Conjugate Addition of Organozinc Compounds to Nitroolefins

Article abstract of DOI:10.1055/s-2003-44355

Symmetrical (R₂Zn) or mixed diorganozinc compounds (R ¹ZnR²) smoothly react with a series of nitroolefins in the presence of catalytic amounts of copper(I) salts and provide synthetically versatile nitro compounds in moderate to good yields. Simple alkyl groups, functionalized residues, or mixed trimethylsilylmethyl organozinc compounds (TMSM)ZnR may be employed for conjugate addition, while the TMSM group is not being transferred. ipso-Substitution is observed in absence of the copper(I) salt. Enantiomerically pure copper(I) complexes with BINOL based chiral phosphoramidite ligands efficiently catalyze the addition of dialkylzinc compounds to nitroalkenes. For instance, diethylzinc addition occurs with high yields and excellent enantioselectivity. Nitrostyrene, 3-nitroacrolein dimethylacetal, and 3-nitroacrylates have been used as substrates. The nitroolefin moiety predominates over the acrylate moiety and acts as the more powerful Michael acceptor. 2-Alkyl-3-nitropropanoates are exclusively obtained with excellent yield and enantioselectivity. The products can easily be transformed into β²-homoamino acids, compounds of high relevance for different areas of preparative organic chemistry.

Full text of DOI:10.1055/s-2003-44355

FEATURE ARTICLE
135
Conjugate Addition of Organozinc Compounds to Nitroolefins
Conjugate
A
dditio
u
n
of
O
rganoz
d
inc
C
ompou
r
nds to N
i
itroolef
u
ins s Rimkus,1 Norbert Sewald*
University of Bielefeld, Department of Chemistry, PO Box 10 01 31, 33501 Bielefeld, Germany
Fax +49(521)1068094; E-mail: norbert.sewald@uni-bielefeld.de
Received 22 September 2003
Dedicated Prof. Dr. Klaus Burger on the occasion of his 65th birthday.
other carbanions) and acceptors ( , -unsaturated re-
agents) that can be employed in this type of reaction.3
Abstract: Symmetrical (R2Zn) or mixed diorganozinc compounds
(R1ZnR2) smoothly react with a series of nitroolefins in the presence
of catalytic amounts of copper(I) salts and provide synthetically
versatile nitro compounds in moderate to good yields. Simple alkyl
groups, functionalized residues, or mixed trimethylsilylmethyl or-
ganozinc compounds (TMSM)ZnR may be employed for conjugate
addition, while the TMSM group is not being transferred. ipso-Sub-
stitution is observed in absence of the copper(I) salt.
Nitroolefins are one of the strongest Michael acceptors
providing a common pathway to nitroalkanes, which are
particularly versatile intermediates in organic synthesis
since the nitro group may be easily transformed into a
wide variety of functionalities.4,5
Our ongoing interest is directed toward conjugate addition
of functionalized and unfunctionalized organozinc re-
agents to aromatic and aliphatic nitroolefins,6–8 which has
also been investigated by other groups.9,10
Enantiomerically pure copper(I) complexes with BINOL based
chiral phosphoramidite ligands efficiently catalyze the addition of
dialkylzinc compounds to nitroalkenes. For instance, diethylzinc
addition occurs with high yields and excellent enantioselectivity.
Nitrostyrene, 3-nitroacrolein dimethylacetal, and 3-nitroacrylates
have been used as substrates. The nitroolefin moiety predominates
over the acrylate moiety and acts as the more powerful Michael ac-
ceptor. 2-Alkyl-3-nitropropanoates are exclusively obtained with
excellent yield and enantioselectivity. The products can easily be
transformed into 2-homoamino acids, compounds of high rele-
vance for different areas of preparative organic chemistry.
Organometallics bearing functional groups are versatile
intermediates for the synthesis of a wide range of more
complex organic compounds.11,12 The use of organozinc
compounds is particularly favored due to their reactivity,
lower basicity, and remarkable functional group toler-
ance. 11,13
1
Introduction
It has been shown earlier that mixed organozinc reagents
(TMSM)ZnR can be efficiently added to a range of
Michael acceptors.14 Since the TMSM15,16 group is a non-
transferable ligand, this type of organometallics is partic-
ularly useful when a highly functionalized or/and chiral
residue R is to be transferred.
2
3
3.1
Synthesis of Nitroolefins
Conjugate Addition of Organozinc Compounds
Conjugate Addition of Functionalized Organozinc Cuprates
and Diorganozinc Compounds
Conjugate Addition of Alkyl Trimethylsilylmethylzinc
Compounds
3.2
3.3
Enantioselective Catalytic Conjugate Addition of Dialkyl-
zinc Compounds
Significant progress in asymmetric conjugate addition has
been reported over the past few years. Especially, phos-
phoramidite-type chiral ligands provided a major break-
through in this field.
3.3.1 Chiral Catalysts
3.3.2 Addition to 3-Nitroacrylates
3.3.3 Addition to 3-Alkyl Substituted 3-Nitroacrylates
3.3.4 Addition to Nitrostyrene and 3-Nitroacrolein Dimethyl-
acetal
4
5
Hence, both chemoselectivity and stereoselectivity are
important issues to be addressed in this context. In this
feature article, we provide an overview on the subject and
summarize recent results of our own work on conjugate
addition of symmetrical and mixed diorganozinc com-
pounds as well as functionalized organozinc cuprates to
aliphatic and aromatic nitroolefins. Enantioselective con-
jugate addition of dialkylzinc compounds catalyzed by
enantiomerically pure phosphoramidite/copper complex-
es will also be discussed.
Synthesis of 2-Homoaminoacids
Conclusions
Key words: asymmetric catalysis, Michael additions, ligands, or-
ganometallic reagents, amino acids
1
Introduction
The conjugate addition of nucleophiles to , -unsaturated
compounds is one of the most powerful bond forming
strategies and has been widely utilized in organic synthe-
sis.2 This is mainly due to the broad spectrum of donors
(organometallic reagents, heteroatom Michael donors,
2
Synthesis of Nitroolefins
The aliphatic nitroolefins 1b–e (Figure 1) were synthe-
sized according to literature procedures17 by dehydrating
nitroalcohols obtained by base-catalyzed nitroaldol reac-
tion of the corresponding nitroalkane and an aldehyde.5,18
Water elimination proceeds by either basic elimination of
trifluoroacetic acid (1b, 1d,e)19a or with N,N -dicyclohex-
SYNTHESIS 2004, No. 1, pp 0135–0146
Advanced online publication: 25.11.2003
DOI: 10.1055/s-2003-44355; Art ID: Z14103SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
3

136
A. Rimkus, N. Sewald
FEATURE ARTICLE
ylcarbodiimide (DCC) in the presence of copper(I) chlo- spectrum of interesting compounds. We have developed
ride (1c).19b Nitrostyrene (1a) has been prepared by an approach towards the synthesis of 2-homoamino acids
conventional nitroaldol condensation.20
via conjugate addition of organozinc reagents to the ni-
troalkenes 1b–e. Nitrostyrene 1a initially was used as a
model substrate.
3.1
Conjugate Addition of Functionalized Orga-
nozinc Cuprates and Diorganozinc Com-
pounds
Figure 1 Nitroolefins
Diorganozinc reagents R2Zn are less readily available
compared to organozinc halides RZnX. However, diorga-
nozinc reagents R2Zn and their transmetallated correlates
RZnCu(CN)R display a significantly higher reactivity and
3
Conjugate Addition of Organozinc Com-
pounds
Recent years have witnessed a remarkable revival of the efficiency towards electrophiles compared to the copper-
use of organozinc reagents in synthetic chemistry.11 In zinc halides RZnCu(CN)X.22 When nitroolefins are used,
particular, conjugate addition reactions, key steps in the useful nitro intermediates can be prepared following this
methodology. The functionalized diorganozinc com-
pounds are easily prepared by an iodine-zinc exchange re-
synthesis of numerous biologically active compounds in-
cluding steroids, prostaglandins, terpenes, and others,12
have been examined. Most favorably, these reactions are action (Scheme 1).22
catalyzed by copper(I) salts. Notably, the source of the cu-
prous ion and even the counterion have been found to in-
fluence the reaction result.21 Often copper(II) triflate is
used as the copper(I) source, because it is easier to purify
and handle and is reduced in situ to copper(I) by the orga-
nozinc compounds. Nitroolefins are highly efficient elec-
trophilic species with a C–C–N atom pattern. They can be
considered as appropriate starting materials for a broad
Scheme 1 Synthesis of the functionalized diorganozinc compounds
Biographical Sketches
Audrius Rimkus was born PhD in Germany under the the
in 1974 in Klaipeda (Lithua- supervision of Prof. S. Niwayama at the Oklaho-
nia). After graduating with a N. Sewald at the Universi- ma State University (Still-
BSc degree in Chemistry ties of Leipzig and water, USA).
group
of
Prof.
from the University of Bielefeld. He is now work-
Vilnius, he studied for a ing as postdoctoral fellow in
Norbert Sewald was born versity of Munich and later development of synthetic
in 1961 in Munich (Germa- at the University of Leipzig. methods, the isolation,
ny). He obtained his Diplo- In 1998 he finished his ha- structure elucidation, and
ma degree in Chemistry and bilitation and was appointed total synthesis of bioactive
his PhD in Organic Chemis- to full Professor of Organic natural products, studies re-
try at the Technical Univer- and Bioorganic Chemistry garding the interaction of
sity of Munich. After a at the University of peptides with proteins or
postdoctoral
with Prof. J. E. Baldwin at search interests in general tion structure of peptides us-
the Dyson Perrins Labora- comprise organic chemistry ing NMR, and the
fellowship Bielefeld in 1999. His re- DNA, analysis of the solu-
tory, University of Oxford, at the interface of biology development of novel mo-
he started independent re- and medical sciences. Spe- lecular tools for biochemi-
search at the Technical Uni- cial focus is placed on the cal research.
