј-biiso-
quinoline (BIQ) as well as mono-isoquinoline (MIQ) de-
rived N-heterocyclic carbene ligands for asymmetric cataly-
sis has been demonstrated.[9]
Introduction
The development of methods for the efficient construc-
tion of chiral compounds constitutes a major goal in mod-
ern synthetic chemistry.[1] Great achievements in the field of
asymmetric catalysis have led to the establishment of several
privileged chiral catalysts and ligand classes.[2] Such ligands
typically combine a flexible and economically feasible syn-
thetic route, enhanced thermal stability, strong binding to
the metal centre, together with excellent enantioselectivities
for a variety of mechanistically diverse reactions. Although
an increasing number of highly successful applications of
monodentate and C1-symmetric ligands have been reported,
a plethora of ligands showing bidentate binding of the
metal and a C2-symmetric ligand scaffold have proven to be
robust and efficient in catalytic processes to achieve excel-
lent stereocontrol for a broad range of substrates.[3,4] Chiral
diphosphanes and diols, such as BINAP,[5a] DuPhos,[5b] and
BINOL,[5c] or bis-oxazoline ligands[5d] serve as examples in
this context. In addition, vicinal diamines represent another
versatile stereochemical control element for ligand design,
for example, in the highly successful class of salen-type li-
gands.[6] Most systems that are used in this respect employ
readily available trans-1,2-diaminocyclohexane (DACH; 1)
or 1,2-diphenylethane-1,2-diamine (DPEN; 2) derivatives
(Figure 1). A further increase of rigidity of DPEN-derived
ligands was exemplified by the incorporation of two phenyl
groups into a 1,1Ј-bi(isoindoline) moiety, such as in ligand
4.[7] However, despite straightforward synthetic access to
structurally related, chiral 1,1Ј-bi(tetrahydroisoquinol-
ines),[8] such diamines have rarely been utilised as chiral li-
Figure 1. Chiral diamine ligands: trans-1,2-diaminocyclohexane
(DACH; 1), 1,2-diphenylethane-1,2-diamine (DPEN; 2), benzyl-
ated diaminocyclohexanes (3), and 1,1Ј-biisoindoline (4).
In the course of our earlier studies on the enantioselec-
tive gold-catalysed desymmetrisation of 1,4-diynes,[10] we
recently reported the preparation of chiral gold carbene
complexes 5 based on a 1,1Ј-bi(tetrahydroisoquinoline)
scaffold (Figure 2).[11]
[a] Institut für Chemie und Biochemie, Freie Universität Berlin,
14195 Berlin, Germany
Fax: +49-30838-53625
E-mail: cczekeli@chemie.fu-berlin.de
[‡] X-ray crystal structure determination
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100488.
Figure 2. Sterically highly encumbered gold carbene complexes.
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5441
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C. Czekelius et al.
FULL PAPER
The synthetic sequence used to obtain the core of the
sterically encumbered carbene complexes 5 was inspired by
a procedure published by Herrmann and co-workers.[9b] By
a modification of the reported synthesis, C2-symmetric di-
amine 8 was prepared utilising a reductive coupling of 3,4-
dihydroisoquinoline 7 with Zn/TMSCl in acetonitrile as a
key step (Scheme 1).[8a,12]
Figure 3. Nickel complexes bearing one and two chiral diamine li-
gands (HIPT = hexaisopropylterphenyl).
(12a) as a benchmark test for our new catalyst (Table 1). In
initial studies with complex 9 no conversion, not even at
higher temperatures, was observed.[14] This was presumably
due to an enhanced stability of 9, which results in insuf-
ficient ligand dissociation and substrate binding (vide in-
fra). However, the addition of an equimolar amount of N-
methylmorpholine (NMM) as additive allowed the reaction
to proceed. After two hours at 80 °C, the addition product
was isolated in quantitative yield and with very good en-
antiopurity (97% ee; Table 1, entry 1 vs. 2). 2-Substituted
malonates were not suitable substrates, resulting in either
low or no conversion (Table 1, entries 3 and 4). The applica-
tion of catalyst 10 resulted in a very similar outcome, but
could be improved by reducing the quantity of the basic
additive to catalytic amounts (5 mol-%) of either NMM or
triethylamine (TEA; Table 1, entries 7 and 8). This indicates
that, under the reaction conditions, complexes 9 and 10
serve as precursors for either the same or a closely related
catalytically active species. This assumption is supported by
the finding that both transformations proceed with very
similar reaction rates irrespective of the type or amount of
base used.
Scheme 1. Stereoselective synthesis of 1,1Ј-bi(tetrahydroisoquin-
oline) 8.
