Enantio- and regioselective conjugate addition of organometallic reagents to linear polyconjugated nitroolefins

Article abstract of DOI:10.1002/chem.201300538

The copper-catalysed conjugate addition of trialkylaluminium and dialkylzinc reagents to polyconjugated nitroolefins (nitrodiene and nitroenyne derivatives) is reported. A reversed Josiphos ligand L7 allows for the selective 1,4- or 1,6-addition with high enantioselectivities. Copyright

Full text of DOI:10.1002/chem.201300538

DOI: 10.1002/chem.201300538
Enantio- and Regioselective Conjugate Addition of Organometallic Reagents
to Linear Polyconjugated Nitroolefins
Matthieu Tissot and Alexandre Alexakis*[a]
Abstract: The copper-catalysed conjugate addition of trialkylaluminium and dia-
Keywords: asymmetric catalysis
conjugate addition · copper · ligand
effects · phosphine ligands
·
lkylzinc reagents to polyconjugated nitroolefins (nitrodiene and nitroenyne deriva-
tives) is reported. A reversed Josiphos ligand L7 allows for the selective 1,4- or
1,6-addition with high enantioselectivities.
Introduction
kinetically disfavoured compared with migration to the 6-
position. This result could be explain by the loss of conjuga-
tion due to reductive elimination at the 4-position, which
could suggest that the migration is the rate-determining
step.
In 2008, we discovered that the selectivity can be altered
in favour of 1,4-addition. Indeed, we reported that the com-
bined use of a NHC ligand and CuACHTNUGTRENUNG(OTf)2 as the catalyst al-
lowed for the conjugate addition of Grignard reagents to
cyclic dienones with 1,4-selectivity, leading to the formation
of enantioenriched quaternary stereogenic centres.[9] The ef-
ficiency of this methodology has also been demonstrated
with a variety of polyconjugated cyclic enones (enynones,
trienones), allowing for the formation of valuable syn-
thons.[10] This selectivity outcome has been previously ob-
served by Yamamoto, who reported that the use of an orga-
nocopper reagent (RCu·BF3) led to 1,4-addition with acyclic
dienoate.[11] The 1,4- and 1,6-selectivities observed with
copper reagents suggest that copper encourages a regiodi-
vergent process as a result of migration of the copper com-
plex (Scheme 1).
In the field of copper-catalysed asymmetric conjugate addi-
tion (ACA), many methodologies have been developed to-
wards a variety of activated alkenes, allowing for the forma-
tion of tertiary and quaternary carbon stereocentres.[1] Ster-
eoselectivity and regioselectivity are two important factors
in this transformation. Use of appropriate reaction condi-
tions, as well as the correct choice of catalyst are essential
for a successful reaction profile. Recent reports on ACA
have documented the development of enantioselective con-
jugate addition to polyconjugated substrates.[2] In particular,
the issue of regioselectivity has been emphasised because of
the presence of several electrophilic sites allowing for 1,2-,
1,4-, 1,6- or even 1,8-addition reactions. In the first example,
as reported by Fillion, 1,6-addition of diorganozinc to diacti-
vated Meldrumꢀs acid has been detailed.[3] Two years later,
Feringa achieved a similar 1,6-selectivity for the addition of
methylmagnesium bromide to dienoates, displaying an ex-
cellent level of regio- and enantioselectivity.[4] Furthermore,
Mauduit and Alexakis developed the addition of diorgano-
zinc reagents to cyclic dienones by using a Cu–diphenyl-
phosphinoazomethinylate salt (DIPPAM) complex. This
methodology afforded exclusively the 1,6-adducts with ex-
cellent enantioselectivities.[5] The preference for the 1,6-se-
lectivity appeared to concur with the general trend observed
by Naef, Krause and others.[6] Nakamura and Krause have
explored the mechanism of the ACA of organocopper re-
agents to polyconjugated carbonyls.[7,8] Density function cal-
culations have also been performed to rationalise the prefer-
ence of lithium organocuprate (R2CuLi) towards the forma-
tion of the remote 1,6-conjugate addition product with poly-
conjugated carbonyl compounds. Calculations indicated that
Scheme 1. Regiodivergence with copper reagents.
1,4-reductive elimination of the copperACTHNUTRGNEUNG(III) intermediate is
[a] Dr. M. Tissot, Prof. A. Alexakis
Furthermore, Krause observed that Gilman cuprates dis-
play an unusual 1,4-selectivity with nitroenynes.[12] This type
of substrate has been studied by the Alexakis group in the
context of organocatalytic reactions.[13]
Department of Organic Chemistry, Universitꢁ de Genꢂve
30, Quai Ernest Ansermet, 1211 Genꢂve-4 (Switzerland)
Fax : (+41)223796522
E-mail: alexandre.alexakis@unige.ch
Nitroolefins have also been shown to be valuable sub-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300538.
strates for copper-catalysed ACA.[14] In 2010, we revealed
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FULL PAPER
the first conjugate addition of trimethylaluminium to poly-
conjugated nitroolefins leading to the exclusive formation of
the 1,4-adduct.[15] A reversed Josiphos ligand L7 in combina-
tion with CuTC gave high enantioselectivities.
Interestingly, the use of nitrodienoates led to 1,6-addition.
In this report we detail the full extent of this work, including
improvements to enantioselectivity for the 1,4-addition and
the development of a 1,6-selective ACA of dimethylzinc
(Scheme 2).
We decided to examine this reaction further in the pres-
ence of a chiral ligand. We first tested the Josiphos ligand
L1, which has demonstrated excellent regio- and enantio-
control in the addition of Grignard reagents to dienoates
(Table 2).[4] As observed previously, methylmagnesium bro-
mide displayed perfect selectivity in favour of the 1,4-adduct
2a. However, no enantioselectivity was detected in the pres-
ence of chiral ligand L1 (Table 2, entry 1). We continued
with dimethylzinc and detected almost an equal amount of
1,4- and 1,6-addition products.
High enantioselectivity was de-
tected for the 1,4-adduct
(86% ee), whereas, no enantio-
selectivity was recorded for the
allene compound 3a derived
from 1,6-addition (Table 2,
entry 2). This outcome could be
due to the ease of racemisation
of allenes in the presence of or-
ganocopper or cuprate catalytic
species.[16] We persevered with
trimethylaluminium, and found
that exclusive 1,4-addition took
Scheme 2. Summary of the study.
Table 2. Organometallic screening for the ACA to nitroenyne S1.
Results and Discussion
1,4-Selective conjugate addition: We first screened three or-
ganometallic reagents to evaluate their reactivity and regio-
selectivity with nitroenyne S1. Triphenylphosphine and
CuTC were used as catalyst, and the reactions were per-
formed in Et2O at À308C (Table 1). These preliminary ex-
Entry
MenM
Conv. [%][a]
2a/3a[a]
ee 2a/3a [%][b]
1
2
MeMgBr
Me2Zn
Me3Al
100
100
27
100:0
42:58
100:0
100:0
0:–
86:0
86:–
87:–
3
4[c]
Me3Al
100
Table 1. Screening of Organometallic reagents.
[a] Determined by GC-MS analysis. [b] Determined by chiral GC analysis
using a chiral stationary phase. [c] Reaction performed at À108C.
place with a good enantioselectivity of 86% ee. These results
highlight the influence that the ligand has on the regiocon-
trol of the reaction that favoured the 1,4-addition process.
However, the reaction did not go to completion, even after
16 h (Table 2, entry 3). Increasing the reaction temperature
to À108C led to a quantitative reaction with an enantiose-
lectivity of 87% ee (Table 2, entry 4).
Entry
MenM
Conv. [%][a]
2a/3a[a]
1
2
3
MeMgBr
Me3Al
Me2Zn
100
100
100
100:0
68:31
18:82
[a] Determined by GC-MS analysis.
periments revealed the exclusive 1,4-addition of the
Grignard reagent, delivering the adduct 2a, whereas trime-
thylaluminium afforded a mixture of regioisomers, with a
preference for the 1,4-adduct (Table 1, entries 1 and 2). This
trend seems to relate to the hardness of the metal: Zn leads
tend towards 1,6-addition, whereas the harder Mg provides
exclusively the 1,4 adduct. This trend has already been ob-
served with dienones and enynones.[10b]
Finally, dimethylzinc reacted mainly in a 1,6-addition fash-
ion, producing allene 3a (Table 1, entry 3). These results
highlighted a difference in terms of regioselectivity that was
dependent on the nature of the organometallic reagents.
With the encouraging regioselective and enantioselective
results obtained with trimethylaluminium, we carried out a
screening of ferrocene-based phosphine ligands (Figure 1).
Other types of phosphorus ligands, such as phosphorami-
dites were evaluated, however, they did not demonstrate
high enantiocontrol. The phosphorus atom directly attached
to the cyclopentadiene cycle is defined as P1 and the second
as P2. We initiated our study with ligand L2, which differs
from L1 by the substituents on the P2 phosphorus atom. In
particular, the presence of a cyclohexyl group instead of
phenyl substituents results in increased electron density on
the phosphorus atom (P2). The 1,4-addition dominated in
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A. Alexakis and M. Tissot
ratio of CuTC/L7 could be re-
duced to 5:5.25 without loss of
enantioselectivity
(Table 4,
entry 2). Solvent screening indi-
cated that use of dichlorome-
thane gave a significant drop in
terms of enantioselectivity, dis-
playing only 9% ee, whereas
use of tetrahydrofuran (THF)
afforded an excellent enantiose-
lectivity of 94% ee, which was
almost as high as that obtained
with diethyl ether (Table 4, en-
tries 3 and 4). As demonstrated
in Table 2, when the reaction
was performed at À308C in di-
Figure 1. Selected ferrocene-based phosphine ligands.
