Organocatalyzed conjugate addition of carbonyl compounds to nitrodienes/nitroenynes and synthetic applications

Article abstract of DOI:10.1002/adsc.200900814

The purpose of this study is to point out the synthetic utility of a new class of Michael acceptors (nitrodienes and nitroenynes). The highly enantioselective organocatalytic Michael addition of carbonyl compounds to these functionalized nitroolefins has been carried out in the presence of (S)-diphenylprolinol silyl ether to achieve some interesting building blocks in high selectivities. The adducts thus obtained can be easily converted by taking advantage of the corresponding unsaturated carbon-carbon bond. In presence of the double bond, metathesis or electrophilic activation could be carried out whereas in the presence of the triple bond electrophilic acti-vation could be conducted. We thus focused on a gold-catalyzed cyclization of the bis-homopropargylic alcohol to afford the corresponding substituted tetrahydrofuran. Then, we also demonstrated that organic and gold catalysts were compatible in a one-pot process. Indeed, we developed a one-pot enantioselective organocatalytic Michael addition to a nitroenyne followed by a gold-catalyzed acetalization/cyclization to achieve tetrahydrofuranyl ethers in high diastereoand enantioselectivities with excellent yields.

Full text of DOI:10.1002/adsc.200900814

FULL PAPERS
DOI: 10.1002/adsc.200900814
Organocatalyzed Conjugate Addition of Carbonyl Compounds to
Nitrodienes/Nitroenynes and Synthetic Applications
Sꢀbastien Belot,a Adrien Quintard,a Norbert Krause,b,* and Alexandre Alexakisa,*
a
Department of Organic Chemistry, University of Geneva. 30 quai Ernest Ansermet, 1211 Geneve 4, Switzerland
Fax : (+41)-223-793-215; phone: (+41)-223-796-522; e-mail: alexandre.alexakis@unige.ch
Organic Chemistry, University of Dortmund. Otto-Hahn-Strasse 6, 44227 Dortmund, Germany
b
E-mail: norbert.krause@tu-dortmund.de
Received: November 20, 2009; Published online: February 19, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900814.
Abstract: The purpose of this study is to point out vation could be conducted. We thus focused on a
the synthetic utility of a new class of Michael accept- gold-catalyzed cyclization of the bis-homopropargylic
ors (nitrodienes and nitroenynes). The highly enan- alcohol to afford the corresponding substituted tetra-
tioselective organocatalytic Michael addition of car- hydrofuran. Then, we also demonstrated that organic
bonyl compounds to these functionalized nitroolefins and gold catalysts were compatible in a one-pot pro-
has been carried out in the presence of (S)-diphenyl- cess. Indeed, we developed a one-pot enantioselec-
prolinol silyl ether to achieve some interesting build- tive organocatalytic Michael addition to a nitroenyne
ing blocks in high selectivities. The adducts thus ob- followed by a gold-catalyzed acetalization/cyclization
tained can be easily converted by taking advantage to achieve tetrahydrofuranyl ethers in high diastereo-
of the corresponding unsaturated carbon-carbon and enantioselectivities with excellent yields.
bond. In presence of the double bond, metathesis or
electrophilic activation could be carried out whereas Keywords: gold catalysis; Michael addition; nitro-
in the presence of the triple bond electrophilic acti- dienes; one-pot procedure; organocatalysis
Introduction
a-keto-a,b-unsaturated esters,[13] a-phosphonate-a,b-
unsaturated esters,[14] b-keto-a,b-unsaturated esters[15]
Over the recent years, organocatalysis has emerged as and b-thioester-a,b-unsaturated esters[16] have been
a new catalytic method leading to an intensive and tested. Most of the 1,4-addition adducts have been
impressive growth.[1] This field is currently improving further transformed to get useful building blocks of
in such a way that it can now be considered as a sus- high molecular complexity.
tainable process, which is one of the main priorities
Therefore, organocatalysis combined with another
for preparative chemistry in the 21st century.[2] Among synthetic transformation appears to represent a new
the various types of activation in organocatalysis, en- powerful tool that can be used in total synthesis.[17]
amine catalysis has been shown to be one of the most
efficient catalytic methods to achieve high molecular conjugate addition of either aldehydes[18] or ketones[19]
complexities and high selectivities.[3]
to b-nitroolefins, catalyzed by a pyrrolidine derivative,
Amongst Michael acceptors, the enantioselective
After the rediscovery of proline as an efficient appeared to be an efficient method to achieve useful
enantioselective catalyst for intermolecular aldolisa- g-nitrocarbonyl building blocks. Non-functionalized b-
tion,[4] many research groups contributed to develop nitroolefins are the most widely used and have been
the field of enamine catalysis and especially the con- successfully converted into substituted pyrrolidines,[6b]
jugate addition of carbonyl compounds to Michael ac- butyrolactones[20] or fused isoxazolines.[21] Some func-
ceptors.[5] Therefore, for several years, a huge effort tionalized nitroolefins such as b-nitroacrolein dimeth-
has been devoted to the development of new Michael yl acetal[22] or 3-nitroacrylate[18j] have also led to syn-
acceptors in order to achieve useful adducts through thetic applications. Furthermore, another nitroolefin
enamine catalysis. For example, alkylidenemalo- was used in the synthesis of (À)-botryodiplodin.[23] In
nates,[6] vinyl ketones,[7] maleimides,[8] vinyl sulfones,[9] order to extend the scope of useful functionalized ni-
chalcones,[10] benzoquinones,[11] vinyl phosphonates,[12] troolefins, we explored the idea of introducing an un-
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Sꢀbastien Belot et al.
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Scheme 1. Summary of the study.
saturated function, such as a carbon-carbon double cohol), as well as some mechanistic insights with 18O-
bond or triple bond (Scheme 1).
marker experiments are also disclosed.
We carried out the organocatalyzed conjugate addi-
tions of carbonyl compounds 1 and 2 to nitrodienes 3
or nitroenynes 5. The obtained adducts 4 and 6 can Results and Discussion
then be easily converted into other useful compounds
by taking advantage of the corresponding unsaturated Nitrodienes
carbon-carbon bond. In the presence of a double
bond, metathesis or electrophilic cyclization can be Nitrodienes 3 are interesting compounds which have
carried out whereas in the presence of the triple not been widely explored. They are easily synthesized
bond, electrophilic activations with gold have been from the corresponding aldehyde through Henry reac-
conducted (Scheme 1). The study has been divided tion and dehydration. A few examples of such a type
into two parts, the nitrodienes 3 and the nitroACTHNUGRTENUNGenynes of Michael acceptor have been described but without
5. Both aldehydes 1 or ketones 2 have been tested as exploiting their synthetic utility.[19a,25] Herein, we
Michael donor and the usefulness of the correspond- report the optimization of the organocatalyzed conju-
ing adducts disclosed with various synthetic transfor- gate addition of isovaleraldehyde 1a to phenyl-nitro-
mations. Herein we report a full account of this diene 3a. This test reaction has been carried out using
work[24] with both several new carbonyl compounds 10 equivalents of isovaleraldehyde 1a in the presence
(ketones and new aldehydes) and new unsaturated of 20 mol% of organocatalyst in chloroform (Table 1).
nitro compounds (nitrodiene with an ester function All organocatalysts used in this study are shown in
and alkylnitroenynes). A new synthetic application Figure 1.
(gold-catalyzed cyclization of bis-homopropargylic al-
l-Proline I did not induce any selectivity (entry 1,
Table 1) whereas (S,S)-N-i-Pr-2,2’-bipyrrolidine II, de-
Table 1. Optimization on nitrodienes: organocatalysts.
Entry
Catalayst
T [8C]/time
Conversion [%]
Yield [%][a]
dr[b] (syn/anti)
ee[c] (syn)
1
2
3
4
5
6
7
I
II
II
III
III
IV
V
23/4 d
23/6 h
À25/4 d
23/2 h
À25/2 d
23/3 d
23/3 d
70
100
45
100
100
0
63
94
40
86
87
0
76/24
69/31
86/14
79/21
95/5
0
0
68
75
80
73
0
100
91
88/12
>99
[a]
Yield of isolated product after flash column chromatography.
Determined by H NMR or chiral SFC on the crude product.
Determined by chiral SFC.
[b]
[c]
1
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Organocatalyzed Conjugate Addition of Carbonyl Compounds to Nitrodienes/Nitroenynes
Figure 1. Organocatalysts used in this study.
veloped in our group,[18b] gave better selectivities at lectivity (entry 2, Table 2) but needed a longer reac-
À258C rather than at room temperature (75% ee, dr: tion time compared to aqueous media. Indeed, beer
86/14, entries 2 and 3, Table 1). (S)-1-(2-Pyrrolidinyl gave the same results in terms of selectivities (entry 6,
methyl) pyrrolidine III afforded good results but in Table 2) but the kinetics of the reaction was im-
different reaction conditions for optimized enantio- proved. A decrease of selectivities has been observed
(238C, 80% ee, entry 4, Table 1) or diastereoselectiv- by increasing the amount of alcohol (entry 6, Table 2).
ity (À258C, dr: 95/5, entry 5, Table 1). Diphenylproli- Subsequently, moderate results were obtained when
nol IV did not induce the reaction (entry 6, Table 1) the reaction was performed in ethanol as the solvent
whereas (S)-diphenylprolinol silyl ether V afforded (entry 8, Table 2). Water alone also proved to be suit-
the best results in terms of enantio- and diastereose- able (entry 7, Table 2) but the slight amount of etha-
lectivities (entry 7, Table 1). It is important to point nol used in the water and ethanol 5% v/v system ap-
out that only 1,4-addition was observed during the peared to be as efficient and also more useful for
preliminary optimization study without any trace of practical reasons (entry 5, Table 2). According to the
1,6-addition adducts.
definition given by Hayashi, our reaction occurred “in
Further optimizations have been conducted by car- the presence of water”.[26] Indeed, experimental obser-
rying out the test reaction in various solvents. Chloro- vations pointed out the fact that the reaction seems to
form and neat conditions led to excellent enantiose- take place in tiny drops in the aqueous media. There-
lectivity and good diastereoselectivity (entries 1 and fore the organic reaction may proceed in a concen-
3, Table 2). Dichloromethane gave better diastereose-
Table 2. Optimization on nitrodienes: solvents.
Entry
Solvent
Time
Yield [%][a]
dr[b] (syn/anti)
ee[c]
1
2
3
4
5
6
7
8
CHCl3
24 h
24 h
2 d
14 h
14 h
20 h
14 h
50 h
91
95
87
89
97
78
88
87
88/12
92/8
87/13
92/8
92/8
80/20
92/8
>99
>99
99
>99
>99
97
CH2Cl2
neat
beer[d]
H2O/EtOH 5% v/v
wine[e]
H2O
EtOH
98
88
65/35
[a]
Yield of isolated product after flash column chromatography.