Synthesis 2004, No. 1, 135–146 © Thieme Stuttgart · New York

FEATURE ARTICLE
Conjugate Addition of Organozinc Compounds to Nitroolefins
137
The organozinc cuprates 423 were applied in conjugate ad- There is a series of reports that under certain circumstanc-
ditions to nitroolefins 1 to give functionalized nitro com- es the nitro group may act as a leaving group in nucleo-
pounds 5 (Scheme 2) in moderate to good yields philic substitutions at nitroalkenes. This ipso-type
(Table 1).
substitution (vinylic substitution) usually takes place,
when nitroolefins bearing an acceptor group are used to-
gether with ‘soft’ nucleophiles.25,26 In contrast, dialkyl-
zinc compounds or mixed diorganozinc compounds
(TMSM)ZnR have been found to smoothly add to ni-
troolefins and other Michael acceptors in a mixture of
THF and the polar co-solvent N-methylpyrrolidone
(NMP) in the absence of any copper or transition metal
catalyst.14 Formation of the ipso-product of type 11
(Scheme 4) has not been observed under these conditions.
However, we found that in the absence of copper(I) salts
the addition of alkyl(trimethylsilylmethyl)zinc reagents27
to nitrostyrene 1a in a THF/NMP mixture leads to pre-
dominant formation of the ipso-substituted products 11
(Scheme 4; Table 2, entries 1 and 2). This side reaction
can be suppressed upon addition of a catalytic amount of
copper(I) salt or copper(II) triflate (ca. 2–4 mol%). Exclu-
sive formation of the 1,4-adduct is then observed in mod-
erate to good yields. Longer reaction times usually are
connected with decreasing yields (Table 2, entry 5).
Scheme 2 Addition of functionalized diorganozinc cuprates to ni-
troolefins
Table 1 Addition of Functionalized Diorganozinc Cuprates to Ni-
troolefins 1a,b
Entry
R1
R2
Yield (%)
Product
5a
1
2
3
Ph
CN
67
66
53
COOMe
COOMe
CN
5b
COOEt
5c
A wide variety of functionalized diorganozinc com-
pounds can be easily prepared via boron-zinc transmetal-
lation.11,12a Diorganozinc compounds like dimyrtanylzinc
6 or bis[2-(ethoxycarbonyl)ethyl]zinc 724 can efficiently
be added to nitroolefins in a copper-catalyzed conjugate
addition reaction, providing access to more complex mol-
ecules 8 and 9 (Scheme 3). Although 6 was employed in
an enantiomerically pure form, no diastereoselectivity
was observed (dr 1:1).
Scheme 4 Addition of (TMSM)ZnR compounds to nitrostyrene
Table 2 Addition of (TMSM)ZnR Compounds to Nitrostyrene 1a.
Effect of the Copper Salt
entry
R
Cu-Salt
–
Yield (%)
10a: 5
1
c-Hexyl
n-Heptyl
c-Hexyl
n-Heptyl
n-Heptyl
11a: 28
2
–
10b: 15
10a: 70
10b: 83
10b: 64
11b: 43
3
CuCl
Cu(OTf)2
Cu(OTf)2
–
–
–
4
5a
a Longer reaction time (24 h).
Further aliphatic residues could be successfully added to
nitroolefins 1a–c under analogous reaction conditions af-
fording the corresponding nitro compounds 10 in moder-
ate to good yields (Scheme 5, Table 3). The addition
results show, that alkyl(trimethylsilylmethyl)zinc re-
agents are suitable for the addition to functionalized ni-
troolefins.
Scheme 3 Conjugate addition of diorganozinc compounds to nitro-
olefins
3.2
Conjugate Addition of Alkyl Trimethylsilyl-
methylzinc Compounds
Noteworthy, the 3-nitroacrylates 1b are dissonant, ambi-
dentate electrophiles (nitroolefin vs. acrylate moiety).
However, the nitroolefin moiety acts as the exclusive
Michael acceptor, giving rise to the exclusive formation
of 2-alkyl-3-nitroacrylates 10d–f.
The trimethylsilylmethyl (TMSM) group is known as a
non-transferable ligand in organocopper and -zinc chem-
istry.16 It can be advantageously employed as a ‘dummy’
ligand (TMSM)ZnR when the transferable moiety R is ex-
pensive or laborious to obtain.
Synthesis 2004, No. 1, 135–146 © Thieme Stuttgart · New York

138
A. Rimkus, N. Sewald
FEATURE ARTICLE
Scheme 5 Copper catalyzed addition of alkyl trimethylsilylmethyl
zinc compounds to nitroolefins
Scheme 6 Synthesis of phosphoramidites
Table 3 Copper Catalyzed Conjugate Addition of Trimethylsilyl-
methylzinc Compounds to Nitroolefins 1a–c
bis(phenylethyl)amine and then racemic BINOL or its
3,3 -dimethyl derivative are reacted subsequently, fol-
lowed by chromatographic resolution of the diastereomer-
ic phosphoramidites. Alternatively, enantiomerically pure
BINOL may be employed which is easily obtained by en-
zymatic resolution with bovine pancreas cholesterol es-
terase.32 The 3,3 -dimethyl derivative of BINOL was
synthesized according to Woodward’s method.33 The
ligands L1 and L2 have been isolated in moderate to good
yield (46–54%). Noteworthy, we determined the specific
optical rotation value [ ]D of the ligand (P,S,S)-L1 as
+15.5 (c = 0.8, CHCl3), which substantially differs from
the data reported by Feringa et al.31 ([ ]D +202.1, c = 0.79,
CHCl3). However, our value has been confirmed by two
other groups.34
Entry
Nitroolefin R2
Yield (%)
Product
10c
1
1a
1b
1b
1b
1c
1c
n-Butyl
72
46
69
56
45
72
2
n-Heptyl
c-Hexyl
n-Hexyl
c-Hexyl
n-Heptyl
10d
10e
3
4
10f
5a
6a
10g
10h
a TMSCl was used instead of TMSBr.
3.3
Enantioselective Catalytic Conjugate Addi-
tion of Dialkylzinc Compounds
Seebach et al. reported that the enantioselective addition
of primary dialkylzinc reagents to aryl substituted ni-
troolefins is achieved using an excess of titanium TAD-
DOLates.28 The catalytic, ligand accelerated addition of
diethylzinc to nitrostyrene was first described by Alexakis
et al.29 In recent years there has been considerable effort
towards catalytic asymmetric conjugate additions of orga-
nozinc compounds to both acyclic and cyclic nitroole-
fins.6–10 Promising results from our previous
investigations6,7 encouraged us to study stereoselective
conjugate additions to 3-nitroacrylates, which are valu-
able substrates en route to the synthesis of 2-homoamino
acids.6,9,10a
Figure 2 Chiral phosphoramidite ligands
3.3.2 Addition to 3-Nitroacrylates
3.3.1 Chiral Catalysts
Feringa et al. argued that low ee values are observed upon
copper(I) catalyzed conjugate addition to nitroacrylates,
because the high reactivity of these derivatives would lead
to a strongly competing blank reaction.9 However,
ourselves6 and others10a found that excellent ee values can
be obtained (Scheme 7), depending on ligand, solvent,
and reaction conditions employed.
Numerous reports are dedicated to the utilization of chiral
ligands in the catalytic enantioselective conjugate addi-
tion of diorganozinc compounds to nitroolefins.6–10 Syn-
theses of BINOL-based enantiomerically pure copper(I)/
phosphoramidite complexes and their applications in con-
jugate additions of dialkylzinc compounds to cyclic and
acyclic enones were first reported by Feringa et al.30
In our investigation, the original procedure described by
Feringa et al.30,31 for the synthesis of phosphoramidites L1
and L2 was modified (Scheme 6, Figure 2). Starting from
phosphorus trichloride, at first enantiomerically pure
Scheme 7 Enantioselective copper(I) catalyzed conjugate addition
to methyl 3-nitroacrylate
Synthesis 2004, No. 1, 135–146 © Thieme Stuttgart · New York

FEATURE ARTICLE
Conjugate Addition of Organozinc Compounds to Nitroolefins
139
Table 4 Enantioselective Copper(I) Catalyzed Conjugate Addition
of Diethylzinc to Methyl 3-Nitroacrylate 1ba
3.3.3 Addition to 3-Alkyl Substituted 3-Nitroacrylates
Hoveyda et al. examined the enantioselective conjugate
addition to cyclic nitroalkenes and reported high ee values
(93–95%) and acceptable diastereomeric ratios
(81:19 83:17).10b We performed analogous additions to
branched, acyclic nitroolefins. Diethylzinc was added to
3-alkyl-substituted 3-nitroacrylates 1d,e catalyzed by
enantiomerically pure copper(I)/phosphoramidite com-
plexes leading to 2,3-disubstituted nitroesters 13
(Scheme 8).
