The use of N-Alkyl-2,2′-bipyrrolidine derivatives as organocatalysts for the asymmetric michael addition of ketones and aldehydes to nitroolefins

Article abstract of DOI:10.1002/adsc.200404037

The direct Michael addition of aldehydes and ketones to nitroolefins, catalyzed by N-i-Pr-2,2′-bipyrrolidine, is described. The desired 1,4-adducts are obtained in excellent yields with enantioselectivities up to 95% ee and dr up to 95:5 of the syn aldehyde addition product. An unexpected inversion of diastereoselectivity was observed for the addition of α-hydroxy ketones to β-arylnitroolefins with enantioselectivities up to 98% ee. The formation of an internal hydrogen bond between the OH group of the α-hydroxy ketone and the tertiary nitrogen of the catalyst leads to the formation of a rigid cis enamine intermediate that accounts for the inversion of the expected diastereoselectivity and the very high ees.

Full text of DOI:10.1002/adsc.200404037

FULL PAPERS
The Use of N-Alkyl-2,2’-bipyrrolidine Derivatives as
Organocatalysts for the Asymmetric Michael Addition of
Ketones and Aldehydes to Nitroolefins
Olivier Andrey,a Alexandre Alexakis,a,* Axel Tomassini,a Gerald Bernardinellib
a
Department of Organic Chemistry, University of Geneva, Sciences II, Quai Ernest Ansermet, 1211 Geneva, Switzerland
Fax: (þ41)-22-328-7396, e-mail: alexandre.alexakis@chiorg.unige.ch
b
Laboratoire de Cristallographie, University of Geneva, Sciences II, Quai Ernest Ansermet 24, 1211 Geneva, Switzerland
Received: February 9, 2004; Accepted: May 21, 2004
Abstract: The direct Michael addition of aldehydes nal hydrogen bond between the OH group of the a-
and ketones to nitroolefins, catalyzed by N-i-Pr-2,2’- hydroxy ketone and the tertiary nitrogen of the cata-
bipyrrolidine, is described. The desired 1,4-adducts lyst leads to the formation of a rigid cis enamine inter-
are obtained in excellent yields with enantioselectivi- mediate that accounts for the inversion of the expect-
ties up to 95% ee and dr up to 95:5 of the syn alde- ed diastereoselectivity and the very high ees.
hyde addition product. An unexpected inversion of
diastereoselectivity was observed for the addition of
a-hydroxy ketones to b-arylnitroolefins with enantio- Keywords: amines; asymmetric catalysis; conjugate
selectivities up to 98% ee. The formation of an inter- addition; nitroolefins; organocatalysis
Introduction
l-proline as a catalyst for the conjugate addition. Barbas
was the first to report the asymmetric Michael addition
The development of non-metallic asymmetric catalysis of ketones to alkylidene malonates[71] and of aldehydes
has received much attention since its rediscovery in to nitrostyrene[84] catalyzed by diamines containing a
the beginning of the 21st century.[1–7] Indeed, since the pyrrolidine moiety.
famous asymmetric annulation catalyzed by l-proline
Three catalytic approaches can be envisaged for the
in 1970s,[8,9] reported by Hajos et al. and Wiechert organocatalyzed Michael additions (Scheme 1). Mecha-
et al., almost nothing new was published, except some nism A involves the formation of an enamine with a chi-
examples of intramolecular Michael additions catalyzed ral amine, generally a chiral pyrrolidine derivative. This
by a stoichiometric amount of l-proline.[10,11] In the enamine is the nucleophile which attacks the Michael
1980s, Agami[12,13] postulated a mechanism involving acceptor.[47,48,71,77,80,84] In the second mechanism B, the
two molecules of l-proline based on non-linear effects amine plays the role of a chiral base which forms an
in the formation of the Wielandꢀs ketone, but recent ion pair between the enolate of the ketone and the chiral
works of Houk and List14 have contradict his results. ammonium.[101–103] The enolate is the nucleophilic spe-
Only recently, many examples of reactions catalyzed cies involved in this type of reactions. Finally, approach
by l-proline were reported, such as aldol reactions,[14–34] C is based on the activation of the Michael acceptor via
Mannich reactions,[35–46] conjugate additions,[47–50] a-ami- the formation of a chiral iminium ion from an unsaturat-
nations,[51–54] a-aminooxylations,[55–57] a-alkylations[58] ed carbonyl and a chiral amine.[49,70,72,74–76,78,79,104,105] This
and related reactions.[59–61] At the same time new amines iminium is then reactive enough to react with a weak nu-
were developed as catalysts. They also were used in aldol cleophile. The first asymmetric addition of ketones or al-
reactions,[62–68] Mannich reactions,[36,69] conjugate ad- dehydes to nitrostyrene described in the literature in-
ditions,[50,70–84] Diels–Alder reactions,[85–92] a-chlorina- volves the first mechanism with an in situ catalytic for-
tions[93,94] and related reactions.[95–99] All these reac-
tions are known under the neologism of organocataly-
sis.
Among all the organocatalyzed reactions, conjugate
addition has received less attention than the aldol or
Mannich reaction although it was one of the most impor-
À
tant C C bond-forming reactions in organic chemis-
try.[100] This is probably due to the poorer efficiency of
Scheme 1.
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DOI:10.1002/adsc.200404037
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Olivier Andrey et al.
FULL PAPERS
mation of a reactive enamine which reacts with the ni- hindrance of the ketones. More bulky ketones such as
trostyrene as Michael acceptor.[47,48,84] We also decided diisopropyl ketone, benzophenone or acetophenone
to test the same approach for our study of new chiral pyr- did not form the corresponding aminal, even after heat-
rolidine-type amines. In this full paper we describe our ing. The aminal formation can be also performed in
contribution in this field, partially reported in two com- methanol starting from the tartrate salt of 2,2’-bipyrroli-
munications.[77,80]
dine obtained after the resolution with tartaric acid.[114]
The aminals were reduced without previous purification
with sodium borohydride in methanol in the presence of
acetic acid. The resulting mono N-alkylated diamines
3a–h were purified by flash chromatography on silica
Results and Discussion
In the course of our studies on C2 symmetrical chiral di- gel. The yields were generally modest, around 50%, de-
amines[106–112] we recently reported a new asymmetric spite the cleanness of the reaction. The yields could be
synthesis of optically pure 2,2’-bipyrrolidine[113] increase by changing the purification method. Indeed,
(Scheme 2) which can also be obtained easily by photo- the diamines 3c, 3g and 3h were obtained in about
dimerization of the pyrrolidine followed by a resolution 90% yield (Table 1, entries 3, 7 and 8) for the reduction
with tartaric acid.[114] This diamine seemed to be an inter- step after purification by kugelrohr distillation instead
esting backbone for the design of new ligands for asym- of chromatography.
metric catalysis.[114–118] For this purpose we have synthe-
sized many N,N’-dialkyl derivatives and 2,2’-bipyrroli-
dine itself. Among the many potential applications, we Asymmetric Addition of Ketones to Nitroolefins
were also interested in their use as organocatalysts. We
started our investigation with the study of the catalytic Optimization of the Organocatalyst and Reaction
activity of our newdiamines for the organocatalyzed Mi- Conditions
chael addition of acetone to nitrostyrene. The first at-
tempts at conjugate addition only confirmed our doubt. At the beginning of this work we had to elucidate the
Indeed, the N,N’-dialkylated derivatives did not cata- parameters that played a role in the selectivity of the
lyze the reaction at all and the 2,2’-bipyrrolidine 1 itself asymmetric Michael addition to nitroolefins. We have
formed only the corresponding aminal 2g. However, this started our investigation with the addition of acetone
aminal could be reduced to give the N-monosubstituted to nitrostyrene (Scheme 3), which is the simplest system.
derivative 3g of the 2,2’-bipyrrolidine (Scheme 2). Indeed, no diastereomers were formed and acetone can
Therefore, we were able to synthesize a variety of poten- be used as reactant and solvent. The first attempts re-
tial organocatalysts. By the same pathway we have pre- vealed that the reaction catalyzed by iPBP 3g was very
pared a wide range of aminals 2a–h and the N-alkyl-2,2’- slow. Only 4% of adduct 6a was formed after 15 h of re-
bipyrrolidines 3a–h were obtained after reduction (Ta- action. The reaction rate was greatly increased when the
ble 1).[119]
reaction was carried out in chloroform with 20% vol of
The aminals 2a–h of aldehydes and ketones were acetone. The main drawback of these new conditions
formed easily. But, this reaction was limited by the steric was the formation of the a,a’-dialkylated acetone in
about 50% yield. This product was possibly formed after
an intramolecular deprotonation at the a’ position by
the anion formed after the first conjugate addition.
The formation of this side product was totally sup-
pressed by the addition of pTSA·H2O. The addition of
pTSA·H2O also enhances the reaction rate, thus the re-
action was fast enough in pure acetone. We then tested
diamines 3a–h to improve the enantioselectivities of
the addition (Table 2).
The influence of the substituents on the 2,2’-bipyrroli-
dine is not very significant. But we can say that small
groups such as Me 3a (entry 1) or Et 3b (entry 2) are
Scheme 2.
Scheme 3.
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N-Alkyl-2,2’-bipyrrolidine Derivatives as Organocatalysts
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Table 1. Formation of the aminals of 2,2’-bipyrrolidine and reduction to the corresponding N-monoalkylated derivatives.
Entry
1
R1
R2
Yield 2 [%][a]
Yield 3 [%][b]
Product
H
H
86
44[c]
3a
3b
2
3
H
H
Me
Ph
99
97
46
90[d]
3c
4
5
H
H
t-Bu
93
96
64
43
3d
3e
Mes
6
H
FeCp2
92
46
3f
7
8
Me
Me
97
94
88[d]
3g
3h
(CH2)5
80[d]
[a]
The crude product was used for the reduction step without further purification.
Yield of isolated product after column chromatography on SiO2.
NaBH3CN and TFA were used in place of NaBH4 and AcOH for the reduction step.
Yield after Kugelrohr distillation.
[b]
[c]
[d]
less selective than bulkier groups. When we have a pri- meric excesses were slightly better than for most of the
mary large group on the nitrogen, the reaction rate is other diamines. The adduct 6a was obtained in good
greatly decreased without enhancement of the enantio- yield with 23% ee using 3g (entry 7) and 30% ee with
selectivities (entries 3–6). Finally, the most interesting 3h (entry 8). On further tests, it appeared that diamine
results were obtained when a secondary group was 3g gave generally the highest enantioselectivities than
used. The reaction rate remains high and the enantio- 3h with other ketones or aldehydes. Thus, in this article
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Olivier Andrey et al.
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Table 2. Asymmetric addition of acetone to nitrostyrene cat-
alyzed by diamines 3a–h.
Entry
cat* 3
Reaction time
Yield[a] [%]
ee[b] [%]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
15 h
15 h
3 d
3 d
7 d
7 d
15 h
15 h
88
79
91
76
25
64
74
89
17
20
17
25
3
17
23
30
Scheme 4.
proline without the problem of reactivity. But the addi-
tion of pTSA·H2O had no effect for our reaction. We
then tested several additives and we found that with
15% of ammonium chloride and 1 equivalent of water
the reaction does take place. We have isolated the addi-
tion product 6e with 70% yield, 91:9 dr and 75% ee (Ta-
ble 3, entry 4). The relative (syn) and absolute configu-
rations of 6e, as shown in Scheme 4, were determined
by comparison with known 1H NMR data and the opti-
3g
3h
[a]
Isolated yield after column chromatography.
[b]
Determined by chiral GC (Lipodex E column). The abso-
lute configuration (R) was determined by comparison
with literature data.[47]
we have focused our attention on asymmetric reactions cal rotation value.[120] We also noted that nothing hap-
catalyzed with iPBP 3g. pens in the presence of NH4Cl without additional water
These first results incited us to test a more crowded ke- (entry 3). That shows the crucial role of water for the
tone to have a chance to obtain better enantioselectivi- protonation and hydrolysis of the intermediate species
ties. Therefore, we examined the addition of cyclohexa- involved in the catalytic cycle. Indeed, we can consider
none to nitrostyrene (Scheme 4). The racemic addition ammonium chloride as a drying agent which traps the
product was obtained with pyrrolidine as achiral cata- forming water during the catalytic cycle, thus stopping
lyst. But, surprisingly, when we performed the asymmet- the reaction. With these new conditions we observed
ric reaction with our chiral catalysts, none of them cata- that the catalysts 3a and 3h gave lower ees and the dia-
lyzed the addition. Then, additives were tested to allow mine 3b furnished almost the same ee as iPBP 3g. More-
the addition reaction catalyzed by iPBP 3g to take place. over, the ammonium chloride can be replaced with a 1.0
Indeed, it is known that additives can have a major role molar solution of hydrochloric acid in methanol to form
in the reactivity of organocatalyzed aldol reac- the hydrochloride of iPBP 3g to obtain the adduct 6e
tions,[62,64,66] Mannich reactions,[36] Diels–Alder reac- with a slight increase of the enantioselectivity (81%
tions[85,86,88,89,91] or Friedel–Crafts alkylations.[72,74,75,78] ee, entry 5). Finally, a simple carboxylic acid can also
Our results are summarized in Table 3.
be used, such as benzoic acid, to activate the reaction
As mentioned above iPBP 3g did not catalyze the ad- (entry 6).
dition of cyclohexanone to nitrostyrene. We thought
that the addition of a catalytic amount of pTSA·H2O
would increase the reaction rate, as for the acetone Asymmetric Addition of Ketones to Nitrostyrene Cata-
case, by forming a mimic l-proline species with the pyr- lyzed by iPBP
rolidine moiety and an ammonium function to replace
the carboxylic group. Indeed, Enders[48] and List[47] had After these first encouraging results we then tested sev-
already reported the asymmetric addition of cyclohexa- eral kinds of symmetrical and non-symmetrical ketones
none and other ketones to nitrostyrene catalyzed by l- (Scheme 5).
Table 3. Addition of cyclohexanone to nitrostyrene catalyzed by iPBP.
Entry
Additive
Reaction time
Yield[a] [%]
dr[b] syn:anti
ee[c] [%]
1
2
3
4
5
6
none
pTSA·H2O
NH4Cl
2 d
2 d
2 d
15 h
15 h
15 h
0
0
0
70
74
76
–
–
–
–
–
–
75
81
77
NH4Cl, H2O 1 equiv.
91: 9
94: 6
92: 8
HCl[d]
PhCOOH
[a]
Yield of isolated product after column chromatography.
Determined by H NMR of the crude product.
Determined by SFC employing chiral phase: Chiralpak AD.
The hydrochloride of iPBP 3g was formed using a solution of 1.0 M HCl in MeOH.
[b]
[c]
[d]
1
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Table 4. Conjugate addition of ketones 5a–f to nitrostyrene catalyzed by iPBP 3g to afford g-nitro ketones 6a–f and 7b–c.
Entry
Ketone
R3
R4
Additive
Conditions
Yield[a]
[%]
rr[b]
dr[c] syn:anti
ee[d]
(syn)
Product
1[e]
2[e]
3[e]
4
5
6
7
8
9
10
11
12
13
14
15
16
5a
H
H
None
rt, 15 h
rt, 15 h
rt, 15 h
rt, 3 d
rt, 4 d
rt, 6 d
rt, 6 d
rt, 6 d
608C, 7 d
rt, 6 d
608C, 7 d
rt, 6 d
29 (15)[g]
–
–
–
–
–
–
29
23
25
32
48
51
37
n.d.
36
n.d.
34
76
67
81
50
17
6a
6a
6a
pTSA·H2O
74 (0)[g]
82 (9)[g]
61
HCl[f]
5b
5c
H
H
Me
Et
None
43: 57 (70)[h]
85: 15
82: 18
80: 20
78: 22
n.d.
70: 30
n.d.
68: 32
n.d.
84: 16
94: 6
69: 31
34: 66
6bþ7b
6bþ7b
6bþ7b
6cþ7c
6cþ7c
6cþ7c
6cþ7c
6cþ7c
6d
6d
6e
6f
6f
pTSA·H2O
99
55
46
trace
81
trace
95
8
65
74
70: 30 (56)[h]
HCl[f]
74: 26 (49)[h]
None
33: 67 (53)[h]
pTSA·H2O
pTSA·H2O
HCl[f]
n.d.
40: 60 (40)[h]
n.d.
HCl[f]
33: 67 (38)[h]
5d
Me
Me
HCl[f]
–
–
–
–
–
HCl[f]
608C, 7 d
rt, 15 h
rt, 6 d
5e
5f
-(CH2)3-
-(CH2)2-
HCl[f]
HCl[f]
6
46
HCl[f]
608C, 6 d
[a]
Yield of isolated product after column chromatography on SiO2.
[b]
[c]
[d]
1
Regioisomeric ratio (6b:7b or 6c:7c) determined by H NMR or GC.
1
Determined by H NMR of crude product.
Determined by GC or SFC employing chiral phases: Lipodex E, Chiralcel OB-H, Chiralpak AD. The relative and absolute
configuration of 6e were determined by comparison with literature data.[120] The stereochemistries of compounds 6a, 6b,7b,
6c, 7c, 6d and 6f have been assigned by assuming an identical reaction pathway and according to literature results.[47,48]
Using only acetone as solvent.