Remarkably, in this step, 8 is formed as a single dia-
stereoisomer, which is in agreement with observations by
Herrmann and co-workers. Overall, 8 was obtained from
chiral phenylethylamine precursor 6 in a yield of 50% over
three steps. As shown in earlier studies, the para-bromo sub-
stituent can be readily modified by means of palladium-
catalysed Suzuki cross-coupling, employing suitable bor-
onic acid coupling partners.[11] This late-stage derivatization
enables easy variation of the steric demand of ligand 8.
In this publication, we wish to report our initial results
using chiral, 3,3Ј-disubstituted 1,1Ј-bi(tetrahydroisoquinol-
ines) as efficient ligands for asymmetric catalysis. This ap-
proach was exemplified in a nickel-catalysed asymmetric
Michael addition of malonates to nitroalkenes.[13]
Table 1. Nickel-catalysed malonate addition to nitrostyrene; appli-
cation of complexes 9 and 10.[a]
Results and Discussion
In addition to using diamine 8 as a precursor for the
generation of NHC ligands, we became interested in evalu-
ating its performance as a chiral diamine ligand itself in
transition-metal-mediated processes. Related structural mo-
tifs (i.e., 3[13c] and 4[7]) have been reported for asymmetric
nickel-catalysed Michael addition reactions (Figure 1). Due
to the higher structural rigidity of diamine 8, we anticipated
that, even at elevated temperatures, the corresponding
nickel complex might perform well in such transformations.
Therefore, we synthesised nickel complexes 9–11, bearing
one and two ligands, from the corresponding diamines by
reaction with NiBr2 in refluxing acetonitrile following pub-
lished procedures (Figure 3).[13c]
Entry
R
Base
Yield [%]
ee [%][e]
1[b]
2[b]
3[b]
4[b]
5[c]
6[c]
7[c]
8[c]
9[d]
10[g]
H (13a)
H (13a)
Ph (13b)
Bn (13c)
H (13a)
H (13a)
H (13a)
H (13a)
H (13a)
H (13a)
–
–
–
97
–
n.d.
93
92
97
97
96
90
NMM (1 equiv.)
NMM (1 equiv.)
NMM (1 equiv.)
NMM (1 equiv.)
TEA (1 equiv.)
NMM (5 mol-%)
TEA (5 mol-%)
NMM (5 mol-%)
NMM (5 mol-%)
quant. (R-14a)
–
18 (R-14b)[f]
99 (R-14a)
99 (R-14a)
97 (R-14a)
99 (R-14a)
93 (R-14a)
99 (R-14a)
[a] Reagents and conditions: catalyst (2 mol-%), toluene, 80–90 °C,
2 h. [b] Complex 9 was employed as catalyst. [c] Complex 10 was
employed as catalyst. [d] Complex 11 was employed as catalyst. [e]
The enantiomeric excess was determined by chiral HPLC analysis
(ChiralPak IA). [f] Conversion was determined by 1H NMR analy-
sis of the crude reaction mixture. [g] The reaction was carried out
Evans and co-workers found the bis(diamine) nickel
complexes from 3 to perform well as efficient catalysts for
the addition of malonates to nitroalkenes.[13c] Therefore, we
chose the addition of diethyl malonate (13a) to nitrostyrene at 120 °C.
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Eur. J. Org. Chem. 2011, 5441–5446

Enantioselective Michael Addition to Nitroalkenes
Given the elevated reaction temperature (80 °C), it is
A deeper insight into the catalyst structure was gained
noteworthy that the enantioselectivities are among the high- by X-ray analysis of the pale-blue single crystals of complex
est that have been observed for this transformation. In fact, 9, which were obtained by slow crystallization at –20 °C
even at 120 °C, the enantiomeric excess was still 90% from a saturated acetonitrile/dichloromethane solution
(Table 1, entry 10). In comparison, Evans and co-workers (Figure 4). The geometry of 9 is consistent with those of
reported a significant attenuation of selectivity when the related known complexes.[7,13] Inspection of the elementary
bis(diamine)-nickel complex from 3b was employed at cell reveals a stair-like, octahedral geometry with the two
higher temperature (89% ee at 80 °C vs. 95% ee at room ligating bromine atoms in the apical positions of the central
temp.).[13c] We assume that the findings mentioned above nickel atom. Furthermore, a clear π-stacking interaction be-
might be traced back to the additional 4-bromophenyl side- tween the para-bromophenyl rings of the two diamine li-
chain and to the high rigidity of the ligand scaffold, which gands is evident, because these moieties are orientated in
leads to improved stereocontrol in the Michael addition. an exactly parallel, staggered conformation, with the closest
The use of sterically more demanding complex 11 did not contacts between the two rings being 3.35 Å. This observa-
result in any improvement in stereoselectivity (Table 1, en- tion may help to explain the inability of complex 9 to per-
try 9).[11]
form adequately as a catalyst for the Michael addition in
To evaluate the substrate scope with respect to the the absence of additives. This behaviour contrasts with that
Michael acceptor, various substituted arylnitroalkenes were of the related catalyst incorporating ligand 3, which is em-
investigated under the same conditions described above ployed as a bis(diamine)-nickel complex.[13c] For complex 9,
(Table 2). For all of the investigated substrates, excellent diamine ligand dissociation and subsequent substrate bind-
yields (92–99%) and enantioselectivities (91–99%) were ob- ing would only occur at the energetic cost of the π-stacking
tained by applying nickel diamine complex 10.