Determined by H NMR or chiral SFC of crude product.
Determined by chiral SFC on the syn adduct.
Heineken.
White wine of Jura, France.
[b]
[c]
[d]
[e]
1
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Table 3. Optimization on nitrodienes: quantities.
Entry
1a [equiv]
V [mol%]
Time [h]
Yield [%][a]
dr[b] (syn/anti)
ee[c] [%]
1
2
3
4
5
6
7
8
10
10
10
10
5
3
2
1,1
20
10
5
1
5
5
5
5
14 h
20 h
48 h
7d
14 h
14 h
14 h
20 h
97
90
91
55
95
97
91
65
92/8
94/6
94/6
nd
94/6
94/6
94/6
94/6
>99
99
>99
nd
>99
>99
>99
>99
[a]
Yield of isolated product after flash column chromatography.
Determined by H NMR or chiral SFC on the crude product.
Determined by chiral SFC.
[b]
[c]
1
trated organic phase with the aldehyde being present aldehyde (entry 8, Table 3). Therefore 5 mol% of or-
as the organic layer and water as the second phase. ganocatalyst and 2 equivalents of aldehyde were
One of the main drawbacks that enamine catalysis chosen as being the best conditions (entry 7, Table 3).
is faced with is the high catalytic loading of amine We then turned out our attention to the absolute
(generally around 15 mol%) and the amount of alde- configuration of the adduct 4a (Scheme 2). We thus
hyde (up to 10 equivalents). In the amine-catalyzed carried out the organocatalytic synthesis of compound
conjugate addition, only a few examples have been 8 starting from either nitroolefin 7 or nitrodiene 3a.
reported with low quantities of both aldehyde and or- Chiral HPLC analyses clearly proved that products 8
ganocatalyst leading to almost perfect diastereo- and had the same absolute configuration from both path-
enantioselectivities.[20,27] To the best of our knowledge ways.
the best results in terms of efficiency and selectivities
Encouraged by these results, we were then able to
have been obtained by the group of Wennemers with probe the scope of the reaction with a wide range of
a tripeptide (0.1 mol%).[28] In our case, we also opti- aldehydes 1a–h and nitrodienes 3a–e (Scheme 3).
mized our conditions in order to decrease both the
In the case of non a-branched aldehyde such as iso-
quantity of aldehyde 1a and the amount of organoca- valeraldehyde 1a, propionaldehyde 1b or butyralde-
talyst V (Table 3). Based on recent studies, optimiza- hyde 1c, all reactions proceeded smoothly with good
tion of these parameters is easier in aqueous media yields (62–99%), good diastereoisomeric ratios (syn/
since several examples in enamine catalysis have been anti: from 72/28 to 94/6) and excellent enantioselectiv-
published (aldol reactions) in which less than 1 mol% ities (from 85 to >99%). Pent-4-enal 1d with phenyl-
of organocatalyst was used.[29]
nitrodiene 3a led to a poor diastereoselectivity where-
By decreasing the amount of organocatalyst V from as hex-5-enal 1e with ethyl-nitrodiene 3e gave good
20 to 5 mol% the reaction times became longer with- diastereo- and enantioselectivities. Furthermore, (S)-
out any influence on the enantioselectivity but with a citronellal 1h as the Michael donor achieved a com-
slight improvement of the diastereoisomeric ratio plex molecule with the formation of three stereogenic
(entry 1 to 3, Table 3). One mol% gave only 60% centers even if the diastereoselectivity was moderate.
conversion after 7 days (entry 4, Table 3). The de- Finally, poor results in terms of enantioselectivity
crease from 10 to 2 equivalents of aldehyde 1a did not have been observed by using a-branched aldehyde
have any influence, either on the diastereo- or on the such as isobutyraldehyde 1f or 2-phenylpropionalde-
enantioselectivities. However, the kinetics of the reac- hyde 1g. On the other hand, aromatic substituted ni-
tion could be improved (entry 3 vs. 5–7, Table 3). This trodienes 3b and 3c gave excellent selectivities with
may be explained by the fact that reactants are closer an improvement for the p-MeO-phenyl nitrodiene in
because the organic phase is more concentrated. Fi- comparison with previously reported work. Alkyl-sub-
nally, we observed some side-reactions (mainly self- stituted nitrodienes 3d and 3e also appeared to be
aldol condensation), by using only 1.1 equivalent of suitable Michael donor with good selectivities.
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Organocatalyzed Conjugate Addition of Carbonyl Compounds to Nitrodienes/Nitroenynes
Scheme 2. Determination of the absolute configuration.
Scheme 3. Scope of the reaction on nitrodienes 3a–e.
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Scheme 4. Enamine and enol mechanisms.
Until now in amine-catalyzed reactions of carbonyl the organocatalyst and another one from the nitrogen
compounds, the observed reactivity and selectivities of the organocatalyst to the oxygen of the nitro func-
have been explained thanks to the enamine mecha- tion (TS2, Scheme 4). In this latter, no incorporation
nism. Many experiments proved it with either 18O- of 18O should be observed. Furthermore, this mecha-
marker[30] or computational studies.[31] However, some nism could also explain the perfect regioselectivity in
recently published works such as the one of Tsogoeva favour of the 1,4-addition and not the 1,6-addition
and mainly Wong brought some evidence in favour of thanks to hydrogen bonding between the nitrogen of
an enol mechanism.[32] Both of them would lead to the organocatalyst to the oxygen of the nitro function.
the same absolute configuration as proved above.
As our process for the Michael addition of alde-
As shown in Scheme 4, in the enamine mechanism, hyde 1 on nitrodienes 3 occurs in aqueous media, we
the facial selectivity is due to steric shielding. Indeed, clearly admit that the enamine formation is not fav-
the hindered function of the organocatalyst frame- oured according to Le Chatelierꢂs principle. Therefore
work prevents interaction involving the attack of the we decided to carry out the organocatalyzed addition
anti-enamine to the Michael acceptor on the opposite of isovaleraldehyde 1a to nitrodiene 3c in 97% 18O-
site (TS1, Scheme 4). Thus, the less hindered Si,Si enriched water under an argon atmosphere
transition state is favoured. In the case of carrying out (Scheme 5). The adduct 17 has been chosen since it
the reaction in 18O-enriched water there would be in- was the easiest ionizable molecule amongst our newly
corporation in the hydrolysis step after the formation generated compounds (Scheme 3). The peak at 309
of the iminium ion, leading to the adduct 4. On the corresponds to an enol mechanism without involve-
other hand, the enol mechanism involves a concerted ment of water whereas the one at 311 corresponds to
À
transition state with simultaneous C C bond forma- the enamine mechanism due to hydrolysis of the imi-
tion between the enol and the nitrodiene, a proton nium ion intermediate.
shift from the oxygen of the enol to the nitrogen of
Scheme 5. 18O-marker experiment followed by ESI-MS.
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Organocatalyzed Conjugate Addition of Carbonyl Compounds to Nitrodienes/Nitroenynes
Scheme 6. Access to tetrahydropyran.
Scheme 7. Access to functionalized cyclohexene.
An ESI-MS method showed that the adduct 17
could be obtained as a mixture of both isotopes in a
60/40 ratio. We also checked this ratio 4 days after the
reaction was completed in order to see if water could
be incorporated on the adduct 17. But the ratio re-
mained the same. Therefore from these experiments,
we could conclude that both mechanisms, enamine
and enol, may be involved in our reaction in an aque-
ous media.
Scheme 8. Conjugate addition to the ester-nitrodiene.
Having these adducts in hand with olefin function-
ality, we then turned out our attention towards their
further synthetic transformation. We thus carried out
the quantitative reduction of adduct 4a into the corre- explained by the fact that the nitro function is more
sponding alcohol 20 with NaBH4 in methanol. Firstly, electron-withdrawing than an ester fuction. The
electrophile cyclization was conducted by treating the adduct 23 is an interesting building block with the
alcohol with PhSeCl at À788C to afford the expected presence of many functionalities.
tetrahydropyran 21 as a mixture of diastereoisomers
We investigated the reaction scope by carrying out
the addition of various ketones 2a–c (acetone, hydrox-
(Scheme 6).
Secondly, we investigated metathesis to take ad- yacetone and cyclohexanone[33]). We thus tested vari-
vantage of the C=C double bond. Starting from the ous catalysts (see Figure 1) such as (S,S)-N-i-Pr-2,2’-
adduct 12, obtained through the addition of hex-5- bipyrrolidine II, (S)-1-(2-pyrrolidinylmethyl)-pyrroli-
enal 1e on ethyl-nitrodiene 3e, we used 2nd generation dine III, a primary amine-thiourea catalyst VI,[19c]
a
Grubbs catalyst in order to obtain the corresponding pyrrolidine-sulfonamide catalyst IX,[19b] and an
functionalized cyclohexene 22 without any erosion of aminal-pyrrolidine organocatalyst VII developed in
the diastereo- and enantioselectivities. (Scheme 7).
our group[18i,34] (Scheme 9).
The functionalized ester-nitrodiene 3f has also been
Amongst the catalyst tested for the optimization,
tested in the organocatalytic conjugate addition of the catalyst VI developed by Jacobsen gave the best
isovaleraldehyde 1a catalyzed by (S)-diphenylprolinol results in the case of the addition of acetone 2a to ni-
silyl ether V (Scheme 8). The conjugate addition pro- trodiene 3a with an excellent 95% ee [Eq. (1) in
ceeded regioselectively on the carbon located in the Scheme 9]. Then, as already described previously for
b-position of the nitro function with good diastereose- nitroolefins,[35] (S,S)-N-i-Pr-2,2’-bipyrrolidine II afford-
lectivity (84/16 in favour of syn) and excellent enan- ed the best enantioselectivity (95% ee) for the addi-
tioselectivity (99% ee). The regioselectivity could be tion of a-hydroxyacetone 2b even if moderate diaste-
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Sꢀbastien Belot et al.
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Scheme 9. Scope of the reaction with various ketones.
reoselectivity has been observed [Eq. (2) in solubility problem that has not been observed in the
Scheme 9). Finally, aminal-pyrrolidine organocatalyst case of nitrodienes 3. Thus, other conditions in organ-
VII appeared to be the best for the addition of cyclo- ic solvents have been screened. It appeared that the
hexanone 2c with very good diastereo- and enantiose- most efficient organocatalyst for the test reaction was
lectivities [Eq. (2) in Scheme 9). Catalysts III and IX (S)-diphenylprolinol silyl ether
V
(entries 2–6,
gave lower selectivities in all cases.