Entry Ligand
Solvent
Toluene
Toluene
Toluene
Et2O
T (°C) ee,%d Isomer
1
2
(M,S,S)-L1
50
30
30
30
78
30
30
30
30
30
78
78
30
10
28
12
68
77
16
67
52
73
12
92
15
36
(+)-12
(+)-12
( )-12
(+)-12
(+)-12
( )-12
(+)-12
(+)-12
(+)-12
( )-12
(+)-12
(+)-12
(+)-12
(M,S,S)-L1
(P,S,S)-L1
(M,S,S)-L1
(M,S,S)-L1
(M,S,S)-L1
(P,R,R)-L2
(M,R,R)-L2
(P,R,R)-L2
(M,R,R)-L2
(P,R,R)-L2
(M,R,R)-L2
(M,S)-L3
3
4
5
Et2O
6
THF
7
Toluene
Toluene
Et2O
8
9
Scheme 8 Addition to 3-alkyl substituted 3-nitroacrylates
10
11b
12b
13c
Et2O
Et2O
Compared to nitroacrylate 1b, the reactivity of 3-alkyl
substituted nitroolefins 1d and 1e seems to be increased
leading to a complete conversion of starting material with-
in 20 minutes or less even at –78 °C. The solvent, reaction
temperature as well as the catalyst amount have been var-
ied (Table 5). Decreasing the amount of catalyst to
0.5 mol% does not have any significant influence on the
diastereoselectivity of the addition (Table 5, entries 1 and
6). Unfortunately, the enantiomers could not be separated
on the chiral GC and HPLC columns tested so far. There-
fore, no ee values can be given yet. The dr values of 13 are
moderate to good, with the best case being 89:11 when the
ligand L1 is employed in toluene at –30 °C (Table 5, entry
8). Products of the Nef reaction, which can be even pre-
dominantly formed under similar reaction/work-up condi-
tions,10b,35 were not observed.
Et2O
Toluene
a Isolated yields of 12 range from 70–94%.
b 0.5 mol% Cu(OTf)2 and 1.0 mol% ligand.
c 3 mol% Cu(OTf)2 and 6 mol% ligand.
d Determined by chiral GC on a FS-Lipodex E column.
Substrate and catalyst as well as the nature of the copper
salt influence the enantioselectivity of conjugate additions
to enolates, as recently investigated by us and Alexakis et
al.21 Even the concentration was found to be a parameter
influencing the ee value.10d The best addition results for
1b were obtained with ligand (P,R,R)–L2 in diethyl ether
at –78 °C, which provides 12 in 94% yield and 92% ee
(Table 4, entry 11). Enantioselectivity drops to 15% ee
when the diastereomeric ligand (M,R,R)-L2 is used under
these reaction conditions (Table 1, entry 12). Even less
than 0.5 mol% of copper(II) and 1.0 mol% of chiral phos-
phoramidite are sufficient for very fast and clean reactions
at –78 °C.
3.3.4 Addition to Nitrostyrene and 3-Nitroacrolein
Dimethylacetal
Conjugate additions of diethylzinc to nitrostyrene 1a and
3-nitroacrolein dimethylacetal 1c catalyzed by copper(I)/
phosphoramidite ligands show varying enantioselectivi-
ties (Scheme 9, Table 6). Only low enantioselectivities
have been induced when the 3,3 -dimethylated ligand L2
was used in the additions to nitrostyrene 1a (entries 1 and
2). In contrast to the substrate 1b (Table 4, entry 11), di-
ethyl ether is obviously not a solvent of choice for addi-
tions to nitrostyrene. The absolute configuration of the
resulting nitro compound 14a has been assigned by com-
paring the retention behavior in chiral GC according to
data reported by Seebach et al.28
In comparison, Pfaltz’s oxazoline-phosphite ligand
(M,S)-L3 (Figure 3) provides 12 with 36% ee in toluene
at –78 °C, which is comparable to the result obtained with
phosphoramidite (M,S,S)-L1 under the same reaction con-
ditions (entries 2 and 13).
The use of dimethylacetal 1c leads to a high enantioselec-
tivity of 86% ee, when the ligand (P,R,R)-L2 is employed
(Table 6, entry 3). This enantioselectivity is comparable
in its absolute value to the result recently obtained by us
using the ligand (M,S,S)-L1 (entry 4), albeit the addition
product has the opposite configuration.
Figure 3 Pfaltz’s oxazoline-phosphite
Synthesis 2004, No. 1, 135–146 © Thieme Stuttgart · New York

140
A. Rimkus, N. Sewald
FEATURE ARTICLE
Table 5 Addition to 3-Alkyl Substituted 3-Nitroacrylates 1d,e
Entry
R
Liganda
Cu(OTf)2 (mol%)
Solvent
Et2O
T (°C)
78
dr (%)
63: 37
65: 35
57: 43
60: 40
45: 55
70: 30
63: 37
89: 11
64: 36
49: 51
57: 43
Conversion (%)
1
2
Me
Me
Me
Me
Me
Me
Me
Me
Et
(P,R,R)-L2
(M,R,R)-L2
(P,R,R)-L2
(M,R,R)-L2
(M,S,S)-L1
(P,R,R)-L2
(M,R,R)-L2b
(M,S,S)-L1
(P,R,R)-L2
(M,R,R)-L2
(P,R,R)-L2b
1.0
1.0
1.0
1.0
1.0
0.5
2.0
1.0
2.0
2.0
2.0
57c
99
99
99
99
99
99
99
74c
99
88c
Et2O
78
3
Toluene
Toluene
Et2O
78
4
78
5
30
6
Et2O
78
7
THF
20
8
Toluene
Et2O
30
9
78
10
11
Et
Et2O
78
Et
Toluene
30
a Ligand to copper salt ratio is 2:1.
b 4.1 mol% of ligand has been used.
c Isolated yield, %.
Table 6 Addition to Nitrostyrene 1a and 3-Nitroacrolein Dimethylacetal 1c
Entry
R
Ligand
Solvent
Et2O
T (°C)
78
ee (%)a
Isomer
(R)28
(R)28
(+)
Yield (%)
1
Ph
(P,R,R)-L2
(M,R,R)-L2
(P,R,R)-L2
(M,S,S)-L1
16
6
99b
79
73
84
2
Ph
Et2O
78
3
(MeO)2CH
(MeO)2CH
Toluene
Toluene
30
87
86
47
30
(-)
a Ee was determined by chiral GC on the FS-Lipodex E (Macherey-Nagel) column.
b Conversion, %.
lates are ideally suited as direct precursors of 2-homo-
amino acids as the side chain R may be introduced by
conjugate addition of diorganozinc compounds R2Zn. The
-nitroester 12 can be reduced and the resulting amino
group protected e.g. by the Boc group. The ester is subse-
quently saponified to give the 2-homoamino acid 16 in an
overall yield of 75% (Scheme 10).
Scheme 9 Addition to nitrostyrene and 3-nitroacrolein dimethyl-
acetal
4
Synthesis of 2-Homoaminoacids
Enantioselective conjugate addition to 3-nitroacrylates
provides an efficient route to 2-homoamino acids
(sidechain at C , amino group at C ),6,9,10a which are found
as components in several biologically active com-
pounds.36,37 Moreover, the corresponding -peptides
adopt novel and unique folding patterns.38 3-Nitroacry-
Scheme 10 Synthesis of the Boc-protected 2-homoamino acid 16
Synthesis 2004, No. 1, 135–146 © Thieme Stuttgart · New York

FEATURE ARTICLE
Conclusions
Conjugate Addition of Organozinc Compounds to Nitroolefins
141
Packard) columns. MALDI-ToF mass spectra were recorded on
Voyager-DE™ (PerSeptive Biosystems) using 2,5-dihydroxybenz-
oic acid (DHB) as matrix.
5
In summary, we have shown that conjugate addition of or-
ganozinc compounds to functionalized nitroalkenes is a
powerful method providing access to a broad variety of
functionalized nitro derivatives. The transferable residue
R of alkyl(trimethylsilyl)zinc compounds [(TMSM)ZnR]
can also be successfully added to aliphatic and aromatic
nitroolefins affording the corresponding nitro compounds
in moderate to good yields. A catalytic amount of cop-
per(I) salt in the reaction medium prevents the formation
of ipso-substituted product.
Microanalyses were performed on CHNS-932 (Leco), CHN-O-
Rapid (Heraeus) and Vario EL (Heraeus) apparatus.
Conjugate Addition of Transmetallated Functionalized Diorga-
nozinc Compounds to Nitroolefins; General Procedure
A mixture of an iodo derivative 2 (4.7 mmol) and neat Et2Zn
(2.95 g, 23.9 mmol) was stirred at 50 °C for 14 h (reaction monitor-
ing by GC of hydrolyzed reaction aliquots). The ethyl iodide
formed, and excess Et2Zn were removed in vacuo (35 °C, 1 h, ca.