Table 3. Screening of ferrocene-based phosphine ligands.
Table 4. Optimisation of the reaction conditions.
Entry
Solvent
T [8C]
Conv. [%][a]
2a/3a[a]
ee 2a [%][b]
Entry
L*
Conv. [%][a]
2a/3a[a]
ee 2a [%][b]
1
Et2O
Et2O
CH2Cl2
THF
THF
THF
À10
À10
À10
À10
À30
À78
100
100
100
100
100
100
100:0
100:0
100:0
100:0
100:0
100:0
95
95
9
94
94
99
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L7
100
100
97
100:0
94:6
100:0
99:1
94:6
100:0
100:0
86
62
65
60
14
92
95
2[c]
3
4
62
5
100
100
98
6[c]
[a] Determined by GC-MS analysis. [b] Determined by chiral GC analysis
using a chiral stationary phase. [c] Reaction performed with CuTC/L7=
5:5.25 mol% in 10 min.
[a] Determined by GC-MS analysis. [b] Determined by chiral GC analysis
using a chiral stationary phase.
this reaction, with a small amount of 1,6-addition product
being observed. However, a drop in enantioselectivity was
also observed, with a final enantiomeric excess of 62%
being observed (Table 3, entry 2). We then tested ligand L3,
with phenyl (P1) and tert-butyl (P2) substituents. A unique
1,4-addition was detected with a moderate 65% ee (Table 3,
entry 3). Ligands L4 and L5, despite being quite similar in
structure, differed greatly in terms of enantioselectivity, af-
fording 60 and 14% ee, respectively (Table 3, entries 4 and
5).
With ligand L6, an excellent enantioselectivity of 92% ee
was observed. This result was further improved through the
use of the reversed Josiphos ligand L7, which delivered an
enantiomeric excess reaching 95% (Table 3, entry 7).
This screening of ligands was particularly difficult to inter-
pret, however, despite highlighting the importance of the
right combination of substituents on P1 and P2. The best li-
gands L6 and L7, possessed the same cyclohexyl substituents
on the P2 atom, and an aromatic substituent on P1. Never-
theless, at this point it was difficult to conclude whether
enantioselectivity was induced by steric or electronic factors.
With the best ligand L7 in hand, we examined the reac-
tion conditions for this transformation in terms of solvent,
temperature and catalyst loading. First, it was found that the
ethyl ether, the reaction did not go to completion. However,
in THF, the reaction proceeded quantitatively with the same
level of enantioselectivity being observed to that when the
reaction was performed at À108C (Table 4, entry 5). Fur-
thermore, excellent enantioselectivity was observed when
the reaction was performed at À788C in THF (99% ee,
Table 4, entry 6).
To conclude this section, we want to add that, following a
screening of ligands, ligand L7 gave the best results for this
highly regio- and enantioselective 1,4-addition to nitroe-
nynes. Two sets of conditions were developed and these
were used in the subsequent studies described below. Condi-
tions A involved the use of Et2O as solvent at a temperature
of À108C, whereas conditions B involved the use of THF at
À788C.
For the next section, we describe our endeavours to vali-
date the optimised reaction conditions for the addition of a
variety of trialkyaluminium reagents and several nitroe-
nynes, nitrodienes analogues and classical nitro-olefins. The
reaction conditions used to synthesise the polyconjugated
nitro-olefins (nitroenynes/nitrodienes) have already been
optimised in our laboratory.[13] Initially, a Henry reaction be-
tween a,b-unsaturated aldehydes and nitromethane, cata-
lysed by lithium aluminium hydride, afforded the nitro-alco-
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Conjugate Addition to Polyconjugated Nitroolefins
FULL PAPER
Table 5. Scope of the reaction with nitroenynes S1–10.
Entry Substrate Cond.[c] Prod. Conv. [%][a] Yield [%] ee 2 [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
S1
S1
S2
S3
S4
S5
S5
S6
S6
S7
S7
S8
S9
S9
S10
A
B
2a
2a
2b
2c
2d
2e
2e
2 f
2 f
2g
2g
2h
2i
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
56
68
74
55
65
69
66
70
59
54
60
64
52
49
62
95
99
90
95
93
95
99
94
97
83
90
95
90
94
88
Scheme 3. Synthesis of polyconjugated nitro-olefins.
A
A
A
A
B
A
B
A
B
hols.[17] Subsequent dehydration produced the polyconjugat-
ed Michael acceptors (S1–S15; Scheme 3).
Having synthesised a library of nitroenynes (Figure 2), we
applied two sets of reaction conditions using the reversed
Josiphos ligand L7. First, we successfully reproduced our
A
A
B
2i
2j
A
[a] Determined by GC-MS analysis. [b] Determined by chiral GC analysis
using a chiral stationary phase. [c] Conditions A: Et2O, À108C; condi-
tions B: THF, À788C.
We then examined the use of substrates with electron-
poor aromatic substituents. Under conditions A, p-bromo-
phenyl-substituted nitroenyne S8 afforded 95% ee (Table 5,
entry 12). We next tested substrate S9, with a p-trifluorome-
thylphenyl substituent, and found that 90% ee was achieved
under conditions A, and this was increased to 94% ee under
conditions B (Table 5, entries 13 and 14). Finally, the scope
of the reaction was further examined with substrate S10,
bearing an isopropyl group at the ortho position. Surprising-
ly, with this substrate, the ee dropped to 88% under condi-
tions A, probably as a result of steric hindrance (Table 5,
entry 15).
To determine the absolute configuration of the conjugate
adduct, 2a was converted into compound 5c upon hydroge-
nation. The R configuration was established by comparison
of the optical rotation of 5c to the previously reported value
for this compound (Scheme 4).[18]
Figure 2. Nitroenynes S1–10.
two previous results with the aliphatic nitroenyne S1 and, as
demonstrated before, conditions B (using THF) afforded the
best ee of 99%. Under conditions A, the enantioselectivity
reached 95% ee (Table 5, entries 1 and 2). Both conditions
promoted formation of the 1,4-adduct in good yield of up to
68%.
We further pursued the use of aliphatic substrates S2–4
under conditions A. Perfect regioselectivities were observed
in favour of the 1,4-adduct, with the degree of enantio-
selectivity ranging from 90 to 95% ee (Table 5, entries 3–5).
The reaction with nitroenyne S5, bearing a trimethylsilyl
(TMS) substituent, was carried out under both conditions.
When the reaction was performed in Et2O at À108C (condi-
tions A), 95% ee was reached, whereas in THF at À788C
(conditions B), the enantioselectivity increased to 99% ee
(Table 5, entries 6 and 7). We continued our investigation
with aromatic nitroenynes, such as S6. Again, use of condi-
tions B gave the best enantioselectivities (up to 97% ee;
Table 5, entries 8 and 9).
Scheme 4. Determination of the absolute configuration of 2a.
We then proceeded to include a variety of trialkylalumini-
um reagents. First, when triethylaluminium was tested under
conditions A, exclusive 1,4-addition was achieved, albeit
with a moderate 62% ee (Table 6, entry 1). Under condi-
tions B, the reaction did not proceed (Table 6, entry 2), dem-
onstrating a significant difference in reactivity potential be-
tween trimethyl- and triethylaluminium reagents. Increasing
the temperature to À508C gave the 1,4-adduct with 53% ee
(Table 6, entry 3).
When an electron-rich aromatic system was probed
through the use of the p-OMe substituted substrate S7, the
enantioselectivity dropped to 83% ee under conditions A,
whereas use of conditions B gave 90% ee (Table 5, en-
tries 10 and 11).
We decided to continue our study of the nucleophiles
with S6 under conditions A. By using tri-n-butyl- and tri-n-
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A. Alexakis and M. Tissot
Table 6. ACA of trialkylaluminium reagents to nitroenyne S6.
Table 7. Scope of the reaction with nitrodienes.
Entry Substrate Cond.[c] Prod. Conv. [%][a] Yield [%] ee 4 [%][b]
Entry
R
Cond.[c] Prod. Conv. [%][a] Yield [%] ee 2 [%][b]
1
2
3
4
5
6
7
S11
S11
S11
S12
S13
S14
S15
A
B
4a
4a
4a
4b
4c
4d
4e
100
0
80
100
100
100
100
70
–
88
–
1
2
3
4
5
6
Et
Et
Et
nBu
nPr
iBu
A
2k
2k
2k
2l
100
0
100
100
100
100
53
–
–
65
68
55
62
–
53
71
60
6
B
B[d]
A
A
A
A
n.d.[e]
50
81
77
84
90
90
B[d]
A
55
59
67
A
A
2m
2n
[a] Determined by GC-MS analysis. [b] Determined by chiral GC analysis
using a chiral stationary phase. [c] Conditions A: Et2O, À108C; condi-
tions B: THF, À788C. [d] Reaction performed at À508C.