Table 4). We also performed other experiments with
pyrrolidine-sulfonamide catalyst IX in 2-propanol and
the best diastereoselectivity has been observed at
room temperature under these conditions (entry 7,
Table 4). The selectivity has then been improved by
Nitroenynes
The stereochemical outcome of the Michael addition performing the reaction at 08C (entry 8, Table 4).
of isovaleraldehyde 1a to phenyl-nitroenyne 5a was These experiments showed the complementarity of
investigated by screening some pyrrolidine-core orga- the reaction since different organocatalysts can be
nocatalysts. Thus, (S,S)-N-i-Pr-2,2’-bipyrrolidine II, used in different solvents. However, the problem for
(S)-1-(2-pyrrolidinylmethyl)-pyrrolidine III, diarylpro- pyrrolidine-sulfonamide catalyst IX is the price and
linol silyl ethers (V and VIII) and pyrrolidine-sulfon- also the solvent (2-propanol) which could be problem-
ACHTUNGTRENNUNGamide catalyst IX were tested in various conditions atic for the development of a one-pot reaction in the
(Table 4). Under the conditions previously developed presence of various alcohols. In chloroform, at À108C
for the addition of aldehydes 1 to nitrodienes 3 and using (S)-diphenylprolinol silyl ether V, a cheaper
[2 equivalents of aldehyde, 5 mol% of (S)-diphenyl- organocatalyst, excellent results were observed in
prolinol silyl ether V in a mixture of water and etha- terms of diastereo- and enantioselectivities (entry 9,
nol 5% v/v], excellent dia- and enantioselectivities Table 4).
could be obtained (entry 1, Table 4). This was an im-
Further optimizations were conducted in order to
provement in comparison with previously reported re- decrease both the excess of aldehyde 1a and the cata-
sults.[24] Indeed, experiments showed that during the lyst loading (Table 5). Decreasing the amount of orga-
work-up and particularly during the concentration of nocatalyst V from 20 to 10 mol% did not have any in-
the reaction mixture epimerization occurs. This could fluence on the diastereo- and enantioselectivities but
be prevented either by analyzing directly on the reac- increased the reaction time (entries 1 and 2, Table 5).
tion mixture or by reducing the adduct 6 into the cor- Moreover, as already described for numerous organo-
responding alcohol.
catalytic reactions in organic solvents, a larger excess
However, the conversion was not complete after 4 of the aldehyde led to cleaner reactions and higher se-
days and the yield remained low probably due to a lectivities. Indeed, in contrast to aqueous media, it ap-
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Organocatalyzed Conjugate Addition of Carbonyl Compounds to Nitrodienes/Nitroenynes
Table 4. Optimization on nitroenynes: organocatalysts.
Entry
Catalyst
T [8C]
Time
Yield [%][a]
dr[b] (syn/anti)
ee[c] [%]
1[d]
2
3
4
5
6
7
8
9
V
II
23
23
23
23
23
23
23
0
3 d
4 h
4 h
7 h
4 d
4 d
4 h
14 h
36 h
60
77
80
82
13
18
79
83
85
94/6
65/35
64/36
70/30
nd
98
82
75
98
nd
nd
95
96
99
III
V
VIII
IX
IX[e]
IX[e]
V
nd
81/19
90/10
96/4
À10
[a]
Yield of isolated product after flash column chromatography.
Determined by H NMR or chiral SFC of crude product.
Determined by chiral SFC.
2 equiv of aldehyde with 5 mol% of V in H2O/EtOH 5% v/v.
Solvent: i-PrOH.
[b]
[c]
[d]
[e]
1
Table 5. Optimization on nitroenynes: quantities.
Entry
1a [equiv]
V [mol%]
Time [h]
Yield [%][a]
dr[b] (syn/anti)
ee[c] [%]
1
2
3
10
10
5
20
10
10
24
36
72
85
83
63
96/4
96/4
89/11
99
99
94
[a]
Yield of isolated product after flash column chromatography.
Determined by H NMR or chiral SFC on the crude product.
Determined by SFC on chiral stationary phase.
[b]
[c]
1
peared difficult to decrease both the quantities of al- excellent selectivities (adduct 31). Nitroenynes bear-
dehyde and organocatalyst at the same time in organ- ing an alkyl chain 5g and 5h also gave excellent re-
ic solvents (entry 3, Table 5).
sults in terms of diastereo- and enantioselectivities
We then applied these optimized conditions to a va- with an excellent 99% ee for the tert-butylnitroenyne
riety of nitroenynes 5a–h (Scheme 10). In almost all (adducts 32 and 33). Finally other aldehydes have also
cases the expected adducts were obtained in good been tested. Propionaldehyde and n-valeraldehyde
yields. Moreover, excellent diastereo- and enantiose- led to excellent diastereo- and enantioselectivities
lectivities have been obtained for the organocatalyzed with 99% ee for both (adducts 34 and 35). Other alde-
conjugate addition of isovaleraldehyde 1a on all aro- hydes such as heptanal and nonanal were also suitable
matic nitroenynes, either electron-rich 28, electron- donors for the organocatalyzed conjugate addition on
deficient 27, 29 or meta-substituted 31. A heteroaro- nitroenynes with excellent diastereo- and enantiose-
matic-substituted nitroenyne such as the 3-thienyl de- lectivities after reduction into the corresponding alco-
rivative is also a suitable Michael acceptor leading to hols 36 and 37.
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Scheme 10. Scope of the reaction on nitroenynes
We investigated the reaction scope by carrying out
the addition of cyclohexanone 2c to the phenyl-nitro-
enyne 5a using an aminal organocatalyst VII. This or-
ganocatalyst, developed in our group,[18i,34] afforded a
good diastereoselectivity of 95/5 in favour of the syn
adduct 38 with an excellent 92% enantioselectivity
(Scheme 11).
We envisaged that the triple bond in the Michael
adducts could be converted into interesting building
blocks mediated by gold. First of all, we carried out
the reduction of the adduct 6a using sodium borohy-
dride in methanol to afford the corresponding bis-ho- Scheme 11. Addition of cyclohexanone to nitroenyne.
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Organocatalyzed Conjugate Addition of Carbonyl Compounds to Nitrodienes/Nitroenynes
Table 6). Thus it appeared that the reactivity of our
bis-homopropargylic alcohol 39 was completely differ-
ent to those already reported in the literature, even
though the structure is similar. Among all gold sour-
ces the combination of Ph3PAuCl and AgBF4 was the
best in terms of isolated yield (entries 2–5, Table 6).
The presence of p-TsOH accelerated the reaction
(entry 6, Table 6). Solvents such as THF or toluene
worked well for this gold-catalyzed reaction whereas
dichloromethane led to degradation (entries 8–10,
Table 6). Finally we proved that the reaction could be
Scheme 12. Reduction of the aldehyde into the alcohol.
mopropargylic alcohol 39. The reduction could be carried out with only 0.2 mol% of catalysts in good
achieved in almost quantitative yield (Scheme 12).
Belting and Krause developed a gold-catalyzed
yield (entry 11, Table 6).
We were then keen to investigate the gold-cata-
tandem cycloisomerization-hydroalkoxylation of vari- lyzed tandem acetalization/cyclization of the bis-ho-
ous homopropargylic alcohols in the presence of an mopropargylic aldehyde 6a into the expected tetrahy-
alcohol and a dual catalyst system.[36] The process has drofuranyl ether 42. This work has been based on
also been extended to bis-homopropargylic alcohols. recent results on gold-catalyzed transformations of
The group of Pale developed a gold-catalysed cycliza- functionalized alkynes.[38] Therefore we tested various
tion of bis-homopropargylic alcohols leading to tetra- gold sources and additives such as silver salts or p-tol-
hydrofurans in the presence of catalytic amounts of uenesulfonic acid. Additional experiments on the
AuCl and K2CO3.[37] These conditions have been effect of the solvents and the temperature have also
tested on alcohol 39 (Table 6).
been conducted (Table 7).
Firstly, we only observed a small amount of the cor-
Among all gold sources, the combination of
responding tetrahydrofuran 40 in the conditions de- Ph3PAuCl and AgBF4 appeared to be the best in
scribed by Pale (entry 1, Table 6). Secondly we ob- terms of diastereoselectivity and isolated yield
served the cyclization under the conditions developed (entry 4, Table 7). Again, the addition of p-TsOH
by Krause, leading to the tetrahydrofuran 40 but no seems to improve slightly the diastereoselectivity in
trace of the hydroalkoxylated compound 41 (entry 6, favour of the cis-compound 42 (entries 4 and 5,
Table 6. Gold-catalyzed cyclization of alcohol 39.
Entry
Au salt
Additive
Solvent
Time
Yield of 40 [%][a]
[c]
1[b]
2[b]
3[b]
4[b]
5[b]
6
7
8
9
AuCl
AuCl
AuCl3
K2CO3
–
–
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH2Cl2
THF
3 h
3 h
2 h
2 h
1 h
30 min
1 h
–
56
60
70
81
85
80
HAuCl4
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
–
AgBF4
AgBF4
AgSbF6
AgBF4
AgBF4
AgBF4
AgBF4
[c]
1 h
–
1 h30
1 h30
3 h
76
78
75
10
Toluene
EtOH
11[d]
[a]
Yield of isolated product after flash column chromatography.
Without addition of p-TsOH.
Full conversion, Traces observed but lot of degradation.
0.2 mol% of Au salt and additive.
[b]
[c]
[d]
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Table 7. Optimization of the gold-catalyzed tandem acetalyzation/cyclization.
Entry
[Au][a]
Additive
Solvent
T [8C]
Time
dr[b]
Yield [%][c]
1
2
AuCl
AuCl3
HAuCl4
LAuCl
LAuCl
LAuCl
LAuCl
–
–
–
–
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CHCl3
CHCl3
CHCl3
23
23
23
23
23
0
23
23
23
23
23
0
1 h
1 h
4
1 h
1 h
1 h
2d
2d
2d
1 h
1 h
1 h
89/11
92/8
93/7
88/12
90/10
91/9
–
62
65
59
80
77
78
0
0
0
80
84
81
3
4[d]
5
AgBF4
AgBF4
AgBF4
–
AgBF4
AgSbF6
AgBF4
AgBF4
AgBF4
6
7
8
–
–
9[d]
10[d,e]
11[e]
12[f]
–
LAuCl
LAuCl
LAuCl
90/10
93/7
96/4
[a]
L=PPh3.
[b]
[c]
[d]
[e]
[f]
1
dr (cis/trans) for the chiral centers (a) and (c) determined by H NMR on the crude product.
Yield of isolated product after flash column chromatography.
Without addition of p-TsOH.
5 equiv. of ethanol.
1.2 equiv. of ethanol.