interaction and may therefore be disfavoured. In the solid
state, complex 9 shows a 2D layer motif stabilized by type II
halogen bonds with a Ni–Br···Br–C distance of 3.433 Å.
Table 2. Nickel-catalysed Michael addition of malonates to aro-
matic nitroalkenes.[a]
Entry R1
R2
Yield [%]
ee [%][b]
1
2
3
4
5
6
7
8
9
10
Ph (12a)
Ph (12a)
Et (13a)
Me (13d) 97 (R-14c)
Et (13a)
97 (R-14a)
97
97
95
91
97
99
97
96
92
97
4-MeO-C6H4 (12b)
2,4-(MeO)2-C6H3 (12c) Et (13a)
4-Cl-C6H4 (12d)
2-Cl-C6H4 (12e)
2-furyl (12f)
2,4-(Me)2-C6H3 (12g)
trans-PhCH=CH (12h) Et (13a)
1-naphthyl (12i) Et (13a)
94 (R-14d)
95 (R-14e)
99 (R-14f)
97 (R-14g)
98 (S-14h)
96 (R-14i)
98 (R-14j)
92 (R-14k)
Et (13a)
Et (13a)
Et (13a)
Et (13a)
Figure 4. Crystal structure of bis(diamine)-nickel complex 9 (Dia-
[a] Reagents and conditions: 13 (1.2 equiv.), 10 (2 mol-%), NMM
(5 mol-%), toluene (0.25 m), 80 °C, 1.5–7 h. [b] Enantiomeric excess
was determined by chiral HPLC analysis (Chiralpak IA or Chi-
ralpak IB).
mond 3.1[16]).
Conclusions
Huang and Xia reported that the use of sterically hin-
A chiral diamine ligand incorporating a 3,3Ј-disubsti-
dered tert-butyl malonate was necessary to obtain the high- tuted 1,1Ј-bi(tetrahydroisoquinoline) scaffold was success-
est selectivity employing a nickel catalyst incorporating di- fully employed in the nickel-catalysed addition of malonic
amine 4.[7] In contrast, using catalyst 10, ethyl (13a) and esters to various nitroolefins. The addition reactions pro-
methyl malonate (13d) also provided the corresponding ceed with excellent yields (92–99%) and enantioselectivities
products in very high selectivity (97% ee; Table 2, entries 1 (91–99% ee) even at elevated temperatures. Herein, the
and 2).[15]
choice of the appropriate base (N-methylmorpholine)
It should be pointed out that, in agreement with Evans’ proved to be essential for highest selectivity. Structural
findings, complexes of ligand 4 with other metals have analysis of nickel complex 9 permitted insights into the
proven to be inferior to the nickel catalysts. In test reac- putative catalyst structure and revealed both aromatic π-
tions, magnesium bromide, zinc chloride and copper(II) stacking interactions as well as close bromine–bromine in-
chloride complexes all showed incomplete conversion to teractions. Further studies aimed at various applications of
product 14a even after four days at 80 °C (80, 45, and 0% the new chiral and highly rigid diamine ligand class are un-
conversion, respectively).
derway and will be reported in due course.
Eur. J. Org. Chem. 2011, 5441–5446
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C. Czekelius et al.