Diamine hydrochloride was formed using a solution of 1.0 M HCl in MeOH.
In parenthesis is given the yield of the double addition product on acetone.
[e]
[f]
[g]
[h]
Enantiomeric excess of the terminal regioisomer 7.
Scheme 5.
Having optimized the catalyst and the reaction condi- for adduct 7c (67:33) (entry 7). In the presence of
tions, we next tested the asymmetric addition of other pTSA·H2O (0.15 equivs.) or the hydrochloride catalyst,
ketones to nitrostyrene 4 using diamine iPBP 3g. Re- the prototropy of the reactive enamine was more favour-
sults are summarized in Table 4. As previously dis- able and the equilibration between the more and the less
cussed, the reactions with acetone, catalyzed by iPBP substituted enamine could occur. That leads to the for-
3g, give a non-negligible quantity of the dinitro adduct mation of the more stable substituted enamine. Thus,
(entry 1). A catalytic amount of pTSA·H2O completely the regioselectivity obtained for the adduct 6b–7b (en-
eliminates the formation of this by-product and also tries 5 and 6) was inverted, indicating that the equilibri-
causes an increase in the reaction rate (entry 2). Dia- um was too slow to involve a Curtin–Hammet kinetics
mine iPBP 3g hydrochloride gave adduct 6a in good which had favoured the adduct 7b. But, the equilibrium
yield and moderate ee (25% ee) (entry 3) but also with between the two enamines certainly takes partially
a small amount of by-product (9%).
place and does not allow us to affirm that the regiocon-
The catalytic Michael addition of non-symmetrical trol of the enamine formation is transposed to the regioi-
ketonessuch asmethyl ethylketone 5b and methylprop- someric ratio of adducts. Only traces of product were ob-
yl ketone 5c introduces the problem of regioselectivity. served for adduct 6c at room temperature after 7 days
In basic conditions, the less hindered methyl group re- (entries 8 and 10), but after 7 days at 608C, the reaction
acts preferentially, in a low regioisomer ratio (rr) for ad- was complete (entries 9 and 11). Nevertheless, the regio-
duct 7b (57:43) (entry 4) and modest regioisomer ratio selectivity was not inverted. We assume that the enam-
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Olivier Andrey et al.
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ine equilibration could occur but that the substituted en- about one of these two mechanisms. A model has been
amine was too hindered to react quickly. In these condi- proposed to explain the absolute configuration of the
tions a Curtin–Hammet kinetics was involved and the adducts (Scheme 6). Two factors are important for
methyl adduct 7c was obtained as the major product good enantioselection; firstly, one face of the enamine
with a slow reaction rate. To avoid the problem of re- must be less accessible and secondly, the equilibrium be-
gioisomers, diethyl ketone 5d was tested. It did not react tween the enamine rotamers must be well shifted to one
at all, either with diamine iPBP 3g or with addition of side. The isopropyl group plays these two roles, it blocks
pTSA·H2O. However, the reaction catalyzed by dia- the back face against the approach of the nitroolefin and
mine iPBP 3g hydrochloride gave adduct 6d. At room it shifts the equilibrium towards one of the two rotamers.
temperature, only 8% were isolated, after 6 days, with This displacement is probably due to the bigger Avalue
good enantioselectivity (76% ee) (entry 12). After 7 of the sp3 carbon, compared to a sp2 one, which interacts
days at 608C, the reaction was complete and adduct 6d sterically with the isopropyl group. Moreover, the Si,Si
was obtained in a moderate yield (65%), goodenantiose- transition state is certainly less stable on account of
lectivity (67% ee) and diastereoselectivity (84:16) (En- the allylic strain (A1,3) present on this transition state.
try 13).
According to our results and to our model the Re,Re ap-
Finally, the adduct 6f was obtained in poor yield (6%) proach is favoured for ketones, but the small difference
and moderate enantioselectivity (50% ee) (entry 15) af- of size of the two sides of the ketones leads to modest
ter 7 days at room temperature in the presence of iPBP enantioselectivities and diastereoselectivities.
3g hydrochloride. Prolonged the heating time (entry 16)
gave a better yield (46%) albeit with a loss of diastereo- the regioselectivity which was never totally controlled.
and enantiocontrol. This drawback was suppressed when we used a-hetero-
The main problem with non-symmetrical ketones was
The syn selectivity we observe is in accordance with substituted ketones such as 5g–j (Table 5, Scheme 7).
Seebachꢀs model.[121–124] It is explained by an acyclic syn- Indeed, the branched adducts 6g and 6h were formed ex-
clinal model, in which there are favourable electrostatic clusively when methoxyacetone 5g or hydroxyacetone
interactions between the nitrogen of the enamine and 5h were used. This regioselectivity could be explained
the nitro group in the transition state. An inverse-elec- by the difference of the acidity of the a and a’ hydrogens
tron-demand hetero-Diels–Alder mechanism, concert- of the ketones. The strongest acidity of the hydrogen
ed or not, as proposed by Jørgensen[90] for the addition next to the oxygen atom leads only to the enol-enamine
of aldehydes to enones could also be postulated. But species. When the oxygen atom is replaced by the nitro-
the resulting cycloadducts would be immediately hydro- gen of the dimethylamino group of 5j this behaviour is
lyzed in the reaction mixture. Thus, we could not argue not observed. Probably the balance between acidity
and steric hindrance was in favour of the terminal enam-
ine which affords the linear addition product 7j.
The use of a-alkoxycarbonyls has already been descri-
bed in aldol reactions[15,25] and Mannich reactions,[35,37,39]
catalyzed by l-proline, with very high stereo- and regio-
selectivities. But the result obtained for the addition of
hydroxyacetone to nitrostyrene catalyzed by iPBP 3g
was astonishing (Table 5, entry 2). The regioselectivity
was fully controlled, as expected, but we had never ob-
Scheme 6.
tained the anti adduct as major product 6h before.
Scheme 7.
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Table 5. Conjugate addition of a-heterosubstituted ketones to nitrostyrene 4.
Entry
Ketone
Catalyst
R3
R4
Conditions
Yield[a]
[%]
rr[b] 6:7
dr[c]
syn:anti
ee[d]
[%]
Product[e]
1
2
3
4
5
6
7
8
5g
5h
(S,S )-iPBP
(S,S )-iPBP
l-proline[f]
8[g]
(S,S )-iPBP
(S,S )-iPBP
l-proline[f]
8
H
H
H
H
Et
H
H
H
OMe
OH
OH
OH
OH
NMe2
NMe2
NMe2
rt, 2 d
rt, 7 d
rt, 4 d
rt, 7 d
608C, 7 d
rt, 3 d
rt, 3 d
rt, 3 d
75
79
67
59
21
52
24
83
>99: 1
>99: 1
>99: 1
>99: 1
>99: 1
>1: 99
>1: 99
>1: 99
83: 17
17: 83
70: 30
51: 49
8: 92
–
69
98
6g (S,R)
6h (R,R)
6h
6h (R,R)
6i (R,R)
7j (R)
11
10[h]
98
5i
5j
62
63
75
–
–
7j (R)
7j (R)
[a]
Yield of isolated product after column chromatography on SiO2.
[b]
[c]
[d]
1
Regioisomeric ratio determined by H NMR or GC.
1
Determined by H NMR of crude product.
Enantiomeric excess of the major regioisomer and diastereomer determined by GC or SFC employing chiral phases: Chir-
alcel OJ, Chiralpak AD.
[e]
Relative and absolute configurations of 6g, 6i and 7j were assigned according to our transition state model (Scheme 6). Re-
lative and absolute configurations of 6h were attributed assuming the same reaction pathway as for 10e.
Using MeOH as solvent.
[f]
[g]
[h]
(S)-(þ)-(1-Pyrrolidinylmethyl)pyrrolidine 8.
(anti): 38% ee
Asymmetric Addition of Hydroxyacetone to Nitroole-
fins Catalyzed by iPBP
The addition of hydroxyacetone was then extended to
nitroolefins other than nitrostyrene (Scheme 9). Un-
fortunately, the addition of hydroxyacetone was not pos-
sible on non-aromatic nitroolefins, such as b-cyclohexyl-
nitroethene 9l or b-(n-butyl)-nitroethene 9k. After sev-
eral days some traces of the product were observed by
TLC but many other products were also formed and
Scheme 8.
Even the syn adduct was obtained in the racemic version the starting material was not totally consumed. The
catalyzed by pyrrolidine. Furthermore, the enantiose- non-aromatic nitroolefins seem to be not reactive
lectivity was almost total (98% ee). At this stage we enough to accept hydroxyacetone and they decompose
had to modify our transition state model. We had as- gently during the long reaction time. In a second step,
sumed that the only way to explain the inversion of dia- the addition of hydroxyacetone to different b-arylni-
stereoselectivity was the formation of the cis enamine. troolefins 9b–j was tested, and the results are summar-
This cis enamine could be formed after the deprotona- ized in Table 6. All reactions were carried out in chloro-
tion of the iminium with the hydroxy group blocked at form with 15% catalyst and 10 equivs. of ketone for a du-
the cis conformation by an internal hydrogen bond ration of 7 days.
(Scheme 8). This hydrogen bond remains on the enam-
We have observed only little differences in enantiose-
ine species and, due to the rigid conformation, the enan- lectivity between the adducts 10b–j. Generally speak-
tiomeric excesses obtained are very high. In addition, ing electron-withdrawing groups on the aryl moiety
the absolute configuration of the adduct, vide infra, gave slightly higher yields and stereoselectivities. The
was in accordance with our model. This result was very relative configuration of the adduct 10e was determined
significant, all the more so since neither l-proline (Ta- by X-ray diffraction of its Mosher ester 10e–mosher[125]
ble 5, entry 3) nor (S)-(þ)-(1-pyrrolidinylmethyl)pyrro-
lidine 8 (Table 5, entry 4) gave such inversion and high
enantioselectivities for this reaction. Screening of differ-
ent solvents has shown that chlorinated solvents, CHCl3
(78%, 98% ee) and CH2Cl2 (68%, 98% ee), gave higher
yields and selectivities. For the aminated ketone 5j, the
best result was obtained with the less hindered diamine
8 that give the linear adduct 7j in 83% yield and 75% ee. Scheme 9.
Adv. Synth. Catal. 2004, 346, 1147–1168
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FULL PAPERS
Table 6. Conjugate addition of hydroxyacetone to nitroole-
fins catalyzed by diamine iPBP.
Table 7. Asymmetric addition of valeraldehyde to nitrostyr-
ene catalyzed by diamines 3a–h in a mixture THF:DMF
(3: 1).
Entry Substrate Ar
Yield[a] dr[b]
ee[c]
[%]
anti:syn [%]
Entry
cat* 3
Reaction
time
Yield[a]
[%]
dr[b]
syn/anti
ee[c]
[%]
1
2
3
4
5
6
7
8
9
9
4
Ph
79
68
65
81
84
83
66
85
83: 17
84: 16
81: 19
87: 13
95: 5
84: 16
88: 12
91: 9
97.6
97.6
97.3
97.8
98.5
98.1
98.1
98.6
98.3
96.3
9b
9c
9d
9e
9f
9g
9h
9i
4-MePh
4-MeOPh
4-ClPh
2-CF3Ph
2,6-Cl2Ph
3,4-Cl2Ph
2,4-Cl2Ph
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
2 d
2 d
2 d
2 d
2 d
2 d
2 d
1 d
74
77
75: 25
73: 27
76: 24
72: 28
76: 24
77: 23
73: 27
77: 23
49
56
53
41
51
55
63
60
100[d]
100[d]
100[d]
100[d]
92
3g
3h
1-naphthyl 68
2-thienyl 66
78: 22
78: 22
85
9j
[a]
Yield of isolated product after column chromatography on
SiO2.
Determined by H NMR or SFC of the crude product.
Determined by chiral SFC of the purified product.
Conversion determined by GC.
[a]
Yield of isolated product after column chromatography on
SiO2.
Determined by H NMR or SFC of the crude product.
[b]
[c]
[d]
1
[b]
[c]
1
Determined by chiral SFC of the purified product.
were curious to explore this chemistry with our 2,2’-bi-
pyrrolidine derivative diamine catalysts.
Optimization of the Organocatalyst and Reaction
Conditions
For the addition of ketones to nitroolefins we have
shown that iPBP 3g was generally the most selective cat-
alyst but the other ones were only slightly less efficient.
This is why we decided to test again the whole range of
diamines for the addition of valeraldehyde 11c to nitro-
styrene 4. All these reaction were performed in a mix-
ture of THF:DMF (3:1).
The results givenabove (Table 7)show that the nature of
the catalyst does not influence much the reaction rate, in
contrast to the behaviour observed with acetone. The dia-
stereoselectivity of the adduct 12c is also not influenced by
the catalyst. However, the enantioselectivity is significant-
ly higher for the catalysts having a secondary substituent
on nitrogen. As for the ketone case, the diamine iPBP
3g (63% ee, entry 7) and 3h (60% ee, entry 8) gave the
best ees. We then focused our attention on iPBP 3g and
Figure 1.
(Figure 1). The absolute configuration of the centre of tested other solvents in an attempt to optimize the condi-
the starting Mosher acid being known, we deduced the tions. The results are summarized in Table 8.
absolute configuration of adduct 10e (R,R). It may be
The conjugate addition of valeraldehyde, run in anhy-
considered that the configuration of the others adducts drous THF, gave only 5% conversion after 2 days at
10b–j is the same.
room temperature (entry 2) but in wet THF the conver-
sion was 65% after 15 hours and the enantiomeric excess
Asymmetric Addition of Aldehydes to Nitroolefins
Barbas was the first to report the asymmetric addition of
naked aldehydes to nitroolefins catalyzed by chiral dia-
mines.[84] He has obtained good enantioselectivities, up
to 78% ee, for the addition of isovaleraldehyde to 9e
but the ees decrease quickly for smaller aldehydes. We Scheme 10.
1154
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N-Alkyl-2,2’-bipyrrolidine Derivatives as Organocatalysts
FULL PAPERS
Table 8. Asymmetric addition of valeraldehyde to nitrostyrene catalyzed by diamines iPBP 3g in different solvent.
Entry
Solvent
Reaction time
Yield[a] [%]
dr[b] syn/anti
ee[c] [%]
1
2
3
4
5
6
THF:DMF 3: 1
anhydrous THF
wet THF
THF:CHCl3 3: 1
CHCl3
2 d
2 d
15 h
3 d
15 h
15 h
92
5[d]
73: 27
n.d.
78: 22
56: 44
73: 27
72: 28
63
n.d.
70
63
72
65[d]
99
99
MeOH
100[d]
59
[a]
Yield of isolated product after column chromatography on SiO2.
Determined by H NMR or SFC of the crude product.
Determined by chiral SFC of the purified product.
Conversion determined by GC.
[b]
[c]
[d]
1
was higher (70% ee, entry 3) than for a THF:DMF mix- Asymmetric Addition of Aldehydes to Nitrostyrene
ture (entry 1). Methanol (entry 6) and THF:CHCl3 mix- Catalyzed by iPBP
ture (entry 4) gave lower ees compared to chloroform
which give the adduct in good yield (99%) and selectivity Then, with the optimal catalyst and solvent, we exam-
(72% ee, syn/anti 73:27). All these reactions were ac- ined a series of aldehydes. The results are summarized
companied with the formation of a substantial amount in Table 9. The highest rate of reaction was observed
of condensation product of the valeraldehyde which is for propionaldehyde 11a, even at À258C (entry 2), the
easily removed by flash chromatography.
reaction went to completion in a reasonable length of
As we have shown previously, Barbas[84] has reported time. Decreasing the temperature had a drastic effect
the addition of aldehydes to nitrostyrene catalyzed by on the enantio- and diastereoselectivity which increased
(S)-(þ)-1-(2-pyrrolidinylmethyl)pyrrolidine 8 and oth- from 77% ee and 75:25 dr (entry 1) to 93% ee and 94:6
er diamines in THF at room temperature with good dr (entry 2) for propionaldehyde 11a. A tangible de-
enantioselectivities. We were curious to see if our new crease of the amount of aldehyde self-condensation
conditions would allow the catalyst 8 to be more selec- was also observed with the lowering of the temperature.
tive than iPBP 3g. Interestingly, our conditions were Butyraldehyde 11b and valeraldehyde 11c also reacted
not optimal at all for this diamine. The enantiomeric ex- at À258C with good enantioselectivity, 81% ee (en-
cesses measured remained really modest (entries 3, 5 try 4) and 87% ee (entry 7) respectively, but the reaction
and 8; Table 9).
took twice as long as that with propionaldehyde 11a. Iso-
valeraldehyde 11d however, reacted only at room tem-
perature and yielded products with a modest enantiose-
Table 9. Conjugate addition of aldehydes 11a–f to nitrostyrene 4 catalyzed by iPBP 3g to afford g-nitro aldehydes 12a–f.