[a] Determined by GC-MS analysis. [b] Determined by chiral GC analysis
using a chiral stationary phase. [c] Conditions A: Et2O, À108C; condi-
tions B: THF, À808C. [d] Reaction performed at À308C. [e] n.d.=not de-
termined.
propylaluminium, product 2 was obtained in 71 and 60% ee,
respectively (Table 6, entries 4 and 5). Finally, use of the trii-
sobutylaluminium reagent led to almost complete loss of
asymmetric induction. Others have already reported the det-
rimental effect of using highly hindered trialkylaluminium
reagents in ACA employing nitroalkenes as Michael accept-
ors.[19]
Table 8. Scope of the reaction with nitroolefins.
We then turned our attention to nitrodienes as polyconju-
gated nitro-olefins. Substrates S11–15 were synthesised by
using the same reaction conditions used for nitroenynes
(Figure 3). First, nitrodiene S11 was examined under condi-
Entry
Substrate
Cond.[c]
Prod.
Conv. [%][a]
ee 5 [%][b]
1
2
3
4
S16
S16
S17
S18
A
B
A
A
5a
5a
5b
5c
100
0
100
100
53
–
24
82
[a] Determined by GC-MS analysis. [b] Determined by chiral GC analysis
using a chiral stationary phase. [c] Conditions A: Et2O, À108C; condi-
tions B: THF, À788C.
hexyl group. However, using the n-heptyl-substituted nitroo-
lefin S18, afforded a good enantioselectivity of 82% ee. De-
termination of the optical rotation of 1,4-adduct 5c con-
firmed that the absolute configuration was R [a]2D0 = +4.6),
by comparison with literature data.[18] This information indi-
cated that, under the same catalytic conditions, facial attack
of the nucleophilic species is the same for nitroenynes
(Scheme 4) and nitrolefins. We hypothesised that with nitro-
dienes, the same facial approach is favoured.
Figure 3. Nitrodienes S11–15.
tions A and it was found that the reaction afforded exclu-
sively the 1,4-adduct 4a with 88% ee (Table 7, entry 1),
which allowed for preferential enantiocontrol with the nitro-
enyne analogue S6 (95% ee under conditions A).
We also examined the reaction under conditions B, how-
ever, no reaction was observed (Table 7, entry 2). When the
reaction was performed at À308C in THF, an 81% ee was
detected (Table 7, entry 3). Conversely, with nitroenynes,
use of conditions A led to higher enantioselectivity.
The enantioselectivities observed with nitroenynes and ni-
trodienes were some of the best results that have been ach-
ieved in the ACA to nitro-olefins, according to the litera-
ture.[14] These reports encouraged us to test two sets of con-
ditions with simple nitro-olefins, which were either commer-
cially available or prepared in our laboratory (Table 8).
Initial attempts, using nitrostyrene S16 under condition-
s A, led to a surprisingly low enantioselectivity of only
53% ee, and the application of conditions B did not result in
any reaction (Table 8, entries 1 and 2). A low enantioselec-
tivity (24% ee) was also reported with S17, bearing a cyclo-
Charette reported that use of the Me-Duphos monoxide
ligand was very effective in the enantioselective copper-cata-
lysed conjugate addition of dialkylzinc reagents to nitroalke-
nes.[14h] Interestingly, he demonstrated that use of the hemi-
labile Me-Duphos monoxide ligand led to good stereocon-
trol, although, conversely, the nonoxidised ligand displayed
no enantioselectivity. To test this hemilability concept, we
synthesised the monoxide ligands of L1 and L7 (Scheme 5).
We then applied the four ligands L1, L1’, L7 and L7’ in
the addition of trimethylaluminium to nitroenyne S3 under
reaction conditions A (Table 9). Our first observation was
that L1 and L7 displayed stereocontrol, whereas the ee was
zero for the oxidised ligands L1’ and L7’. Consequently, we
did not observe a positive hemilability effect as described by
Charette. Moreover, this observation highlighted that ster-
eoselectivity required two chelating phosphorus atoms (P1
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Conjugate Addition to Polyconjugated Nitroolefins
FULL PAPER
Table 9. Study of the ligand structure.
Scheme 5. Mono-oxidation of L1 and L7.
Entry
Ligand
Conv. [%][a]
ee 2c [%][b]
1
2
3
4
L7
L1
L7’
L1’
100
28
10
8
95
65
0
and P2). This also appeared to be important for the reactivi-
ty, because very low conversion was obtained after one hour
with the oxidised ligands.
0
[a] Determined by GC-MS analysis. [b] Determined by chiral GC analysis
using a chiral stationary phase.
1,6-Selective conjugate addition: Wendisch and
Mikami used nitroenoates as Michael acceptors.
Table 10. ACA to nitrodienoate S19–20.
They reported a copper-catalysed ACA with respect
to the nitro group.[14b,i] The strong inductive effect
of the nitro group favoured conjugate addition, de-
spite addition onto the ester group. Inspired by this
work, nitrodienoates S19–20 were synthesised ac-
cording to the procedure used for polyconjugated
nitro-olefins (Scheme 2).
Entry Substrate MenM
Cond.[c] Conv. [%][a] 6/7[a]
Yield [%] ee [%][b]
6
7
As expected, conjugate addition proceeds with
respect to the nitro group. Grignard reagents af-
forded 1,4-adduct 6 exclusively without enantiose-
lectivity (Table 10, entry 1). Interestingly, dimethyl-
zinc and trimethylaluminium displayed unusual re-
gioselectivities. We previously reported that, com-
pared with dimethylzinc, trimethylaluminium gave
a larger ratio of 1,4- to 1,6-addition in favour of the
1,4-product. However, in this case, the tendency is
1
2
3
4
5
S19
S19
S19
S19
S20
MeMgBr
Me2Zn
Me3Al
Me3Al
Me3Al
A
A
A
B
B
100
100
100
100
100
100:0
64:36 n.d.
45:55 n.d.
3:97 68 (7a)
5:95 71 (7b)
–
0
–
76
91
92
93
n.d. 90
n.d. 91
[a] Determined by GC-MS analysis. [b] Determined by chiral GC analysis using a
chiral stationary phase. [c] Conditions A: Et2O, À108C; conditions B: THF, À788C.
reversed because the aluminium reagent displayed a ratio of
1,4- to 1,6-addition product of 45:55, whereas the zinc re-
agent afforded the 1,4-product mainly (ratio of 64:36;
Table 10, entries 2 and 3). High enantioselectivities were de-
tected for both the 1,4- (93% ee) and 1,6- (91% ee) adducts
upon the addition of trimethylaluminium reagents, showing
the high versatility of the catalyst.
By using THF at À788C (conditions B), almost exclusive
formation of the 1,6-adduct was achieved, with an enantiose-
lectivity reaching 90% ee (Table 10, entry 4). Applying these
conditions to substrate S20, led to a ratio of 1,4- to 1,6-addi-
tion products of 5:95 and an enantioselectivity reaching
91% ee (Table 10, entry 5). This switch in regioselectivity
was unexpected, but could be rationalised by invoking a co-
ordination of the carbonyl moiety to the catalyst, which, in
turn, favours the migration step. However, it is important to
note that better regioselectivity was observed in more highly
coordinating solvents such as THF.
Scheme 6. Synthesis of lactam 8.
In 2002, Hoveyda discovered that the asymmetric conju-
gate addition of diethylzinc to cyclic nitro-olefin afforded
the chiral a-substituted cyclohexanone through a Nef trans-
formation.[14e]
Concerning ACA to nitrodienes and nitroenynes, we
never observed this type of transformation, even under
strongly acidic conditions, suggesting that this reaction
worked specifically with a-substituted nitro-olefins.
Because we were interested in the influence of a-substitu-
tion on polyconjugated nitro-olefins for the ACA, and also
wanted to examine the potential to convert the conjugate
addition products directly into carbonyl derivatives, we de-
cided to examine a-substituted nitrodienes. Our investiga-
tion started with an investigation of three organometallic re-
agents: methyl magnesium bromide, trimethylaluminium,
and dimethylzinc, with nitrodiene S11 and a-substituted ni-
trodiene S21 to establish the effect of a-substitution on re-
gioselectivity (Table 11); CuTC and PPh3 were chosen as
catalyst.
To demonstrate the versatility of the nitro group in syn-
thesis, we transformed the 1,6-addition product 7a into
lactam 8 through a reduction/cyclisation tandem reaction
(Scheme 6). This transformation did not lead to any erosion
of the enantioselectivity, delivering the heterocycle in
91% ee.
Chem. Eur. J. 2013, 19, 11352 – 11363
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11357

A. Alexakis and M. Tissot
Table 11. Screening of the organometallic reagents with S11 and S21.
step is crucial for the Nef reaction, as already repor-
ted.[14e] Use of NH4Claq (1m) resulted in complete
conversion into the Nef product, whereas use of
HClaq (1m) resulted in only partial conversion. To
improve the enantioselectivity, a ligand screening
was performed with phosphoramidite and phos-
phine amine ligands, using toluene as solvent (L8,
L9 and L10) (Figure 4). With the phosphoramidite
ligand L8, an equal mixture of 1,4- and 1,6-addition
adducts were obtained, demonstrating that the re-
gioselectivity was also dependent on the ligand and,
moreover, the 1,6-Nef product displayed a moder-
ate enantioselectivity of 73% ee (Table 12, entry 4).