Table 7). Ph3PAuCl and AgBF4 have also been tested
Both primary and secondary alcohols [ethanol,
separately in the tandem acetalization/cyclization but methanol, butanol, methallyl alcohol, benzyl alcohols,
no reaction occurred (entries 7 and 8, Table 7). We (R)-2-phenylpropanol and 2-propanol or cyclohexa-
envisaged that the active catalyst in the reaction mix- nol] afforded the expected tetrahydrofuranyl ethers
ture should be Ph3PAuBF4. Moreover, we also tried a with good to excellent diastereoselectivities (from 92/
silver catalyst alone which was efficient in the case of 8 to 97/3 in favour of the cis compound). Unfortu-
the tandem silver-catalyzed acetalization/cyclization nately, no reaction occurred in presence of water and
of 1-alkynyl-2-carbonyl quinoline substrates devel- tert-butanol. Moreover, other nucleophiles such as
oped by Belmont[38b] but AgSbF6 did not catalyze the thiols, phenols or anilines have also been tested but
reaction (entry 9, Table 7). We envisaged that the unsuccessfully.
one-pot process should be achievable in the best sol-
The use of 4-chlorobenzyl alcohol in the tandem
vent of the organocatalyzed step, that is, chloroform, acetalization/cyclization gave access to a crystalline
in the presence of a small excess of ethanol. This pa- product which enabled us to solve the crystal struc-
rameter was indeed the key element to develop the ture and prove the absolute and relative configuration
one-pot reaction. Fortunately, under these conditions, of the corresponding tetrahydrofuranyl ether 50. This
we observed a slight improvement of the diastereose- was determined to be cis (Figure 2, see supporting in-
lectivity (entry 10 vs. entry 4, Table 7). Again, the ad- formations). We assume that all other tetrahydrofur-
dition of p-TsOH improved the diastereoselectivity anyl ethers synthesized have the same cis-configura-
(entry 11, Table 7). Finally, we performed the reaction tion for stereogenic centers (a) and (c).
with a slight excess of ethanol (1.2 equiv). in the pres-
A deuterium labelling experiment has been con-
ence of p-TsOH in chloroform at 08C. Under those ducted in order to propose a plausible mechanism.
conditions an excellent diastereoselectivity of 96/4 Therefore the tandem acetalization/cyclization of deu-
could be achieved.
terated methanol with the adduct 6a has been carried
Having found the best conditions for the tandem in the presence of Ph3PAuCl, AgBF4 and p-TsOH in
acetalization/cyclization reaction, we were then able chloroform. According to the NMR spectra, the deu-
to probe the scope of the reaction with a wide range terium was located on the exocyclic double bond
of alcohols on the adduct 6a (Scheme 13).
(adduct 51) (Scheme 14).
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Organocatalyzed Conjugate Addition of Carbonyl Compounds to Nitrodienes/Nitroenynes
Scheme 13. Scope of the sequential reaction.
The gold-catalyzed acetalyzation/cyclization reac- through the attack of the corresponding alcohol (in-
tion also occured in the absence of the Brønsted acid termediate A). Based on forming the hemiacetal salt
(entry 4, Table 7) which may indicate that the reaction B, we postulated that the triple bond is activated
may firstly be initiated by Ph3PAuBF4, which acts as a through the formation of a p-complex towards the
oxophilic Lewis acid. The aldehyde functionality of attack of the oxygen atom. This leads to the tetrahy-
the bis-homopropargylic aldehyde 6a is activated drofuran ether C which consequently undergoes pro-
todemetalation thanks to HBF4 to afford the corre-
sponding tetrahydrofuranyl ether 51.
Organic chemists have already demonstrated that
gold catalysis and organocatalysis were compatible,
complementary, and even cooperative. For example,
Dixon and Kirsch showed that enamine catalysis and
gold catalysis were compatible in the cascade Michael
addition and cyclization reactions.[40] Dixon also docu-
mented an Au(I) and chiral Brønsted acid multicata-
lyst cascade in the enantioselective cyclization cas-
cade.[41] Gong reported that the gold catalysis and
Brønsted acid catalysis are compatible in the gold-cat-
alyzed hydroamination and transfer hydrogenation.[42]
However, those works refer to dual or cooperative
catalysis. Furthermore, some asymmetric gold-cata-
lyzed cyclizations are known, using either chiral li-
gands or chiral anions,[43] but to the best of our knowl-
edge, there is no example in the literature in which
Figure 2. Single-crystal X-ray structure analysis of 50. Ther-
mal ellipsoids shown at 70% probability.[39]
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Sꢀbastien Belot et al.
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Scheme 14. Proposed mechanism for the gold-catalyzed tandem acetalyzation/cyclization.
organocatalysis and gold are compatible in a enantio- Table 8. Mimic of the one-pot process.
selective one-pot process, even if there are some in
tandem catalysis.[44]
In our case, to prepare the one-pot process using
two previously optimized conditions, we performed a
compatibility study. All the reactants and catalysts of
both the organocatalyzed conjugate addition and the
gold-catalyzed tandem acetalization/cyclization reac-
tion were mixed together. Therefore, we carried out
the gold-catalyzed tandem acetalization/cyclization of
the bis-homopropargylic aldehyde 6a in the presence
of isovaleraldehyde 1a, diphenylprolinol silyl ether V,
Ph3PAuCl, AgBF4 and p-TsOH. In particular, the in-
fluence of the amount of amine organocatalyst V rela-
tive to the acidic additive has been studied at differ-
ent temperatures (Table 8).
Interestingly, no reaction occurred when a lower
amount of p-TsOH was used in comparison with di-
phenylprolinol silyl ether V (entries 1 and 3, Table 8).
This observation is clearly in contradiction with previ-
ously reported works in which amine catalysts were
compatible with gold catalysts.[40–44] Indeed, in our
case, it seems that the acid prevents the deactivation
of the gold catalyst, by interacting with the amine or-
ganocatalyst. The amount of p-TsOH should be at
least the same as the one of diphenylprolinol silyl
ether V so that the reaction can occur (entry 2,
Entry V [x1
mol%]
p-TsOH [x2
mol%]
T
dr[a] (cis/
[8C] trans)
Yield
[%][b]
1
2
3
4
5
6
7
8
20
10
10
0
10
25
50
100
25
23
23
23
0
0
0
–
0
84
0
87
79
84
81
89
10
10
10
10
10
10
10
90/10
–
91/9
92/8
93/7
95/5[c]
0
À10 93/7
[a]
dr are given for the chiral centers (a) and (c). Deter-
mined by H NMR or SFC on chiral stationary phase on
1
the crude product.
Yield of isolated product after flash column chromatog-
raphy on SiO2.
[b]
[c]
Epimerization of syn-6a into the anti-6a occurs.
Table 8). We then tested the influence of an excess of is very slow. On using only a slight excess of p-TsOH
the acidic additive on the reaction at 08C. p-TsOH at À108C the diastereoselectivity was very good
has a significant effect since the increase of the quan- (entry 8, Table 8).
tity afforded an improvement of the diastereoselectiv-
We then applied our optimized conditions to dem-
ity in favour of the cis-tetrahydrofuranyl ether 42 (en- onstrate the real one-pot enantioselective organocata-
tries 4–7). Nevertheless, the epimerization of the syn- lyzed conjugate addition and gold-catalyzed acetaliza-
adduct 6a into the anti-adduct 6a was observed [chiral tion/cyclization (Scheme 15). The first attempt on the
center (a)], leading to another diastereoisomer after test reaction enabled us to prove that our model
the gold-catalyzed reaction. Fortunately this reaction fitted with the one-pot process. Therefore, encouraged
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Organocatalyzed Conjugate Addition of Carbonyl Compounds to Nitrodienes/Nitroenynes
Conclusions
We have demonstrated the synthetic utility of a new
class of Michael acceptors in the organocatalytic Mi-
chael addition of carbonyl compounds. Indeed, these
functionalized nitroolefins appeared to be valuable
starting materials with the aim of getting interesting
building blocks. On the one hand with nitrodienes,
metathesis and electrophilic cyclization have been
conducted in presence of the C=C double bond
whereas on the other hand gold catalysis enabled
transformations in presence of the carbon-carbon
triple bond. We thus conducted the gold-cyclization of
the bis-homopropargylic alcohol leading to the corre-
sponding substituted tetrahydrofuran. Then, we also
demonstrated that organocatalysts and gold catalysts
are compatible in a one-pot process. Indeed, we de-
veloped a one-pot reaction consisting in an enantiose-
lective organocatalytic Michael addition to a nitro-
AHCTUNGTREGeNNUN nyne followed by a subsequent gold-catalyzed acetal-
ization/cyclization. This enabled us to obtain nitro-
substituted tetrahydrofuranyl ethers in high diastereo-
and enantioselectivities and with excellent yields.
Experimental Section
Synthesis of Various Propargylic Aldehydes from the
Corresponding Alkynes (n-BuLi)
General Procedure 1a: To a solution of the corresponding
alkyne (50.0 mmol) in dry THF (125 mL) was added drop-
wise at À408C under nitrogen a 2.5 N solution of n-BuLi in
hexanes (20 mL, 50.0 mmol). During the addition, the tem-
perature was maintened between À35 and À408C. After
completion of the addition, anhydrous DMF (7.75 mL,
100.0 mmol) was added in one portion and the reaction mix-
ture was allowed to warm to room temperature and aged
for 30 min. The reaction mixture was then poured into a vig-
ourously stirred biphasic solution prepared from a 10%
aqueous solution of KH2PO4 (270 mL, 200 mmol) and
MTBE (250 mL) cooled to 58C. Layers were separated and
the organic one was washed with water (2ꢃ200 mL). The
combined aqueous layer were then extracted with MTBE
(150 mL) and finally the combined organic layers were
dried over MgSO4, filtered and concentrated under reduced
pressure to give the propargylic aldehyde. Depending on the
purity it was not necessary to purify it.
Scheme 15. Scope of the one-pot reaction.
by these results we then probed the scope of the reac-
tion with various nitroenynes 5a–f and alcohols (etha-
nol, methanol and 2-propanol) (Scheme 15). Pleasing-
ly, in all cases, the tetrahydrofuranyl ethers 42–44 and
52–56 were obtained in the one-pot process with ex-
cellent yields, even better that those obtained for the
sequential route (Scheme 15). Moreover, excellent
enantioselectivities were obtained in all cases with
also very good diastereoselectivities, not only for the
intermediate (syn/anti) but also for the final com-
pound (cis/trans). The process seems to be applicable
to various nitroenynes independently of the substitu-
tion pattern and the electronic character of the func-
tional group attached to the aromatic ring. Moreover,
Synthesis of Various Propargylic Aldehydes from the
Corresponding Aryl Iodide (Sonogashira and
Oxidation)
General Procedure 1b: To a solution of the corresponding
aryl iodide (13.4 mmol) in NEt3 (100 mL) was added at
room temperature PdCl2ACHTNUTRGNE(UNG PPh3)2 (0.47 g, 0.07 mmol), CuI
(0.13 g, 0.07 mmol) and propargylic alcohol (1.0 mL,
17.4 mmol). The resulting dark reaction mixture was stirred
during 15 h at room temperature. Then NEt3 was removed
it tolerates heteroaromatic functions such as 3-thienyl. by concentration under reduced pressure and the resulting
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black oil was purified by flash column chromatography on
silica gel using a mixture of ethyl acetate and cyclohexane.