Entry
Aldehyde
R5
Conditions
Yield[a] [%]
dr[b] syn:anti
ee[c] (syn) [%]
Product
1
2
3
4
5
6
7
8
9
11a
Me
rt, 1h30
99
71
86
70
93
99
98
83
99
19
72
75: 25
94: 6
94: 6
90: 10
94: 6
73: 27
96: 4
94: 6
87: 13
72: 28
–
77
12a
12a
12a
12b
12b
12c
12c
12c
À258C, 2d
À258C, 15 h
À258C, 4 d
À258C, 15 h
rt, 15 h
À258C, 4 d
À258C, 15 h
rt, 2 d
93
60[d]
81
11b
11c
Et
Pr
53[d]
72
87
56[d]
73
11d
11e
11f
i-Pr
12d
12e
12f (R)
10
11
Ph
rt, 2 d
rt, 3 d
26
80
Me,Me[e]
[a]
Yield of isolated product after column chromatography on SiO2.
Determined by H NMR or SFC of the crude product.
[b]
[c]
1
Determined by chiral SFC of the purified product. Relative (syn) and absolute configurations of aldehydes 12a, 12b and 12d
were determined by comparison with known literature data.[84] The stereochemistries of aldehydes 12c, 12e and 12f have
been tentatively assigned by comparison to analogous compounds.
[d]
[e]
Reaction catalyzed by (S)-(þ)-1-(2-pyrrolidinylmethyl)pyrrolidine 8.
Isobutyraldehyde.
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FULL PAPERS
We were delighted to see that the addition occurred
both to the aromatic and to the non-aromatic nitroole-
fins, whereas this was not the case for hydroxyacetone.
Interestingly, the nature of the nitroolefins has no influ-
ence on the enantioselectivity which is around 93% ee in
all cases, whatever the nitroolefin, having aromatic (en-
tries 1–5) or non-aromatic groups (entries 6–8). We
just observed a decrease of the diastereoselectivity
Scheme 11.
lectivity (73% ee) (entry 9). Isobutyraldehyde 11f afford (syn/anti 73:27) with the adduct 13m (entry 8) and a
after three days at room temperature a product contain- loss of reactivity with the nitroolefin 9n.[126] Indeed, a
ing a quaternary centre, 12f, with 80% ee (entry 11). Fi- strong withdrawing group CF3 does not allow the reac-
nally, phenylacetaldehyde 11e gave the addition product tion to take place at À258C (entry 9). But, the adduct
12e in poor (19%) yield and enantioselectivity (26%, en- 13n was isolated after one day at room temperature in
try 10). This result shows the limitation of the method. In 42% yield, 91% ee and a ratio syn/anti of 77:23 (en-
fact, when we have a too acidic hydrogen in the a posi- try 10). However, a prolonged reaction time (3 days)
tion to the carbonyl, the reaction takes a new pathway. does not increase the yield and an epimerization to the
The mechanism involving a deprotonation by the amine anti adduct occurs.
to give an enolate (see Scheme 1, mechanism type B)
The transition state model proposed in Scheme 13 can
could be postulated instead of the mechanism involving explain the absolute configuration. There is no funda-
an enamine. This new pathway is, in our case, less selec- mental difference between the transition state for ke-
tive in terms of enantio- and diastereoselectivity.
tones (Scheme 6) and for aldehydes (Scheme 13) except
the inversion of the relative size of the two sides of the
carbonyl group or enamine. For the case of ketones,
the smallest side is the one with the double bond of the
enamine while the hydrogen was the smallest group
for aldehydes. Hence, the Si,Si transition state is well
Asymmetric Addition of Propionaldehydes to Nitro-
olefins Catalyzed by iPBP
The high velocity and selectivity observed for the addi- favoured compared to the Re,Re and the enantioselec-
tion reaction of propionaldehyde to nitrostyrene led us tivities are high.
to experiment with other nitroolefins. The results are
summarized in Table 10.
Scheme 12.
Scheme 13.
Table 10. Conjugate addition of propionaldehyde 11a to nitroolefins catalyzed by iPBP 3g to afford g-nitro aldehydes 12a and
13b–n.
Entry
Substrate
R6
Reaction time
Yield[a] [%]
dr[b] syn:anti
ee[c] (syn) [%]
Product
1
2
3
4
5
6
7
8
9
4
Ph
2 d
3 d
3 d
3 d
2 d
15 h
3 d
3 d
3 d
71
88
64
74
66
70
76
73
94: 6
95: 5
94: 6
92: 8
94: 6
90: 10
85: 15
73: 27
n.d.
93
94
93
95
93
93
96
90
n.d.
91
12a
13b
13c
13e
13j
13k
13l
13m
13n
13n
9b
9c
9e
9j
9k
9l
9m
9n
9n
4-MePh
4-MeOPh
2-CF3Ph
2-Thienyl
Butyl
c-Hexyl
CH(OMe)2
CF3
traces
42
10
CF3
1 d, rt
77: 23
[a]
Yield of isolated product after column chromatography on SiO2.
Determined by H NMR or SFC of the crude product.
Determined by chiral SFC of the purified product. The stereochemistries of aldehydes 13b –m have been tentatively as-
signed by comparison to 12a.
[b]
[c]
1
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N-Alkyl-2,2’-bipyrrolidine Derivatives as Organocatalysts
FULL PAPERS
Scheme 14.
Scheme 15.
From a synthetic point of view, the possibility to add
propionaldehyde with high enantioselectivity on any
kind of nitroolefins is very interesting. We have demon- the reaction takes place. Note that we have observed al-
strated this potential with the first asymmetric synthesis most the reverse reaction rate when we performed these
of (À)-botryodiplodin[127] (Scheme 14). In few steps, reactions with a unique nitroolefin.
starting from an asymmetric addition of propionalde-
Thus, we can say that not only the Michael acceptor
hyde to the nitroolefin 14 catalyzed by (S,S)-iPBP 3g, character has an influence on the reaction rate but also
we were able to isolate the natural product with 93% ee. the availability of the catalyst which is trapped by the
substrate in some cases. Finally, the fastest reactions
are observed with moderate Michael acceptors such as
NMR Investigation
4 or 9k.
During our study on the asymmetric addition of propio-
naldehyde tothe wholerange ofnitroolefins we have no- Conclusion
ticed significant differences of behaviour between these
Michael acceptors. A better understanding of the reac- In conclusion, we have confirmed that asymmetric orga-
tivity of the nitroolefins was achieved after we had run nocatalysis is a powerful tool for organic synthesis. In-
several racemic test reactions in NMR tubes deed, we were able to obtain the conjugate addition of
(Scheme 15).
aldehydes and ketones to nitroolefins without any previ-
The first things we have observed were that pyrroli- ous protection, or particular precautions, with high
dine quickly adds to most of the nitroolefins to give yields and selectivities. Furthermore, the temperature
1
the adduct 15 clearly identified by H NMR. But this range, À258C to room temperature, used for these reac-
1,4 addition was not observed on the a,b-dialkylnitro- tions could be very interesting from an industrial point
ethylenes, indicating their poor Michael acceptor char- of view. The main drawbacks of organocatalysis remain
acter. The reversibility of the addition was proved with its low reaction rate and high catalyst loading which
the fast isomerization of cis-nitrostyrene to trans-nitro- must be absolutely improved in the future. Some origi-
styrene with a catalytic amount of pyrrolidine. After nal works using ionic liquid[46,128,129] or high pressure[28,43]
having formed the pyrrolidine adduct 15 we have added have already been published; we can also imagine that
propionaldehyde. This experiment has revealed two microwave or sonication would increase the reaction
groups of nitroolefins, the first one (4, 9k and 9l) showed rate. We have also shown that l-proline is not a universal
a partial disappearance of the pyrrolidine adduct 15 and organocatalyst. Generally speaking, we can say that l-
a fast formation of propionaldehyde adduct 17 without proline is a catalyst for the 1,2 additions of enamine,
the clear identification of the enamine 16. The second namely aldol reaction, Mannich reaction, additions to
group (9m, 9n and 14) revealed no disappearance of nitroso or diaza compounds. And chiral pyrrolidines
the pyrrolidine adduct 15 and a slower formation of without a proton donating group, such as carboxylic or
the propionaldehyde adduct. By adding pyrrolidine in hydroxy group, are catalysts for conjugate additions to
default to several mixtures of two nitroolefins we were nitroolefins,[47,48,77,80,84] vinyl ketones[81] or alkylidene-
able to classify them in terms of Michael acceptor char- malonates.[71] New catalysts and new substrates are
acter. The following sequence was obtained according to now in development in our laboratories in accordance
adduct 15 formed predominantly: 9l<4<9k<14 ꢀ9m
ꢀ9n. When propionaldehyde was added to these mix-
tures we observed the normal reactivity, that means
that the more of an acceptor the substrate is, the fastest
with this final conclusion.
Adv. Synth. Catal. 2004, 346, 1147–1168
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Olivier Andrey et al.
FULL PAPERS
2.00 (m, 1H), 1.77–1.55 (m, 6H), 1.43–1.32 (m, 1H);
13C NMR (100.6 MHz, C6D6): d¼141.07 (s), 128.42 (2C, d),
128.14 (2C, d), 127.44 (d), 87.36 (d), 71.06 (d), 70.91 (d),
51.77 (t), 47.75 (t), 30.82 (t), 29.23 (t), 26.00 (t), 24.98 (t).
(S,S)-2,2’-Bipyrrolidine pivaldehyde aminal (2d): Product
was formed according to General Procedure 1 using diethyl
ether as solvent and pivaldehyde (0.31 g, 0.39 mL,
3.57 mmol). Removal of the solvent gave a yellow oil; yield:
Experimental Section
General Remarks
All reactions were run under an atmosphere of N2. Tetrahydro-
furan, Et2O and CH2Cl2 were distilled from Na/benzophenone
or CaH2, CHCl3 was stabilized with 1% of ethanol and used
without previous distillation. 1H NMR and 13C NMR were
measured on a Bruker 500 FT NMR or 400 FT NMR. Chemical
shift are reported as d values in ppm. Coupling constants are re-
ported in Hz. Multiplicity is indicated as follows: s (singlet), d
(doublet), t (triplet), q (quartet), quint (quintet), m (multiplet),
dd (doublet of doublet), bs (broad singlet). IR were recorded
on Perkin-Elmer 1600, [a]D20 were recorded on a Perkin-Elmer
241 polarimeter and GC/MSon an HP6890 with EI (70 eV) as
source; m/z (%).Gas chromatography program is given in a
shortened form: 1008C-2-10-170 indicates 1008C as starting
temperature then 2 minutes at 1008C then an rate of 108C/mi-
nutes up to 1708C. The same symbolism was used for supercrit-
ical fluid chromatography (SFC) where8C is replaced with %
of methanol.
1
690 mg (93%); H NMR (400 MHz, C6D6): d¼3.21–3.16 (m,
1H), 2.97 (s, 1H), 2.90 (dt, 1H, J¼9.8, 5.8 Hz), 2.82 (q, 1H,
J¼7.7 Hz), 2.51 (dt, 1H, J¼9.1, 6.3 Hz), 2.41–2.40 (m, 2H),
1.90–1.67 (m, 2H), 1.65–1.46 (m, 4H), 1.26–1.14 (m, 2H),
1.08 (s, 9H); 13C NMR (100.6 MHz, C6D6): d¼93.31 (d),
73.00 (d), 67.66 (d), 55.38 (t), 47.65 (t), 35.12 (s), 27.66 (t),
27.52 (t), 27.28 (3C, q), 26.97 (t), 24.39 (t).
(S,S)-2,2’-Bipyrrolidine mesitylaldehyde aminal (2e):
Product was formed according to General Procedure 1 using
diethyl ether as solvent and mesitylaldehyde (0.53 g, 0.52 mL,
3.57 mmol). Removal of the solvent gave a yellow oil; yield:
1
923 mg (96%); H NMR (400 MHz, C6D6): d¼6.82 (s, 1H),
6.79 (s, 1H), 4.98 (s, 1H), 3.08–3.06 (m, 2H), 2.82 (s, 3H),
2.74–2.67 (m, 2H), 2.55 (s, 3H), 2.42–2.33 (m, 2H), 2.13 (s,
3H), 1.90–1.82 (m, 1H), 1.65–1.38 (m, 6H), 1.30–1.22 (m,
1H); 13C NMR (100.6 MHz, C6D6): d¼138.05 (s), 137.76 (s),
135.80 (s), 132.85 (s), 131.26 (d), 129.13 (d), 86.23 (d), 69.71
(d), 69.61 (d), 51.95 (t), 47.44 (t), 30.22 (t), 29.40 (t), 25.89 (t),
25.60 (t), 21.88 (q), 20.44 (q), 20.37 (q).
Aminal Formation Starting from 2,2’-Bipyrolidine
General Procedure 1: To a solution of 2,2’-bipyrrolidine[113] 1 or
2,2’-bipyrrolidinium tartrate salt[114] (3.57 mmol) in THF or di-
ethyl ether (15 mL) for 2,2’-bipyrrolidine or MeOH (15 mL)
for 2,2’-bipyrrolidinium tartrate salt was added molecular
sieves 4 Š (~0.5 g) and ketone or aldehyde (3.57 mmol). The
mixture was stirred overnight, then K2CO3 was added and
the mixture was stirred for 1 hour and then filtered. Solvent
was removed to give the crude aminal 2a–h which was used
without purification for the next step.
(S,S)-2,2’-Bipyrrolidine formaldehyde aminal (2a): Prod-
uct was formed according to General Procedure 1 using diethyl
ether as solvent and aqueous formaldehyde 40% as aldehyde
(0.27 g, 3.57 mmol). Removal of the solvent gave a pale yellow
oil; yield: 467 mg (86%); 1H NMR (400 MHz, C6D6): d¼3.65 (s,
2H), 2.94–2.89 (m, 2H), 2.84 (dt, 2H, J¼10.1, 6.5 Hz), 2.51 (dt,
2H, J¼10.1, 6.8 Hz), 1.69–1.44 (m, 6H), 1.31–1.24 (m, 2H);
13C NMR (100.6 MHz, C6D6): d¼77.89 (t), 70.07 (2C, d),
52.82 (2C, t), 29.84 (2C, t), 25.08 (2C, t).
(S,S)-2,2’-Bipyrrolidine acetaldehyde aminal (2b): Prod-
uct was formed according to General Procedure 1 using THF
as solvent and acetaldehyde (0.16 g, 0.2 mL, 3.57 mmol). Re-
moval of the solvent gave a pale yellow oil; yield: 593 mg (quan-
titative); 1H NMR (400 MHz, C6D6): d¼3.59 (q, 1H, J¼
6.1 Hz), 3.07–3.02 (m, 1H), 2.98 (dt, 1H, J¼2.6, 7.2 Hz),
2.83–2.68 (m, 3H), 2.31–2.25 (m, 1H), 1.92–1.84 (m, 1H),
1.72–1.35 (m, 6H), 1.28 (d, 3H, J¼6.0 Hz), 1.18–1.12 (m,
1H); 13C NMR (100.6 MHz, C6D6): d¼80.03 (d), 70.88 (d),
70.40 (d), 50.83 (t), 45.88 (t), 30.38 (t), 28.85 (t), 25.38 (t),
25.08 (t), 17.87 (t).
(S,S)-2,2’-Bipyrrolidine ferrocene carboxaldehyde aminal
(2f): Product was formed according to General Procedure 1 us-
ing diethyl ether as solvent and ferrocenecarboxyaldehyde
(764 mg, 3.57 mmol). Removal of the solvent gave a dark
brown oil; yield: 1.11 g (92%); 1H NMR (400 MHz, C6D6):
d¼4.76 (s, 1H), 4.58–4.57 (m, 1H), 4.33–4.32 (m, 1H), 4.02
(s, 5H), 3.99–3.95 (m, 2H), 3.13 (q, 1H, J¼6.7 Hz), 3.07–3.01
(m, 2H), 2.84 (dt, 1H, J¼10.3, 6.3 Hz), 2.57 (q, 1H, J¼
8.8 Hz), 2.52–2.47 (m, 1H), 1.90–1.82 (m, 1H), 1.73–1.49 (m,
5H), 1.43–1.36 (m, 1H), 1.26–1.18 (m, 1H); 13C NMR
(100.6 MHz, C6D6): d¼89.32 (s), 84.35 (d), 70.75 (d), 70.36
(d), 68.60 (5C, d), 68.13 (d), 67.62 (d), 67.14 (d), 66.31 (d,
53.12 (t), 47.39 (t), 30.18 (t), 28.60 (t), 26.86 (t), 24.57 (t).
(S,S)-2,2’-Bipyrrolidine acetone aminal (2g): Product was
formed according to General Procedure 1 using diethyl ether
as solvent and acetone (5 mL). Removal of the solvent gave
a pale yellow oil; yield: 623 mg (97%). The product was also ob-
tained starting from bipyrrolidinium tartrate salt dissolved in
1
methanol and acetone. H NMR (400 MHz, C6D6): d¼3.22–
3.16 (m, 2H), 2.81–2.71 (m, 4H), 1.73–1.62 (m, 6H), 1.30–
1.22 (m, 2H), 1.21 (s, 6H); 13C NMR (100.6 MHz, C6D6): d¼
79.86 (s), 70.05 (2C, d), 46.97 (2C, t), 29.82 (2C, t), 27.10 (2C,
t), 25.99 (2C, t).