The more elaborate phosphoramidite L9, was
also used, affording mainly the 1,6-adduct in excel-
lent 93% ee (Table 12, entry 5). Finally, Simplephos
ligand L10, which is a ligand developed in the Alex-
Entry
Substrate
MenM
Conv. [%][a]
9/10[a]
1
S11
S21
S11
S21
S11
S21
MeMgBr
MeMgBr
Me3Al
Me3Al
Me2Zn
Me2Zn
100
100
100
100
100
100
85:15
60:40
58:42
20:80
13:86
5:95
2[b]
3
4[b]
5[c]
6[b][c]
[a] Determined by 1H NMR spectroscopic analysis. [b] Nef product formation. [c] Re-
action performed at À108C.
With the most reactive methyl magnesium bromide re-
agent, the reaction proceeded in favour of the 1,4-addition
product with S11, in a ratio 85:15 (Table 11, entry 1). Inter-
estingly, when the same reaction conditions were applied to
a-substituted nitrodiene S21, the 1,6-addition product was
formed in higher amounts, demonstrating the influence of
the a-substitution on regioselectivity. As expected, partial
formation of the Nef products 11 and 12, derived from both
1,4- and 1,6-additions, were detected. We then probed the
use of trimethylaluminium as the organometallic reagent,
Figure 4. Selected chiral ligands.
observing that the a-substitution again influenced the regio-
selective outcome. We noted that the ratio of 1,4-addition to
1,6-addition shifted from 58:42 with S11 to 20:80 with S21.
Interestingly, transformation into the Nef adduct was more
significant; this outcome is probably due to the Lewis acid
character of the aluminium reagents, which promoted an
aluminium nitronate, which, in turn, favoured the Nef reac-
tion.
Finally, we tested the conjugate addition of dimethylzinc.
In this case, 1,6-addition occurred preferentially with S11
(Table 11, entry 5) and almost exclusively with S21
(Table 11, entry 6). The Nef transformation occurred quanti-
tatively with S21, producing a,b-unsaturated ketone 12
(Table 11, entry 6).
Table 12. Optimisation of the 1,6-ACA of dialkylzinc reagents to S21.
Entry
R2Zn
Solvent
T
[8C]
L*
Conv.
[%][a]
11/12[a]
ee 12
[%][b]
1[c]
2[c]
Me2Zn
Me2Zn
Me2Zn
Me2Zn
Me2Zn
Me2Zn
Me2Zn
Et2Zn
Et2O
À10
À10
À10
À10
À10
À10
À30
À30
À10
À30
L7
L7
L7
L8
L9
L10
L7
L7
L7
L9
100
100
100
100
100
100
10
100
100
100
<1:99
12:88
<1:99
50:50
11:89
<1:99
<1:99
<1:99
<1:99
n.d.
80
20
91
73
93
89
n.d.
29
6
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
3[c]
4[d]
5[d]
6[d]
7[c]
Encouraged by the last result, we examined different con-
ditions with dialkylzinc reagent and chiral phosphorus li-
gands (Figure 4).
8[c]
9[c]
Et2Zn
Et2Zn
10[c,e]
62
When dimethylzinc was employed in the presence of the
reversed Josiphos ligand L7, CuTC, with diethyl ether as sol-
vent (conditions A), chiral enone 12 was obtained as the
major isomer with 80% ee (Table 12, entry 1). When diethyl
ether was replaced by dichloromethane, a mixture of 1,4-
and 1,6-adduct was observed in a 11/12 ratio of 12:88. More-
over, low levels of enantiocontrol was observed for the 1,6-
addition product 12 (Table 12, entry 2). With toluene as sol-
vent, a clean reaction was observed, with exclusive forma-
tion of the Nef adduct in 91% ee (Table 12, entry 3). It is
important to note that the conditions use for the hydrolysis
[a] Determined by 1H NMR spectroscopic analysis. [b] Determined by
chiral SFC analysis using a chiral stationary phase. [c] Reaction per-
formed with CuTC/L=5:5.25 mol%. [d] Reaction performed with CuTC/
L=5:10 mol%. [e] Partial transformation into the Nef product.
akis laboratory,[20] afforded exclusively the 1,6-adduct with
an enantioselectivity of 89% ee (Table 12, entry 6). We de-
cided to pursue the reaction further with the ferrocene-
based phosphine ligand L7 and decreased the reaction tem-
perature to À308C. Unfortunately, the conversion dropped
11358
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ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 11352 – 11363

Conjugate Addition to Polyconjugated Nitroolefins
FULL PAPER
Table 13. 1,6-ACA of dimethylzinc to a-substituted nitrodienes S21–S27.
dramatically (Table 12, entry 7). With the more reactive di-
ethylzinc under the same reaction conditions, however, a
low enantioselectivity of 29% ee was detected (Table 12,
entry 8). Increasing the temperature to À108C afforded an
almost racemic mixture (Table 12, entry 9). A screening of
other ligands was undertaken to improve these poor results
but, unfortunately, we were only able to increase the ee to
62% by using L9. The regioselectivity was not perfect and
transformation into the Nef product was only partially ach-
ieved (Table 12, entry 10).
Having established the appropriate conditions for the
tandem 1,6-ACA/Nef reaction, we synthesised a small li-
brary of a-substituted nitrodienes S21–S27, using the same
methodology that was previously used for the synthesis of
nitroenynes and nitrodienes. Linear nitroalkanes were utilis-
ed instead of nitromethane to perform the Henry reaction.
However, this reaction required a longer reaction time to
generate the substrates in good yields (Figure 5).
Entry
Substrate
Prod.
Conv. [%][a]
Yield [%]
ee 12 [%][b]
1
2
3
4
5
6
7
S21
S22
S23
S24
S25
S26
S27
12a
12b
12c
12d
12e
12 f
12g
100
100
100
100
100
100
100
56
70
74
55
64
62
65
89
92
92
93
91
92
80
[a] Determined by 1H NMR spectroscopic analysis. [b] Determined by
chiral SFC analysis using a chiral stationary phase.
converted into the 1,6-Nef adduct in one pot, with high
regio- and enantioselectivities.
The S configuration of 12a was established by comparison
of the optical rotation with the reported value for this com-
pound.[21] This efficient one-pot transformation allowed
direct access to enantioenriched a,b-unsaturated ketone 12
(Scheme 7). These types of chiral compounds are usually
synthesised through two-step procedures[21,22] involving
asymmetric allylic alkylation (AAA) followed by cross
metathesis.[23] From a synthetic point of view, an additional
asymmetric conjugate addition on the enone 12 could poten-
tially deliver vicinal dialkyl arrays such as 13, as already
demonstrated by Feringa.[21]
Figure 5. a-Substituted nitrodienes S21–S27.
We began to explore the scope of the reaction with re-
spect to the electrophiles by using a variety of alkyl chain
lengths at the a-position. Nitrodienes S21, S22 and S23 af-
forded the 1,6-addition products exclusively with similar
levels of enantioselectivity (up to 92% ee) and good yields
(Table 13, entries 1–3). The optimised reaction conditions
were then applied to nitrodiene S24, bearing an aryl sub-
stituent with an electron-donating substituent at the para-
position.
Scheme 7. Iterative 1,6-/1,4-ACA.
The 1,6-addition reaction proceeded with high enantio-
control (93% ee) (Table 13, entry 4). The substrate analogue
S25, with the para-bromo phenyl substituent, was also
tested, affording the 1,6-adduct with a slightly lower enan-
tioselectivity of 91% ee (Table 13, entry 5). This demonstrat-
ed that electronic factors do not exert a significant influence
on the stereoselectivity of the reaction. Finally, we probed
the use of aliphatic substrates S26 and S27. Again, the reac-
tion displayed excellent regiocontrol and complete forma-
tion of the Nef adduct. The enantioselectivities reached 92
and 80% ee, respectively (Table 13, entries 6 and 7). This in-
vestigation showed that the a-substituted nitrodienes were
Conclusion
We have described a highly regioselective and enantioselec-
tive ACA of trimethylaluminum reagents to nitroenynes and
nitrodienes using ferrocene-based phosphine ligand L7 and
CuTC as the catalytic system. The reaction proceeded exclu-
sively in a 1,4-additon fashion. Whereas Me3Al afforded
high levels of enantioselectivities up to 99% ee, other trial-
kylaluminium reagents reached up to 71% ee. Interestingly,
we discovered that the regioselectivity could be switched to
1,6-addition by applying a slight modification in the sub-
strate design. In fact, the use of nitrodienoate allowed pref-
Chem. Eur. J. 2013, 19, 11352 – 11363
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11359

A. Alexakis and M. Tissot
C10H16
:
136.1252 [MÀHNO2]+; found: 136.1254. [a]2D5 = +8.49 (c=1,
erential formation of the 1,6-adduct with an enantioselectivi-
ty of up to 91% ee. Finally, we turned our attention to a-
substituted nitrodienes. Initially, by comparison with classic
nitrodienes, we observed that this substitution pattern influ-
enced the regioselectivity in favour of the 1,6-addition prod-
uct. However, by using a similar catalytic system, with
ligand L7 and CuTC, the addition of dimethylzinc promoted
exclusive 1,6-addition. Moreover, the resulting 1,6-nitronate
can be directly converted into the a,b-unsaturated ketone
upon acidic work-up, through a Nef reaction. This reaction
was applied to a small library of a-substituted nitrodienes
and delivered valuable a,b-unsaturated ketones in good
enantioselectivities of up to 93% ee. Surprisingly, the addi-
tion of diethylzinc was more problematic, displaying low
enantioselectivity and only partial conversion into the Nef
product.