0.01 mbar). The resulting oil was dissolved in anhyd THF (4 mL)
and added to a THF solution (5 mL) of CuCN (211 mg, 2.4 mmol)
and LiCl (199 mg, 4.7 mmol) at –20 °C. The resulting light-green
Diethylzinc can be efficiently added to nitrostyrene, 3-ni-
troacrylates and 3-nitroacrolein dimethylacetal. The addi- solution was cooled to –78 °C, and TMSCl (598 mg, 5.5 mmol) was
added, followed by a solution of nitroolefin (2.3 mmol) in THF
tion to 3-nitroacrylates or 3-nitroacrolein dimethylacetal,
respectively, provides nitro precursors of 2-homoamino
(1.5 mL) dropwise. The reaction mixture was slowly allowed to
warm up –10 °C overnight. Then Et2O was added (20 mL) and the
mixture was quenched with a solution of sat. NH4Cl (10 mL). The
aqueous layer was extracted with Et2O (2 × 10 mL). The combined
acids. Enantioselectivities up to 92% ee and chemical
yields up to 94% are obtained in the presence of copper(I)
salts and BINOL-type ligands in the frame of ligand-ac-
celerated asymmetric catalysis. The nitroolefin moiety
present in the 3-nitroacrylates, which are ambidentate
electrophiles, acts as the predominant Michael acceptor,
giving rise to the unambiguous formation of 2-alkyl-3-ni-
troacrylates. Consequently, 3-nitroacrylates are ideally
suited as valuable precursors in the catalytic asymmetric
synthesis of 2-homoamino acids.
organic layers were washed with brine (10 mL), dried (MgSO4),
and filtered. The solvent was evaporated, and the residual oil was
purified by flash chromatography to afford the product.
6-Nitro-5-phenylhexanenitrile (5a)
Colorless oil; yield: 67% (196 mg).
IR (neat): 2937 (w), 2246 (w), 1550 (s), 1454 (w), 1430 (w), 1380
(m), 1043 (w), 763 (w), 701 (w) cm–1.
1H NMR (250 MHz): = 1.38–1.71 (2 H, m), 1.72–1.98 (2 H, m),
2.29 (2 H, t, J = 7.0 Hz), 3.48 (1 H, m), 4.57 (2 H, d, J = 7.6 Hz),
7.07–7.52 (5 H, m).
13C NMR (63 MHz): = 17.0, 23.0, 31.9, 43.8, 80.6, 119.3, 127.5,
128.2, 129.3, 138.1.
All moisture and air sensitive reactions were performed in flame-
dried glassware under argon or nitrogen. THF and Et2O were dis-
tilled from sodium benzophenone ketyl immediately prior to use.
Toluene was distilled first over CaH2 and then over sodium, Et3N
was distilled over CaH2. Petroleum ether (PE, bp 30–60 °C) and
EtOAc were used for flash chromatography and were distilled over
CaH2. All other reagents were used as received.
MS (EI): m/z (%) = 184 (19), 158 (10), 132 (30), 130 (42), 118 (44),
117 (54), 116 (91), 115 (24), 104 (31), 103 (36), 91 (100), 90 (21),
89 (49), 78 (28), 77 (39), 65 (24), 51 (24), 41 (22), 39 (27).
Analytical TLC was performed on silica gel plates 60 F254 on alumi-
num foil (Merck). The compounds were visualized by illumination
with UV light, staining with iodine or cerium sulfate/ammonium
molybdate solution. Flash column chromatography was carried out
with silica gel 60 (40–63 m) from Merck.
Anal. Calcd for C12H14N2O2 (218.25): C, 66.04; H, 6.47; N, 12.84.
Found: C, 66.12; H, 6.23; N, 12.79.
Methyl 5-Cyano-2-(nitromethyl)pentanoate (5b)
Colorless oil; yield: 66% (310 mg).
Melting points were determined using a melting point apparatus B-
540 (Büchi) and are uncorrected. IR spectra were collected on a FT/
IR-410 (Jasco) spectrometer from the neat oil film (NaCl plates) or
from a solid in a KBr pellet. Peaks are reported in cm–1 with the fol-
lowing abbreviations for signal intensity: s, strong; m, medium; w,
weak; br, broad.
1H NMR spectra were recorded in CDCl3 at 200 MHz, 250 MHz, or
500 MHz; 13C NMR spectra were recorded at 50 MHz, 63 MHz, or
126 MHz; 31P NMR spectra were recorded at 81 MHz or 202 MHz.
TMS was used as an internal standard (1H, 13C) and 85% phosphoric
acid (H3PO4) as an external standard (31P). Shift values are reported
in parts per million (ppm). Abbreviations for signal coupling are as
follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet.
IR (neat): 2956 (s), 2246 (m), 1735 (s), 1560 (s), 1436 (s), 1380 (s),
1207 (s), 1058 (m), 970 (m), 736 (w) cm–1.
1H NMR (250 MHz): = 1.56–1.94 (4 H, m), 2.41 (2 H, t,
J = 6.6 Hz), 3.23 (1 H, m), 3.78 (3 H, s), 4.46 (1 H, dd, J = 14.3,
5.2 Hz), 4.76 (1 H, dd, J = 14.3, 8.6 Hz).
13C NMR (63 MHz): = 17.0, 22.9, 28.2, 42.3, 52.7, 75.1, 118.6,
171.7.
MS (CI): m/z (%) = 202 (10), 201 (100), 169 (41), 154 (11), 122
(27).
Anal. Calcd for C8H12N2O4 (200.19): C, 48.00; H, 6.04; N, 14.00.
Found: C, 48.17; H, 5.98; N, 13.88.
1-Methyl 6-Ethyl 2-(Nitromethyl)-hexanedioate (5c)
Colorless oil; yield: 53% (150 mg).
Capillary gas chromatography was performed on a GC-17A (Shi-
madzu) gas chromatograph using a HP-5MS (25 m, 0.25 mm ID,
0.33 m, Hewlett Packard) column. Enantiomer separations were
performed on FS-Lipodex E (50 m, 0.25 mm ID, Macherey-Nagel)
column.
IR (neat): 2958 (m), 1735 (s), 1558 (s), 1438 (w), 1378 (m), 1203
(m), 1180 (m), 1031 (m) cm–1.
1H NMR (250 MHz): = 1.26 (3 H, t, J = 7.1 Hz), 1.56–1.80 (4 H,
m), 2.34 (2 H, t, J = 6.9 Hz), 3.23 (1 H, m), 3.76 (3 H, s), 4.13 (2 H,
q, J = 7.1 Hz), 4.46 (1 H, dd, J = 14.3, 4.9 Hz), 4.76 (1 H, dd,
J = 14.3, 9.2 Hz).
EI mass spectra (70 eV) were recorded using GC-MS on a HP 5890
gas chromatograph (Hewlett Packard) with an HP 5972 A integrat-
ed mass detector unit (Hewlett Packard) or a GCMS-QP5050A
(Shimadzu) on HP-5MS (30 m, 0.25 mm ID, 0.25 m, Hewlett
Synthesis 2004, No. 1, 135–146 © Thieme Stuttgart · New York

142
A. Rimkus, N. Sewald
FEATURE ARTICLE
13C NMR (63 MHz): = 14.2, 22.0, 28.6, 33.6, 42.7, 52.5, 60.6,
75.0, 172.4, 172.8.
Ethyl 4-Phenyl-5-nitropentanoate (9); Conjugate Addition of
Bis[2-(ethoxycarbonyl)ethyl]zinc (7) to Nitrostyrene (1a)
Anhyd ZnCl2 (305 mg, ca. 2.24 mmol) was heated to its melting
point in vacuo (ca. 0.01 mbar). The residue was weighed (285 mg,
2.09 mmol), Et2O (9 mL) was added, and the mixture was sonicat-
ed until the salt dissolved. 1-Ethoxy-1-(trimethylsilyl-
oxy)cyclopropane24 (0.91 g, 5.22 mmol) was added, and the mix-
ture was stirred for 4 h at r.t. Et2O (ca. 6–7 mL) was removed under
reduced pressure, and the residual solution was diluted with hexane
(8 mL). The supernatant liquid was separated, and the solvent was
removed in vacuo to give 7 as an oil. Et2O (3 mL) was added, and
the mixture was added dropwise at –40 °C to a solution of 1a
(155 mg, 1.04 mmol) and Cu(OTf)2 (8 mg, 0.02 mmol, 2 mol% re-
ferring to nitroolefin) in Et2O (5 mL). The reaction mixture was al-
lowed to warm up to 0 °C overnight. It was diluted with Et2O
(20 mL) and quenched by addition of a solution of sat. aq NH4Cl
(20 mL). The aqueous layer was extracted with Et2O (3 × 30 mL).
The combined organic layers were washed with brine (20 mL),
dried (MgSO4), and filtered. The solvent was evaporated, and the
residual oil was purified by flash chromatography (PE) to afford the
product.
MS (CI): m/z (%) = 249 (15), 248 (100), 214 (8), 203 (6), 202 (9),
201 (37), 169 (6), 155 (8).
Anal. Calcd for C10H17NO6 (247.25): C, 48.58; H, 6.93; N, 5.67.
Found: C, 48.56; H, 6.84; N, 5.67.
Conjugate Addition of Dimyrtanylzinc (6) to Nitroolefins; Gen-
eral Procedure
TMSCl (0.19 mL, 1.53 mmol) was added dropwise at –30 °C to a
solution of nitroolefin (1.53 mmol) and Cu(OTf)2 (29 mg,
0.08 mmol, 5 mol% referring to nitroolefin) in THF (5 mL). The
mixture was stirred for 10 min, and
a
solution of
dimyrtanylzinc12a,39 6 (ca. 3.5 mmol, ca. 1 M solution in THF) was
added dropwise. The mixture was stirred for 4 h at –30 °C and di-
luted with THF (10 mL). Aqueous HCl solution (10%, 5 mL) was
added and stirring was continued for 15 min. The mixture was
poured into a mixture containing Et2O (100 mL) and sat. aq NH4Cl
(50 mL), stirred for 20 min and filtered over Celite®. The layers
were separated. The aqueous layer was washed with Et2O (2 ×
30 mL). The combined organic layers were washed with brine
(30 mL), dried (MgSO4), and filtered. The solvent was evaporated,
and the residual oil was purified by flash chromatography to afford
the product.