FULL PAPER
18.2 min [(S)-14a]; ee = 97%. 1H NMR (400 MHz, CDCl3): δ =
1.04 (t, J = 6.8 Hz, 3 H, CO2CH2CH3), 1.26 (t, J = 6.8 Hz, 3 H,
CO2CH2CH3), 3.82 [d, J = 9.5 Hz, 1 H, (CO2Et)2CH], 4.01 (q, J =
6.9 Hz, 2 H, CO2CH2CH3), 4.15–4.31 (m, 3 H, CO2CH2CH,
CHCH2), 4.79–5.00 (m, 2 H, CHCH2), 6.77–6.99 (m, 5 H,
ArH) ppm. [α]2D5 = –8.8 (c = 1.0, CHCl3). The absolute configura-
tion was assigned as (R) by comparison of the optical rotation with
the reported literature value: ref.[13c] [α]2D5 = +7.3 (c = 1.07, CHCl3)
[95% ee, (S)-enantiomer]. The spectroscopic data corresponded to
those reported in the literature.[17]
Experimental Section
General Remarks: Chemicals were purchased from commercial sup-
pliers and used without further purification unless otherwise noted.
All reactions were performed under an argon atmosphere in pre-
dried glassware. Flash chromatography was carried out using
Merck silica gel 60 (0.040–0.063 mm). 1H and 13C NMR spectra
were recorded at room temperature with a Bruker AC 250, JOEL
ECX 400, JOEL Eclipse 500, or Bruker Advance 3 (700 MHz)
spectrometer. Enantiomeric ratios were determined with a Hitachi
LaChrome HPLC System using hexane/2-propanol as eluents with
Chiralpak IA or Chiralpak IB columns and UV as well as refrac-
tive index (RI) detection. Optical rotation values were measured
with a Perkin–Elmer 241 polarimeter, a concentration of c = 1.0
represents 10 mg per mL of solvent. Melting points (m.p.) were
determined with a Büchi 510 apparatus and are uncorrected. High-
resolution mass spectra (HRMS) were determined with an Agilent
6210 ESI-TOF MS instrument; flow rate: 4 μL/min; spray voltage
4 kV, and the desolvation gas set to 15 psi. All other parameters
were optimized for maximal abundance of [M + H]+ or [M + Na]+.
IR spectra were recorded with a JASCO 6200 FTIR spectrometer.
(R)-Dimethyl 2-(2-Nitro-1-phenylethyl)malonate (14c): trans-β-Ni-
trostyrene (12a; 74.6 mg, 500 μmol) dimethyl malonate (13d;
1.2 equiv., 79.3 mg, 600 μmol, 69.0 μL), NMM (0.05 equiv., 2.5 mg,
25.0 μmol, 2.7 μL), and nickel complex 10 (0.02 equiv., 7.9 mg,
10.0 μmol) in toluene (2 mL) were reacted according to GP1 for
3 h at 80 °C. After cooling to room temperature, the reaction mix-
ture was directly purified by column chromatography on silica gel
(hexane/EtOAc, 5:1) to obtain the title compound 14c as a colour-
less oil (136.5 mg, 485 μmol, 97%). HPLC (column IA, 254 nm; n-
hexane/iPrOH, 80:20; flow: 1.0 mL/min): Rt = 9.0 [(R)-14c],
12.0 min [(S)-14c]; ee = 97%. 1H NMR (400 MHz, CDCl3): δ
(ppm) = 3.56 (s, 3 H, OMe), 3.76 (s, 3 H, OMe), 3.87 [d, J = 9.4 Hz,
(CO2Me)2CH], 4.25 (ddd, J = 9.0, 9.0, 5.2 Hz, CHCH2), 4.99 (dd,
J = 13.2, 8.9 Hz, 1 H, CHCH2,b), 4.94 (dd, J = 13.1, 5.3 Hz, 1 H,
CHCH2,a), 7.19–7.37 (m, 5 H, ArH) ppm. [α]2D5 = –7.8 (c = 0.77,
CHCl3). The absolute configuration was assigned as (R) by com-
parison of the optical rotation with the reported literature value:
ref.[13c] [α]2D5 = +6.2 (c = 1.38, CHCl3) [94% ee, (S)-enantiomer].
The spectroscopic data corresponded to those reported in the lit-
erature.[13c]
Synthesis of Diamine-Nickel Complexes
Bis(diamine)-Nickel Complex 9: A mixture of nickel(II) bromide
(19.0 mg, 87.1 μmol) and diamine 8 (100 mg, 174 μmol) in acetoni-
trile (5 mL) was heated for 5 h at reflux. The solvent was removed
by distillation and the residue was dissolved in dichloromethane
(8 mL). After filtration through a glass frit (porosity 4) the solvent
was removed in vacuo and the nickel complex was obtained as a
brown solid (211 mg, 154 μmol, 89%).