CHCl3) for 95% ee. The enantiomeric excess was determined by GC on
a chiral stationary phase (HYDRODEX B-6-TBDM column, method:
60–0–1–170–5, 45 cmsÀ1): tR1 =67.63, tR2 =67.92 min.
(3-Methyl-4-nitrobut-1-yn-1-yl)cyclohexane (2b): The reaction was per-
formed according to general procedure 1. The crude product was purified
by column chromatography (cyclohexane/ethyl acetate, 98:2) to afford
2b (74%) as a yellow oil. 1H NMR (400 MHz, CDCl3): d=4.40 (dd, J=
11.9, 7.3 Hz, 1H), 4.29 (dd, J=12.1, 7.6 Hz, 1H), 3.29 (m, 1H), 2.31 (m,
1H), 1.23–1.74 ppm (m, 13H); 13C NMR (100 MHz, CDCl3): d=88.1,
80.4, 32.7, 28.9, 25.9, 25.6, 24.7, 18.6 ppm. HRMS (EI): m/z calcd for
C11H16
:
148.1252 [MÀHNO2]+; found: 148.1252. [a]2D5 = +9.0 (c=1,
CHCl3) for 90% ee. The enantiomeric excess was determined by GC on
a chiral stationary phase (HYDRODEX B-6-TBDM column, method:
60–0–1–170–5, 45 cmsÀ1): tR1 =84.52, tR2 =84.85 min.
2,2-Dimethyl-5-(nitromethyl)hex-3-yne (2c): The reaction was performed
according to general procedure 1. The crude product was purified by
column chromatography (cyclohexane/ethyl acetate, 98:2) to afford 2c
1
(55%) as a pale-yellow oil. H NMR (400 MHz, CDCl3): d=4.39 (dd, J=
11.8, 7.0 Hz, 1H), 4.28 (dd, J=11.8, 7.6 Hz, 1H), 3.27 (m, 1H), 1.23 (d,
J=6.8 Hz, 3H), 1.17 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=92.3,
80.3, 65.4, 31.0, 27.2, 25.4, 18.5 ppm; HRMS (EI): m/z calcd for C9H14
:
122.1096 [MÀHNO2]+; found: 122.1096; [a]D25 = +13.7 (c=1, CHCl3) for
95% ee. The enantiomeric excess was determined by GC on a chiral sta-
tionary phase (HYDRODEX B-6-TBDM column, method: 60–0–1–170–
5, 45 cmsÀ1): tR1 =51.33, tR2 =51.93 min.
Experimental Section
General remarks: All reactions were conducted in an inert atmosphere.
Unless otherwise stated, all reagents were purchased from commercial
suppliers and used without further purification. All solvents employed in
the reactions were dried on alumina columns and degassed prior to use.
Organic solutions were concentrated under reduced pressure with a
1-[(4-Methyl-5-nitropent-2-ynyloxy)methyl]benzene (2d): The reaction
was performed according to general procedure 1. The crude product was
purified by column chromatography (cyclohexane/ethyl acetate, 98:2) to
afford 2d (65%) as a yellow oil. 1H NMR (400 MHz, CDCl3): d=7.30–
7.36 (m, 5H), 4.56 (s, 2H), 4.46 (dd, J=12.1, 7.3 Hz, 1H), 4.34 (dd, J=
12.1, 7.1 Hz, 1H), 4.14 (d, J=2.0 Hz, 2H), 3.39 (m, 1H), 1.31 ppm (d, J=
6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=137.4, 128.5, 128.2, 128.0,
85.0, 79.6, 79.3, 71.7, 57.3, 25.5, 18.1 ppm; HRMS (EI): m/z calcd for
C13H13O: 185.0966 [MÀH2NO2]+; found: 185.0965; [a]2D5 = +7.3 (c=1,
CHCl3) for 93% ee. The enantiomeric excess was determined by GC on
a chiral stationary phase (LIPODEX E column, method: 60–0–1–170–5,
45 cmsÀ1): tR1 =58.51, tR2 =60.03 min.
1
Bꢄchi rotary evaporator. H (400 MHz) and 13C (100 MHz) NMR spectra
were recorded in CDCl3, and chemical shift (d) are given in ppm relative
to residual CHCl3. Evolution of the reaction was followed by GC-MS
with a Hewlett Packard (EI mode) HP6890–5973. Optical rotations were
measured at 208C in a 1 cm cell in the stated solvent; [a]D values are
given in 10À1 degcm2 gÀ1 (concentration c given as g/100 mL). Enantio-
meric excesses were determined by chiral-GC (capillary column, 10 psi
H2). Temperature programs are described as follows: initial temperature
(8C), initial time (min), temperature gradient (8C/min), final temperature
(8C), retention time (tR in min). All Grignard reagents except ethyl and
methyl magnesium bromide (Aldrich) were synthesised in Et2O by addi-
tion of the corresponding bromide onto magnesium. Flash chromatogra-
phy was performed by using silica gel 32–63 mm (60 ꢅ). Syntheses of
starting substrates are described in the Supporting Information.
Trimethyl(3-methyl-4-nitrobut-1-ynyl)silane (2e): The reaction was per-
formed according to general procedure 1. The crude product was purified
by column chromatography (cyclohexane/ethyl acetate, 98:2) to afford 2e
1
(69%) as a pale-yellow oil. H NMR (400 MHz, CDCl3): d=4.45 (dd, J=
12.0, 6.7 Hz, 1H), 4.31 (dd, J=12.4, 8.1 Hz, 1H), 3.35 (m, 1H), 1.27 (d,
J=7.1 Hz, 3H), 0.14 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=
104.2, 88.1, 79.6, 26.2, 18.1, À0.1 ppm; HRMS (CI): m/z calcd for
C8H16NO2Si: 186.0950 [M+H]+; found: 186.0951; [a]2D5 = +12.3 (c=1,
CHCl3) for 95% ee. The enantiomeric excess was determined by GC on
a chiral stationary phase (HYDRODEX B-6-TBDM column, method:
60–0–1–170–5, 45 cmsÀ1): tR1 =37.67, tR2 =38.62 min.
General procedure 1: 1,4-ACA of trialkylaluminium reagents to polycon-
jugated nitro-olefins (methods A and B): A flame-dried Schlenk tube
was charged with CuTC (5 mol%) and the chiral ligand (5.25 mol%).
Et2O (method A) or THF (method B) (3 mL) was added and the mixture
was stirred at RT for 30 min before being cooled to À108C (method A)
or À788C (method B). Trialkylaluminium (0.7–2m in hexane or heptane,
2 equiv.) was added dropwise over 1 min by using a syringe. The solution
was stirred for 5 min, and the nitro compound (0.5 mmol, 2 equiv.) was
then added dropwise into either Et2O (method A) or THF (method B)
(0.5 mL). The reaction mixture was stirred for an additional 1 h at À108C
(method A) or 12 h at À788C (method B). The flask was removed from
the cooling bath and an aq. solution of tartaric acid (1m, 2 mL) was
added slowly. The reaction mixture was stirred for 0.5 h, then the latter
was extracted with Et2O. The organic phase was dried over magnesium
sulfate, concentrated, and the crude product was purified by chromatog-
raphy. Gas chromatography or supercritical fluid chromatography on a
chiral stationary phase revealed the enantiomeric excess.
1-(3-Methyl-4-nitrobut-1-ynyl)benzene (2 f): The reaction was performed
according to general procedure 1. The crude product was purified by
column chromatography (cyclohexane/ethyl acetate, 98:2) to afford 2 f
(70%) as a pale-yellow oil. 1H NMR (400 MHz, CDCl3): d=7.38 (m,
2H), 7.29 (m, 3H), 4.55 (dd, J=12.1, 7.1 Hz, 1H), 4.42 (dd, J=12.4,
7.6 Hz, 1H), 3.56 (m, 1H), 1.38 ppm (d, J=6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=131.7, 128.4, 128.3, 122.5, 87.5, 83.4, 79.6, 26.0,
18.2 ppm; HRMS (EI): m/z calcd for C11H11NO2: 189.0790 [M]+; found:
189.0792; [a]2D5 = +24.1 (c=1, CHCl3) for 94% ee. The enantiomeric
excess was determined by GC on a chiral stationary phase (HYDRO-
DEX B-6-TBDM column, method: 60–0–1–170–5, 45 cmsÀ1): tR1 =95.12,
t
R2 =95.58 min.