Then to a solution of the purified alcohol (13.4 mmol) in dry
dichloromethane (100 mL) was added at room temperature
MnO2 (23 g, 268 mmol). The resulting dark reaction mixture
was stirred during 15 h at room temperature. Then filtration
on celite, concentration under reduced pressure and purifi-
cation by flash column chromatography on silica gel using a
mixture of ethyl acetate and cyclohexane gave the expected
propargylic aldehyde.
3-(m-Tolyl)propiolaldehyde
From 1-ethynyl-3-methylbenzene according to General Pro-
cedure 1a. Flash column chromatography is not necessary.
Orange oil; yield: 6.48 g (90%). 1H NMR (400 MHz,
CDCl3): d=9.39 (s, 2H), 7.40 (m, 1H), 7.29 (m, 2H), 2.35 (s,
3H); 13C NMR (100 MHz, CDCl3): d=176.9, 138.6, 133.8,
132.3, 130.5, 128.7, 119.2, 95.6, 88.3, 21.2.
3-(Thiophen-3-yl)propiolaldehyde
From 3-ethynylthiophene according to General Procedure
1a. Flash column chromatography is not necessary. Orange
oil; yield: 6.0 g (88%). H NMR (400 MHz, CDCl3): d=9.39
(s, 1H), 7.81 (dd, 1H, J=3.0 and 1.3 Hz), 7.35 (dd, 1H, J=
5.0 and 3.0 Hz), 7.40 (dd, 1H, J=5.0 and 1.3 Hz); 13C NMR
(100 MHz, CDCl3): d=176.8, 135.0, 130.4, 126.6, 118.9, 90.7,
88.9.
(E)-3-Cyclohexylacrylaldehyde
1
To a solution of propiolaldehyde diethyl acetal (1.00 g,
7.8 mmol, 1 equiv.) in dry Et2O (16 mL), copper(I) bromide
(56 mg, 5% mol) was added. To the mixture, cooled to 08C,
cyclohexylmagnesium chloride (1.2 equiv, 2.4M solution in
Et2O) was slowly added. The mixture, warmed to room tem-
perature, was stirred for 1 hour, then quenched with H2SO4
(4 mL of 10% aqueous solution). After 15 min the water
phase was extracted with Et2O and organic phase was
washed with brine and dried over Na2SO4. The crude mate-
rial was ready for use in the next step without any further
4,4-Dimethylpent-2-ynal
From 3,3-dimethyl-1-butyne (65.0 mmol) according to Gen-
eral Procedure 1a. Flash column chromatography is not nec-
essary. The concentration under reduced pressure has to be
controlled (min 500 mbar at 408C) due to the high volatility
1
purification. H NMR (400 MHz, CDCl3): d=1.34–1.16 (m,
5H), 1.83–1.68 (m, 5H), 2.35–2.20 (m, 1H,), 6.06 (dd, 1H,
J=15.6 and 7.8 Hz), 6.77 (dd, 1H, J=15.6 and 6.2 Hz), 9.49
(d, 1H, J=8.0 Hz); 13C NMR (100 MHz, CDCl3): d=25.6,
25.8, 31.4, 40.8, 130.5, 163.9, 194.6. NMR data were in close
agreement with the literature values.[45]
1
of the compound. Orange oil; yield: 4.70 g (66%). H NMR
(400 MHz, CDCl3): d=9.17 (s, 1H), 1.28 (s, 9H); 13C NMR
(100 MHz, CDCl3): d=177.6, 106.4, 80.3, 31.7, 30.0.
Synthesis of Nitrodienes and Nitroenynes from the
Corresponding Aldehyde and Nitromethane
3-Phenylpropiolaldehyde
From phenylacetylene according to General Procedure 1a.
General Procedure 2: To a slurry of LiAlH4 (114 mg,
3.0 mmol) in dry THF (150 mL), which had been stirred for
30 min at 08C, was added nitromethane (8.2 mL, 150 mmol).
After 30 min the corresponding aldehyde (30.0 mmol) was
added in one portion at 08C. The mixture was stirred at 08C
for 14 h. Then 1 N HCl and water were added to the reac-
tion mixture which was extracted two times with dichloro-
methane. The combined organic layers were dried over
Na2SO4 and concentrated under reduced pressure to give an
orange oil which can be used without purification for the
next step, depending on the purity. Then, to a solution of
freshly prepared nitro-alcohol (30.0 mmol), in dry dichloro-
methane (300 mL) was added at À408C trifluoroacetic anhy-
dride (4.4 mL, 31.5 mmol) and then NEt3 (8.8 mL,
63.0 mmol). The reaction mixture was then allowed to warm
at room temperature during the appropriate time until com-
pletion of the reaction. Then the reaction mixture was dilut-
ed in dichloromethane and the organic phases were washed
with water, aqueous saturated solution of NH4Cl and brine.
The organic layer was dried over MgSO4, filtered and con-
centrated under reduced pressure. Then the resulting oil/
solid is quickly filtered on silica gel in a filter using a mix-
ture of ethyl acetate and cyclohexane as eluant and then if
necessary followed by purification by a quick flash column
chromatography on silica gel.
Flash column chromatography is not necessary. Orange oil;
yield: 5.72 g (88%). H NMR (400 MHz, CDCl3): d=9.42 (s,
1H), 7.61 (dd, 2H, J=8.2 and 1.3 Hz), 7.48 (m, 1H), 7.40 (t,
2H, J=7.5 Hz); 13C NMR (100 MHz, CDCl3): d=176.9,
133.4, 131.4, 128.8, 119.5, 95.2, 88.5; MS (EI mode): m/z=
130, calculated for C9H6O: 130.1 [M].
1
3-(4-Bromophenyl)propiolaldehyde
From 1-bromo-4-iodobenzene according to General Proce-
dure 1b. Purification by flash column chromatography on
silica gel (AcOEt/cyclohexane: 15/85) provides a yellow oil;
yield: 2.46 g (88% over two steps). 1H NMR (400 MHz,
CDCl3): d=9.41 (s, 1H), 7.55 (d, 2H, J=8.6 Hz), 7.46 (d,
2H, J=8.6 Hz); 13C NMR (100 MHz, CDCl3): d=176.7,
134.6, 132.3, 126.4, 118.4, 93.7, 89.2.
3-(4-Methoxyphenyl)propiolaldehyde
From 1-iodo-4-methoxybenzene according to General Proce-
dure 1b. Purification by flash column chromatography on
silica gel (AcOEt/cyclohexane: 10/90) provides a yellow oil;
yield: 1.76 g (82% over two steps). 1H NMR (300 MHz,
CDCl3): d=9.38 (s, 1H), 7.55 (d, 2H, J=8.9 Hz), 6.90 (d,
2H, J=8.9 Hz), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3):
d=176.8, 162.2, 135.3, 114.6, 111.2, 96.7, 88.8, 55.6.
AHCTUNGTREGUN[NN (1E,3E)-4-nitrobuta-1,3-dienyl]benzene (3a)
Starting from cinnamaldehyde according to known proce-
dure; yield: 40%.[46]
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Organocatalyzed Conjugate Addition of Carbonyl Compounds to Nitrodienes/Nitroenynes
6.43 (d, 1H, J=15.6 Hz), 4.25 (q, 2H, J=7.3 Hz), 1.31 (t,
1-Chloro-4-[(1E,3E)-4-nitrobuta-1,3-dienyl]benzene
(3b)
3H, J=7.3 Hz); 13C NMR (100 MHz, CDCl3): d=165.0,
143.7, 135.2, 135.0, 133.4, 61.5, 14.3; FT-IR: n=3102, 2990,
2855, 1702, 1609, 1504, 1364, 1342, 1302, 1218, 1180, 1140,
1001, 963, 845, 738, 685 cmÀ1.
From (E)-3-(4-chlorophenyl)acrylaldehyde[47] and nitrome-
thane according to General Procedure 2. Purification by re-
crystallization (MeOH, À208C) gave a orange solid; yield:
1
24% for the two steps. H NMR (400 MHz, CDCl3): d=6.84
(E)-(4-Nitrobut-3-en-1-ynyl)benzene (5a)
(dd, 1H, J=15.6 and 11 Hz), 7.10 (d, 1H, J=15.6 Hz), 7.42
(m, 4H), 7.24 (d, 1H, J=12.8 Hz), 7.76 (dd, 1H, J=12.8
and 11.6 Hz); 13C NMR (100 MHz, CDCl3): d=121.1, 128.8,
129.3, 133.6, 136.1, 138.7, 138.9, 144.7; FT-IR: n=3101, 2934,
1622, 1608, 1589, 1505, 1489, 1328, 1157, 1088, 1012, 988,
971, 828, 744 cmÀ1.
From 3-phenylpropiolaldehyde according to General Proce-
dure 2. Purification by flash column chromatography on
silica gel (AcOEt/cyclohexane: 90/10) provided a yellow oil;
yield: 64% overall for two steps. 1H NMR (400 MHz,
CDCl3): d=7.36 (s, 2H), 7.43 (m, 3H), 7.53 (dd, 2H, J=8.1
and 1.2 Hz); 13C NMR (100 MHz, CDCl3): d=82.0, 105.3,
121.1, 121.3, 128.8, 130.5, 132.4, 145.6; FT-IR: n=3111, 3034,
2928, 2198, 1594, 1520, 1488, 1443, 1337, 1301, 1036, 966,
934, 834, 686 cmÀ1.
1-Methoxy-4-[(1E,3E)-4-nitrobuta-1,3-dienyl]benzene
(3c)
From commercially available (E)-3-(4-methoxyphenyl)acry-
laldehyde and nitromethane according to General Procedure
2. Purification by flash column chromatography on silica gel
(AcOEt/cyclohexane: 5/95) gave a yellow powder; yield:
(E)-1-Bromo-4-(4-nitrobut-3-en-1-ynyl)benzene (5b)
From 3-(4-bromophenyl)propiolaldehyde according to Gen-
eral Procedure 2. Purification by flash column chromatogra-
phy on silica gel (AcOEt/cyclohexane: 90/10) provided an
orange solid; yield: 42% overall for two steps. 1H NMR
(400 MHz, CDCl3): d=7.53 (d, 2H, J=8.5 Hz), 7.39–7.35
(m, 4H); 13C NMR (100 MHz, CDCl3): d=145.9, 133.7,
132.2, 125.3, 120.8, 120.1, 103.8, 82.9; FT-IR: n=3106, 3033,
2203, 1615, 1578, 1503, 1326, 1028, 1010, 966, 924, 823,
724 cmÀ1.