(S,S)-2,2’-Bipyrrolidine cyclohexanone aminal (2h): Prod-
uct was formed according to General Procedure 1 using THFas
solvent and cyclohexanone (0.35 g, 0.37 mL, 3.57 mmol). Re-
moval of the solvent gave a pale yellow oil; yield: 800 mg
(87%); 1H NMR (400 MHz, C6D6): d¼3.33–3.27 (m, 2H),
2.96 (dt, 2H, J¼9.8, 7.3 Hz), 2.90–2.84 (m, 2H), 1.95–1.67
(m, 11H), 1.48–1.36 (m, 7H); 13C NMR (100.6 MHz, C6D6):
d¼82.26 (s), 70.01 (2C, d), 45.84 (2C, t), 34.82 (2C, t), 29.95
(2C, t), 27.14 (2C, t), 26.01 (t), 24.55 (2C, t).
(S,S)-2,2’-Bipyrrolidine benzaldehyde aminal (2c): Prod-
uct was formed according to General Procedure 1 using diethyl
ether as solvent and benzaldehyde (0.38 g, 0.36 mL,
3.57 mmol). Removal of the solvent gave a pale yellow oil;
1
yield: 791 mg (97%); H NMR (400 MHz, C6D6): d¼7.92 (d,
2H, J¼7.1 Hz), 7.38 (t, 2H, J¼7.6 Hz), 7.28–7.23 (m, 1H),
4.96 (s, 1H), 3.36–3.27 (m, 2H), 2.95 (dt, 1H, J¼11.1,
6.6 Hz), 2.76 (q, 1H, J¼8.7 Hz), 2.50–2.46 (m, 2H), 2.08–
1158
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Adv. Synth. Catal. 2004, 346, 1147–1168

N-Alkyl-2,2’-bipyrrolidine Derivatives as Organocatalysts
FULL PAPERS
NH), 1.95–1.86 (m, 1H), 1.84–1.67 (m, 5H), 1.61–1.54 (m,
1H), 1.47–1.38 (m, 1H); 13C NMR (100.6 MHz, CDCl3): d¼
140.44 (s), 128.52 (2C, d), 128.13 (2C, d), 126.61 (d), 67.61
(d), 63.69 (d), 60.77 (t), 54.84 (t), 46.61 (t), 28.13 (t), 27.99 (t),
25.00 (t), 23.72 (t); IR (CHCl3): n¼3126 m, 2964 s, 2874 s,
2793 m, 2360 w, 1491 w, 1454 m, 1373 w, 1279 w, 1112 w, 1093
w, 1076 w, 905 m cmÀ1; MS(EI): m/z¼162 (1), 161 (17), 160
(100), 159 (2), 108 (2), 92 (4), 91 (54), 70 (7), 65 (1), 52 (2);
HRMS: calcd. for C15H22N2: 230.1783; found: 230.1740.
Reduction of 2,2’-Bipyrrolidine Aminal to N-Alkyl-
2,2’-bipyrrolidine
(S,S)-N-Methyl-2,2’-bipyrrolidine (3a): To a solution of ami-
nal 2a (404 mg, 2.65 mmol) in MeOH (15 mL) was added in
portions at 08C NaBH3CN (1.5 equivs., 3.98 mmol, 250 mg)
then trifluoroacetic acid (4 equivs., 10.6 mmol, 1.21 g,
0.81 mL). The solution was stirred for 1.5 h at 08C and then di-
luted with ether (20 mL) and hydrolyzed with aqueous NaOH
(5 mL) and water (10 mL). The solution was decanted; the
aqueous phase was extracted four times with ether. The com-
bined organic phases were washed with brine, dried over K2
CO3, filtered, and concentrated under reduced pressure to
give a yellow oil (yield: 343 mg, 84%) which was purified by
flash chromatography on silica gel (c-hexane/EtOAc, 7:3þ
5% MeOH þ10% Et3N) to give a pale yellow oil; yield:
178 mg (44%); [a]D20: À22.7 (c 1.1, CHCl3); 1H NMR
(400 MHz, CDCl3): d¼3.03–2.93 (m, 3H), 2.81–2.75 (m,
1H), 2.42 (s, 3H), 2.27–2.17 (m, 2H), 1.95 (bs, 1H, NH),
1.88–1.79 (m, 1H), 1.77–1.62 (m, 5H), 1.55–1.45 (m, 1H),
1.39–1.29 (m, 1H); 13C NMR (100.6 MHz, CDCl3): d¼69.53
(d), 63.60 (d), 58.21 (t), 46.87 (t), 42.83 (q), 28.31 (t), 28.07
(t), 24.94 (t), 23.35 (t); IR (CHCl3): n¼3148 m, 2969 s, 2875 s,
2789 m, 1672 w, 1457 m, 1270 w, 1212 m, 1144 w, 1094 w, 1047
w, 907 m cmÀ1; MS(EI): m/z¼120 (4), 105 (8), 86 (7), 85
(10), 84 (100), 83 (9), 82 (9), 70 (14), 69 (4), 68 (4), 55 (5), 47
(5); HRMS: calcd. for C9H18N2: 154.1461; found: 154.1470.
General Procedure 2: To a solution of aminal 2b–h
(2.5 mmol) in MeOH (10 mL) was added in portions at 08C
NaBH4 (1.5 equivs., 3.75 mmol, 142 mg) then acetic acid (4
equivs., 10.0 mmol, 0.60 g, 0.57 mL). The solution was stirred
3 hours at 08C and then diluted with diethyl ether (20 ml)
and hydrolyzed with 30% aqueous NaOH (5 mL) and water
(10 mL). The solution was decanted; the aqueous phase was ex-
tracted two times with EtOAc. The combined organic phases
were washed with brine, dried over K2CO3, filtered, concen-
trated under reduced pressure and purified by flash chroma-
tography on silica gel using (c-hexane/EtOAc 8:2þ10%
Et3N) as eluent.
(S,S)-N-(2,2-Dimethylpropyl)-2,2’-bipyrrolidine
(3d):
The aminal 2d (531 mg, 2.55 mmol) was reduced according to
General Procedure 2 to give a colourless oil; yield: 344 mg
(64%); [a]2D0: À49.8 (c 0.45, CHCl3); 1H NMR (400 MHz,
CDCl3): d¼3.13 (ddd, 1H, J¼10.1, 6.6, 4.8 Hz), 3.03–2.97
(m, 1H), 2.94 (q, 1H, J¼6.9 Hz), 2.82–2.75 (m, 1H), 2.61 (q,
1H, J¼6.5 Hz), 2.52 (d, 1H, J¼13.1 Hz), 2.31 (dt, 1H, J¼9.8,
7.5 Hz), 2.19 (d, 1H, J¼13.1 Hz), 2.07 (bs, 1H, NH), 1.79–
1.63 (m, 6H), 1.47–1.35 (m, 2H), 0.89 (s, 9H); 13C NMR
(100.6 MHz, CDCl3): d¼70.71 (t), 70.62 (d), 63.02 (d), 57.73
(t), 46.51 (t), 32.91 (s), 28.69 (3C, q), 27.34 (t), 26.98 (t), 25.09
(t), 24.57 (t); IR (CHCl3): n¼3180 m, 2946 s, 2874 m, 2342 w,
1477 w, 1459 w, 1396 w, 1360 w, 1103 w, 909 w cmÀ1; MS(EI):
195 (2), 153 (3), 141 (11), 140 (100), 126 (2), 124 (2), 96 (2),
84 (13), 83 (4), 82 (3), 71 (6), 70 (62), 68 (2), 56 (1), 55 (5);
HRMS: calcd. for C13H26N2: 210.2096; found: 210.2100.
(S,S)-N-(2,4,6-Trimethylphenyl)methyl-2,2’-bipyrrolidine
(3e): The aminal 2e (923 mg, 3.41 mmol) was reduced accord-
ing to General Procedure 2 to give a pale yellow oil; yield:
402 mg (43%); [a]D20: À24.9 (c 0.80, CHCl3); 1H NMR
(400 MHz, CDCl3): d¼6.83 (s, 2H), 3.92 (d, 1H, J¼12.1 Hz),
3.49 (d, 1H, J¼12.4 Hz), 3.14 (q, 1H, J¼6.9 Hz), 2.86 (ddd,
1H, J¼10.1, 7.3, 5.2 Hz), 2.79–2.62 (m, 3H), 2.39 (s, 6H),
2.32 (dt, 1H, J¼6.6, 9.1 Hz), 2.26 (s, 3H), 1.92–1.87 (m, 1H),
1.90 (bs, 1H, NH), 1.79–1.50 (m, 6H), 1.47–1.40 (m, 1H);
13C NMR (100.6 MHz, CDCl3): d¼137.48 (2C, s), 135.95 (s),
133.31 (s), 128.89 (2C, d), 67.97 (d), 61.77 (d), 53.50 (t), 53.23
(t), 46.65 (t), 27.55 (t), 27.19 (t), 25.59 (t), 23.59 (t), 20.81 (q),
20.39 (2C, q); IR (CHCl3): n¼3009 b, 2964 s, 2918 s, 2865 m,
1743 m, 1612 w, 1459 m, 1378 m, 1116 w, 909 m, 850 m cmÀ1
;
(S,S)-N-Ethyl-2,2’-bipyrrolidine (3b): The aminal 2b
(300 mg, 1.80 mmol) was reduced according to General Proce-
dure 2 to give a yellow oil; yield: 135 mg (46%); [a]2D0: À39.2 (c
1.25, CHCl3); 1H NMR (400 MHz, CDCl3): d¼3.13–3.08 (m,
1H), 3.04–2.96 (m, 2H), 2.94–2.88 (m, 1H), 2.81–2.75 (m,
1H), 2.44 (ddd, 1H, J¼5.7, 7.2, 8.5 Hz), 2.34–2.25 (m, 3H),
1.61 (m, 6H), 1.54–1.46 (m, 1H), 1.36–1.27 (m, 1H), 1.07 (t,
3H, J¼7.2 Hz); 13C NMR (100.6 MHz, CDCl3): d¼68.18 (d),
64.16 (d), 54.20 (t), 50.58 (t), 46.52 (t), 28.30 (t), 28.22 (t),
24.67 (t), 23.61 (t), 14.00 (q); IR (CHCl3): n¼3163 m, 2969 s,
MS(EI): m/z¼203 (11), 202 (55), 134 (15), 133 (100), 132
(6), 131 (1), 119 (2), 118 (3), 117 (4), 116 (1), 115 (2), 105 (4),
91 (4), 88 (3), 79 (1), 77 (1), 71 (1), 70 (20), 68 (2), 55 (1);
HRMS: calcd. for C18H28N2: 272.2252; found: 272.2200.
(S,S)-N-(Ferrocenyl)methyl-2,2’-bipyrrolidine (3f): The
aminal 2f (1.11 g, 3.30 mmol) was reduced according to Gener-
al Procedure 2 to give a brown oil; yield: 513 mg (46%); [a]2D0:
À35.9 (c 0.125, CHCl3); 1H NMR (400 MHz, CDCl3): d¼
4.19–4.15 (m, 2H), 4.11–4.08 (m, 7H), 3.85 (d, 1H, J¼
12.9 Hz), 3.37 (d, 1H, J¼12.9 Hz), 3.03–2.89 (m, 3H), 2.80
(dt, 1H, J¼9.9, 7.8 Hz), 2.59 (ddd, 1H, J¼8.3, 7.6, 5.1 Hz),
2.32 (q, 1H, J¼8.5 Hz), 2.00 (bs, 1H, NH); 1.84–1.60 (m,
6H), 1.52–1.44 (m, 1H), 1.39–1.31 (m, 1H); 13C NMR
(100.6 MHz, CDCl3): d¼84.82 (s), 69.87 (d), 69.75 (d), 68.38
(5C, d), 67.93 (d), 67.74 (d), 66.97 (d), 63.95 (d), 55.57 (t),
54.58 (t), 46.49 (t), 28.26 (t), 27.95 (t), 24.75 (t), 23.69 (t); IR
(CHCl3): n¼3009 m, 2964 s, 2865 m, 2493 w, 1743 m, 1464 w,
2875 s, 2803 m, 1457 m, 1381 m, 1281 m, 1094 m, 1051 m cmÀ1
;
¼
MS(EI): m/z 105 (3), 99 (17), 98 (100), 97 (5), 84 (8), 82 (3), 70
(21), 69 (3), 68 (4), 56 (3), 55 (3); HRMS: calcd. for C10H20N2:
168.1624; found: 168.1627.
(S,S)-N-Benzyl-2,2’-bipyrrolidine (3c): The aminal 2c
(696 mg, 3.05 mmol) was reduced according to General Proce-
dure 2 to give after bulb-to-bulb distillation (1758C/0.4 mbar) a
colourless oil; yield: 632 mg (90%); [a]2D0: À50.7 (c 0.84,
CHCl3); 1H NMR (400 MHz, CDCl3): d¼7.36–7.21 (m, 5H),
4.21 (d, 1H, J¼13.4 Hz), 3.40 (d, 1H, J¼13.1 Hz), 3.06 (q,
1H, J¼7.3 Hz), 2.98 (dt, 1H, J¼9.8, 6.2 Hz), 2.92 (dt, 1H, J¼
9.8, 4.8 Hz), 2.81 (dt, 1H, J¼10.1, 7.6 Hz), 2.69 (ddd, 1H, J¼
9.8, 6.8, 5.6 Hz), 2.25 (dt, 1H, J¼9.1, 8.3 Hz), 1.98 (bs, 1H,
1373 m, 1279 w, 1098 m, 1053 w, 1026 w, 999 w, 909 s cmÀ1
;
MS(EI): m/z¼338 (Mþ, 3), 269 (4), 268 (10), 201 (2), 200
(17), 199 (100), 198 (1), 197 (7), 134 (1), 122 (2), 121 (23), 119
(1), 70 (12), 56 (3); HRMS: calcd. for C19H26FeN2: 338.1445;
found: 338.1440.
Adv. Synth. Catal. 2004, 346, 1147–1168
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Olivier Andrey et al.
FULL PAPERS
1
(S,S)-N-Isopropyl-2,2’-bipyrrolidine (3g): The aminal 2g
(480 mg, 2.66 mmol) was reduced according to General Proce-
dure 2 to give after bulb-to-bulb distillation (708C/0.2 mbar) a
colourless oil; yield:427 mg (88%); [a]2D0: À29.6 (c 0.48, CHCl3);
1H NMR (400 MHz, CDCl3): d¼3.13 (hept, 1H, J¼6.6 Hz),
3.02–2.96 (m, 1H), 2.86–2.71 (m, 4H), 2.63–2.57 (m, 1H),
2.04 (bs, 1H, NH), 1.78–1.59 (m, 6H), 1.53–1.47 (m, 1H),
1.34–1.26 (m, 1H), 1.09 (d, 3H, J¼6.8 Hz), 0.93 (d, 3H, J¼
6.3 Hz); 13C NMR (100.6 MHz, CDCl3): d¼64.67 (d), 64.37
(d), 51.09 (d), 46.22 (t), 46.09 (t), 29.07 (t), 28.10 (t), 24.55
(2C, t), 22.61 (q), 14.92 (q); IR (CHCl3): n¼3163 m, 2959 s,
2875 s, 2495 w, 1458 w, 1384 w, 1263 w, 1165 w, 1096 w, 1059 w
cmÀ1; MS(EI): m/z¼113 (13), 112 (100), 111 (1), 98 (4), 97
(1), 96 (2), 71 (2), 70 (38), 69 (1), 68 (2); HRMS: calcd. for
C11H22N2: 182.1783; found: 182.1780.
(5R)]; H NMR (400 MHz, CDCl3): d¼7.37–7.23 (m, 5H),
4.72 (dd, 1H, J¼6.8, 12.4 Hz), 4.63 (dd, 1H, J¼7.8, 12.4 Hz),
4.05 (quint, 1H, J¼7.2 Hz), 2.90 (d, 2H, J¼7.1 Hz), 2.43 (dq,
1H, J¼17.7, 7.3 Hz), 2.36 (dq, 1H, J¼17.7, 7.3 Hz), 1.02 (t,
3H, J¼7.0 Hz); 13C NMR (100.6 MHz, CDCl3): d¼208.22
(s), 138.93 (s), 129.05 (2C, d), 127.87 (d), 127.37 (2C d), 79.51
(t), 44.92 (t), 39.13 (d), 36.49 (t), 26.91 (t), 7.54 (q).