Diamine-Nickel Complex 10: A mixture of nickel(II) bromide
(57.1 mg, 261 μmol) and diamine 8 (150 mg, 261 μmol) in acetoni-
trile (3 mL) was heated for 3 h at reflux. The solvent was removed
by distillation and the residue was dissolved in dichloromethane
(5 mL). After filtration through a glass frit (porosity 4), the solvent
was removed in vacuo and the nickel complex was obtained as a
brown solid (204 mg, 257 μmol, 98%).
(R)-Diethyl 2-[1-(4-Methoxyphenyl)-2-nitroethyl]malonate (14d):
Nitrostyrene 12b (89.6 mg, 500 μmol), diethyl malonate (13a;
1.2 equiv., 96.1 mg, 600 μmol, 90.7 μL), NMM (0.05 equiv., 2.5 mg,
25.0 μmol, 2.7 μL), and nickel complex 10 (0.02 equiv., 7.9 mg,
10.0 μmol) in toluene (2 mL) were reacted according to GP1 for
6 h at 80 °C. After cooling to room temperature, the reaction mix-
ture was directly purified by column chromatography on silica gel
(hexane/EtOAc, 5:1) to obtain the title compound 14d as a colour-
less oil (159.5 mg, 470 μmol, 94%). HPLC (column IA, 254 nm; n-
hexane/iPrOH, 70:30; flow: 0.7 mL/min): Rt = 12.2 [(R)-14d],
36.4 min [(S)-14d]; ee = 95%. 1H NMR (400 MHz, CDCl3): δ =
1.07 (t, J = 7.0 Hz, 3 H, CO2CH2CH3), 1.27 (t, J = 7.0 Hz, 3 H,
CO2CH2CH3), 3.72–3.81 [m, 4 H, OMe, (CO2Et)2CH], 4.02 (q, J
= 7.2 Hz, 2 H, CO2CH2CH3), 4.14–4.28 (m, 3 H, CO2CH2CH,
CHCH2), 4.80 (dd, J = 13.6, 9.2 Hz, 1 H, CHCH2,b), 4.89 (dd, J =
13.0, 4.8 Hz, 1 H, CHCH2,a), 6.82 (d, J = 9.2 Hz, 2 H, ArH), 7.15
(d, J = 9.2 Hz, 2 H, ArH) ppm. [α]2D5 = –7.0 (c = 1.0, CHCl3). The
absolute configuration was assigned as (R) by comparison of the
Diamine-Nickel Complex 11: A mixture of nickel(II) bromide
(15.9 mg, 72.6 μmol) and HIPT-diamine 8-HIPT (100 mg,
72.6 μmol) in acetonitrile (3 mL) was heated for 3 h at reflux. The
solvent was removed by distillation and the residue was dissolved
in dichloromethane (3 mL). After filtration through a glass frit (po-
rosity 4) the solvent was removed in vacuo and the nickel complex
was obtained as a brown solid (110 mg, 68.6 μmol, 95%).
Asymmetric Ni-Catalysed 1,4-Addition Reactions
General Procedure for the Ni-Catalysed 1,4-Addition of Malonates
to Nitroalkenes (GP1): The corresponding nitroalkene in toluene
(4 mL/mmol substrate) was treated with the respective malonate
(1.2–2.0 equiv.), the nickel catalyst (2 mol-%), and suitable base
(0.05–1.0 equiv.). The mixture was stirred for the denoted time at
the stated temperature before being directly purified by column
chromatography on silica gel (hexane/EtOAc).