1
39% for the two steps. H NMR (400 MHz, CDCl3): d=3.85
(s, 3H), 6.73 (dd, 1H, J=15.2 and 11.6 Hz), 6.92 (d, 2H, J=
8.6 Hz), 7,10 (d, 1H, J=15.4 Hz), 7.20 (d, 1H, J=13.1 Hz),
7.47 (d, 2H, J=8.8 Hz), 7.77 (t, 1H, J=12.6 Hz); 13C NMR
(100 MHz, CDCl3): d=55.6, 114.6, 118.5, 128.1, 129.6, 137.6,
140.0, 146.1, 161.6; FT-IR: n=3096, 2942, 1841, 1619, 1594,
1572, 1515, 1490, 1322, 1252, 1178, 1159, 1023, 992, 976,
837 cmÀ1.
ACHTUNGTRENNUNG[(1E,3E)-4-Nitrobuta-1,3-dienyl]cyclohexane (3d)
(E)-1-Methoxy-4-(4-nitrobut-3-en-1-ynyl)benzene (5c)
From (E)-3-cyclohexylacrylaldehyde and nitromethane ac-
cording to General Procedure 2. Purification by flash
column chromatography on silica gel (AcOEt/cyclohexane:
5/95) gave an orange oil; yield: 34% for the two steps.
1H NMR (400 MHz, CDCl3): d=1.21 (m, 5H), 1.72 (m,
5H), 2.18 (m, 1H), 6.15 (dd, 1H, J=15.2 and 11.6 Hz), 6.37
(dd, 1H, J=15.2 and 7.0 Hz), 7.07 (d, 1H, J=13.1 Hz), 7.57
(m, 1H); 13C NMR (100 MHz, CDCl3): d=25.6, 25.8, 31.8,
41.6, 120.7, 137.4, 139.8, 156.6; FT-IR: n=2926, 2853, 1637,
1552, 1513, 1449, 1336, 1265, 1168, 993, 975, 845, 740 cmÀ1.
From 3-(4-methoxyphenyl)propiolaldehyde according to
General Procedure 2. Purification by flash column chroma-
tography on silica gel (AcOEt/cyclohexane: 90/10) provided
an orange oil; yield: 47% overall for two steps. 1H NMR
(400 MHz, CDCl3): d=7.47 (d, 2H, J=9.1 Hz), 7.37 (d, 2H,
J=13.4 Hz), 7.32 (d, 2H, J=13.4 Hz), 6.90 (d, 2H, J=
9.1 Hz), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
161.5, 144.7, 134.3, 121.6, 114.5, 113.2, 106.5, 81.8, 55.6.
(E)-1-(4-Nitrobut-3-en-1-ynyl)-4-trifluoromethyl)-
benzene (5d)
ACHTUNGTRENNUNG(1E,3E)-1-Nitrohexa-1,3-diene (3e)
From 3-[4-(trifluoromethyl)phenyl]propiolaldehyde accord-
ing to General Procedure 2. Purification by flash column
chromatography on silica gel (AcOEt/cyclohexane: 90/10)
provided a brown oil; yield: 52% overall for two steps.
1H NMR (400 MHz, CDCl3): d=7.65 (d, 2H, J=8.0 Hz),
7.62 (d, 2H, J=8.0 Hz), 7.39 (d, 1H, J=13.4 Hz), 7.35 (d,
1H, J=13.4 Hz); 13C NMR (100 MHz, CDCl3): d=146.5,
132.6, 125.8, 125.7, 124.9, 120.3, 102.6, 83.5.
From commercially available (E)-pent-2-enal and nitrome-
thane according to General Procedure 2. Purification by
flash column chromatography on silica gel (AcOEt/cyclo-
hexane: 5/95) provided a dark orange oil; yield: 29% for the
1
two steps. H NMR (400 MHz, CDCl3): d=1.08 (t, 3H, J=
7.6 Hz), 2.28 (m, 2H), 6.18 (q, 1H, J=13.4 Hz), 6.48 (m,
1H), 7.06 (d, 1H, J=13.2 Hz), 7.58 (t, 1H, J=12.6 Hz);
13C NMR (100 MHz, CDCl3): d=12.6, 26.7, 122.3, 137.6,
137.6, 139.6, 152.8; FT-IR: n=2970, 1639, 1609, 1506, 1335,
1167, 991, 967, 858, 819, 738 cmÀ1.
(E)-1-Methyl-3-(4-nitrobut-3-en-1-ynyl)benzene (5e)
From 3-(m-tolyl)propiolaldehyde according to General Pro-
cedure 2. Purification by flash column chromatography on
silica gel (AcOEt/cyclohexane: 90/10) provided an orange
oil; yield: 59% overall for two steps. 1H NMR (400 MHz,
CDCl3): d=7.35–7.24 (m, 6H), 2.37 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=145.5, 138.6, 132.9, 131.5, 129.6,
128.7, 121.2, 121.0, 105.7, 105.7, 81.8, 21.3.
ACHTUNGTRENNUNG(2E,4E)-Ethyl 5-Nitropenta-2,4-dienoate (3f)
From ethyl trans-4-oxo-2-butenoate according to General
Procedure 2. Purification by flash column chromatography
on silica gel (AcOEt/cyclohexane: 85/15) provided a yellow
solid; yield: 64% for the two steps. 1H NMR (400 MHz,
CDCl3): d=7.60 (t, 1H, J=12.3 Hz), 7.27–7.34 (m, 2H),
Adv. Synth. Catal. 2010, 352, 667 – 695
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683

Sꢀbastien Belot et al.
FULL PAPERS
J=7.0 Hz), 1.18 (d, 3H, J=7.0 Hz), 2.10–2.17 (m, 1H),
2.53–2.57 (m, 1H), 3.43–3.49 (m, 1H), 4.43 (dd, 1H, J=12.0
and 9.2 Hz), 4.55 (dd, 1H, J=12.0 and 3.8 Hz), 5.95 (dd,
1H, J=15.5 and 9.8 Hz), 6.56 (d, 1H, J=15.5 Hz), 7.27–7.35
(m, 5H), 7.89 (d, 1H, J=2.2 Hz); 13C NMR (125 MHz,
CDCl3): d=17.7, 21.7, 28.4, 40.4, 58.3, 78.3, 125.0, 126.7,
128.3, 128.8, 134.9, 136.1, 204.2; FT-IR: n=3028, 2964, 1716,
1548, 1495, 1449, 1379, 1196, 971, 750, 694 cmÀ1; HR-MS
(ESI mode): m/z=279.1687, calculated for C15H19NO3 [M+
NH4]+: 279.1703; [a]2D0: +121.7 (c 1.25, 96% ee, syn/anti 94:6,
CHCl3).
(E)-3-(4-Nitrobut-3-en-1-ynyl)thiophene (5f)
From 3-(thiophen-3-yl)propiolaldehyde according to Gener-
al Procedure 2. Purification by flash column chromatogra-
phy on silica gel (AcOEt/cyclohexane: 90/10) provided a
yellow solid; yield: 32% overall for two steps. 1H NMR
(400 MHz, CDCl3): d=7.67 (dd, 1H, J=2.8 and 1.0 Hz),
7.35 (m, 3H), 7.19 (dd, 1H, J=4.0 and 1.3 Hz); 13C NMR
(100 MHz, CDCl3): d=145.3, 132.5, 129.9, 126.4, 121.2,
120.6, 100.6, 82.1.
(E)-1-Nitronon-1-en-3-yne (5g)
AHCTUNGTREG(NNUN 2R,3R)-2-Isopropyl-3-(nitromethyl)-5-phenyl-
pentanal (8)
From the commercially available aldehyde according to
General Procedure 2. Purification by flash column chroma-
tography on silica gel (AcOEt/cyclohexane: 90/10) provided
To a solution of (2R,3R,E)-2-isopropyl-3-(nitromethyl)-5-
phenylpent-4-enal 3a (54 mg, 0.21 mmol) in methanol
(2 mL) was added 10% palladium on charcoal. The reaction
mixture was stirred during five minutes under a hydrogen
atmosphere and then filtered on celite. After concentration
under reduced pressure the residue was purified by a flash
column chromatography on silica gel using a mixture of
ethyl acetate and cyclohexane (AcOEt/cyclohexane: 15/85)
as eluant to afford a yellow oil; yield: 24 mg (43%). The
enantiomers were separated on chiral SFC (column OD:
2%-2-1-15%, 2 mLminÀ1, 308C, 200 bar): RT: 5.7 min (S,S),
1
a yellow oil; yield: 53%. H NMR (400 MHz, CDCl3): d=
0.98 (m, 3H, J=2.9 Hz), 1.44 (m, 4H), 1.64 (m, 2H), 2.49
(td, 2H, J=9.4 and 3.0 Hz), 7.19 (dt, 1H, J=17.8 and
3.0 Hz), 7.32 (d, 1H, J=10.3 Hz); 13C NMR (100 MHz,
CDCl3): d=13.9, 20.1, 22.2, 27.7, 31.1, 73.7, 108.8, 122.1,
145.6.
(E)-5,5-Dimethyl-1-nitrohex-1-en-3-yne (5h)
From 4,4-dimethylpent-2-ynal according to General Proce-
dure 2. Purification by flash column chromatography on
silica gel (AcOEt/cyclohexane: 90/10) provided an orange
oil; yield: 76% for the two steps. 1H NMR (300 MHz,
CDCl3): d=7.20 (d, 1H, J=13.4 Hz), 7.12 (d, 1H, J=
13.4 Hz), 1.27 (s, 9H); 13C NMR (75 MHz, CDCl3): d=
145.5, 122.0, 116.0, 72.4, 30.4, 28.9; FT-IR: n=3113, 2973,
2870, 2234, 2201, 1616, 1523, 1341, 1265, 968, 939, 836,
756 cmÀ1.
1
5.9 min (R,R); H NMR (400 MHz, CDCl3): d=1.03 (d, 3H,
J=6.6 Hz), 1.14 (d, 3H, J=7.1 Hz), 1.82 (m, 2H), 2.14 (m,
1H), 2.54 (m, 1H), 2.73 (m, 3H), 4.57 (m, 2H), 7.21 (d, 2H,
J=6.8 Hz), 7.27 (m, 1H), 7.34 (m, 2H), 9.87 (d, 1H, J=
2.8 Hz); 13C NMR (100 MHz, CDCl3): d=19.9, 21.2, 27.2,
31.9, 32.7, 35.7, 58.1, 126.5, 128.4, 128.7, 140.7, 204.9; FT-IR:
n=2966, 2872, 1716, 1553, 1455, 1382, 1108, 1075, 749,
700 cmÀ1; HR-MS (ESI mode): m/z=261.1869, calculated
for C15H25N2O3 [M+NH4]+: 261.1865.