Colorless oil; yield: 65% (170 mg).
IR (neat): 2981 (w), 1731 (s), 1552 (s), 1454 (m), 1378 (m), 1182
(m), 1159 (m), 1037 (m), 765 (w), 701 (m) cm–1.
1H NMR (250 MHz): = 1.21 (3 H, t, J = 7.2 Hz), 1.88–2.24 (4 H,
m), 3.49 (1 H, m), 4.08 (2 H, q, J = 7.2 Hz), 4.51–4.64 (2 H, m),
7.12–7.43 (5 H, m).
13C NMR (63 MHz): = 14.2, 28.1, 31.7, 43.7, 60.6, 80.6, 127.6,
128.0, 129.1, 138.3, 172.5.
(1S,2S,5S)-6,6-Dimethyl-2-(3 -nitro-2 -phenyl-1 -propyl)bicy-
clo[3.1.1]heptane (8a)
Colorless oil (mixture of diastereomers 1:1); yield: 74% (325 mg).
IR (neat): 2910 (s), 1552 (s), 1495 (w), 1468 (w), 1454 (w), 1378
(m), 762 (m), 700 (m) cm–1
1H NMR (500 MHz): = 0.98 (6 H, s), 1.13 (3 H, s), 1.20 (3 H, s),
1.36 (1 H, m), 1.53 (1 H, m), 1.64–1.98 (18 H, m), 2.22 (1 H, m),
2.29 (1 H, m), 3.47–3.57 (2 H, m), 4.45–4.57 (4 H, m), 7.15–7.21 (4
H, m), 7.23–7.29 (2 H, m), 7.30–7.36 (4 H, m).
13C NMR (126 MHz): = 21.3, 22.8; 23.2, 23.4; 26.2, 26.3; 28.0,
28.1; 33.3, 33.6; 37.6, 38.0; 38.6, 38.7; 40.4, 40.7; 41.2, 41.3; 42.3,
42.4; 44.7, 47.3; 81.1, 81.4; 127.5, 127.7, 128.9, 139.2, 139.7.
MS (CI): m/z (%) = 252 (10), 219 (14), 218 (100), 172 (11).
Anal. Calcd for C13H17NO4 (251.28): C, 62.14; H, 6.82; N, 5.57.
Found: C, 62.19; H, 6.89; N, 5.60.
Conjugate Addition of Alkyl(trimethylsilylmethyl)zinc Com-
pounds to Nitroolefins; General Procedure
1,2-Dibromoethane (0.07 mL, 0.8 mmol) was added dropwise to a
stirred mixture of Zn dust (0.52 g, 8.0 mmol) in THF (2.5 mL) at r.t.
under argon, whilst heating with a heat gun to boil the solvent gen-
tly. After ca. 1 min the reaction mixture foams and the heating is in-
terrupted. After 1–3 min, this heating-cooling procedure is repeated
twice more. Upon complete addition the mixture was cooled to r.t.
and then TMSCl (0.07 mL, 0.55 mmol) was added dropwise over
5 min, again with gentle heating. After complete addition, the mix-
ture was stirred at r.t. for further 5 min. THF solutions (1.5 mL) of
the appropriate iodo derivative (2.0 mmol) and of dodecane (ca.
0.4 mL) as internal standard for GC analysis were added dropwise
over 5 min, and then the reaction was stirred at 50 °C for 2–4 h. The
zinc insertion reaction was monitored by GC analysis. When the re-
action was complete, the reaction mixture was cooled to r.t. and the
excess zinc dust allowed to settle for 15 min. The pale gray solution
was transferred to a flame dried flask that contained a solution of
copper salt (0.05 mmol, 5 mol% referring to nitroolefin) in THF
(2.0 mL) cooled to –40 °C. A solution of trimethylsilylmethyllithi-
um (1 M in pentane, 2.0 mL, 2.0 mmol) was added dropwise to the
alkyl zinc iodide solution, which was then stirred at –40 °C for 1 h.
NMP (0.33 mL, 3.4 mmol), TMSBr (0.35 mL, 2.7 mmol) and then
nitroolefin (1.1 mmol) in THF (1.5 mL) were subsequently added
dropwise at –40 °C. The reaction was allowed to warm up to
–30 °C, stirred at this temperature for 3 h and finally allowed to
warm up slowly to r.t. overnight. The reaction mixture was poured
into sat. NH4Cl solution (10 mL) and stirred at r.t. for 10 min. The
resulting solution was extracted with Et2O (3 × 30 mL). The com-
bined extracts were washed with brine (30 mL), dried (MgSO4), and
concentrated in vacuo. The crude residue was purified by column
chromatography.
MS (CI): m/z (%) = 309 (18), 255 (18), 254 (20), 253 (100), 131
(10), 110 (11).
Anal. Calcd for C18H25NO2 (287.40): C, 75.22; H, 8.77; N, 4.84.
Found: C, 75.32; H, 9.19; N, 4.84.
Ethyl 3-{(1 S,2 S,5 S)-6 ,6 -Dimethylbicyclo[3.3.1]hept-2 -yl}-2-
(nitromethyl)propanoate (8b)
Colorless oil (mixture of diastereomers 1:1); yield: 89% (368 mg).
IR (neat): 2912 (s, br), 1736 (s), 1558 (s), 1439 (m), 1379 (m), 1248
(m), 1203 (m), 1174 (m) cm–1.
1H NMR (250 MHz): = 0.99 (6 H, 2 s), 1.19 (6 H, s), 1.39–1.50 (2
H, m), 1.54–1.63 (2 H, m), 1.63–2.09 (16 H, m), 2.30–2.41 (2 H, m),
3.18–3.29 (2 H, m), 3.74 (3 H, s), 3.75 (3 H, s), 4.40 (1 H, dd,
J = 14.3, 10.4 Hz), 4.41 (1 H, dd, J = 14.3, 10.1 Hz), 4.70 (1 H, dd,
J = 14.4, 2.5 Hz), (1 H, dd, J = 14.4, 2.5 Hz).
13C NMR (126 MHz): = 22.0, 22.1; 23.2; 26.2; 28.0; 33.4, 33.5;
36.8, 37.1; 38.5, 38.5; 38.6, 38.6; 41.2, 41.2; 41.4, 41.5; 45.8, 46.2;
52.4, 52.5; 75.2, 75.7; 173.1, 173.2.
MS (EI): m/z (%) = 234 (4), 82 (34), 81 (33), 79 (32), 69 (100), 67
(87), 55 (91), 41 (94), 18 (61), 15 (37).
Anal. Calcd for C14H23NO4 (269.34): C, 62.43; H, 8.61; N, 5.20.
Found: C, 62.47; H, 8.70; N, 5.34.
Synthesis 2004, No. 1, 135–146 © Thieme Stuttgart · New York

FEATURE ARTICLE
Conjugate Addition of Organozinc Compounds to Nitroolefins
143
1-Cyclohexyl-2-nitro-1-phenylethane (10a)
MS (EI): m/z (%) = 160 (17), 119 (10), 118 (100), 117 (14), 105
White crystals; yield: 70% (174 mg); mp 64–65 °C.
(11), 104 (23), 91 (55).
IR (KBr): 2915 (s), 2852 (s), 1548 (s), 1442 (s), 1380 (s), 755 (s),
700 (s) cm–1.
Anal. Calcd for C12H17NO2 (207.27): C, 69.54; H, 8.27; N, 6.76.
Found: C, 69.59; H, 8.17; N, 6.79.
1H NMR (200 MHz): = 0.77–1.88 (11 H, m), 3.27 (1 H, ddd,
J = 9.9, 8.0, 5.9 Hz), 4.62 (1 H, dd, J = 12.3, 9.9 Hz), 4.80 (1 H, dd,
J = 12.3, 5.9 Hz), 7.06–7.43 (5 H, m).
Methyl 2-(Nitromethyl)nonanoate (10d)
Colorless oil; yield: 46% (80 mg).
IR (neat,): 2959 (w), 2926 (m), 2856 (m), 1739 (s), 1559 (s), 1438
(m), 1379 (s), 1251 (w), 1203 (w), 1174 (w) cm–1.
1H NMR (250 MHz): = 0.88 (3 H, t, J = 6.9 Hz), 1.14–1.48 (9 H,
m), 1.46–1.78 (3 H, m), 3.20 (1 H, m), 3.75 (3 H, s), 4.41 (1 H, dd,
J = 14.2, 4.9 Hz), 4.73 (1 H, dd, J = 14.2, 9.2 Hz).
13C NMR (63 MHz): = 14.0, 22.6, 26.6, 28.9, 29.2, 29.3, 31.7,
43.0, 52.3, 75.2, 172.8.
13C NMR (50 MHz): = 26.5, 31.0, 31.4, 41.3, 50.7, 79.3, 127.9,
128.7, 129.1, 139.3.
MS (EI): m/z (%) = 186 (24), 105 (17), 104 (100), 91 (23), 83 (20),
55 (50), 41 (24).
Anal. Calcd for C14H19NO2 (233.31): C, 72.07; H, 8.21; N, 6.0.
Found: C, 72.32; H, 7.91; N, 5.98.