optical rotation with the reported literature value: ref.[13c] [α]2D5
=
+7.7 (c = 1.01, CHCl3) [95% ee, (S)-enantiomer]. The spectroscopic
data corresponded to those reported in the literature.[13c]
(R)-Diethyl 2-[1-(2,4-Dimethoxyphenyl)-2-nitroethyl]malonate (14e):
Nitrostyrene 12c (105 mg, 500 μmol), diethyl malonate (13a;
1.2 equiv., 96.1 mg, 600 μmol, 90.7 μL), NMM (0.05 equiv., 2.5 mg,
(R)-Diethyl 2-(2-Nitro-1-phenylethyl)malonate (14a): trans-β-Nitro-
styrene (12a; 74.6 mg, 500 μmol), diethyl malonate (13a; 1.2 equiv.,
96.1 mg, 600 μmol, 90.7 μL), NMM (0.05 equiv., 2.5 mg, 25.0 μmol, 2.7 μL), and nickel complex 10 (0.02 equiv., 7.9 mg,
25.0 μmol, 2.7 μL), and nickel complex 10 (0.02 equiv., 7.9 mg, 10.0 μmol) in toluene (2 mL) were reacted according to GP1 for
10.0 μmol) in toluene (2 mL) were reacted according to GP1 for 24 h at 80 °C. After cooling to room temperature, the reaction mix-
2 h at 80 °C. After cooling to room temperature, the reaction mix-
ture was directly purified by column chromatography on silica gel
(hexane/EtOAc, 5:1) to obtain the title compound 14a as a colour-
less oil (150.4 mg, 486 μmol, 97%). HPLC (column IA, 254 nm; n-
hexane/iPrOH, 80:20; flow: 1.0 mL/min): Rt = 8.7 [(R)-14a],
ture was directly purified by column chromatography on silica gel
(hexane/EtOAc, 6:1) to obtain the title compound 14e as a colour-
less oil (176 mg, 476 μmol, 95%). HPLC (column IA, 215 nm; n-
hexane/iPrOH, 75:25; flow: 0.8 mL/min): Rt = 7.86 [(R)-14e],
11.7 min [(S)-14e]; ee = 91%. 1H NMR (400 MHz, CDCl3): δ =
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Enantioselective Michael Addition to Nitroalkenes
1.03 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 1.27 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 4.21 (q, J = 7.1 Hz, 2 H, CO2CH2CH3), 4.34–4.40
CO2CH2CH3), 3.76 (s, 3 H, OMe), 3.84 (s, 3 H, OMe), 3.69 (q, J
(m, 1 H, CHCH2), 4.87 (dd, J = 11.5, 3.3 Hz, 1 H, CHCH2,b), 4.91
= 7.1 Hz, 2 H, CO2CH2CH3), 4.11 [d, J = 10.3 Hz, 1 H, (CO2- (dd, J = 11.5, 6.2 Hz, 1 H, CHCH2,a), 6.21 (d, J = 3.3 Hz, 1 H,
Et)2CH], 4.17–4.32 (m, 3 H, CO2CH2CH3, CHCH2), 4.82 (dd, J = ArH), 6.28 (dd, J = 1.9, 3.3 Hz, 1 H, ArH), 7.33 (dd, J = 0.8,
12.7, 4.5 Hz, 1 H, CHCH2,a), 4.98 (dd, J = 12.7, 9.6 Hz, 1 H,
CHCH2,b), 6.38 (dd, J = 8.3, 2.4 Hz, 1 H, ArH), 6.42 (d, J =
2.4 Hz, 1 H, ArH), 7.04 (d, J = 8.3 Hz, 2 H, ArH) ppm. The abso-
lute configuration was assigned as (R) by analogy. The spectro-
scopic data corresponded to those reported in the literature.[13c]
1.9 Hz, 1 H, ArH) ppm. The absolute configuration was assigned
as (S) by analogy. The spectroscopic data corresponded to those
reported in the literature.[13c]
(R)-Diethyl 2-[1-(2,4-Dimethylphenyl)-2-nitroethyl]malonate (14i):
Nitrostyrene 12g (88.6 mg, 500 μmol), diethyl malonate (13a;
1.2 equiv., 96.1 mg, 600 μmol, 90.7 μL), NMM (0.05 equiv., 2.5 mg,
(R)-Diethyl 2-[1-(4-Chlorophenyl)-2-nitroethyl]malonate (14f): Ni-
trostyrene 12d (91.8 mg, 500 μmol), diethyl malonate (13a; 25.0 μmol, 2.7 μL), and nickel complex 10 (0.02 equiv., 7.9 mg,
1.2 equiv., 96.1 mg, 600 μmol, 90.7 μL), NMM (0.05 equiv., 2.5 mg,
25.0 μmol, 2.7 μL), and nickel complex 10 (0.02 equiv., 7.9 mg,
10.0 μmol) in toluene (2 mL) were reacted according to GP1 for