Optimized Addition of Aldehyde to Nitrodiene
Catalyzed by Catalyst 3
AHCTUNGTREG(NNNU 2R,3R,E)-2-Methyl-3-(nitromethyl)-5-phenylpent-4-
enal (9)
General Procedure 3 in water/ethanol 5% v/v: To a solution
of (S)-(À)-(diphenyltrimethylsiloxymethyl)-pyrrolidine
V
From propionaldehyde 1b and [(1E,3E)-4-nitrobuta-1,3-di-
enyl]benzene 3a according to General Procedure 3 (10 h) to
give a mixture of diastereomers (syn/anti: 94/6) as a yellow
oil. The crude product was purified by flash column chroma-
tography on silica gel (AcOEt/cyclohexane: 15/85) to pro-
vide a yellow oil; yield: 63 mg (81%). Enantiomers and dia-
stereoisomers were separated on chiral SFC after reduction
(0.02 mmol, 5 mol%) in water/ethanol 5% v/v (2 mL) was
added at 258C the nitrodiene (0.34 mmol) and the corre-
sponding aldehyde (0.67 mmol, 2 equiv.). The reaction mix-
ture was stirred at 258C. The evolution of the reaction was
monitored by TLC until completion and then the reaction
mixture was extracted three times with Et2O. The combined
organic layers were dried over Na2SO4, filtered and finally
concentrated under reduce pressure to be purified by a flash
column chromatography on silica gel using a mixture of
ethyl acetate and cyclohexane as eluant.
1
to the corresponding alcohol. H NMR (400 MHz, CDCl3):
d=1.23 (d, 3H, J=7.2 Hz), 2.63 (m, 1H), 3.51 (m, 1H), 4.59
(m, 2H), 5.97 (dd, 1H, J=15.9 and 9.4 Hz), 6.56 (d, 1H, J=
15.9 Hz), 7.25–7.37 (m, 5H), 9.70 (d, 1H, J=1.3 Hz);
13C NMR (100 MHz, CDCl3): d=11.1, 42.1, 47.5, 77.7, 123.7,
126.7, 128.4, 128.8, 135.4, 136.0, 202.2; FT-IR: n=3020, 2977,
1721, 1550, 1494, 1450, 1379, 971, 750, 694 cmÀ1; HR-MS
(ESI mode): m/z=251.1397, calculated for C13H21N2O3 [M+
NH4]+: 251.1393.
ACHTUNGTRENNUNG(2R,3R,E)-2-Isopropyl-3-(nitromethyl)-5-phenylpent-
4-enal (3a)
From isovaleraldehyde 1a and [(1E,3E)-4-nitrobuta-1,3-di-
enyl]benzene 3a according to General Procedure 3 (12 h) to
give a mixture of diastereoisomers (syn/anti: 94/6) as a
yellow oil. The crude product was purified by flash column
chromatography on silica gel (AcOEt/cyclohexane: 15/85) to
provide a yellow oil; yield: 80 mg (91%). The enantiomers
were separated on chiral SFC (OD column: 2%-2-1-15%
MeOH, 200 bar, 2 mLminÀ1, 308C: RT: 6.5 min (S,S),
AHCTUNGTREG(NNNU 2R,3R,E)-2-Methyl-3-(nitromethyl)-5-phenylpent-4-
en-1-ol
To a solution of 2-methyl-3-(nitromethyl)-5-phenylpent-4-
enal 9 (100 mg, 0.43 mmol) in methanol (1 mL) was added
portion by portion NaBH4 (25 mg, 0.64 mmol, 1.3 equiv.) at
08C. The reaction mixture was stirred during one hour at
1
6.8 min (R,R); H NMR (500 MHz, CDCl3): d=0.98 (d, 3H,
684
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 667 – 695

Organocatalyzed Conjugate Addition of Carbonyl Compounds to Nitrodienes/Nitroenynes
08C and was then hydrolyzed with a saturated aqueous solu-
tion of NH4Cl. The resulting mixture was extracted with di-
ethyl ether and with ethyl acetate. The combined organic
layers were then dried over Na2SO4, filtered, concentrated
under reduced pressure to give a mixture of diastereomers
(syn/anti: 82/18) as a yellow oil. The crude product was puri-
fied by flash column chromatography on silica gel (AcOEt/
cyclohexane: 25/75) to provide a yellow oil; yield: 82 mg
(81%). The enantiomers were separated on chiral SFC (AD
column: 10%-2-1-25% MeOH, 200 bar, 2 mLminÀ1, 308C):
RT: 7.4 min (S,S), 8.8 min (R,R); 1H NMR (400 MHz,
CDCl3): d=0.96 (d, 3H, J=6.8 Hz), 1.89 (m, 1H), 3.31
(hept, 1H), 3.58 (m, 2H), 4.56 (m, 2H), 6.02 (dd, 1H, J=
15.6 and 9.6 Hz), 6.56 (d, 1H, J=15.9 Hz), 7.25–7.36 (m,
5H); 13C NMR (100 MHz, CDCl3): d=12.9, 37.6, 43.9, 65.8,
78.9, 124.6, 126.5, 128.0, 128.7, 134.9, 136.5; FT-IR: n=3389,
2965, 2923, 1548, 1495, 1450, 1380, 1030, 970, 907, 728, 693,
649 cmÀ1; HR-MS (ESI mode): m/z=253.1546, calculated
for C13H21N2O3 [M+NH4]+: 253.1540.
AHCTUNGTREG(NNNU 2R,3R,E)-2-(But-3-enyl)-3-(nitromethyl)hept-4-enal
(12)
From hex-6-en-1-al 1e[48] and (1E,3E)-1-nitrohexa-1,3-diene
3a according to General Procedure 3 (36 h) to give a mixture
of diastereomers (syn/anti: 90/10) as a yellow oil. The crude
product was purified by flash column chromatography on
silica gel (AcOEt/cyclohexane: 10/90) to provide a yellow
oil; yield: 58 mg (81%). The enantiomers were separated on
chiral GC (column Hydrobex-B-6-TBDM: 120-85-1-170,
45 cm/s): RT: 77.5 min (S,S), 79.8 min (R,R); 1H NMR
(400 MHz, CDCl3): d=0.93 (t, 3H, J=7.3 Hz), 1.63 (m,
2H), 2.00 (m, 4H), 2.40 (m, 1H), 3.19 (hept, 1H), 4.33 (m,
1H, J=11.8 and 9.1 Hz), 4.43 (m, 1H, J=11.8 and 4.9 Hz),
5.01 (m, 2H), 5.17 (dd, 1H, J=15.4 and 9.3 Hz), 5.68 (m,
2H), 9.63 (d, 1H, J=2.0 Hz); 13C NMR (100 MHz, CDCl3):
d=13.5, 25.6, 25.7, 31.0, 41.2, 52.2, 78.0, 116.2, 123.4, 137.0,
138.7, 203.0; FT-IR: n=2963, 2933, 1722, 1641, 1551, 1436,
1379, 1188, 972, 913, 760 cmÀ1.
ACHTUNGTRENNUNG(2R,3R,E)-3-(Nitromethyl)-5-phenyl-2-propylpent-4-
enal (10)
(3R)-2,2-Dimethyl-3-(nitromethyl)-5-phenylpent-4-
enal (13)
From pentanal 1c and [(1E,3E)-4-nitrobuta-1,3-dienyl]ben-
zene 3a according to General Procedure 3 (10 h) to give a
mixture of diastereomers (syn/anti: 93/7) as a yellow oil. The
crude product was purified by flash column chromatography
on silica gel (AcOEt/cyclohexane: 15/85) to provide a
yellow oil; yield: 79 mg (90%). The enantiomers were sepa-
rated on chiral SFC (OB column: 2%-2-1-15% MeOH, 200
bar, 2 mLminÀ1, 308C): RT: 7.6 min (S,S), 8.6 min (R,R);
1H NMR (400 MHz, CDCl3): d=0.93 (t, 3H, J=7.2 Hz),
1.27–1.84 (m, 4H), 2.52 (m, 1H), 3.40 (m, 1H), 4.52 (m,
2H), 5.97 (dd, 1H, J=15.8 and 9.5 Hz), 6.53 (d, 1H, J=
15.8 Hz), 7.26–7.33 (m, 5H), 9.70 (d, 1H, J=2.2 Hz);
13C NMR (100 MHz, CDCl3): d=14.2, 20.4, 29.1, 41.6, 53.0,
77.8, 124.4, 126.7, 128.3, 128.8, 135.2, 136.0, 203.0; HR-MS
(ESI mode): m/z=279.1703, calculated for C15H23N2O3 [M+
NH4]+: 279.1706.
From isobutyraldehyde 1f and [(1E,3E)-4-nitrobuta-1,3-di-
enyl]benzene 3a according to General Procedure 3 with 10
mol% catalyst (5 days) to give a yellow oil. The crude prod-
uct was purified by flash column chromatography on silica
gel (AcOEt/cyclohexane: 15/85) to provide a yellow oil;
yield: 60 mg (72%). The enantiomers were separated on
chiral SFC (OB column: 2%-2-1-15% MeOH, 200 bar,
2 mLminÀ1, 308C): RT: 6.4 min (S), 7.5 min (R); 1H NMR
(400 MHz, CDCl3): d=1.17 (s, 3H), 1.18 (s, 3H), 3.30 (td,
1H, J=9.8 and 5.0 Hz), 4.51 (m, 2H), 6.03 (dd, 1H, J=15.7
and 9.8 Hz), 6.54 (d, 1H, J=15.7 Hz), 7.25–7.37 (m, 5H),
9.53 (s, 1H); 13C NMR (100 MHz, CDCl3): d=19.2, 21.1,
47.3, 47.9, 76.8, 122.9, 126.7, 128.3, 128.7, 136.0, 136.4, 203.9;
FT-IR: n=3060, 2977, 1722, 1552, 1494, 1449, 1379, 1266,
970, 886, 734, 693 cmÀ1
265.1546, calculated for C14H21N2O3 [M+NH4]+: 265.1552.
; HR-MS (ESI mode): m/z=
ACHTUNGTRENNUNG(2R,3R,E)-2-Allyl-3-(nitromethyl)-5-phenylpent-4-
enal (11)
AHCTUNGTREG(NNNU 2R,3R,E)-2-Methyl-3-(nitromethyl)-2,5-diphenyl-
From pent-4-enal 1d and ([1E,3E)-4-nitrobuta-1,3-dienyl]-
benzene 3a according to General Procedure 3 (36 h) to give
a mixture of diastereomers (syn/anti: 52/48) as a yellow oil.