1-Nitro-2-phenylheptan-4-one (7c): From propan-2-one 5c
and nitrostyrene according to General Procedure 3 to obtain a
mixture of 2 regioisomers: 3-(2-nitro-1-phenylethyl)pentan-2-
one 6c and 7c as a colourless oil. The compound 6c was not iso-
lated for analysis. The enantiomeric excess of 7c was deter-
mined by SFC [Chiralpak AD, 2 mL/min, 200 bar, MeOH
2%-4-2-15, 308C, Rt: 6.6 min (5R) and 7.8 min (5S)]; mp 32–
1
348C (pentane); H NMR (400 MHz, CDCl3): d¼7.36–7.18
(S,S)-N-Cyclohexyl-2,2’-bipyrrolidine (3h): The aminal 2h
(400 mg, 1.82 mmol) was reduced according to General Proce-
dure 2 to give after bulb-to-bulb distillation (1208C/2 mbar) a
colourless oil; yield: 324 mg (80%); [a]2D0: À35.9 (c 0.32,
CHCl3); 1H NMR (400 MHz, CDCl3): d¼3.01–2.97 (m, 1H),
2.85–2.54 (m, 6H), 1.93 (bs, 1H, NH), 1.80–1.56 (m, 11H),
1.56–1.45 (m, 1H), 1.30–1.15 (m, 5H), 1.09–1.01 (m, 1H);
13C NMR (100.6 MHz, CDCl3): d¼64.62 (d), 64.01 (d), 60.69
(d), 47.51 (t), 46.09 (t), 33.36 (t), 28.97 (t), 27.89 (t), 26.43 (t),
26.30 (t), 26.15 (t), 25.74 (t), 24.98 (t), 24.47 (t); IR (CHCl3):
n¼3148 m, 2933 s, 2845 s, 1446 m, 1374 w, 1263 m, 1090 m,
1051 w, 907 m, 889 m cmÀ1; MS(EI): m/z¼153 (14), 152
(92), 105 (4), 96 (4), 83 (4), 71 (6), 70 (100), 69 (3), 55 (10);
HRMS: calcd. for C14H26N2: 222.2113; found: 222.2096.
(m, 5H), 4.72 (dd, 1H, J¼6.8, 12.4 Hz), 4.62 (dd, 1H, J¼7.8,
12.4 Hz), 4.04 (quint, 1H, J¼7.2 Hz), 2.91 (dd, 1H, J¼6.8,
17.7 Hz), 2.87 (dd, 1H, J¼7.1, 17.7 Hz), 2.38 (dt, 1H, J¼16.9,
7.3 Hz), 2.32 (dt, 1H, J¼16.9, 7.1 Hz), 1.56 (hex, 2H, J¼
7.4 Hz), 0.86 (t, 3H, J¼7.5 Hz); 13C NMR (100.6 MHz,
CDCl3): d¼207.75 (s), 138.89 (s), 128.97 (2C, d), 127.79 (d),
127.33 (2C, d), 79.45 (t), 45.22 (t), 45.12 (t), 39.02 (d), 16.96
(t), 13.51 (q); IR (CHCl3): n¼3033 w, 2973 m, 2876 w, 1713 s,
1555 s, 1495 w, 1455 w, 1428 w, 1378 m cmÀ1; MS(EI): m/z¼
188 (9), 145 (18), 117 (12), 105 (18), 104 (23), 91 (12), 86 (41),
84 (63), 71 (100), 49 (12), 47 (5).
(4S,5R)-4-Methyl-6-nitro-5-phenylhexan-3-one
(6d):
From pentan-3-one 5d and nitrostyrene according to General
Procedure 3 to obtain two diastereoisomers, syn-6d (major)
and anti-6d (minor) as a pale yellow oil. The enantiomeric ex-
cess was determined by SFC [Chiralcel OB-H, 2 mL/min, 200
bar, MeOH 2%-2-1-15, 308C, Rt: 4.4 min (4R,5S) and 5.7 min
(4S,5R)]. Syn isomer 6d: [a]2D0: þ3.4 [c 0.83, ee¼67%
(4S,5R), CHCl3]. Spectroscopic data are in agreement with
published data.[48]
2-(S)-(2-Nitro-1-(R)-phenyl)-cyclohexanone (6e): From
cyclohexanone 5e and nitrostyrene according to General Pro-
cedure 3. The enantiomeric excess was determined by SFC
[Chiralpak AD, 2 mL/min, 200 bar, 10% MeOH, 308C, Rt:
4.9 min (2R,1’S) and 5.7 min (2S,1’R)); [a]2D0: À17.9 [c 0.87,
ee¼67% (2S,1’R), CHCl3]. Spectroscopic data are in agree-
ment with published data.[120]
Addition of Unmodified Aldehydes or Ketones to
Nitroolefins Catalyzed by Amines
General Procedure 3: To a solution of pyrrolidine or chiral di-
amine (0.05 mmol, 15 mol %) in solvent (3 mL) was added at
the appropriate temperature the aldehyde (10 equivs.,
3.35 mmol) or the ketone (10 equivs. 3.35 mmol or 20–30
vol %) and the nitroolefin (0.335 mmol). The evolution of the
reaction was controlled by TLC until the conversion was com-
plete. The solution was then hydrolyzed with 1 N HCl (2 mL).
The layers were separated and the aqueous phase was extract-
ed with CH2Cl2 (2ꢁ3 mL). The combined organic phases were
dried over MgSO4, filtered, concentrated and purified by flash
column chromatography on silica gel using a mixture of cyclo-
hexane and ethyl acetate as eluent.
(4R)-4-Phenyl-5-nitropentan-2-one (6a): From nitrostyr-
ene and acetone according to General Procedure 3 to obtain
a white solid. The enantiomeric excess was determined by
GC [Lipodex E, 1208C-0-2-170, Rt: 17.3 min (4R) and
17.8 min (4S)]; [a]2D0: À2.2 [c 0.67, ee¼17% (4R), CHCl3].
Spectroscopic data are in agreement with published data.[130]
2-(S)-(2-Nitro-1-(R)-phenyl)-cyclopentanone (6f): From
cyclopentanone 5f and nitrostyrene according to General Pro-
cedure 3. The enantiomeric excess was determined by SFC
[Chiralpak AD, 2 mL/min, 200 bar, 10% MeOH, 308C, Rt:
5.0 min (2R,1’S) and 5.9 min (2S,1’R)]. Spectroscopic data are
in agreement with published data.[132]
(3S,4R)-3-Methoxy-5-nitro-4-phenylpentan-2-one (6g):
From methoxyacetone 5g and nitrostyrene according to Gen-
eral Procedure 3 to obtain two inseparable diastereoisomers,
(syn, major) 6g and (anti, minor) 6g’ as a pale yellow oil. The
enantiomeric excess was determined by GC [Hydrodex B-3P,
1508C isotherm, Rt: 28.7 min (3R,4S) and 29.3 min (3S,4R)].
(3S,4R)-3-Methyl-5-nitro-4-phenylpentan-2-one
(6b):
From butan-2-one 5b and nitrostyrene according to General
Procedure 3 to obtain a mixture of 2 regioisomers, 6b and 7b,
as a colourless oil. The enantiomeric excess was determined
by SFC [Chiralcel OB-H, 2 mL/min, 200 bar, 1% MeOH,
308C, Rt: 7.1 min (3R,4S) and 9.4 min (3S,4R)]. Spectroscopic
data are in agreement with published data.[131]
(5S)-5-Phenyl-6-nitrohexan-3-one (7b): The enantiomeric
excess was determined by SFC [Chiralcel OB-H, 2 mL/min,
200 bar, 1% MeOH, 308C, Rt: 10.1 min (5S) and 11.8 min
1
Syn isomer: H NMR (400 MHz, CDCl3): d¼7.35–7.20 (m,
5H), 4.93 (dd, 1H, J¼8.4, 12.9 Hz), 4.66 (dd, 1H, J¼6.8,
12.9 Hz), 3.93–3.80 (m, 2H), 3.45 (s, 3H), 1.77 (s, 3H),
13C NMR (100.6 MHz, CDCl3): d¼209.91 (s), 134.45 (s),
128.98 (2C, d), 128.84 (2C, d), 128.38 (d), 86.77 (d), 76.53 (t),
59.80 (q), 46.34 (d), 26.61 (q). Anti isomer: 1H NMR
(400 MHz, CDCl3): d¼7.35–7.20 (m, 5H), 4.86 (dd, 1H, J¼
5.6, 13.4 Hz), 4.72 (dd, 1H, J¼8.6, 13.2 Hz), 3.93–3.80 (m,
1160
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N-Alkyl-2,2’-bipyrrolidine Derivatives as Organocatalysts
FULL PAPERS
2H), 3.67 (s, 3H), 2.03 (s, 3H); 13C NMR (100.6 MHz, CDCl3):
d¼208.12 (s), 135.35 (s), 129.13 (2C, d), 128.49 (d), 128.11
(2C, d), 88.16 (d), 76.73 (t), 58.82 (q), 45.90 (d), 26.23 (q). Iso-
mer mixture: IR (CHCl3): n¼3029 m, 3011 w, 2937 w, 2834 w,
1713 s, 1556 s, 1495 w, 1456 w, 1427 w, 1378 s, 1357 m, 1120 s,
1054 w, 909 m cmÀ1; MS(EI): m/z¼194 (11), 148 (12), 147
(100), 117 (29), 115 (10), 104 (14), 91 (18), 77 (10).
(3R*,4S*)-3-Hydroxy-5-nitro-4-phenylpentan-2-one
(syn-6h): From hydroxyacetone 5h and nitrostyrene according
to General Procedure 3 using pyrrolidine as achiral catalyst at
room temperature to obtain two inseparable diastereoisomers
(syn/anti 75:25), syn-6h and anti-6h as a pale yellow oil. The
enantiomers were separated by SFC (Chiralcel OJ, 2 mL/
min, 200 bar, 5% MeOH, 308C, Rt: 3.1 min and 3.5 min).
1H NMR (400 MHz, CDCl3): d¼7.41–7.23 (m, 5H), 5.03 (dd,
1H, J¼7.8, 13.4 Hz), 4.74 (dd, 1H, J¼7.1, 13.4 Hz), 4.54–
4.52 (m, 1H), 4.03 (dt, 1H, 3.0, 7.6 Hz), 3.75 (d, 1H, J¼
4.8 Hz), 2.17 (s, 3H); 13C NMR (100.6 MHz, CDCl3): d¼
206.30 (s), 133.81 (s), 128.99 (2C, d), 128.69 (d), 128.53 (2C,
d), 77.00 (d, t), 45.72 (d), 25.52 (q).
(3R,4R)-3-Hydroxy-5-nitro-4-phenylpentan-2-one (anti-
6 h): From hydroxyacetone 5h and nitrostyrene according to
General Procedure 3 using diamine (S,S)-iPBP at room tem-
perature to obtain two inseparable diastereoisomers (syn/anti
17:83), syn-6h and anti-6h as a pale yellow oil. The enantiomer-
ic excess was determined by SFC [Chiralcel OJ, 2 mL/min, 200
bar, 5% MeOH, 308C, Rt: 4.3 min (3S,4S) and 5.1 min
(3R,4R)]; 1H NMR (400 MHz, CDCl3): d¼7.41–7.23 (m,
5H), 4.82 (dd, 1H, J¼76.3, 13.6 Hz), 4.66 (dd, 1H, J¼8.3,
13.6 Hz), 4.42–4.38 (m, 1H), 3.83 (dt, 1H, J¼7.6, 5.9 Hz),
3.76–3.74 (m, 1H), 2.06 (s, 3H); 13C NMR (100.6 MHz,
CDCl3): d¼207.99 (s), 137.15 (s), 129.36 (2C, d), 128.45 (d),
128.03 (2C, d), 78.70 (d), 76.06 (t), 46.90 (d), 26.51 (q). Isomer
mixture: MS(EI): m/z¼180 (8), 134 (11), 133 (100), 105 (97),
104 (96), 103 (30), 91 (39), 79 (24), 78 (23), 77 (38), 74 (10),
55 (11), 51 (18).
(2S*,3R*)-3-Hydroxy-1-nitro-2-phenyl-heptan-4-one
(syn-6i): From 1-hydroxypentan-2-one 5i and nitrostyrene ac-
cording to General Procedure 3 using pyrrolidine as achiral
catalyst in i-PrOH to obtain two inseparable diastereoisomers
(syn/anti 69:31), syn-6i and anti-6i as a colourless oil. The enan-
tiomers were separated by SFC (Chiralpak AS-H, 2 mL/min,
200 bar, 3% MeOH, 308C, Rt: 3.2 min and 3.7 min); 1H NMR
(400 MHz, CDCl3): d¼7.30–7.23 (m, 5H), 5.04 (dd, 1H, J¼
8.1, 13.4 Hz), 4.73 (dd, 1H, J¼6.9, 13.4 Hz), 4.51 (d, 1H, J¼
2.5 Hz), 4.03 (dt, 1H, J¼3.2. 7.5 Hz), 3.77 (bs, 1H), 2.53–2.38
(m, 2H), 1.72–1.45 (m, 2H), 0.84 (t, 3H, J¼7.4 Hz);
13C NMR (100.6 MHz, CDCl3): d¼208.64 (s), 133.89 (s),
128.97 (2C, d), 128.66 (d), 128.47 (2C, d), 77.06 (t), 76.39 (d),
45.99 (d), 40.15 (t), 16.82 (t), 13.60 (q).
(s), 129.37 (2C, d), 128.55 (d), 128.05 (2C, d), 78.21 (d), 76.17
(t), 47.19 (d), 41.28 (t), 16.97 (t), 13.60 (q).
(4R)-1-Dimethylamino-5-nitro-4-phenylpentan-2-one
(7j): From N,N-dimethylaminoacetone 5j and nitrostyrene ac-
cording to General Procedure 3 to obtain a pale yellow oil. The
enantiomeric excess was determined by SFC [Chiralpak AD,
2 mL/min, 200 bar, 5% MeOH, 308C, Rt: 6.7 min (4S) and
7.3 min (4R)]; [a]2D0: À4.6 [c 3.20, CHCl3, 75% ee (4R)];
1H NMR (400 MHz, CDCl3): d¼7.36–7.21 (m, 5H), 4.71 (dd,
1H, J¼7.0, 12.3 Hz), 4.63 (dd, 1H, J¼7.7, 12.4 Hz), 4.05
(quint., 1H, J¼7.2 Hz), 3.03 (dd, 1H, J¼7.1, 17.3 Hz), 3.02 (s,
2H), 2.90 (dd, 1H, J¼7.2, 17.5 Hz), 2.20 (s, 6H); 13C NMR
(100.6 MHz, CDCl3): d¼206.35 (s), 138.78 (s), 129.06 (2C, d),
127.93 (d), 127.49 (2C, d), 79.53 (t), 69.46 (t), 45.79 (2C, q),
42.78 (t), 39.13 (d); IR (CHCl3): n¼3031 w, 2950 w, 2830 w,
2783 w, 1725 m, 1556 s, 1496 w, 1456 w, 1378 m, 1217 w, 1042
w, 909 w cmÀ1; MS(EI): m/z¼104 (4), 59 (9), 58 (100), 57 (4).
(3R*,4S*)-3-Hydroxy-5-nitro-4-(4-methylphenyl)pen-
tan-2-one (syn-10b): From hydroxyacetone 5h and nitroolefin
9b according to General Procedure 3 using pyrrolidine as achi-
ral catalyst at room temperature to obtain two inseparable di-
astereoisomers (syn/anti 77:23), syn-10b and anti-10b as a pale
yellow solid. The enantiomers were separated by SFC (Chiral-
pak AS-H, 2 mL/min, 200 bar, 5% MeOH, 308C, Rt: 2.7 min
1
and 2.9 min); H NMR (400 MHz, CDCl3): d¼7.13 (d, 2H,
J¼8.1 Hz), 7.09 (d, 2H, J¼8.1 Hz), 5.01 (dd, 1H, J¼8.1,
13.4 Hz), 4.71 (dd, 1H, J¼7.1, 13.4 Hz), 4.52–4.51 (m, 1H),
4.00 (dt, 1H, J¼3.0, 7.6 Hz), 3.75–3.68 (m, 1H), 2.29 (s, 3H),
2.18 (s,3H); 13C NMR (100.6 MHz, CDCl3): d¼206.36 (s),
138.49 (s), 130.66 (s), 129.68 (2C, d), 128.27 (2C, d), 77.09 (t),
77.04 (d), 45.41 (d), 25.52 (q), 21.07 (q).
(3R,4R)-3-Hydroxy-5-nitro-4-(4-methylphenyl)pentan-
2-one (anti-10b): From hydroxyacetone 5h and nitroolefin 9b
according to General Procedure 3 using diamine (S,S)-iPBP at
room temperature to obtain two inseparable diastereoisomers
(syn/anti 16:84), syn-10b and anti-10b as a pale yellow solid.