2-Methyl-1-nitronon-3-yne (2a): The reaction was performed according
to general procedure 1. The crude product was purified by column chro-
matography (cyclohexane/ethyl acetate, 98:2) to afford 2a (56%) as a
pale-yellow oil. 1H NMR (400 MHz, CDCl3): d=4.40 (dd, J=12.0,
7.2 Hz, 1H), 4.28 (dd, J=12.0, 7.6 Hz, 1H), 3.28 (m, 1H), 2.11 (td, J=
7.1, 2.3 Hz, 2H), 1.44 (m, 2H), 1.30 (m, 4H), 1.24 (d, J=7.1 Hz, 3H),
0.88 ppm (t, J=7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=84.2, 80.5,
78.6, 31.3, 28.7, 25.9, 22.5, 18.8, 14.3 ppm; HRMS (EI): m/z calcd for
1-Methoxy-4-(3-methyl-4-nitrobut-1-ynyl)benzene (2g): The reaction was
performed according to general procedure 1. The crude product was puri-
fied by column chromatography (cyclohexane/ethyl acetate, 98:2) to
1
afford 2g (54%) as a yellow oil. H NMR (400 MHz, CDCl3): d=7.32 (d,
J=8.8 Hz, 2H), 6.81 (d, J=8.8 Hz, 2H), 4.53 (dd, J=12.1, 7.1 Hz, 1H),
4.40 (dd, J=12.1, 7.6 Hz, 1H),3.80 (s, 1H), 3.53 (m, 1H), 1.36 ppm (d,
J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=159.7, 133.2, 114.6,
11360
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Chem. Eur. J. 2013, 19, 11352 – 11363

Conjugate Addition to Polyconjugated Nitroolefins
FULL PAPER
113.9, 86.1, 83.3, 79.9, 55.3, 26.1, 18.3 ppm; HRMS (EI): m/z calcd for
C12H13NO3: 219.0895 [M]+; found: 219.0898; [a]D25 = +20.2 (c=1, CHCl3)
for 83% ee. The enantiomeric excess was determined by SFC on a chiral
stationary phase (Chiralcel OD column, method: MeOH 0%-2–1–15,
58C): tR1 =5.59, tR2 =5.99 min.
by column chromatography (cyclohexane/ethyl acetate, 98:2) to afford
2m (68%) as a pale-yellow oil. H NMR (400 MHz, CDCl3): d=7.40 (m,
1
2H), 7.30 (m, 3H), 4.54 (dd, J=12.1, 7.6 Hz, 1H), 4.46 (dd, J=12.4,
7.1 Hz, 1H), 3.48 (m, 1H), 1.49–1.68 (m, 4H), 0.99 ppm (t, J=7.6 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=131.8, 128.4, 128.3, 122.7, 86.6,
84.4, 78.8, 34.12, 31.3, 20.2, 13.7 ppm; HRMS (EI): m/z calcd for
C13H15NO2: 217.1103 [M]+; found: 217.1105; [a]D25 =À7.7 (c=1, CHCl3)
for 60% ee. The enantiomeric excess was determined by SFC on a chiral
stationary phase (Chiralcel OD column, method: MeOH 0%-2–1–15,
58C): tR1 =9.63, tR2 =10.21 min.
1-Bromo-4-(3-methyl-4-nitrobut-1-ynyl)benzene (2h): The reaction was
performed according to general procedure 1. The crude product was puri-
fied by column chromatography (cyclohexane/ethyl acetate, 98:2) to
afford 2h (64%) as a pale-yellow crystal. 1H NMR (400 MHz, CDCl3):
d=7.42 (d, J=8.6 Hz, 2H), 7.24 (d, J=8.6 Hz, 2H), 4.53 (dd, J=12.4,
7.6 Hz, 1H), 4.41 (dd, J=12.1, 7.3 Hz, 1H), 3.54 (m, 1H), 1.37 ppm (d,
J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=133.1, 131.5, 122.6,
121.4, 88.7, 82.4, 79.5, 26.0, 18.0 ppm; HRMS (EI): m/z calcd for
C11H10BrNO2: 266.9895 [M]+; found: 266.9893; [a]2D5 = +20.8 (c=1,
CHCl3) for 95% ee. The enantiomeric excess was determined by GC on
a chiral stationary phase (HYDRODEX B-6-TBDM column, method:
60–0–1–170–5, 45 cmsÀ1): tR1 =137.76, tR2 =138.43 min.
[5-Methyl-3-(nitromethyl)hex-1-yn-1-yl]benzene (2n): The reaction was
performed according to general procedure 1. The crude product was puri-
fied by column chromatography (cyclohexane/ethyl acetate, 98:2) to
afford 2n (55%) as a pale-yellow oil. 1H NMR (400 MHz, CDCl3): d=
7.40 (m, 2H), 7.30 (m, 3H), 4.54 (dd, J=12.1, 7.8 Hz, 1H), 4.44 (dd, J=
12.1, 6.8 Hz, 1H), 3.51 (m, 1H), 1.96 (m, 1H), 1.59 (m, 1H), 1.32 (m,
1H), 0.99 ppm (t, J=7.6 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=
131.8, 128.4, 128.3, 122.7, 86.6, 84.3, 79.1, 41.0, 29.9, 26.0, 23.3, 21.4 ppm;
HRMS (EI): m/z calcd for C14H17NO2: 231.1259 [M]+; found: 231.1262;
[a]2D5 =À2.1 (c=1, CHCl3) for 6% ee. The enantiomeric excess was deter-
mined by SFC on a chiral stationary phase (Chiralcel OD column,
method: MeOH 0%-2–1–15, 58C): tR1 =6.29, tR2 =6.90 min.
1-(3-Methyl-4-nitrobut-1-yn-1-yl)-4-(trifluoromethyl)benzene (2i): The
reaction was performed according to general procedure 1. The crude
product was purified by column chromatography (cyclohexane/ethyl ace-
tate, 98:2) to afford 2i (52%) as a brown oil. 1H NMR (400 MHz,
CDCl3): d=7.55 (d, J=8.3 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 4.55 (dd,
J=12.1, 7.3 Hz, 1H), 4.44 (dd, J=12.1, 7.1 Hz, 1H), 3.58 (m, 1H),
1.40 ppm (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=132.0,
126.4, 125.3, 125.2, 122.5, 90.1, 82.2, 79.4, 26.0, 18.0 ppm; HRMS (EI): m/
z calcd for C12H10F3NO2: 257.0664 [M]+; found: 257.0667; [a]D25 = +16.2
(c=1, CHCl3) for 90% ee. The enantiomeric excess was determined by
GC on a chiral stationary phase (LIPODEX E column, method: 60–0–1–
170–5, 45 cmsÀ1): tR1 =70.90, tR2 =71.39 min.
1-[(E)-3-Methyl-4-nitrobut-1-enyl]benzene (4a): The reaction was per-
formed according to general procedure 1. The crude product was purified
by column chromatography (cyclohexane/ethyl acetate, 98:2) to afford 4a
(70%) as yellow crystals. 1H NMR (400 MHz, CDCl3): d=7.36–7.30 (m,
4H), 7.27–7.23 (m, 1H), 6.50 (d, J=16 Hz, 1H), 6.05 (dd, J=15.9,
7.8 Hz, 1H), 4.38 (m, 2H), 3.22 (m, 1H), 1.23 ppm (d, J=6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=136.4, 131.8, 128.8, 128.6, 127.8, 126.3,
80.9, 36.4, 17.5 ppm; HRMS (EI): m/z calcd for C11H13NO2: 191.0946
[M]+; found: 191.0949; [a]2D5 = +79.7 (c=1, CHCl3) for 88% ee. The
enantiomeric excess was determined by GC on a chiral stationary phase
(LIPODEX E column, method: 60–0–1–170–5, 45 cmsÀ1): tR1 =73.07,
1-Isopropyl-2-(3-methyl-4-nitrobut-1-ynyl)benzene (2j): The reaction was
performed according to general procedure 1. The crude product was puri-
fied by column chromatography (cyclohexane/ethyl acetate, 98:2) to
1
afford 2j (62%) as a brown oil. H NMR (400 MHz, CDCl3): d=7.36 (d,
t
R2 =73.51 min.
J=7.8 Hz, 1H), 7.23–7.30 (m, 2H), 7.11 (m, 1H), 4.56 (dd, J=12.1,
7.3 Hz, 1H), 4.44 (dd, J=12.1, 7.32 Hz, 1H), 3.60 (m, 1H), 3.35 (m, 1H),
1.41 (d, J=6.8 Hz, 3H), 1.25 ppm (d, J=7.1 Hz, 6H); 13C NMR
(100 MHz, CDCl3): d=150.6, 132.5, 128.8, 125.5, 124.9, 121.3, 91.1, 82.2,
79.8, 31.5, 26.3, 23.0, 18.3 ppm; HRMS (EI): m/z calcd for C14H17NO2:
231.1259 [M]+; found: 231.1258; [a]D25 = +15.3 (c=1, CHCl3) for 88% ee.
The enantiomeric excess was determined by GC on a chiral stationary
phase (HYDRODEX B-6-TBDM column, method: 60–0–1–170–5,
45 cmsÀ1): tR1 =106.90, tR2 =107.35 min.
1-Methoxy-4-[(E)-3-methyl-4-nitrobut-1-enyl]benzene (4b): The reaction
was performed according to general procedure 1. The crude product was
purified by column chromatography (cyclohexane/ethyl acetate, 98:2) to
afford 4b (50%) as a yellow solid. 1H NMR (400 MHz, CDCl3): d=7.28
(d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 6.44 (d, J=15.9 Hz, 1H),
5.90 (dd, J=15.6, 7.8 Hz, 1H), 4.36 (m, 2H), 3.80 (s, 3H), 3.19 (m, 1H),
1.21 ppm (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=159.3,
131.2, 129.2, 127.5, 126.6, 113.9, 81.1, 55.3, 36.5, 17.6 ppm. HRMS (EI):
m/z calcd for C12H15NO3: 221.1052 [M]+; found: 221.1054; [a]D25 = +70.5
(c=1, CHCl3) for 77% ee. The enantiomeric excess was determined by
SFC on a chiral stationary phase (Chiralcel OB column, method: MeOH
0%-2–1–15, 58C): tR1 =8.77, tR2 =9.48 min.