(E)-1-Cyclohexyl-2-phenylethene (11a)
Colorless oil; yield: 28% (50 mg).
MS (CI): m/z (%) = 255 (5), 254 (34), 233 (4), 232 (29), 200 (65),
198 (59), 196 (16), 186 (16), 185 (100), 173 (28), 142 (82), 141
(11), 140 (34).
IR (neat): 3025 (s), 2924 (s), 2850 (s), 1492 (m), 1446 (s), 963 (s),
742 (s), 692 (s) cm–1.
1H NMR (200 MHz): = 1.08–1.95 (10 H, m), 2.18 (1 H, m), 6.22
(1 H, dd, J = 6.6, 16.1 Hz), 6.40 (1 H, d, J = 16.1 Hz), 7.14–7.47 (5
H, m).
13C NMR (50 MHz): = 26.6, 26.7, 33.5, 41.7, 126.5, 127.2, 127.8,
129.0, 137.3, 138.6.
Anal. Calcd for C11H21NO4 (231.29): C, 57.12; H, 9.15; N, 6.06.
Found: C, 57.82; H, 9.09; N, 5.72.
Methyl 2-Cyclohexyl-3-nitropropanoate (10e)
Colorless oil; yield: 69% (453 mg).
IR (neat): 2931 (s), 2854 (m), 1735 (s), 1558 (s), 1438 (m), 1376
(m), 1253 (w), 1203 (m), 1172 (w), 1041 (w) cm–1.
1H NMR (250 MHz): = 0.97–1.36 (5 H, m), 1.59–1.84 (6 H, m),
3.11 (1 H, m), 3.74 (3 H, s), 4.44 (1 H, dd, J = 14.6, 4.0 Hz), 4.79 (1
H, dd, J = 14.6, 10.5 Hz).
13C NMR (63 MHz): = 25.9, 26.1, 26.2, 30.4, 30.5, 38.5, 48.7,
52.2, 73.9, 172.4.
MS (EI): m/z (%) = 186 (24), 129 (27), 128 (23), 117 (10), 115 (23),
105 (11), 104 (100), 91 (20).
1-Nitro-2-phenylnonane (10b)
Light yellow oil; yield: 64% (106 mg).
IR (neat): 2927 (s), 2856 (m), 1554 (s), 1454 (w), 1376 (m), 1056
(w), 763 (w), 701 (m) cm–1.
MS (CI): m/z (%) = 215 (19), 183 (53), 181 (55), 179 (19), 168 (79),
156 (69), 125 (100), 123 (68), 121 (39), 111 (17), 109 (17).
1H NMR (250 MHz): = 0.86 (3 H, m), 1.11–1.35 (10 H, m), 1.60–
1.73 (2 H, m), 3.44 (1 H, m), 4.47–4.61 (2 H, m), 7.13–7.41 (5 H,
m).
13C NMR (63 MHz): = 14.0, 22.6, 26.9, 29.0, 29.3, 31.7, 33.1,
44.4, 81.1, 127.5, 127.6, 128.8, 128.9, 129.0, 139.6.
Methyl 2-(Nitromethyl)octanoate (10f)
Colorless oil; yield: 56% (131 mg).
IR (neat): 2954 (m), 2931 (m), 2858 (m), 1739 (s), 1558 (s), 1438
(m), 1380 (m), 1253 (w), 1203 (m), 1176 (m), 1049 (w) cm–1.
1H NMR (250 MHz): = 0.88 (3 H, t, J = 6.9 Hz), 1.17–1.42 (8 H,
m), 1.46–1.79 (2 H, m), 3.19 (1 H, m), 3.75 (3 H, s), 4.42 (1 H, dd,
J = 14.3, 4.9 Hz), 4.74 (1 H, dd, J = 14.3, 9.5 Hz).
13C NMR (50 MHz): = 14.0, 22.5, 26.6, 28.9, 29.3, 31.5, 42.9,
52.4, 75.2, 172.8.
MS (CI): m/z (%) = 273 (13), 272 (69), 219 (11), 218 (16), 217 (21),
216 (100), 214 (35), 203 (16), 189 (28).
(E)-1-Phenyl-1-nonene (11b)
Colorless oil; yield: 43% (176 mg).
1H NMR (250 MHz): = 0.89 (3 H, t, J = 7.0 Hz), 1.17–1.36 (8 H,
m), 1.32–1.57 (2 H, m), 2.21–2.27 (2 H, m), 6.22 (1 H, dt,
J = 15.8 Hz, 6.6 Hz), 6.38 (1 H, d, J = 15.8 Hz), 7.12–7.40 (5 H, m).
MS (CI): m/z (%) = 241 (1), 240 (13), 219 (13), 218 (100), 186 (23),
184 (14), 173 (11), 172 (10), 171 (36), 139 (7), 128 (5).
13C NMR (63 MHz): = 14.1, 22.7, 29.2, 29.4, 29.7, 31.9, 33.1,
125.9, 126.7, 128.5, 129.7, 131.3, 138.0.
Anal. Calcd for C10H19NO4 (217.26): C, 55.28; H, 8.81; N, 6.45.
Found: C, 55.07; H, 8.95; N, 6.76.
MS (CI): m/z (%) = 246 (2), 245 (14), 204 (15), 203 (100), 202 (43),
201 (19), 190 (12), 189 (81), 175 (7), 141 (9), 133 (13), 119 (14),
117 (19), 105 (26).
2-Cyclohexyl-1,1-dimethoxy-3-nitropropane (10g)
Light yellow oil; yield: 45% (64 mg).
IR (neat): 2927 (s), 2852 (s), 1554 (s), 1448 (m), 1380 (m), 1205
(m), 1130 (m), 1068 (s), 966 (m), 732 (m) cm–1.
1H NMR (200 MHz): = 0.82–1.84 (11 H, m), 2.53 (1 H, m), 3.34
(3 H, s), 3.36 (3 H, s), 4.29 (1 H, dd, J = 13.5, 5.6 Hz), 4.35 (1 H, d,
J = 4.8 Hz), 4.51 (1 H, dd, J = 13.5, 6.4 Hz).
Anal. Calcd (%) for C15H22 (202.34): C, 89.04; H, 10.96; found: C,
88.97; H, 11.15.
2-Phenyl-1-nitrohexane (10c)
Light yellow oil; yield: 72% (180 mg).
IR (neat): 2960 (m), 2931 (m), 2859 (m), 1552 (s), 1454 (m), 1378
(m), 763 (m), 700 (s) cm–1.
13C NMR (50 MHz): = 26.7, 26.8, 26.9, 30.0, 31.1, 37.6, 45.8,
54.8, 56.0, 74.3, 105.4.
1H NMR (200 MHz): = 0.84 (3 H, t, J = 6.6 Hz), 1.05–1.41 (4 H,
m), 1.60–1.79 (2 H, m), 3.44 (1 H, m), 4.55 (2 H, m), 7.13–7.41 (5
H, m).
13C NMR (50 MHz): = 14.2, 22.8, 29.4, 33.1, 44.8, 81.5, 128.0,
128.0, 129.4, 140.1.
MS (EI): m/z (%) = 153 (5), 75 (100), 71 (10), 55 (9), 47 (11), 41
(13).
Anal. Calcd for C11H21NO4 (231.29): C, 57.12; H, 9.15; N, 6.06.
Found: C, 57.18; H, 9.04; N, 6.03.
Synthesis 2004, No. 1, 135–146 © Thieme Stuttgart · New York

144
A. Rimkus, N. Sewald
FEATURE ARTICLE
1,1-Dimethoxy-2-(nitromethyl)nonane (10h)
Colorless oil; yield: 72% (120 mg).
O,O -(P)-3,3 -Dimethyl-1,1 -binaphthyl-2,2 -diyl)-N,N-(R,R)-
bis(1-phenylethyl)phosphoramidite [(P,R,R)-L2]
29
Colorless crystals; yield: 49% (0.39 g); mp 116–123 °C; [ ]D
IR (neat):2929 (s), 2858 (s), 1554 (s), 1466 (m), 1381 (s), 1190 (m),
1117 (s), 1072 (s), 970 (w), 723 (w) cm–1.
+467.9 (c = 2.96, CHCl3).
IR (KBr): 3056 (w), 2962 (m), 2921 (m), 1498 (m), 1448 (m), 1411
(m), 1240 (m), 1205 (m), 1141 (m), 1085 (m), 900 (s), 773 (s), 746
(s), 696 (m) cm–1.
1H NMR (500 MHz): = 1.48–1.80 (6 H, br m), 2.40 (3 H, s), 2.72
(3 H, s), 4.55 (2 H, br m), 6.96–7.37 (16 H, m), 7.74–7.82 (4 H, m).
1H NMR (250 MHz): = 0.88 (3 H, t, J = 6.6 Hz), 1.19–1.41 (10 H,
m), 1.57 (2 H, m), 2.53 (1 H, m), 3.39 (3 H, s), 3.40 (3 H, s), 4.28 (1
H, d, J = 4.9 Hz), 4.29 (1 H, dd, J = 12.9, 6.6 Hz), 4.54 (1 H, dd,
J = 12.8, 5.8 Hz).
13C NMR (63 MHz): = 14.1, 22.6, 26.7, 27.7, 29.1, 29.6, 31.8,
40.9, 54.9, 56.1, 75.6, 105.8.