The enantiomeric excess was determined by SFC [Chiralpak
AS-H, 2 mL/min, 200 bar, 5% MeOH, 308C, Rt: 3.1 min
1
(3S,4S) and 3.4 min (3R,4R)]; H NMR (400 MHz, CDCl3):
d¼7.24 (d, 2H, J¼8.1 Hz), 7.19 (d, 2H, J¼8.1 Hz), 4.81 (dd,
1H, J¼6.2, 13.4 Hz), 4.64 (dd, 1H, J¼8.5, 13.4 Hz), 4.37 (d,
1H, J¼5.6 Hz), 3.78 (dt, 1H, J¼8.6, 5.8 Hz), 3.75–3.68 (m,
1H), 2.35 (s, 3H), 2.04 (s, 3H); 13C NMR (100.6 MHz, CDCl3):
d¼208.13 (s), 138.37 (s), 133.94 (s), 130.02 (2C, d), 127.88
(2C, d), 78.76 (t), 76.31 (d), 46.72 (d), 26.65 (q), 21.11 (q); MS
(EI): m/z¼237 (1), 190 (8), 164 (52), 148 (14), 147 (100), 119
(35), 118 (90), 117 (30), 115 (13), 105 (26), 99 (12), 97 (64), 91
(29), 87 (12), 86 (60), 85 (17), 84 (91), 77 (13), 74 (16), 71
(12), 57 (23), 47 (17); HRMS: calcd. for C12H15NO4: 237.1001;
found: 237.1008.
(2R,3R)-3-Hydroxy-1-nitro-2-phenylheptan-4-one (anti-
6i): From 1-hydroxypentan-2-one 5i and nitrostyrene accord-
ing to General Procedure 3 using diamine (S,S)-iPBP to obtain
two inseparable diastereoisomers, syn-6i and anti-6i as a col-
ourless oil. The enantiomeric excess was determined by SFC
[Chiralpak AS-H, 2 mL/min, 200 bar, 3% MeOH, 308C, Rt:
3.8 min (2S,3S) and 4.2 min (2R,3R)]; 1H NMR (400 MHz,
CDCl3): d¼7.41–7.35 (m, 5H), 4.80 (dd, 1H, J¼6.1,
13.4 Hz), 4.67 (dd, 1H, J¼8.6, 13.6 Hz), 4.38 (t, 1H, J¼4.8
HZ), 3.83 (dt, 1H, J¼8.3, 5.7 Hz), 3.68 (d, 1H, J¼5.3 Hz),
2.28 (t, 2H, J¼7.3 Hz), 1.63–1.54 (m, 2H), 0.85 (t, 3H, J¼
7.3 Hz); 13C NMR (100.6 MHz, CDCl3): d¼210.42 (s), 137.18
(3R*,4S*)-3-Hydroxy-5-nitro-4-(4-methoxyphenyl)pen-
tan-2-one (syn-10c): From hydroxyacetone 5h and nitroolefin
9c according to General Procedure 3 using pyrrolidine as achi-
ral catalyst at room temperature to obtain two inseparable di-
astereoisomers (syn/anti 80:20), syn-10c and anti-10c as a pale
yellow solid. The enantiomers were separated by SFC (Chiral-
pak AS-H, 2 mL/min, 200 bar, 5% MeOH, 308C, Rt: 3.2 min
1
and 3.5 min); H NMR (400 MHz, CDCl3): d¼7.16 (d, 2H,
J¼8.6 Hz), 6.79 (d, 2H, J¼8.6 Hz), 4.97 (dd, 1H, J¼7.7,
13.4 Hz), 4.69 (dd, 1H, J¼7.5, 13.4 Hz), 4.50–4.48 (m, 1H),
3.97 (dt, 1H, J¼3.0, 7.6 Hz), 3.78–3.73 (m, 1Hsyn þ2Hanti),
3.74 (s, 3H), 2.14 (s, 3H); 13C NMR (100.6 MHz, CDCl3): d¼
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Olivier Andrey et al.
FULL PAPERS
206.55 (s), 159.63 (s), 129.57 (2C, d), 125.65 (s), 114.29 (2C, d),
77.26 (t), 77.08 (d), 55.16 (q), 45.01 (d), 25.48 (q).
133.43 (Cquat), 132.70 (CH), 129.80 (CH), 128.64 (CH), 128.29
(q, Cquat, JC-F ¼29.6 Hz), 126.77 (q, CH, JC-F ¼5.8 Hz), 124.13
(q, CF3, JC-F ¼273.7 Hz), 76.22 (CH), 75.58 (CH2), 39.39
(CH), 25.25 (CH3).
(3R,4R)-3-Hydroxy-5-nitro-4-(4-methoxyphenyl)pentan-
2-one (anti-10c): From hydroxyacetone 5h and nitroolefin 10c
according to General Procedure 3 using diamine (S,S)-iPBP at
room temperature to obtain two diastereoisomers inseparable
by column chromatography (syn/anti 19:81), syn-10c and anti-
10c as a pale yellow solid. The enantiomeric excess was deter-
mined by SFC [Chiralpak AS-H, 2 mL/min, 200 bar, 5%
MeOH, 308C, Rt: 4.1 min (3S,4S) and 4.7 min (3R,4R)]. A sam-
ple was recrystallized from diethyl ether to give the isomer anti-
10c optically pure for analysis; mp 109–1128C (ether); [a]2D0: À
(3R,4R)-3-Hydroxy-5-nitro-4-[2-(trifluoromethyl)phe-
nyl]pentan-2-one (anti-10e): From hydroxyacetone 5h and ni-
troolefin 9e according to General Procedure 3 using diamine
(S,S)-iPBP at room temperature to obtain two inseparable di-
astereoisomers (syn/anti 5:95), syn-10e and anti-10e as a pale
yellow oil. The enantiomeric excess was determined by SFC
[Chiralcel OD-H, 2 mL/min, 200 bar, 5% MeOH, 308C, Rt:
3.1 min (3S,4S) and 3.6 min (3R,4R)]; [a]2D0: À32.0 [c 3.32,
CHCl3, dr 95:5, 99% ee (3R,4R)]; 1H NMR (400 MHz,
CDCl3): d¼7.77 (d, 1H, J¼7.8 Hz), 7.75 (d, 1H, J¼8.1 Hz),
7.63 (t, 1H, J¼7.6 Hz), 7.53–7.42 (m, 1Hanti þ2Hsyn), 4.77
(dd, 1H, J¼7.3, 13.9 Hz), 4.61 (dd, 1H, J¼6.3, 13.7 Hz),
1
47.3 (c 8.6, CHCl3); H NMR (400 MHz, CDCl3): d¼7.28 (d,
2H, J¼8.6 Hz), 6.91 (d, 2H, J¼8.6 Hz), 4.80 (dd, 1H, J¼6.0,
13.4 Hz), 4.63 (dd, 1H, J¼8.6, 13.4 Hz), 4.38–4.36 (m, 1H),
3.81 (s, 3H), 3.76 (dt, 1H, J¼8.6, 5.9 Hz), 3.68–3.67 (m, 1H),
2.01 (s, 3H); 13C NMR (100.6 MHz, CDCl3): d¼208.06 (s),
159.63 (s), 129.13 (2C, d), 128.80 (s), 114.71 (2C, d), 78.81 (t),
76.48 (d), 55.31 (q), 46.42 (d), 26.68 (q); MS(EI): m/z¼253
(3), 180 (18), 135 (16), 134 (100), 121 (8), 91 (7), 77 (5);
HRMS: calcd. for C12H15NO5: 253.0950; found: 253.0953.
(3R*,4S*)-4-(4-Chlorophenyl)-3-hydroxy-5-nitropentan-
2-one (syn-10d): From hydroxyacetone 5h and nitroolefin 9d
according to General Procedure 3 using pyrrolidine as achiral
catalyst at room temperature to obtain two inseparable diaster-
eoisomers (syn/anti 75:25), syn-10d and anti-10d as a colour-
less oil. The enantiomers were separated by SFC (Chiralpak
AS-H, 2 mL/min, 200 bar, 5% MeOH, 558C, Rt: 3.5 min and
3.7 min); 1H NMR (400 MHz, CDCl3): d¼7.32–7.29 (m,
2H), 7.26–7.22 (m, 2H), 5.02 (dd, 1H, J¼7.6, 13.6 Hz), 4.75
(dd, 1H, J¼7.5, 13.6 Hz), 4.54 (dd, 1H, J¼3.0, 4.6 Hz), 4.05
(dt, 1H, J¼2.8, 7.6 Hz), 3.78 (d, 1H, J¼4.5 Hz), 2.21 (s, 3H);
13C NMR (100.6 MHz, CDCl3): d¼205.93 (s), 134.79 (s),
132.28 (s), 129.83 (2C, d), 129.26 (2C, d), 76.97 (t), 76.89 (d),
45.12 (d), 25.48 (q).
4.58–4.50 (m, 2Hanti þ2Hsyn), 4.37 (bs, 1H), 2.37 (s, 3H);
13
¼
C NMR (100.6 MHz, CDCl3): d¼206.96 (C O), 136.60
¼
(Cquat), 132.77 (CH), 129.52 (CH), 128.01 (q, Cquat, JC-F
29.9), 128.27 (CH), 126.47 (q, CH, JC-F ¼5.8), 124.34 (q, CF3,
JC-F ¼273.7), 78.31 (CH), 73.72 (CH2), 40.10 (CH), 25.24
(CH3); IR (CHCl3): n¼3459 w, 3029 w, 2979 w, 2928 w, 2874
w, 1717 s, 1608 w, 1559 s, 1456 w, 1380 m, 1363 m, 1314 s,
1167 s, 1118 s, 1038 m, 968 w, 909 w cmÀ1; MS(EI): m/z¼201
(68), 182 (10), 181 (77), 173 (31), 172 (100), 171 (27), 169
(11), 159 (19), 153 (83), 151 (37), 140 (11), 133 (62), 127 (12),
103 (11), 97 (21), 77 (10), 75 (10), 73 (12), 61 (10), 57 (17), 55
(12).
(2R,1’R,2’R)-3,3,3-Trifluoro-2-methoxy-2-phenylpro-
pionic acid 1-acetyl-3-nitro-2-(2-trifluoromethylphenyl)-
propyl ester (10e–mosher): To a solution of alcohol (anti-
10e) (33 mg, 0.113 mmol) in dry CH2Cl2 (0.8 mL) was added
(R)-Mosherꢀs acid (0.170 mmol, 40 mg) then a solution of
DCC (0.198 mmol, 41 mg) and DMAP (0.028 mmol, 3.5 mg)
in dry CH2Cl2 (1.0 mL). The white mixture was stirred over-
night at room temperature then directly purified by flash chro-
matography on silica gel (c-hexane/EtOAc, 9:1) to give a col-
ourless solid; yield: 55 mg (96%); mp 129–1328C (ether);
1H NMR (400 MHz, CDCl3): d¼7.71 (d, 1H, J¼7.8 Hz), 7.55
(d, 1H, J¼7.6 Hz), 7.51–7.37 (m, 4H), 7.37 (t, 1H, J¼
7.8 Hz), 7.10 (t, 1H, J¼7.7 Hz), 6.99 (d, 1H, J¼7.8 Hz), 5.27
(d, 1H, J¼1.8 Hz), 4.82–4.73 (m, 2H), 4.64 (dt, 1H, J¼1.8,
6.9 Hz), 3.77 (s, 3H), 2.44 (s, 3H); 13C NMR (75.5 MHz,
CDCl3): d¼200.82 (s), 165.74 (s), 134–120 (15C), 80.29 (d),
73.27 (t), 56.13 (q), 37.37 (d), 26.90 (q).
(3R,4R)-4-(4-Chlorophenyl)-3-hydroxy-5-nitropentan-
2-one (anti-10d): From hydroxyacetone 5h and nitroolefin 9d
according to General Procedure 3 using diamine (S,S)-iPBP at
room temperature to obtain two inseparable diastereoisomers
(syn/anti 13:87), syn-10d and anti-10d as a colourless oil. The
enantiomers were separated by SFC [Chiralpak AS-H, 2 mL/
min, 200 bar, 5% MeOH, 558C, Rt: 4.4 min (3S,4S) and
1
4.7 min (3R,4R)]; H NMR (400 MHz, CDCl3): d¼7.41–7.32
(m, 4H), 4.77 (dd, 1H, J¼6.0, 13.6 Hz), 4.64 (dd, 1H, J¼8.6,
13.6 Hz), 4.39 (t, 1H, J¼4.8 Hz), 3.89 (ddd, 1H, J¼4.6, 6.0,
8.3 Hz), 3.79 (d, 1H, J¼4.8 Hz), 2.19 (s, 3H); 13C NMR
(100.6 MHz, CDCl3): d¼207.48 (s), 135.82 (s), 134.52 (s),
129.53 (2C, d), 129.47 (2C, d), 78.60 (d), 75.66 (t), 45.99 (d),
26.32 (q); MS(EI): m/z¼260 (<1), 259 (<1), 258 (<1), 257
(<1), 169 (18), 165 (55), 141 (15), 140 (37), 139 (40), 138
(100), 132 (13), 125 (23), 103 (58), 102 (11), 77 (28), 75 (10),
74 (19), 51 (11).
(3R*,4S*)-4-(2,6-Dichlorophenyl)-3-hydroxy-5-nitro-
pentan-2-one (syn-10f): From hydroxyacetone 5h and nitro-
olefin 9f according to General Procedure 3 using pyrrolidine
as achiral catalyst at room temperature to obtain two insepara-
ble diastereoisomers (syn/anti 54:46), syn-10f and anti-10f, as a
colourless oil. The enantiomers were separated by SFC (Chir-
alpak AS-H, 2 mL/min, 200 bar, 5% MeOH, 308C, Rt: 5.8 min
1
(3R*,4S*)-3-Hydroxy-5-nitro-4-[2-(trifluoromethyl)phe-
nyl]pentan-2-one (syn-10e): From hydroxyacetone 5h and ni-
troolefin 9e according to General Procedure 3 using pyrroli-
dine as achiral catalyst at room temperature to obtain two in-
separable diastereoisomers (syn/anti 74:26), syn-10e and
and 6.4 min); H NMR (500 MHz, CDCl3): d¼7.42–7.39 (m,
1H), 7.34–7.32 (m, 1H), 7.21 (t, 1H, J¼8.0 Hz), 5.19–5.13
(m, 1H), 5.02–4.98 (m, 2H), 4.74–4.68 (m, 1H), 2.91 (d, 1H,
J¼5.3 Hz), 2.32 (s, 3H); 13C NMR (125.8 MHz, CDCl3): d¼
208.67 (s), 137.80 (s), 134.87 (s), 131.74 (s), 130.30 (d), 130.00
(d), 129.19 (d), 75.96 (d), 74.44 (t), 42.42 (d), 26.32 (q).
1
anti-10e as a pale yellow oil; H NMR (400 MHz, CDCl3):
d¼7.83 (d, 1H, J¼7.8 Hz), 7.71 (d, 1H, J¼7.3 Hz), 7.53–
7.42 (m, 2Hsyn þ1Hanti), 5.09–5.03 (m, 1H), 4.71–4.67 (m,
1H), 4.58–4.50 (m, 2Hsyn þ2Hanti), 4.02–3.96 (m, 1H), 2.07 (s,
(3R,4R)-4-(2,6-Dichlorophenyl)-3-hydroxy-5-nitropen-
tan-2-one (anti-10f): From hydroxyacetone 5h and nitroolefin
9f according to General Procedure 3 using diamine (S,S)-iPBP
to obtain two inseparable diastereoisomers (syn/anti 16:84),
3H); 13C NMR (100.6 MHz, CDCl3): d¼206.85 (C O),
¼
1162
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FULL PAPERS
syn-10fand anti-10f as a colourlessoil. Theenantiomeric excess
was determined by SFC [Chiralpak AS-H, 2 mL/min, 200 bar,
5% MeOH, 308C, Rt: 4.3 min (3R,4R) and 5.1 min (3S,4S)];
1H NMR (400 MHz, CDCl3): d¼7.41–7.38 (m, 2H), 7.25 (t,
1H, J¼8.0 Hz), 5.27 (dd, 1H, J¼6.1, 14.1 Hz), 5.04 (dd, 1H,
J¼7.2, 14.1 Hz), 4.86 (dd, 1H, J¼6.6, 9.6 Hz), 4.69 (ddd, 1H,
J¼6.3, 7.1, 9.6 Hz), 3.71 (d, 1H, J¼6.8 Hz), 1.85 (s, 3H);
13C NMR (100.6 MHz, CDCl3): d¼207.69 (s), 137.19 (s),
134.84 (s), 132.09 (s), 130.53 (d), 130.40 (d), 129.50 (d), 75.04
(d), 74.88 (t), 43.81 (d), 26.73 (q); MS(EI): m/z¼203 (55),
201 (84), 177 (12), 176 (10), 175 (66), 174 (33), 173 (100), 172
(37), 161 (11), 159 (17), 139 (26), 138 (17), 137 (70), 136 (10),
125 (10), 103 (15), 102 (46), 101 (52), 99 (11), 77 (14), 75 (27),
74 (15), 73 (14), 63 (10), 51 (18).
130.46 (d), 129.94 (d), 127.91 (d), 76.17 (d), 75.98 (t), 39.79
(d), 25.48 (q).
(3R,4R)-4-(3,4-Dichlorophenyl)-3-hydroxy-5-nitropen-
tan-2-one (anti-10h): From hydroxyacetone 5h and nitroolefin
9h according to General Procedure 3 using diamine (S,S)-iPBP
at room temperature to obtain two inseparable diastereoisom-
ers (syn/anti 9:91), syn-10h and anti-10h, as a colourless oil.