[3-(Nitromethyl)pent-1-yn-1-yl] (2k): The reaction was performed ac-
cording to general procedure 1. The crude product was purified by
column chromatography (cyclohexane/ethyl acetate, 98:2) to afford 2k
(53%) as an orange oil. 1H NMR (400 MHz, CDCl3): d=7.40 (m, 2H),
7.30 (m, 3H), 4.55 (dd, J=12.1, 7.5 Hz, 1H), 4.47 (dd, J=12.4, 7.3 Hz,
1H), 3.41 (m, 1H), 1.58–1.74 (m, 2H), 1.14 ppm (t, J=7.3 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=131.8, 128.4, 128.3, 122.7, 86.4, 84.5,
78.4, 33.0, 25.4, 11.3 ppm; HRMS (EI): m/z calcd for C12H13NO2:
203.0946 [M]+; found: 203.0948; [a]D25 =À4.5 (c=1, CHCl3) for 62% ee.
The enantiomeric excess was determined by SFC on a chiral stationary
(E)-Ethyl 2-methyl-5-nitropent-3-enoate (4c): The reaction was per-
formed according to general procedure 1. The crude product was purified
by column chromatography (cyclohexane/ethyl acetate, 98:2) to afford 4c
(55%) as an orange oil. 1H NMR (400 MHz, CDCl3): d=7.06 (d, J=
8.6 Hz, 2H), 6.78 (d, J=8.4 Hz, 2H), 5.93 (d, J=15.8 Hz, 1H), 5.90 (dd,
J=15.9, 7.8 Hz, 1H), 3.53 (m, 2H), 2.65 (m, 1H), 0.62 ppm (d, J=15.8,
6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=134.9, 133.4, 130.7, 129.5,
128.7, 127.5, 80.8, 36.4, 17.5 ppm; HRMS (EI): m/z calcd for
C11H12ClNO2: 225.0557 [M]+; found: 225.0557; [a]2D5 = +63.0 (c=1,
CHCl3) for 84% ee. The enantiomeric excess was determined by SFC on
a chiral stationary phase (Chiralcel OB column, method: MeOH 0%-2–
1–15, 58C): tR1 =7.17, tR2 =7.63 min.
phase (Chiralcel OD column, method: MeOH 0%-2–1–15, 58C): tR1
4.41, tR2 =4.85 min.
=
[3-(Nitromethyl)hept-1-yn-1-yl]benzene (2l): The reaction was per-
formed according to general procedure 1. The crude product was purified
by column chromatography (cyclohexane/ethyl acetate, 98:2) to afford 2l
(65%) as a red oil. 1H NMR (400 MHz, CDCl3): d=7.40 (m, 2H), 7.30
(m, 3H), 4.54 (dd, J=12.1, 7.8 Hz, 1H), 4.46 (dd, J=12.1, 7.1 Hz, 1H),
3.46 (m, 1H), 0.92–1.63 (m, 6H), 0.94 ppm (t, J=7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=131.8, 128.4, 128.3, 122.7, 86.7, 84.4, 78.8, 31.8,
31.5, 29.0, 22.3, 14.0 ppm; HRMS (EI): m/z calcd for C14H17NO2:
231.1259; found: 231.1261; [a]2D5 =À13.7 (c=1, CHCl3) for 71% ee. The
enantiomeric excess was determined by SFC on a chiral stationary phase
(Chiralcel OD column, method: MeOH 0%-2–1–15, 58C): tR1 =4.70,
(E)-(3-Methyl-4-nitrobut-1-en-1-yl)cyclohexane (4d): The reaction was
performed according to general procedure 1. The crude product was puri-
fied by column chromatography (cyclohexane/ethyl acetate, 98:2) to
afford 4d (59%) as a yellow oil. 1H NMR (400 MHz, CDCl3): d=5.49
(dd, J=15.4, 6.6 Hz, 1H), 5.21 (dd, J=15.4, 6.6 Hz, 1H), 4.25 (m, 2H),
2.95 (m, 1H), 1.88 (m, 1H), 1.62–1.72 (m, 6H), 1.03–1.29 ppm (m, 7H);
13C NMR (100 MHz, CDCl3): d=139.1, 126.7, 81.5, 40.5, 36.3, 32.9, 26.1,
26.0, 17.8 ppm; HRMS (EI): m/z calcd for C11H18: 150.1409 [MÀHNO2]+;
found: 150.1407; [a]2D5 = +27.6 (c=1, CHCl3) for 90% ee. The enantio-
meric excess was determined by GC on a chiral stationary phase (LIPO-
tR2 =5.30 min.
[3-(Nitromethyl)hex-1-yn-1-yl]benzene (2m): The reaction was per-
formed according to general procedure 1. The crude product was purified
Chem. Eur. J. 2013, 19, 11352 – 11363
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11361

A. Alexakis and M. Tissot
DEX E column, method: 60–20–1–170–5, 45 cmsÀ1): tR1 =67.07, tR2
67.68 min.
=
dropwise over 1 min by using a syringe. The solution was stirred for
5 min, then the nitro compound (0.5 mmol, 1 equiv) in a solution of tol-
uene (1 mL) was added dropwise. The reaction mixture was stirred for
24 h at À108C. Finally, the reaction was quenched at 08C with an aq. sol-
ution of NH4Cl (1m, 2 mL) during 10 min. The latter was extracted three
times with diethyl ether, then the organic phase was dried over magnesi-
um sulfate, concentrated, and the crude product was purified by chroma-
tography. Gas chromatography or supercritical fluid chromatography on
a chiral stationary phase revealed the enantiomeric excess.
(E)-(3-Methyl-4-nitrobut-1-en-1-yl) (4e): The reaction was performed ac-
cording to general procedure 1. The crude product was purified by
column chromatography (cyclohexane/ethyl acetate, 98:2) to afford 4e
(67%) as a yellow solid. 1H NMR (400 MHz, CDCl3): d=5.51 (dd, J=
15.4, 6.8 Hz, 1H), 5.21 (dd, J=15.4, 6.8 Hz, 1H), 4.25 (m, 2H), 2.95 (m,
1H), 2.22 (m, 1H), 1.09 (d, J=6.8 Hz, 3H), 0.94 ppm (d, J=6.8 Hz, 6H);
13C NMR (100 MHz, CDCl3): d=140.2, 126.2, 81.5, 36.1, 31.0, 22.4, 22.3,
17.7 ppm; HRMS (EI): m/z calcd for C8H14: 110.1096 [MÀHNO2]+;
found: 110.1096; [a]2D5 = +24.9 (c=1, CHCl3) for 90% ee. The enantio-
meric excess was determined by GC on a chiral stationary phase (LIPO-
AHCTUNGERTG(NNUN S,E)-6-Phenylhept-4-en-3-one (12b): The reaction was performed ac-
cording to general procedure 3. The crude product was purified by
column chromatography (cyclohexane/ethyl acetate, 98:2) to afford 12a
(56%) as a pale-yellow oil. 1H NMR (400 MHz, CDCl3): d=7.39–7.30
(m, 2H), 7.29–7.17 (m, 3H), 6.92 (dd, J=16.0, 6.6 Hz, 1H), 6.07 (d, J=
16.0 Hz, 1H), 3.64 (m, 1H), 2.25 (s, 3H), 1.45 ppm (d, J=7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=198.96, 151.72, 143.28, 129.69, 128.80,
127.36, 126.88, 42.27, 27.03, 20.20 ppm; HRMS (EI): m/z calcd for
C12H14O: 188.1201 [M]+; found: 188.1200; [a]D20 =À15.6 (c=1, CH3Cl) for
89% of ee. The enantiomeric excess was determined by chiral SFC on a
chiral stationary phase (Chiralcel OB column, method: MeOH 2%-2–1–
15, 408C): tR1 =7.48, tR2 =7.92 min.
DEX
14.03 min.
General procedure 2: Copper-catalysed 1,6-ACA of trialkylaluminium re-
agents to polyconjugated nitrodienoates (method B): flame-dried
E tR1 =13.41, tR2 =
column, method: 60–0–1–170–5, 45 cmsÀ1):
A
Schlenk tube was charged with copper salt (5 mol%) and the chiral
ligand (5.25 mol%). THF (3 mL) was added and the mixture was stirred
at RT for 30 min. The mixture was stirred for 30 min before being cooled
to À808C. Trimethylaluminium (2m in hexane, 2 equiv.) was added drop-
wise over 1 min by using a syringe. The solution was stirred for 5 min,
and the nitro compound (0.5 mmol) was then added in one portion. The
reaction mixture was stirred for an additional 12 h at À788C. The flask
was removed from the cooling bath, and an aq. solution of tartaric acid
(1m, 2 mL) were added slowly. The reaction mixture was stirred for 0.5 h,
then the latter was extracted with diethyl ether. The organic phase was
dried over magnesium sulfate, concentrated, and the crude product was
purified by chromatography. Gas chromatography on a chiral stationary
phase revealed the enantiomeric excess.