4 h at 80 °C. After cooling to room temperature, the reaction mix-
10.0 μmol) in toluene (2 mL) were reacted according to GP1 for ture was directly purified by column chromatography on silica gel
4 h at 80 °C. After cooling to room temperature, the reaction mix-
ture was directly purified by column chromatography on silica gel
(hexane/EtOAc, 5:1) to obtain the title compound 14f as a colour-
less oil (169.4 mg, 493 μmol, 99%). HPLC (column IA, 254 nm; n-
hexane/iPrOH, 80:20; flow: 1.0 mL/min): Rt = 11.9 [(R)-14f],
35.9 min [(S)-14f]; ee = 97%. 1H NMR (400 MHz, CDCl3): δ =
(hexane/EtOAc, 5:1) to obtain the title compound 14i as a colour-
less oil (161.6 mg, 493 μmol, 99%). HPLC (column IA, 254 nm; n-
hexane/iPrOH, 80:20; flow: 1.0 mL/min): Rt
= 5.4 [(R)-14i],
13.1 min [(S)-14i]; ee = 96%. 1H NMR (400 MHz, CDCl3): δ =
1.02 (t, J = 7.2 Hz, 3 H, CO2CH2CH3), 1.26 (t, J = 7.2 Hz, 3 H,
CO2CH2CH3), 2.24 (s, 3 H, Ar-CH3), 2.38 (s, 3 H, Ar-CH3), 3.77
1.08 (t, J = 7.2 Hz, 3 H, CO2CH2CH3), 1.26 (t, J = 7.1 Hz, 3 H, [d, J = 9.6 Hz, 1 H, (CO2Et)2CH], 3.98 (mc, 2 H, CO2CH2CH3),
CO2CH2CH3), 3.79 [d, J = 9.1 Hz, 1 H, (CO2Et)2CH], 4.03 (q, J = 4.22 (mc, 2 H, CO2CH2CH3), 4.51 (ddd, J = 9.2, 9.2, 5.0 Hz, 1 H,
7.2 Hz, 2 H, CO2CH2CH3), 4.23 (mc, 3 H, CO2CH2CH, CHCH2,a), CHCH2), 4.80 (dd, J = 12.7, 8.8 Hz, 2 H, CHCH2,b), 6.92–7.04 (m,
4.83 (dd, J = 13.2, 9.3 Hz, 1 H, CHCH2,b), 4.92 (dd, J = 13.2,
4.7 Hz, 1 H, CHCH2,a), 7.20 (d, J = 8.4 Hz, 2 H, ArH), 7.30 (d, J
= 8.5 Hz, 2 H, ArH) ppm. [α]2D5 = –8.7 (c = 1.0, CHCl3). The abso-
lute configuration was assigned as (R) by comparison of the optical
rotation with the reported literature value: ref.[18] [α]2D5 = –8.56 (c =
1.02, CHCl3) [Ͼ 99% ee, (R)-enantiomer]. The spectroscopic data
corresponded to those reported in the literature.[13c]
3 H, ArH) ppm. 13C NMR (100.5 MHz, CDCl3): δ = 13.75, 14.05
(CO2CH2CH3), 19.49, 21.01 (2ϫAr-CH3), 37.61 (CHCH2), 54.90
[(CO2Et)2CH], 61.87, 62.18 (CO2CH2CH3), 77.79 (CHCH2), 126.0,
127.2, 131.6, 132.0, 136.8, 137.7 (C-Ar), 167.1, 167.8
(2ϫC=O) ppm. HRMS (ESI): calcd. for C17H23NNaO6+ 360.1418;
found 360.1427. [α]2D5 = –2.9 (c = 1.0, CHCl3). The absolute config-
uration was assigned as (R) by analogy.
(R)-Diethyl 2-[1-(2-Chlorophenyl)-2-nitroethyl]malonate (14g): Ni-
trostyrene 12e (91.8 mg, 500 μmol), diethyl malonate (13a;
1.2 equiv., 96.1 mg, 600 μmol, 90.7 μL), NMM (0.05 equiv., 2.5 mg,
25.0 μmol, 2.7 μL), and nickel complex 10 (0.02 equiv., 7.9 mg,
(R)-Diethyl 2-[2-Nitro-1-(1-styryl)ethyl]malonate (14j): Nitroalkene
12h (87.6 mg, 500 μmol), diethyl malonate (13a; 1.2 equiv., 96.1 mg,
600 μmol, 90.7 μL), NMM (0.05 equiv., 2.5 mg, 25.0 μmol, 2.7 μL),
and nickel complex 10 (0.02 equiv., 7.9 mg, 10.0 μmol) in toluene
10.0 μmol) in toluene (2 mL) were reacted according to GP1 for (2 mL) were reacted according to GP1 for 6 h at 80 °C. After cool-
6 h at 80 °C. After cooling to room temperature, the reaction mix-
ture was directly purified by column chromatography on silica gel
(hexane/EtOAc, 6:1) to obtain the title compound 14g as a colour-
less oil (168.4 mg, 490 μmol, 97%). HPLC (column IA, 215 nm; n-
hexane/iPrOH, 75:25; flow: 0.8 mL/min): Rt = 6.75 [(R)-14g],
21.6 min [(S)-14g]; ee = 99%. 1H NMR (400 MHz, CDCl3): δ =
ing to room temperature, the reaction mixture was directly purified