The enantiomeric excess was determined by SFC [Chiralpak
AS-H, 2 mL/min, 200 bar, 5% MeOH, 308C, Rt: 4.0 min
1
(3S,4S) and 4.3 min (3R,4R)]; H NMR (400 MHz, CDCl3):
d¼7.48 (d, 1H, J¼2.3 Hz), 7.45 (d, 1H, J¼8.6 Hz), 7.31 (dd,
1H, J¼2.2, 8.5 Hz), 4.70–4.58 (m, 3H), 4.37–4.33 (m, 1H),
3.82 (d, 1H, J¼4.0 Hz), 2.36 (s, 3H); 13C NMR (100.6 MHz,
CDCl3): d¼207.03 (s), 134.81 (s), 134.25 (s), 133.78 (s),
129.98 (d), 129.75 (d), 128.10 (d), 77.55 (d), 73.16 (t), 41.04
(d), 25.45 (q); MS(EI): m/z¼292 (1), 203 (49), 202 (10), 201
(75), 188 (12), 176 (14), 175 (50), 174 (70), 173 (77), 172
(100), 166 (15), 161 (18), 159 (28), 139 (20), 138 (16), 137
(57), 136 (12), 125 (11), 111 (10), 103 (14), 102 (44), 101 (38),
99 (12), 77 (10), 75 (26), 74 (24), 73 (19), 51 (17); HRMS: calcd.
for C11H1135Cl2NO4: 291.00651; found: 291.00262.
(3R*,4S*)-4-(3,4-Dichlorophenyl)-3-hydroxy-5-nitro-
pentan-2-one (syn-10g): From hydroxyacetone 5h and nitro-
olefin 9g according to General Procedure 3 using pyrrolidine
as achiral catalyst at room temperature to obtain two insepara-
ble diastereoisomers (syn/anti 74 26), syn-10g and anti-10g, as a
colourless oil. The enantiomers were separated by SFC (Chir-
alcel OJ, 2 mL/min, 200 bar, 5% MeOH, 308C, Rt: 6.0 min and
1
6.7 min); H NMR (500 MHz, CDCl3): d¼7.40 (d, 1H, J¼
(3R*,4S*)-4-(1-Naphthyl)-3-hydroxy-5-nitropentan-2-
one (syn-10i): From hydroxyacetone 5h and nitroolefin 9i ac-
cording to General Procedure 3 using pyrrolidine as achiral
catalyst at room temperature to obtain two inseparable diaster-
eoisomers (syn/anti 76:24), syn-10i and anti-10i, as a colourless
oil. The enantiomers were separated by (Chiralpak AS-H,
2 mL/min, 200 bar, 5% MeOH, 308C, Rt: 4.5 min and
2.2 Hz), 7.38 (d, 1H, J¼8.2 Hz), 7.13 (dd, 1H, J¼2.2, 8.2 Hz),
4.98 (dd, 1H, J¼7.5, 13.7 Hz), 4.72 (dd, 1H, J¼7.6, 13.7 Hz),
4.51 (t, 1H, J¼3.2 Hz), 4.00 (dt, 1H, J¼2.9, 7.6 Hz), 3.78 (d,
1H, J¼4.2 Hz), 2.21 (s, 3H); 13C NMR (125.8 MHz, CDCl3):
d¼205.56 (s), 137.67 (s), 133.93 (s), 133.19 (s), 130.95 (d),
130.37 (d), 127.83 (d), 76.74 (t), 76.73 (d), 44.80 (d), 25.44 (q).
(3R,4R)-4-(3,4-Dichlorophenyl)-3-hydroxy-5-nitropen-
tan-2-one (anti-10 g): From hydroxyacetone 5h and nitroole-
fin 9g according to General Procedure 3 using diamine (S,S)-
iPBP at room temperature to obtain two inseparable diaster-
eoisomers (syn/anti 12:88), syn-10g and anti-10g as a colourless
oil. The enantiomeric excess was determined by SFC [Chiralcel
OJ, 2 mL/min, 200 bar, MeOH 5%-6-2-20, 308C, Rt: 7.7 min
1
5.1 min); H NMR (500 MHz, CDCl3): d¼8.18 (d, 1H, J¼
8.5 Hz), 7.88 (d, 1H, J¼8.5 Hz), 7.80 (d, 1H, J¼8.2 Hz), 7.71
(d, 1H, J¼7.0 Hz), 7.62 (t, 1H, J¼7.4 Hz), 7.53 (t, 1H, J¼
7.7 Hz), 7.39 (t, 1H, J¼7.7 Hz), 5.19–5.00 (m, 2H), 4.77–4.72
(m, 2H), 3.98 (bs, 1H), 1.96 (s, 3H); 13C NMR (125.8 MHz,
CDCl3): d¼206.75 (s), 134.08 (s), 130.97 (s), 130.20 (s),
129.56 (d), 129.17 (d), 127.21 (d), 126.14 (d), 126.03 (d),
125.45 (d), 121.71 (d), 76.77 (d), 76.57 (t), 38.51 (d), 25.52 (q).
(3R,4R)-4-(1-Naphthyl)-3-hydroxy-5-nitropentan-2-one
(anti-10i): From hydroxyacetone 5h and nitroolefin 9i accord-
ing to General Procedure 3 using diamine (S,S)-iPBP at room
temperature to obtain two inseparable diastereoisomers (syn/
anti 22:78), syn-10i and anti-10i, as a colourless oil. The enan-
tiomeric excess was determined by SFC [Chiralpak AS-H,
2 mL/min, 200 bar, 5% MeOH, 308C, Rt: 5.8 min (3S,4S) and
1
(3S,4S) and 9.1 min (3R,4R)]; H NMR (400 MHz, CDCl3):
d¼7.54 (d, 1H, J¼2.3 Hz), 7.47 (d, 1H, J¼8.4 Hz), 7.27 (dd,
1H, J¼2.3, 8.4 Hz), 4.67 (dd, 1H, J¼6.2, 13.9 Hz), 4.59 (dd,
1H, J¼8.3, 13.9 Hz), 4.38–4.34 (m, 1H), 3.89 (ddd, 1H, J¼
3.6, 6.3, 8.1 Hz), 3.80–3.75 (m, 1H), 2.25 (s, 3H); 13C NMR
(100.6 MHz, CDCl3): d¼207.06 (s), 136.69 (s), 133.40 (s),
132.85 (s), 131.23 (d), 130.16 (d), 127.47 (d), 78.42 (d), 75.06
(t), 45.34 (d), 26.06 (q); MS(EI): m/z¼292 (1), 203 (41), 202
(11), 201 (63), 188 (13), 176 (13), 175 (32), 174 (69), 172
(100), 168 (12), 16 (35), 161 (14), 159 (21), 139 (17), 138 (17),
137 (48), 125 (12), 111 (11), 103 (15), 102 (43), 101 (32), 99
(10), 77 (10), 75 (24), 74 (26), 73 (21), 55 (10), 51 (15);
HRMS: calcd. for C11H1135Cl2NO4: 291.00651; found:
291.00864.
(3R*,4S*)-4-(2,4-Dichlorophenyl)-3-hydroxy-5-nitro-
pentan-2-one (syn-10 h): From hydroxyacetone 5h and nitro-
olefin 9e according to General Procedure 3 using pyrrolidine
as achiral catalyst at room temperature to obtain two insepara-
ble diastereoisomers (syn/anti 80:20), syn-10h and anti-10h, as
a colourless oil. The enantiomers were separated by SFC (Chir-
alpak AS-H, 2 mL/min, 200 bar, 5% MeOH, 308C, Rt: 3.2 min
and 3.4 min); 1H NMR (500 MHz, CDCl3): d¼7.52 (d, 1H, J¼
8.5 Hz), 7.41 (d, 1H, J¼2.2 Hz), 7.21 (dd, 1H, J¼2.2, 8.5 Hz),
4.98 (dd, 1H, J¼8.5, 13.7 Hz), 4.75 (ddd, 1H, J¼3.2, 6.5,
8.4 Hz), 4.61 (dd, 1H, J¼6.5, 13.6 Hz), 4.58 (t, 1H, J¼
3.8 Hz), 3.79 (d, 1H, J¼4.1 Hz), 2.23 (s, 3H); 13C NMR
(125.8 MHz, CDCl3): d¼206.27 (s), 135.15 (s), 134.36 (s),
1
7.1 min (3R,4R)]; H NMR (400 MHz, CDCl3): d¼8.13 (d,
1H, J¼8.6 Hz), 7.93–7.91 (m, 1H), 7.86 (d, 1H, J¼8.4 Hz),
7.66–7.49 (m, 4H), 5.19–4.83 (m, 2H), 4.77–4.69 (m, 1H),
4.55–4.49 (m, 1H), 3.85 (d, 1H, J¼4.8), 2.12 (s, 3H);
13C NMR (100.6 MHz, CDCl3): d¼207.99 (s), 134.19 (s),
133.22 (s), 130.90 (s), 129.57 (d), 129.05 (d), 127.34 (d), 126.27
(d), 125.62 (d), 125.27 (d), 121.89 (d), 78.51 (d), 75.11 (t), 40
(broad signal, d), 26.22 (q); EI (MS): m/z¼274 (2), 273 (10),
200 (8), 183 (8), 155 (23), 154 (100), 153 (30), 152 (13), 141
(9); HRMS: calcd. for C15H15NO4: 273.10011; found: 273.10020.
(3R*,4S*)-3-Hydroxy-5-nitro-4-(thien-2-ylphenyl)pen-
tan-2-one (syn-10j): From hydroxyacetone 5h and nitroolefin
9j according to General Procedure 3 using pyrrolidine as achi-
ral catalyst at room temperature to obtain two inseparable di-
astereoisomers (syn/anti 68:32), syn-10j and anti-10j, as a
brown oil. The enantiomers were separated by SFC (Chiralcel
OJ, 2 mL/min, 200 bar, 5% MeOH, 308C, Rt: 3.5 min and
1
3.7 min); H NMR (400 MHz, CDCl3): d¼7.22 (dd, 1H, J¼
0.8, 5.0 Hz), 6.95 (dd, 1H, J¼1.3, 3.5 Hz), 6.92 (dd, 1H, J¼
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FULL PAPERS
3.5, 5.0 Hz), 4.96 (dd, 1H, J¼7.7, 13.5 Hz), 4.67 (dd, 1H, J¼7.0,
13.5 Hz), 4.48–4.42 (m, 2Hsyn þ1Hanti), 3.93–3.92 (m, 1H), 2.22
(s, 3H); 13C NMR (100.6 MHz, CDCl3): d¼205.67 (s), 134.22
(s), 127.37 (d), 126.80 (d), 126.47 (d), 77.57 (t), 76.34 (d),
41.88 (d), 25.24 (q).
matography a white solid. The enantiomeric excess was deter-
mined by SFC [Chiralpak AS-H, 2 mL/min, 200 bar, 2%
MeOH, 308C, Rt: 5.6 min (2S,3S) and 7.9 min (2R,3R)]. The
product was recrystallized from diethyl ether for analysis; mp
1
168–1718C (racemate, ether); H NMR (400 MHz, CDCl3):
(3R,4R)-3-Hydroxy-5-nitro-4-(thien-2-ylphenyl)pentan-
2-one (anti-10j): From hydroxyacetone 5h and nitroolefin 9j
according to General Procedure 3 using diamine (S,S)-iPBP
at room temperature to obtain two inseparable diastereoisom-
ers (syn/anti 22:78), syn-10j and anti-10j, as a brown oil. The
enantiomeric excess was determined by SFC [Chiralcel OJ,
2 mL/min, 200 bar, 5% MeOH, 308C, Rt: 4.6 min (3S,4S) and
d¼9.57 (d, 1H, J¼2.0 Hz), 7.48–7.27 (m, 10H), 4.50 (dd, 1H,
J¼10.4, 12.6 Hz), 4.41 (dd, 1H, J¼4.3, 12.6 Hz), 4.32 (dt, 1H,
J¼4.3, 10.4 Hz), 4.09 (dd, 1H, J¼2.0, 10.6 Hz); 13C NMR
(100.6 MHz, CDCl3): d¼196.86 (s), 137.08 (s), 132.41 (s),
129.81 (2C, d), 129.43 (2C, d), 129.12 (2C, d), 128.95 (d),
128.28 (d), 128.17 (2C, d), 78.45 (t), 61.70 (d), 44.39 (d); IR
(CHCl3): n¼3066 w, 3033 w, 2924 w, 2828 w, 2725 w, 1728 s,
1
5.0 min (3R,4R)]; H NMR (400 MHz, CDCl3): d¼7.29 (dd,
1557 s, 1495 w, 1455 w, 1431 w, 1379 m, 1077 w, 1031 w cmÀ1
;
1H, J¼1.0, 5.1 Hz), 7.05 (dd, 1H, J¼0.8, 3.6 Hz), 6.99 (dd,
1H, J¼3.6, 5.1 Hz), 4.75 (dd, 1H, J¼6.0, 13.5 Hz), 4.62 (dd,
1H, J¼8.1, 13.5 Hz), 4.48–4.42 (m, 1Hanti þ2Hsyn), 4.21 (dt,
1H, J¼8.1, 5.4 Hz), 3.76–3.74 (m, 1H), 2.15 (s, 3H);
13C NMR (100.6 MHz, CDCl3): d¼205.67 (s), 134.22 (s),
127.37 (d), 126.80 (d), 126.47 (d), 77.57 (t), 76.34 (d), 41.88
(d), 25.24 (q); MS(EI): m/z¼211 (1), 182 (7), 156 (20), 139
(11), 112 (7), 111 (24), 110 (100), 109 (9), 97 (17).
MS(EI): m/z¼269 (5), 193 (14), 177 (10), 120 (100), 115
(21), 105 (17), 104 (91), 102 (15), 90 (71), 77 (13), 65 (12);
HRMS: calcd. for C16H15NO3: 269.1052; found: 269.1064.
(3R)-2-Dimethyl-4-nitro-3-phenylbutyraldehyde (12f):
From isobutyraldehyde and nitrostyrene according to the Gen-
eral Procedure 3 to give a white solid. The enantiomeric excess
was determined by chiral GC [Hydrodex-B-3P, 1408C iso-
therm, Rt: 46.8 min (3R) and 47.6 min (3S)]; mp (racemate)
74–768C; [a]2D0: þ6.5 [c 0.91, ee¼80% (3R), CHCl3];
1H NMR (400 MHz, CDCl3): d¼9.55 (s, 1H), 7.38–7.30 (m,
3H), 7.24–7.22 (m, 2H), 4.89 (dd, 1H, J¼11.2, 13.1 Hz), 4.72
(dd, 1H, J¼4.3, 13.1 Hz), 3.82 (dd, 1H, J¼4.1, 11.3 Hz), 1.15
(s, 3H), 1.02 (s, 3H); 13C NMR (100.6 MHz, CDCl3): d¼
204.36 (s), 135.44 (s), 129.13 (2C, d), 128.74 (d), 128.17 (2C,
d), 76.35 (t), 48.44 (d), 48.27 (s), 21.66 (q), 18.85 (q); IR
(CHCl3): n¼3031 w, 2969 w, 2933 w, 2816 w, 2778 w, 1727 m,
1559 s, 1496 w, 1467 w, 1455 w, 1436 w, 1378 m, 1221 s, 1217 s,
1213 s, 1210 s, 881 w cmÀ1; MS(EI): m/z¼221(<1), 150 (7),
145 (14), 105 (19), 104 (100), 103 (10), 91 (48), 77 (10), 72 (29).
(2R,3S)-2-Methyl-4-nitro-3-(4-methylphenyl)butyralde-
hyde (13b): From propionaldehyde and nitroolefin 9b accord-
ingtotheGeneralProcedure3usingthediamine(S,S)-iPBPat
À258C for 3 days to give a pale yellow oil (yield: 88%, 94% ee).
The enantiomeric excess was determined by GC [Chiraldex B-
TA, 1458C isotherm, Rt: 22.2 min (2S,3R) and 22.8 min
(2R,3S)]; [a]2D0: þ36.7 [c 0.13, ee¼94% (2R,3S), CHCl3];
1H NMR (400 MHz, CDCl3): d¼9.71 (d, 1H, J¼1.8 Hz), 7.15
(d, 2H, J¼7.8 Hz), 7.05 (d, 2H, J¼8.1 Hz), 4.78 (dd, 1H, J¼
5.6, 12.6 Hz), 4.66 (dd, 1H, J¼9.3, 12.6 Hz), 3.78 (dt, 1H, J¼
5.6, 9.1 Hz), 2.79–2.71 (m, 1H), 2.33 (s, 3H), 1.00 (d, 3H, J¼
7.1 Hz); 13C NMR (100.6 MHz, CDCl3): d¼202.45 (s), 137.90
(s), 133.42 (s), 129.78 (2C, d), 127.95 (2C, d), 78.26 (t), 48.52
(d), 43.75 (d), 21.07 (q), 12.55 (q); MS(EI): m/z¼221 (2),
174 (23), 146 (16), 145 (16), 131 (18), 118 (73), 117 (25), 105
(45), 99 (30), 91 (20), 71 (16), 70 (82), 59 (57), 58 (100), 57
(53), 55 (67); HRMS: calcd. for C12H15NO3: 221.1052; found:
221.1044.