AHCTUNGTERG(NNUN S,E)-2-Phenyldec-3-en-5-one (12c): The reaction was performed accord-
ing to general procedure 3. The crude product was purified by column
chromatography (cyclohexane/ethyl acetate, 98:2) to afford 12c (74%) as
a pale-yellow oil. 1H NMR (400 MHz, CDCl3): d=7.36–7.30 (m, 2H),
7.26–7.22 (m, 1H), 7.21–7.17 (m, 2H), 6.95 (dd, J=15.9, 6.7 Hz, 1H),
6.08 (d, J=15.9 Hz, 1H), 3.62 (m, 1H), 2.52 (t, J=7.4 Hz, 2H), 1.73–1.55
(m, 2H), 1.44 (d, J=7.0 Hz, 3H), 1.39–1.11 (m, 4H), 0.88 ppm (t, J=
7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=201.08, 150.35, 143.44,
128.80, 128.73, 127.33, 126.78, 42.23, 40.20, 31.49, 23.92, 22.46, 20.29,
13.92 ppm; HRMS (EI): m/z calcd for C16H22O: 230.1671 [M]+; found:
230.1671; [a]2D0 =À8.4 (c=1, CH3Cl) for 92% of ee. The enantiomeric
excess was determined by chiral SFC on a chiral stationary phase (Chiral-
(E)-Ethyl 2-methyl-5-nitropent-3-enoate (7a): The reaction was per-
formed according to general procedure 2. The crude product was purified
by column chromatography (cyclohexane/ethyl acetate, 98:2) to afford 7a
(68%) as an orange oil. 1H NMR (400 MHz, CDCl3): d=6.02 (dd, J=
15.6, 7.6 Hz, 1H), 5.86 (m, 1H), 4.91 (d, J=7.0 Hz, 2H), 4.14 (q, J=
7.1 Hz, 2H), 3.22 (m, 1H), 1.31 (d, J=7.1 Hz, 3H), 1.26 ppm (t, J=
7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=173.5, 139.2, 120.0, 77.0,
61.1, 42.5, 16.8, 14.2 ppm; HRMS (EI): m/z calcd for C8H13NO4: 187.0845
[M+]; found: 187.0845; [a]D25 = +6.4 (c=1, CHCl3) for 90% ee. The enan-
tiomeric excess was determined by GC on a chiral stationary phase (LIP-
cel ID column, method: MeOH 2%-2–1–15, 408C): tR1 =6.29, tR2 =
8.00 min.
AHCTUNGERTG(NNUN S,E)-5-(4-Methoxyphenyl)hex-3-en-2-one (12d): The reaction was per-
formed according to general procedure 3. The crude product was purified
by column chromatography (cyclohexane/ethyl acetate, 98:2) to afford
1
12d (55%) as a pale-yellow oil. H NMR (400 MHz, CDCl3): d=7.11 (d,
ODEX E column, method: 60–0–1–170–5, 45 cmsÀ1): tR1 =45.57, tR2
46.27 min.
=
J=8.6 Hz, 2H), 6.94–6.86 (m, 1H), 6.87 (d, J=8.7 Hz, 2H), 6.05 (d, J=
16.0 Hz, 1H), 3.80 (s, 3H), 3.59 (m, 1H), 2.24 (s, 3H), 1.41 ppm (d, J=
7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=198.95, 158.46, 152.06,
135.26, 129.40, 128.28, 114.14, 55.29, 41.41, 26.99, 20.25 ppm. HRMS (EI):
m/z calcd for C13H16O2: 204.1150 [M]+; found: 204.1152; [a]D20 =À11.0
(c=1, CH3Cl) for 93% of ee. The enantiomeric excess was determined
by chiral SFC on a chiral stationary phase (Chiralcel OD column,
method: MeOH 2%-2–1–15, 408C): tR1 =7.92, tR2 =8.41 min.
(E)-tert-Butyl 2-methyl-5-nitropent-3-enoate (7b): The reaction was per-
formed according to general procedure 2. The crude product was purified
by column chromatography (cyclohexane/ethyl acetate, 98:2) to afford
1
7b (71%) as an orange oil. H NMR (400 MHz, CDCl3): d=6.00 (dd, J=
15.6, 7.6 Hz, 1H), 5.84 (m, 1H), 4.91 (d, J=6.8 Hz, 2H), 3.13 (m, 1H),
1.43 (s, 12H), 1.27(d, J=7.3 Hz, 3H), 1.26 ppm (t, J=7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=172.8, 139.8, 119.6, 81.2, 43.5, 28.0, 26.9,
16.8 ppm; HRMS (EI): m/z calcd for C10H17NO4: 215.1158 [M+]; found:
215.1158; [a]2D5 = +8.9 (c=1, CHCl3) for 91% ee. The enantiomeric
excess was determined by GC on a chiral stationary phase (LIPODEX E
column, method: 60–20–1–170–5, 45 cmsÀ1): tR1 =62.34, tR2 =63.19 min.
AHCTUNGERTG(NNUN S,E)-5-(4-Bromophenyl)hex-3-en-2-one (12e): The reaction was per-
formed according to general procedure 3. The crude product was purified
by column chromatography (cyclohexane/ethyl acetate, 98:2) to afford
12e (64%) as a pale-yellow oil. 1H NMR (400 MHz, CDCl3): d=7.45 (d,
J=8.5 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 6.86 (dd, J=16.0, 6.6 Hz, 1H),
6.05 (d, J=16.0 Hz, 1H), 3.84–3.41 (m, 1H), 2.24 (s, 3H), 1.42 ppm (d,
J=7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=198.61, 150.71, 142.22,
131.86, 129.87, 129.08, 120.68, 41.67, 27.14, 20.09 ppm; HRMS (EI): calcd
for C12H13BrO: 252.0150 [M]+; found: 252.0149; [a]2D0 =À13.4 (c=1,
CH3Cl) for 91% of ee. The enantiomeric excess was determined by chiral
SFC on a chiral stationary phase (Chiralcel AD column, method: MeOH
2%-2–1–15, 408C): tR1 =9.05, tR2 =9.64 min.
3-Methylpiperidin-2-one (8): RaNi (0.28 mL) was added to a solution of
1,6-adduct 7a (0.187 g, 1.00 mmol) in MeOH (11.5 mL). The mixture was
hydrogenated at 200 psi for 48 h, then the catalyst was filtered and the fil-
trate was concentrated. The crude product was purified by chromatogra-
phy (methanol/diethyl ether, 3:97) to afford 8 (65%) as a brown oil.
1H NMR (400 MHz, C6H6): d=6.25 (brs, 1H), 3.29 (m, 2H), 2.36 (m,
1H), 1.95 (m, 1H), 1.84 (m, 1H), 1.72 (m, 1H), 1.47 (m, 1H), 1.20 ppm
(d, J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=172.8, 139.8, 119.6,
81.2, 43.5, 28.0, 26.9, 16.8 ppm; HRMS (EI): m/z calcd for C6H11NO:
113.0841 [M]+; found: 113.0843; [a]D25 = +38.5 (c=1, CHCl3).
AHCTUNGERTG(NNUN R,E)-6-Methyltridec-4-en-3-one (12g): The reaction was performed ac-
cording to general procedure 3. The crude product was purified by
column chromatography (cyclohexane/ethyl acetate, 98:2) to afford 12g
1
(65%) as a pale-yellow oil. H NMR (400 MHz, CDCl3): d=6.71 (dd, J=
General procedure 3: Copper-catalysed 1,6-ACA of dialkylzinc reagents
to polyconjugated a-substituted nitro-olefins:
A
flame-dried Schlenk
16.0, 7.9 Hz, 1H), 6.05 (d, J=15.9 Hz, 1H), 2.57 (q, J=7.4 Hz, 2H),
2.42–2.16 (m, 1H), 1.46- 1.20 (m, 12H), 1.10 (t, J=7.3 Hz, 3H), 1.04 (d,
J=6.7 Hz, 3H), 0.91–0.81 ppm (m, 3H); 13C NMR (100 MHz, CDCl3):
d=201.49, 152.52, 128.25, 36.73, 36.16, 33.23, 31.83, 29.61, 29.21, 27.24,
22.64, 19.51, 14.08, 8.22 ppm; HRMS (EI): calcd for C14H26O: 210.1984
tube was charged with CuTC (0.025 mmol, 0.05 equiv) and the chiral
ligand (0.0262 mmol, 0.0525 equiv). Toluene (3 mL) was added and the
mixture was stirred at RT for 10 min, before being cooled to À108C. Di-
alkylzinc (1–1.2m in hexane or toluene, 1.5 mmol, 3 equiv) was added
11362
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ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 11352 – 11363

Conjugate Addition to Polyconjugated Nitroolefins
FULL PAPER
[M]+; found: 210.1984; [a]2D0 =À18.2 (c=1, CH3Cl) for 80% of ee. The
[10] a) M. Tissot, A. Pꢁrez Hernꢇndez, D. Mꢄller, M. Mauduit, A. Alexa-
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230.42, tR2 =231.87 min.
=
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Acknowledgements
The authors thank the Swiss National Research Foundation (grant No.:
200020–144344) for financial support. We also thank Dr. Beth Ashbridge
from Memorial Sloan-Kettering Cancer Center for correction of the
manuscript and for fruitful discussions.
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Received: February 11, 2013
Revised: April 17, 2013
Published online: July 12, 2013
Chem. Eur. J. 2013, 19, 11352 – 11363
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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