by column chromatography on silica gel (hexane/EtOAc, 6:1) to
obtain the title compound 14j as a colourless oil (165.0 mg,
495 μmol, 98%). HPLC (column IB, 215 nm; n-hexane/iPrOH,
98:2; flow: 1.0 mL/min): Rt = 7.86 [(R)-14j], 11.7 min [(S)-14j]; ee
= 92%. 1H NMR (400 MHz, CDCl3): δ = 1.23 (t, J = 7.1 Hz, 3 H,
1.10 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 1.23 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 1.27 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 3.66 [d, J
CO2CH2CH3), 4.03–4.09 [m, 3 H, CO2CH2CH3, (CO2)2CH], 4.15– = 7.3 Hz, 1 H, (CO2)2CH], 3.70–3.78 (m, 1 H, CHCH2), 4.15–4.27
4.24 (m, 2 H, CO2CH2CH), 4.74 (mc, 1 H, CHCH2), 4.94 (dd, J =
13.5, 4.4 Hz, 1 H, CHCH2,b), 5.09 (dd, J = 13.5, 8.5 Hz, 1 H,
(m, 4 H, CO2CH2CH3), 4.69 (dd,
CHCH2,b), 4.76 (dd, J = 12.7, 5.0 Hz, 1 H, CHCH2,a), 6.21 (dd, J
J = 8.14, 12.6 Hz, 1 H,
CHCH2,a), 7.20–7.27 (m, 3 H, ArH), 7.37–7.42 (m, 1 H, ArH) ppm. = 15.8, 9.2 Hz, 1 H, Ar-CH=CH), 6.58 (d, J = 15.8 Hz, 1 H, Ar-
The absolute configuration was assigned as (R) by analogy. The
spectroscopic data corresponded to those reported in the litera-
ture.[13c]
CH), 7.22–7.34 (m, 5 H, ArH) ppm. The absolute configuration
was assigned as (R) by analogy. The spectroscopic data corre-
sponded to those reported in the literature.[13c]
(S)-Diethyl 2-[1-(2-Furyl)-2-nitroethyl]malonate (14h): Nitroalkene (R)-Diethyl 2-[1-(Naphth-1-yl)-2-nitroethyl]malonate (14k): Nitro-
12f (69.6 mg, 500 μmol), diethyl malonate (13a; 1.2 equiv., 96.1 mg, alkene 12i (99.6 mg, 500 μmol), diethyl malonate (13a) (1.2 equiv.,
600 μmol, 90.7 μL), NMM (0.05 equiv., 2.5 mg, 25.0 μmol, 2.7 μL),
and nickel complex 10 (0.02 equiv., 7.9 mg, 10.0 μmol) in toluene
(2 mL) were reacted according to GP1 for 6 h at 80 °C. After cool-
ing to room temperature, the reaction mixture was directly purified
by column chromatography on silica gel (hexane/EtOAc, 6:1) to
obtain the title compound 14h as a colourless oil (148.0 mg,
96.1 mg, 600 μmol, 90.7 μL), NMM (0.05 equiv., 2.5 mg,
25.0 μmol, 2.7 μL), and nickel complex 10 (0.02 equiv., 7.9 mg,
10.0 μmol) in toluene (2 mL) were reacted according to GP1 for
4 h at 80 °C. After cooling to room temperature, the reaction mix-
ture was directly purified by column chromatography on silica gel
(hexane/EtOAc, 5:1) to obtain the title compound 14k as a colour-
495 μmol, 98%). HPLC (column IA, 215 nm; n-hexane/iPrOH, less oil (165.3 mg, 460 μmol, 92%). HPLC (column IA, RI; n-hex-
75:25; flow: 0.8 mL/min): Rt = 7.42 [(S)-14h], 8.57 min [(R)-14h];
ane/iPrOH, 80:20; flow: 1.0 mL/min): Rt = 8.3 [(R)-14k], 20.0 min
1
ee = 97%. H NMR (400 MHz, CDCl3): δ = 1.19 (t, J = 7.1 Hz, [(S)-14k]; ee = 97%. 1H NMR (400 MHz, CDCl3): δ = 1.07 (t, J =
3 H, CO2CH2CH3), 1.25 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 3.89 7.1 Hz, 3 H, CO2CH2CH3), 1.22 (t, J = 7.0 Hz, 3 H, CO2CH2CH3),
[d, J = 7.9 Hz, 1 H, (CO2)2CH], 4.13 (q, J = 7.1 Hz, 2 H,
3.96 (mc, 2 H, CO2CH2CH3), 4.08 [d, J = 8.6 Hz, 1 H, (CO2Et)2-
5445
Eur. J. Org. Chem. 2011, 5441–5446
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org

C. Czekelius et al.
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Received: April 6, 2011
Published Online: August 8, 2011
5446
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 5441–5446