(2R,3S)-2-Methyl-4-nitro-3-phenylbutyraldehyde (12a):
From propionaldehyde and nitrostyrene according to the Gen-
eral Procedure 3 to give a pale yellow oil. The enantiomeric ex-
cess was determined by SFC [Chiralcel OD-H, 2 mL/min, 200
bar, MeOH2%-2-1-15, 308C, Rt: 6.13 min (2S,3R)and 6.76 min
(2R,3S)] or by GC (Hydrodex-B-3P, 1358C isotherm, Rt ¼
56.4 min (2R,3S) and 57.6 min (2S, 3R)); [a]2D0: þ28.2 [c 2.69,
ee¼78% (2R,3S), CHCl3]. Spectroscopic data are in agree-
ment with published data.[84]
(2R,3S)-2-Ethyl-4-nitro-3-phenylbutyraldehyde
(12b):
From butyraldehyde and nitrostyrene according to the Gener-
al Procedure 3 to give a pale yellow oil. The enantiomeric ex-
cess was determined by GC [Hydrodex-B-3P, 1458C isotherm,
Rt: 43.0 min (2R,3S) and 43.9 min (2S,3R)]. Spectroscopic data
are in agreement with published data.[84]
2-(R)-(2-Nitro-1-(S)-phenylethyl)-pentanal (12c): From
valeraldehyde and nitrostyrene according to the General Pro-
cedure 3 to give a pale yellow oil. The enantiomeric excess was
determined by SFC [Chiralcel OD-H, 2 mL/min, 200 bar, 2%
MeOH, 108C, Rt: 5.6 min (1’R,2S) and 6.2 min (1’S, 2R)];
[a]2D0: þ24.0 [c 0.89, ee¼72% (1’S,2R), CHCl3]; 1H NMR
(400 MHz, CDCl3): d¼9.74 (d, 1H, J¼2.2 Hz), 7.41–7.32
(m, 3H), 7.24–7.22 (m, 2H), 4.75 (dd, 1H, J¼4.4, 10.2 Hz),
4.69 (dd, 1H, J¼4.7, 10.2 Hz), 3.83 (dt, 1H, J¼4.3, 7.8 Hz),
2.75 (tt, 1H, J¼2.6, 7.6 Hz), 1.56–1.47 (m, 1H), 1.44–1.32
(m, 2H), 1.25–1.17 (m, 1H), 0.84 (t, 3H, J¼5.7 Hz);
13C NMR (100.6 MHz, CDCl3): d¼203.33 (s), 136.80 (s),
129.11 (2C, d), 128.15 (d), 128.01 (2C, d), 78.44 (t), 53.78 (d),
43.13 (d), 29.44 (t), 19.75 (t), 13.94 (q).
(2R,3S)-2-(Methylethyl)-4-nitro-3-phenylbutyraldehyde
(12d): From isovaleraldehyde and nitrostyrene according to
the General Procedure 3 to give a pale yellow oil. The enantio-
meric excess was determined by SFC [Chiralcel OD-H, 2 mL/
min, 200 bar, 1% MeOH, 58C, Rt: 7.00 min (2S,3R) and
7.53 min (2R, 3S)] or by GC (Hydrodex-B-3P, 1508C isotherm,
Rt: 38.4 min (2R,3S) and 39.8 min (2S,3R)); [a]2D0: þ48.5 [c 0.93,
ee¼68% (2R,3S), CHCl3]. Spectroscopic data are in agree-
ment with published data.[84]
(2R,3S)-2-Methyl-4-nitro-3-(4-methoxyphenyl)butyral-
dehyde (13c): From propionaldehyde and nitroolefin 9c ac-
cording to the General Procedure 3 using the diamine (S,S)-
iPBP at À258C for 3 days (yield: 64%, 93% ee) to give a
pale yellow oil. The enantiomeric excess was determined by
GC [Chiraldex B-TA, 1558C isotherm, Rt: 30.7 min (2S,3R)
and 31.5 min (2R, 3S)]; [a]2D0: þ28.1 [c 0.23, ee¼93%
(2R,3S), CHCl3]; 1H NMR (400 MHz, CDCl3): d¼9.73 (d,
1H, J¼1.9 Hz), 7.11 (d, 2H, J¼8.9 Hz), 6.89 (d, 2H, J¼
8.7 Hz), 4.80 (dd, 1H, J¼5.6, 12.6 Hz), 4.66 (dd, 1H, J¼9.3,
12.6 Hz), 3.81 (s, 3H), 3.80 (dt, 1H, J¼5.6, 9.2 Hz), 2.81–2.71
(m, 1H), 1.03 (d, 3H, J¼7.2 Hz); 13C NMR (100.6 MHz,
(2S,3S)-4-Nitro-2,3-diphenylbutyraldehyde (12e): From
phenylacetaldehyde and nitrostyrene according to the General
Procedure 3 to give after separation of diastereomers by chro-
1164
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N-Alkyl-2,2’-bipyrrolidine Derivatives as Organocatalysts
FULL PAPERS
CDCl3): d¼202.49 (s), 159.30 (s), 129.15 (2C, d), 128.36 (s),
114.47 (2C, d), 78.37 (t), 55.27 (q), 48.61 (d), 43.38 (d), 12.07
(q). MS(EI) : 237 (9), 190 (11), 162 (11), 135 (11), 134 (100),
121 (24), 91 (13), 55 (11); HRMS: calcd. for C12H15NO4:
237.1001; found: 237.0980.
(t), 46.64 (d), 43.56 (d), 38.00 (d), 31.64 (t), 30.00 (t), 26.39
(t), 26.26 (t), 26.08 (t), 10.77 (q); IR (CHCl3): n¼3028 w,
2932 s, 2856 m, 1725 m, 1554 s, 1518 w, 1450 m, 1381 w, 1333
w, 1223 w, 1157 w, 991 w cmÀ1; MS(EI): m/z¼113 (10), 109
(100), 108 (15), 99 (18), 95 (28), 85 (13), 83 (94), 82 (11), 81
(55), 79 (10), 75 (99), 73 (49), 71 (13), 70 (14), 69 (20), 68
(18), 67 (53), 58 (35), 55 (100).
(2R,3S)-2-Methyl-4-nitro-3-(2-trifluoromethylphenyl)-
butyraldehyde (13e): From propionaldehyde and nitroolefin
9e according to the General Procedure 3 using the diamine
(S,S)-iPBP at À258C for 3 days to give a pale yellow oil (yield:
74%, 95% ee). The enantiomeric excess was determined by
GC [Hydrodex-B-6-TBDM, 1008C-0-2-170, Rt: 26.6 min
(2S,3R) and 26.9 min (2R,3S)]; [a]2D0: þ48.8 [c 1.02, ee¼95%
(2R,3S), CHCl3]; 1H NMR (400 MHz, CDCl3): d¼9.77 (d,
1H, J¼1.8 Hz), 7.73 (d, 1H, J¼8.1 Hz), 7.59 (t, 1H, J¼
7.7 Hz), 7.44 (t, 1H, J¼7.7 Hz), 7.35 (d, 1H, J¼7.8 Hz), 4.86
(dd, 1H, J¼7.3, 12.4 Hz), 4.71 (dd, 1H, J¼4.8, 12.4 Hz), 4.13
(ddd, 1H, J¼4.8, 7.3, 9.8 Hz), 3.08 (quint, 1H, J¼7.8 Hz),
1.00 (d, 3H, J¼7.6 Hz); 13C NMR (125.8 MHz, CDCl3): d¼
(2R,3R)-3-(Dimethoxymethyl)-2-methyl-4-nitrobutyral-
dehyde (13m): From propionaldehyde and nitroolefin 9m ac-
cording to the General Procedure 3 using the diamine (S,S)-
iPBP at À258C for 3 days to give a mixture of inseparable di-
astereoisomer (syn/anti 75/25) as a colourless oil (yield: 73%,
90% ee). The enantiomeric excess was determined by GC [Hy-
drodex-B-6-TBDM, 1208C isotherm, Rt: 20.1 min (2S,3S) and
1
20.8 min (2R,3R)]; syn isomer: H NMR (400 MHz, CDCl3):
d¼9.59 (s, 1H), 4.61 (dd, 1H, J¼6.3, 13.4 Hz), 4.38 (dd, 1H,
J¼7.1, 13.4 Hz), 4.33 (d, 1H, J¼6.6 Hz), 3.36 (s, 3H), 3.35 (s,
3H), 3.13 (dq, 1H, J¼3.6, 6.6 Hz), 2.58 (dq, 1H, J¼3.5,
7.2 Hz), 1.16 (d, 3H, J¼7.3 Hz); 13C NMR (100.6 MHz,
CDCl3): d¼201.78 (s), 103.80 (d), 73.75 (t), 55.86 (q), 54.60
(q), 44.64 (d), 41.46 (d), 9.79 (q); anti isomer: 1H NMR
(400 MHz, CDCl3): d¼9.60 (d, 1H, J¼1.5 Hz), 4.56 (dd, 1H,
J¼6.3, 13.7 Hz), 4.39 (dd, 1H, J¼6.0, 13.9 Hz), 4.37 (d, 1H,
J¼4.9 Hz), 3.38 (s, 3H), 3.36 (s, 3H), 2.71–2.63 (m, 1H), 3.04
(quint, 1H, J¼5.8 Hz), 1.15 (d, 3H, J¼7.3); 13C NMR
(100.6 MHz, CDCl3): d¼201.74 (s), 104.69 (d), 73.18 (t),
55.80 (q), 55.69 (q), 44.42 (d), 41.24 (d), 11.02 (q); isomer mix-
ture: MS(EI): m/z¼205(<1), 127 (7), 101 (9), 99 (13), 83 (6),
75 (100), 71 (14), 69 (13), 67 (16), 55 (14), 47 (17).
(2R,3R)-4,4,4-Trifluoro-2-methyl-3-(nitromethyl)butyr-
aldehyde (13n): From propionaldehyde and nitroolefin 9n[126]
according to the General Procedure 3 using the diamine
(S,S)-iPBP at room temperature for 1 day to give a mixture
of inseparable diastereoisomer (syn/anti 77/23) as a yellow oil
(yield: 42%, 91% ee). The enantiomeric excess of syn-13n
was determined by GC [Hydrodex-B-3P, 908C-0-1, Rt:
10.3 min (2S,3S) and 10.9 min (2R,3R)]; syn isomer: 1H NMR
(400 MHz, CDCl3): d¼9.65 (s, 1H), 4.77 (dd, 1H, J¼6.3,
14.6 Hz), 4.56 (dd, 1H, J¼5.7, 14.6 Hz), 3.74–3.63 (m ,1H),
2.85 (dq, 1H, J¼3.3, 7.6 Hz), 1.35 (dq, 3H, J¼7.6, 1.5 Hz);
13C NMR (100.6 MHz, CDCl3): d¼199.38 (Cquat.), 125.63 (q,
¼
201.70 (C O), 136.29 (Cquat.), 132.61 (CH), 129.44 (q, JC-F
29.6 Hz, Cquat.), 128.15 (CH), 128.05 (CH), 126.83 (q, JC-F
¼
¼
5.9 Hz, CH), 126.28 (q, JC-F ¼276 Hz, CF3), 77.92 (CH2),
48.52 (CH), 39.24 (CH), 12.78 (CH3); MS(EI): m/z¼186
(27), 177 (28), 172 (38), 159 (100), 151 (18), 133 (13), 117
(16), 58 (14), 57 (15), 55 (28).
(2R,3S)-2-Methyl-4-nitro-3-(thien-2-yl)butyraldehyde
(13j): From propionaldehyde and nitroolefin 9j according to
the General Procedure 3 using the diamine (S,S)-iPBP at
À258C for 2 days to give a brown oil (yield: 66%, 93% ee,
not very pure). The enantiomeric excess was determined by
GC [Hydrodex-B-6-TBDM, 1458C isotherm, Rt: 22.4 min
1
(2R,3S) and 22.9 min (2S,3R)]; H NMR (400 MHz, CDCl3):
d¼9.70 (d, 1H, J¼1.2 Hz), 7.27–7.24 (m, 1H), 6.98–6.90 (m,
2H), 4.79 (dd, 1H, J¼5.8, 12.9 Hz), 4.69 (dd, 1H, J¼8.8,
12.9 Hz), 4.25 (dt, 1H, J¼6.1, 8.2 Hz), 2.79 (dquint, 1H, J¼
1.2, 6.1 Hz), 1.14 (d, 3H, J¼7.3 Hz); 13C NMR (100.6 MHz,
CDCl3): d¼201.71 (s), 138.85 (s), 127.13 (d), 126.76 (d),
125.34 (d), 78.41 (t), 48.85 (d), 39.45 (d), 11.53 (q).
(2R,3R)-2-Methyl-3-nitromethylheptanal (13k): From
propionaldehyde and nitroolefin 9k according to the General
Procedure 3 to give a mixture of two inseparable diastereomers
as a pale yellow oil. The enantiomers were separated by chiral
GC [Lipodex E, 1108C isotherm, Rt: 25.8 min (2S,3S) and
JC-F ¼281 Hz, Cquat.), 71.17 (CH2), 43.49 (CH), 42.15 (q, JC-F
¼
1
28 Hz, CH), 10.60 (CH3); anti isomer: H NMR (400 MHz,
CDCl3): d¼9.62 (s, 1H), 4.61 (dd, 1H, J¼7.6, 14.4 Hz), 4.42
(dd, 1H, J¼5.0, 14.4 Hz), 3.95–3.85 (m, 1H), 2.98 (dq, 1H,
J¼3.3, 7.6 Hz), 1.31 (dq, 1H, J¼7.6, 0.8 Hz); 13C NMR
1
27.0 min (2R,3R)]; H NMR (400 MHz, CDCl3): d¼9.68 (s,
1H), 4.49 (dd, 1H, J¼6.0, 12.4 Hz), 4.40 (dd, 1H, J¼7.8,
12.4 Hz), 2.80–2.76 (m, 1H), 2.54 (dq, 1H, J¼4.3, 7.1 Hz),
1.39–1.23 (m, 6H), 1.14 (d, 3H, J¼7.1 Hz), 0.89 (t, 3H, J¼
6.8 Hz); 13C NMR (100.6 MHz, CDCl3): d¼202.79 (s), 77.08
(t), 47.03 (d), 37.28 (d), 29.10 (t), 28.06 (t), 22.62 (t), 13.83
(q), 8.92 (q); IR (CHCl3): n¼3029 w, 2962 m, 2933 m, 2864 w,
1727 m, 1553 s, 1466 w, 1382 m, 1108 w cmÀ1; MS(EI): m/z¼
83 (22), 82 (14), 81 (12), 71 (10), 70 (14), 69 (79), 67 (11), 59
(17), 58 (35), 57 (33), 56 (15), 55 (100).
(100.6 MHz, CDCl3): d¼199.36 (Cquat.), 126.07 (q, JC-F
281 Hz, Cquat.), 70.27 (CH2), 43.18 (CH), 40.27 (q, JC-F
¼
¼
28 Hz, CH), 9.44 (CH3); isomer mixture: IR (CHCl3): n¼
3030 w, 2933 w, 1735 m, 1566 s, 1465 w, 1435 w, 1380 m, 1263
w, 1176 m, 1139 s, 984 w cmÀ1; MS(EI): m/z¼153 (12), 133
(10), 123 (21), 105 (37), 104 (15), 103 (75), 101 (23), 91 (47),
85 (18), 83 (25), 77 (100), 73 (20), 69 (15), 65 (29), 62 (37), 61
(68), 59 (69), 57 (19), 56 (18), 55 (83), 53 (21), 51 (25), 47
(31), 45 (38).
(2R,3R)-3-Cyclohexyl-2-methyl-4-nitrobutyraldehyde
(13l): From propionaldehyde and nitroolefin 9l according to
the General Procedure 3 to give a mixture of two inseparable
diastereomers as a pale yellow oil. The enantiomers were sep-
arated by chiral GC [Chirasil-dex-CB, 908C-0-1-170, Rt:
1
56.3 min (2R,3R) and 57.3 min (2S,3S)]; H NMR (400 MHz,
CDCl3): d¼9.68 (s, 1H), 4.59 (dd, 1H, J¼5.3, 13.4 Hz), 4.38 Acknowledgements
(dd, 1H, J¼6.8, 13.4 Hz), 2.61–2.54 (m, 2H), 1.81–1.56 (m,
5H), 1.50–1.41 (m, 1H), 1.27–0.90 (m, 5H), 1.20 (d, 3H, J¼
7.0 Hz); 13C NMR (100.6 MHz, CDCl3): d¼203.20 (s), 75.83
We thank the Swiss National Science Foundation (grant 20-
61891-00) for financial support.
Adv. Synth. Catal. 2004, 346, 1147–1168
asc.wiley-vch.de
ꢁ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1165

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