13C NMR (126 MHz):
= 17.7, 18.9, 23.3, 23.3, 52.6 (d,
J = 12.2 Hz), 122.5, 122.5, 124.3, 124.3, 124.8, 125.0, 125.4, 125.5,
127.0, 127.3, 127.5, 127.7, 127.9, 129.8, 130.1, 130.4, 130.7, 130.8,
131.7, 132.1, 132.3, 149.3, 149.5, 149.6.
31P NMR (202 MHz): = 143.9 (s).
MS (CI): m/z (%) = 216 (32), 214 (54), 182 (26), 170 (11), 169
(100).
Anal. Calcd for C12H25NO4 (247.34): C, 58.27; H, 10.19; N, 5.66.
Found: C, 58.54; H, 10.28; N, 5.61.
MALDI-ToF MS: m/z calcd for C39H34NO2P [M + H]+, 568.66;
Synthesis of Phosphoramidites; General Procedure
found: 569.00.
A solution of bis(1-phenylethyl)amine (2.06 g, 9.16 mmol) and
Et3N (1.05 g, 10.38 mmol) in toluene (8 mL) was added dropwise
under argon to the solution of PCl3 (1.25 g, 9.16 mmol) in toluene
(120 mL). The mixture was stirred at 70 °C for 6 h and allowed to
cool to r.t. Et3N (2.10 g, 20.76 mmol) was added dropwise under ar-
gon. The reation mixture was cooled to –78 °C and a solution of
BINOL (9.17 mmol) or its 3,3 -dimethyl derivative, resp., in a mix-
ture of toluene (24 mL) and THF (4 mL) was added dropwise. The
mixture was allowed to warm up slowly to r.t. and was stirred for an
additional 12 h. The mixture was filtered and the solvents were re-
moved under reduced pressure. The diastereomers were purified
and separated by column chromatography.
Anal. Calcd for C38H34NO2P (567.66): C, 80.40, H, 6.04, N, 2.47.
Found: C, 80.35, H, 6.74, N, 2.36.
O,O -(M)-3,3 -Dimethyl-1,1 -binaphthyl-2,2 -diyl)-N,N-(R,R)-
bis(1-phenylethyl)phosphoramidite [(M,R,R)-L2]
Colorless crystals; yield: 49% (0.39 g); mp 171–173 °C; [ ]D
29
–92.0 (c = 2.98, CHCl3).
IR (KBr): 3019 (w), 2958 (m), 2917 (m), 2850 (m), 1596 (m), 1498
(m), 1465 (m), 1409 (m), 1236 (m), 1130 (m), 1093 (s), 900 (s), 775
(s), 748 (s), 692 (s) cm–1.
1H NMR (500 MHz): = 1.62 (6 H, d, J = 7.0 Hz), 1.91 (3 H, s),
2.67 (3 H, s), 4.54 (2 H, m), 6.98–7.04 (4 H, m), 7.06–7.36 (12 H,
m), 7.67–7.86 (4 H, m).
O,O -(M)-1,1 -Binaphthyl-2,2 -diyl)-N,N-(S,S)-bis(1-phenyleth-
yl)phosphoramidite [(M,S,S)-L1]
13C NMR (126 MHz):
= 17.5, 17.5, 23.1 (br), 54.8 (d,
29
Colorless crystals; yield: 46% (1.15 g); mp 102–104 °C; [ ]D
J = 10.9 Hz), 121.6, 121.7, 124.0, 124.1, 124.3, 124.6, 124.8, 125.0,
126.9, 126.9, 127.0, 127.3, 127.5, 127.9, 128.1, 129.1, 129.7, 130.1,
130.3, 131.2, 131.2, 131.7, 131.8, 143.2, 149.0, 149.2, 149.2.
31P NMR (202 MHz): = 147.8 (s).
MALDI-ToF MS: m/z calcd for C38H34NO2PK [M + K]+, 606.75;
C39H34NO2P [M+H]+, 568.66; found: 606.79 [M + K]+; 568.88 [M
+ H]+.
–485.7 (c = 0.7, CHCl3).
IR (KBr): 3057 (w), 2970 (w), 2927 (w), 1590 (m), 1460 (m), 1327
(m), 1231 (s), 1204 (m), 947 (s) cm–1.
1H NMR (200 MHz): = 1.76 (6 H, d, J = 7.2 Hz), 4.55 (2 H, dq,
J = 11.5, 7.2 Hz), 7.03–7.71 (18 H, m.), 7.85–8.07 (4 H, m).
13C NMR (50 MHz): = 22.6 (d, J = 8.2 Hz), 52.7 (d, J = 12.2 Hz),
122.3, 122.4, 123.0, 124.6, 122.7, 125.1, 125.3, 126.6, 127.2, 127.7,
127.8, 128.3, 128.5, 128.6, 128.7, 128.9, 130.0, 130.8, 131.0, 132.0,
133.4, 143.4, 150.2, 150.6, 150.8.
Anal. Calcd for C38H34NO2P (567.66): C, 80.40, H, 6.04, N, 2.47.
Found: C, 80.39, H, 6.04, N, 2.54.
31P NMR (81 MHz): = 146.5 (t, J = 11.5 Hz).
Phosphoramidite/Copper(I) Catalyzed Conjugate Addition of
Dialkylzinc Compounds to Nitroolefins; General Procedure
Copper(II) triflate (0.5–2.0 mol% referring to nitroolefin) and the
corresponding phosphoramidite (1.0–4.1 mol%) were dissolved in
a corresponding dry solvent (catalyst concentration: ca. 5 mM) and
stirred for 1 h at r.t. under argon. The clear solution was cooled to
the appropriate temperature and the solution of Et2Zn (1.5 equiv;
1 M in hexane) was added dropwise followed by a solution of ni-
troolefin (ca. 1 M in the corresponding solvent). Dodecane was
used as an inner standard for determination of the conversion. The
reaction progress was monitored by GC analysis. The reaction was
quenched by addition of a solution of sat. aq NH4Cl solution. The
organic layer was separated and the aqueous layer was extracted
with Et2O (2 ×). The combined organic layers were washed with
brine, dried (over Na2SO4 or MgSO4) and filtered. The solvents
were removed under reduced pressure and the resulting oil was pu-
rified by column chromatography to afford the product.
MS (EI): m/z (%) = 434 (100), 105 (77), 268 (21), 79 (16), 77 (13),
239 (9), 315 (7), 252 (6), 391 (5); Anal. Calcd for C36H30NO2P
(539.62): C, 80.13, H, 5.60, N, 2.60, O, 5.93. Found: C, 80.24, H,
5.75, N, 2.48, O, 5.52.
O,O -(P)-1,1 -Binaphthyl-2,2 -diyl)-N,N-(S,S)-bis(1-phenyleth-
yl)phosphoramidite [(P,S,S)-L1]
Colorless crystals; yield: 54% (1.35 g); mp 87–89 °C; [ ]D +15.5
(c = 0.8, CHCl3).
IR (KBr): 3057 (w), 2970 (w), 2927 (w), 1590 (m), 1460 (m), 1327
(m), 1231 (s), 1204 (m), 947 (s) cm–1.
1H NMR (200 MHz): = 1.74 (6 H, d, J = 7.1 Hz), 4.47 (2 H, dq,
J = 11.0, 7.1 Hz), 7.12–7.68 (18 H, m), 7.75–8.09 (4 H, m).
13C NMR (50 MHz):
= 23.5 (d, J = 11.8 Hz), 55.0 (d,
J = 11.1 Hz), 121.7, 121.8, 123.0, 123.1, 124.7, 124.7, 125.0, 125.1,
126.4, 126.6, 127.3, 127.7, 127.9, 128.3, 128.5, 128.6, 128.7, 128.9,
130.2, 130.9, 131.0, 131.9, 133.4, 133.4, 143.7, 150.4, 151.0, 151.2.
31P NMR (81 MHz): = 151.6 (t, J = 11.0 Hz).
Methyl 2-(Nitromethyl)butanoate (12)
Colorless oil; yield: 94% (2.89 g).
IR (neat): 2971 (m), 2881 (w), 1737 (s), 1556 (s), 1438 (m), 1380
(s), 1257 (s), 1205 (s), 1182 (s), 971 (w), 848 (w) cm–1.
MS (EI): m/z (%) = 434 (100), 105 (77), 268 (21), 79 (16), 77 (13),
239 (9), 315 (7), 252 (6), 391 (5).
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FEATURE ARTICLE
Conjugate Addition of Organozinc Compounds to Nitroolefins
145
1H NMR (200 MHz): = 0.98 (3 H, t, J = 7.5 Hz), 1.71 (2 H, m),
3.17 (1 H, m), 3.75 (3 H, s), 4.43 (1 H, dd, J = 14.3, 4.4 Hz), 4.75
(1 H, dd, J = 14.3, 9.2 Hz).
13C NMR (126 MHz): = 9.5, 10.8, 10.8, 14.1, 21.6, 24.1, 48.4,
61.2, 89.1, 172.1.
Methyl 2-[(tert-Butoxycarbonyl)aminomethyl]butanoate (15)
Dried ammonium formate (296 mg, 4.69 mmol) and Pd/C (56 mg,
10%) were added under an argon atmosphere to a solution of the ni-
tro compound (0.86 mmol) in abs. MeOH (2.0 mL). While the mix-
ture was stirred for 30 min, gas evolution was observed. The
solution was then filtered through a plug of Celite®. The Celite®
plug was washed with abs. MeOH (8 mL). Anhyd Et3N (0.25 mL,
1.80 mmol) and Boc2O (242 mg, 1.11 mmol) were added to the fil-
trate and the mixture was stirred under an argon atomsphere for 12
h at r.t. Then H2O (8 mL) was added, the solution was cooled to
0 °C, and acidified to ca. pH 3 with 1 N KHSO4 solution. The mix-
ture was extracted with EtOAc (5 × 15 mL). The combined organic
layers were dried over MgSO4, filtered, and evaporated in vacuo.
The Boc protected 2-homoaminoacid ester 15 was purified by flash
chromatography.
13C NMR (50 MHz): = 11.5, 23.0, 44.6, 52.8, 75.4, 173.1.
MS (EI): m/z (%) = 130 (15), 87 (22), 83 (48), 73 (25), 59 (91), 56
(13), 55 (100), 45 (16), 41 (29), 39 (22), 30 (19), 29 (31), 27 (34),
15 (30).
Anal. Calcd for C6H11NO4 (161.16): C, 44.72; H, 6.88, N, 8.69.
Found: C, 45.00; H, 6.94; N 8.55.
Ethyl 2-Ethyl-3-nitrobutanoate (13d)
Colorless oil; yield: 57% (101 mg, both diastereomers).
IR (neat): 2979 (m), 1734 (s), 1555 (s), 1460 (m), 1390 (m), 1273
(m), 1190 (m), 1107 (m) cm–1.
Anal. Calcd for C8H15NO4 (189.21): C, 50.78; H, 7.99; N, 7.40.
Found: C, 51.35; H, 8.38; N, 6.90.
Colorless oil; yield for 2 steps: 79% (395 mg); [ ]D26 –23.9 (c = 1.0,
Diastereomer 1:
CHCl3).
1H NMR (500 MHz): = 0.94 (3 H, t, J = 7.5 Hz), 1.29 (3 H, t,
J = 7.2 Hz), 1.55 (3 H, d, J = 6.6 Hz), 1.56 (1 H, m), 1.70 (1 H, m),
2.92 (1 H, ddd, J = 9.2, 9.2, 4.2 Hz), 4.20 (2 H, q, J = 7.2 Hz), 4.74
(1 H, dq, J = 9.2, 6.7 Hz).
13C NMR (126 MHz): = 11.2, 14.2, 17.5, 22.8, 51.2, 61.2, 84.0,
171.4;
IR (neat): 3379 (m), 2973 (s), 1718 (s), 1520 (s), 1457 (w), 1438
(w), 1366 (m), 1272 (s), 1252 (s), 1173 (s) cm–1.
1H NMR (250 MHz): = 0.94 (3 H, t, J = 7.5 Hz), 1.43 (9 H, s),
1.60 (2 H, m), 2.53 (1 H, m), 3.28 (2 H, m), 3.70 (3 H, s), 4.86 (1 H,
br s).
13C NMR (126 MHz): = 11.5, 22.9, 28.4, 41.4, 47.2, 51.7, 79.4,
155.9, 175.4.
MS (EI): m/z (%) =191 (9), 190 (100), 159 (4), 144 (7), 145 (5), 143
(8), 115 (6).
Diastereomer 2
MS (EI): m/z (%) = 184 (32), 176 (92), 158 (79), 144 (33), 133 (15),
132 (100), 126 (63), 100 (20).
1H NMR (500 MHz): = 0.95 (3 H, t, J = 7.5 Hz), 1.27 (3 H, t,
J = 7.1 Hz), 1.59 (3 H, d, J = 6.9 Hz), 1.63 (2 H, m), 2.99 (1 H, ddd,
J = 9.1, 9.1, 4.2 Hz), 4.18 (2 H, q, J = 7.1 Hz), 4.82 (1 H, dq,
J = 9.1, 6.9 Hz).
Anal. Calcd for C11H21NO4 (231.29): C, 57.12; H, 9.15; N, 6.06.
Found: C, 57.43; H, 9.10; N, 5.80.
2-[(tert-Butoxycarbonyl)aminomethyl]butanoic Acid (16)
LiOH·H2O (629 mg, 15.0 mmol) was added at 0 °C to a solution of
15 (360 mg, 1.56 mmol) in THF (35 mL). The mixture was stirred
at 0 °C for 6 h and then allowed to warm up to r.t. Stirring was con-
tinued for further 18 h. H2O (5 mL) was added and the mixture was
acidified to ca. pH 3 with 1N HCl. The solution was extracted with
EtOAc (4 × 30 mL) and the combined organic layers were dried
over MgSO4, filtered, and evaporated in vacuo to afford the product.
13C NMR (126 MHz): = 11.1, 14.2, 17.4, 22.8, 51.4, 61.2, 84.1,
172.0.
Ethyl 2-Ethyl-3-nitropentanoate (13e)
Colorless oil; yield: 74% (276 mg, both diastereomers).
IR (neat): 2969 (m), 2939 (m), 1731 (s), 1554 (s), 1461 (m), 1376
(m), 1272 (m), 1184 (m), 1025 (w); cm–1.
26
Anal. Calcd for C9H17NO4 (203.24): C, 53.19; H, 8.43; N, 6.89.
Found: C, 53.35; H, 8.39; N, 6.89.
White powder; yield: 95% (322 mg); mp 51–53 °C; [ ]D –17.3
(c = 1.3, MeOH).
1H NMR (250 MHz): = 1.03 (3 H, t, J = 7.5 Hz), 1.46 (9 H, s),
1.75 (2 H, m), 3.18 (1 H, m), 4.44 (1 H, dd, J = 14.4, 5.0 Hz), 4.75
(1 H, dd, J = 14.4, 8.9 Hz), 5.20 (br s, 1 H), 9.57 (br s, 1 H).
Diastereomer 1
1H NMR (500 MHz): = 0.92 (3 H, t, J = 7.5 Hz), 0.96 (3 H, t,
J = 7.3 Hz), 1.29 (3 H, t, J = 7.2 Hz), 1.54 (1 H, m), 1.71 (2 H, m),
1.98 (1 H, m), 2.87 (1 H, ddd, J = 10.0, 10.0, 3.5 Hz), 4.20 (2 H, q,
J = 7.2 Hz), 4.59 (1 H, ddd, J = 10.4, 10.4, 3.5 Hz).
13C NMR (126 MHz): = 10.3, 11.0, 11.0, 14.2, 23.0, 25.7, 50.6,
61.2, 91.0, 171.6.
IR (KBr): 3385 (m), 2972 (m), 1686 (s), 1528 (s), 1270 (s), 1171 (s)
cm–1.
13C NMR (126 MHz): = 11.0, 22.4, 28.3, 44.1, 74.7, 80.8, 158.4,
176.9.
MS (EI): m/z (%) = 205 (11), 204 (100), 173 (4), 159 (7), 158 (10),
157 (19), 129 (12).
Anal. Calcd for C10H19NO4 (217.26): C, 55.28; H, 8.81; N, 6.45.
Found: C, 55.24. H, 8.69; N, 6.00.
Diastereomer 2
1H NMR (500 MHz): = 0.94 (3 H, t, J = 7.5 Hz), 0.97 (3 H, t,
J = 7.1 Hz), 1.26 (3 H, t, J = 7.0 Hz), 1.63 (1 H, m), 1.75 (1 H, m),
1.91 (1 H, m), 2.02 (1 H, m), 3.00 (1 H, dt, J = 9.3, 4.2 Hz), 4.17 (2
H, q, J = 7.0 Hz), 4.71 (1 H, dt, J = 9.3, 3.6 Hz).
Acknowledgment
We gratefully acknowledge support from the Konrad Adenauer
Foundation, the University of Bielefeld (Ph.D. grants to A.R.), and
Fonds der Chemischen Industrie. Prof. Dr. Andreas Pfaltz ge-
nerously provided a sample of the chiral ligand (M,S)-L3.
Synthesis 2004, No. 1, 135–146 © Thieme Stuttgart · New York

146
A. Rimkus, N. Sewald
FEATURE ARTICLE
(16) TMSM group as a non-transferrable ligand: Bertz, S. H.;
Eriksson, S. H.; Miao, G.; Snyder, J. P. J. Am. Chem. Soc.
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(17) (a) Shin, C.; Yamaura, M.; Inui, E.; Ishida, Y.; Yoshimura,
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(12) (a) Knochel, P.; Perea, J. J. A.; Jones, P. Tetrahedron 1998,
54, 8275; and references cited therein. (b) Arnold, L. A.;
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(13) (a) Knochel, P.; Jones, P.; Langer, F. Organozinc Reagents:
A Practical Approach In The Practical Approach in
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(34) The data of (P,S,S)-L1 have been confirmed (private
communications) by Prof. A. Alexakis, University of
Geneva, Switzerland {[ ]D +8.3 (c = 0.75, CHCl3)} and
Prof. N. Krause, University of Dortmund, Germany {[ ]D
+10.5 (c = 0.75, CHCl3)}.
(35) Jubert, C.; Knochel, P. J. Org. Chem. 1992, 5431.
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(15) For synthesis of (TMSM)ZnR see: Berger, S.; Langer, F.;
Lutz, C.; Knochel, P.; Mobley, T. A.; Reddy, Ch. K. Angew.
Chem. Int. Ed. 1997, 36, 1496.
(37) (a) Mayachi, N.; Shibasaki, M. J. Org. Chem. 1990, 55,
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(39) Langer, F.; Devasagayaraj, A.; Chavant, P.-Y.; Knochel, P.
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Synthesis 2004, No. 1, 135–146 © Thieme Stuttgart · New York