The crude product was purified by flash column chromatog-
raphy on silica gel (AcOEt/cyclohexane: 15/85) to provide a
yellow oil; yield: 73 mg (84%). The enantiomers were sepa-
rated on chiral SFC (OB column : 2%-2-1-15% MeOH, 200
bar, 2 mLminÀ1, 308C): RT: 8.5 min (S,S), 9.1 min (R,R).
1H NMR (400 MHz, CDCl3, syn and anti isomer 1/1): d=
2.35 (m, 1H), 2.42 (m, 2H), 2.63 (m, 3H), 4.51–4.66 (m,
4H), 5.17 (m, 4H), 5.77 (m, 2H), 6.00 (dd, 1H, J=15.8 and
9.5 Hz), 6.08 (dd, 1H, J=15.6 and 9.6 Hz), 6.54 (d, 2H, J=
15.6 Hz), 7.26–7.33 (m, 10H), 9.70 (s, 1H), 9.71 (d, 1H, J=
1.5 Hz). FT-IR: n=3065, 2917, 1719, 1640, 1549, 1495, 1434,
1379, 1266, 970, 919, 735, 695 cmÀ1.
pent-4-enal (14)
From 2-phenylpropanal 1g and [(1E,3E)-4-nitrobuta-1,3-di-
enyl]benzene 3a according to General Procedure 3 (4 days)
to give a mixture of diastereomers (syn/anti: 95/5) as a
yellow oil. The crude product was purified by flash column
chromatography on silica gel (AcOEt/cyclohexane: 15/85) to
provide a yellow oil; yield: 81 mg (78%). The enantiomers
were separated on chiral SFC (OJ column: 2%-2-1-15%
MeOH, 200 bar, 2 mLminÀ1, 308C): RT: 7.3 min (S,S),
1
7.9 min (R,R); H NMR (400 MHz, CDCl3): d=1.60 (s, 3H),
3.62 (m, 1H), 4.45 (dd, 1H, J=12.4 and 3.3 Hz), 4.66 (t, 1H,
J=11.7 Hz), 5.95 (dd, 1H, J=15.8 and 9.6 Hz), 6.37 (d, 1H,
J=15.9 Hz), 7.21–7.47 (m, 10H), 9.59 (s, 1H); 13C NMR
(100 MHz, CDCl3): d=18.5, 48.8, 56.2, 77.5, 123.8, 126.6,
127.3, 128.1, 128.4, 128.7, 129.5, 136.0, 136.3, 137.8, 201.1;
FT-IR: n=3028, 2978, 1720, 1600, 1551, 1495, 1447, 1377,
1332, 1266, 1074, 969, 918, 736, 694 cmÀ1; HR-MS (ESI
mode): m/z=327.1703, calculated for C19H23N2O3 [M+
NH4]+: 327.1703.
Adv. Synth. Catal. 2010, 352, 667 – 695
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asc.wiley-vch.de
685

Sꢀbastien Belot et al.
FULL PAPERS
A
ACHTUNGTRENNUNG
3-en-2-yl]octa-4,6-dienal (15)
pent-4-enal (18)
From (S)-citronellal 1h and [(1E,3E)-4-nitrobuta-1,3-dienyl]-
benzene 3a according to General Procedure 3 (4 days) to
give a mixture of diastereomers (67/31/1/1) as a yellow oil.
The crude product was purified by flash column chromatog-
raphy on silica gel (AcOEt/cyclohexane: 15/85) to provide a
From isovaleraldehyde 1a and [(1E,3E)-4-nitrobuta-1,3-di-
enyl]cyclohexane 3d according to General Procedure 3 (2
days) to give a mixture of diastereomers (syn/anti: 94/6) as a
yellow oil. The crude product was purified by flash column
chromatography on silica gel (AcOEt/cyclohexane: 15/85) to
provide a yellow oil; yield: 66 mg (62%). The enantiomers
were separated on chiral SFC (IC column: 2%-2-1-15%
MeOH, 200 bar, 2 mLminÀ1, 308C): RT: 4.8 min (S,S),
1
yellow oil; yield: 74 mg (66%). H NMR (400 MHz, CDCl3):
d=9.85 (d, 1H, J=2.0 Hz), 7.27–7.35 (m, 5H), 6.53 (d, 1H,
J=15.7 Hz), 5.92 (dd, 1H, J=15.7 and 9.9 Hz), 4.95 (m,
1H), 4.55 (dd, 1H, J=4.5 and 4.0 Hz), 4.41 (dd, 1H, J=9.1
and 4.0 Hz), 3.51 (m, 1H), 2.56 (m, 1H), 2.00 (m, 2H), 1.87
(m, 1H), 1.50–1.72 (m, 2H), 1.52 (s, 3H), 1.51 (s, 3H), 1.16
(d, 3H, J=7.1 Hz).
1
6.3 min (R,R); H NMR (400 MHz, CDCl3): d=0.93 (d, 3H,
J=7.1 Hz), 1.15 (d, 3H, J=7.0 Hz), 1.25 (m, 6H), 1.64 (m,
4H), 1.93 (m, 1H), 2.08 (m, 1H), 2.36 (m, 1H), 3.20 (m,
1H), 4.24 (dd, 1H, J=11.6 and 9.8 Hz), 4.43 (dd, 1H, J=
11.4 and 4.0 Hz), 5.92 (ddd, 1H, J=15.2, 9.6 and 1.0 Hz),
6.49 (dd, 1H, J=15.4 and 6.8 Hz), 9.83 (d, 1H, J=2.5 Hz);
13C NMR (100 MHz, CDCl3): d=17.5, 21.6, 26.0, 26.2, 28.1,
32.8, 40.2, 40.7, 58.2, 78.7, 122.7, 142.6, 204.6; HR-MS (ESI
mode): m/z=285.2172, calculated for C15H25N2O3 [M+
NH4]+: 285.2160.
ACHTUNGTRENNUNG(2R,3R,E)-5-(4-Chlorophenyl)-2-isopropyl-3-(nitro-
methyl)pent-4-enal (16)
From isovaleraldehyde 1a and 1-chloro-4-[(1E,3E)-4-nitro-
buta-1,3-dienyl]benzene 3b according to General Procedure
3 (36 h) to give a mixture of diastereomers (syn/anti: 92/8)
as a yellow oil. The crude product was purified by flash
column chromatography on silica gel (AcOEt/cyclohexane:
15/85) to provide a yellow solid; yield: 93 mg (92%). The
enantiomers were separated on chiral SFC (IC column: 2%-
2-1-15% MeOH, 200 bar, 2 mLminÀ1, 308C): RT: 6.9 min
(S,S), 7.8 min (R,R); 1H NMR (400 MHz, CDCl3): d=0.96
(d, 3H, J=6.8 Hz), 1.18 (d, 3H, J=7.1 Hz), 2.09 (m, 1H),
2.54 (m, 1H), 3.44 (m, 1H), 4.41 (dd, 1H, J=11.9 and
9.1 Hz), 4.54 (dd, 1H, J=11.8 and 3.8 Hz), 5.92 (dd, 1H, J=
15.9 and 9.8 Hz), 6.49 (d, 1H, J=15.9 Hz), 7.23–7.28 (m,
4H), 9.87 (d, 1H, J=2.0 Hz); 13C NMR (100 MHz, CDCl3):
d=17.7, 21.6, 28.4, 40.3, 58.1, 78.1, 125.7, 127.8, 128.9, 133.6,
134.0, 134.5, 204.1; FT-IR: n=2968, 2925, 1704, 1594, 1557,
1543, 1494, 1466, 1435, 1408, 1385, 1237, 1013, 980, 855, 819,
797, 674, 629 cmÀ1; HR-MS (ESI mode): m/z=313.1313, cal-
culated for C15H22N2O3Cl [M+NH4]+: 313.1306.
AHCTUNGTREG(NNNU 2R,3R,E)-2-Isopropyl-3-(nitromethyl)hept-4-enal
(19)
From isovaleraldehyde 1a and (1E,3E)-1-nitrohexa-1,3-
diene 3e according to General Procedure 3 (36 h) to give a
mixture of diastereomers (syn/anti: 90/10) as a yellow oil.
The crude product was purified by flash column chromatog-
raphy on silica gel (AcOEt/cyclohexane: 10/90) to provide a
yellow oil; yield: 58 mg (81%). The enantiomers were sepa-
rated on Chiral GC (Hydrodex-B-3P column: 110-0-1-145-
20-170-3, 50 cm/s): RT: 26.9 min (R,R), 27.4 min (S,S);
1H NMR (400 MHz, CDCl3): d=1.00 (m, 6H), 1.21 (d, 3H,
J=7.0 Hz), 2.06 (m, 2H), 2.15 (m, 1H), 2.43 (m, 1H), 3.29
(m, 1H), 4.24 (dd, 1H, J=11.6 and 9.9 Hz), 4.49 (dd, 1H,
J=11.6 and 4.0 Hz), 5.92 (ddd, 1H, J=15.4 and 9.6 Hz),
6.49 (dt, 1H, J=15.2 and 6.3 Hz), 9.89 (d, 1H, J=2.5 Hz);
13C NMR (100 MHz, CDCl3): d=13.5, 17.6, 21.6, 25.6, 28.1,
40.1, 58.2, 78.6, 124.3, 138.3, 204.6; FT-IR: n=2964, 2876,
1717, 1551, 1463, 1434, 1379, 972, 738 cmÀ1.
ACHTUNGTRENNUNG(2R,3R,E)-2-Isopropyl-5-(4-methoxyphenyl)-3-(nitro-
methyl)pent-4-enal (17)
AHCTUNGTREG(NNNU 2R,3R,E)-2-Isopropyl-3-(nitromethyl)-5-phenylpent-
From isovaleraldehyde 1a and 1-methoxy-4-[(1E,3E)-4-ni-
trobuta-1,3-dienyl]benzene 3c according to General Proce-
dure 3 (4 days) to give a mixture of diastereomers (syn/anti:
87/13) as a yellow oil. The crude product was purified by
flash column chromatography on silica gel (AcOEt/cyclo-
hexane: 15/85) to provide a yellow oil; yield: 90 mg (89%).
The enantiomers were separated on chiral SFC (OJ column:
2%-2-1-15% MeOH, 200 bar, 2 mLminÀ1, 308C): RT:
7.2 min (S,S), 7.6 min (R,R); 1H NMR (400 MHz, CDCl3):
d=0.97 (d, 3H, J=6.8 Hz), 1.18 (d, 3H, J=6.8 Hz), 2.13 (m,
1H), 2.52 (m, 1H), 3.42 (m, 1H), 3.80 (s, 1H), 4.41 (dd, 1H,
J=11.8 and 9.1 Hz), 4.53 (dd, 1H, J=11.8 and 4.0 Hz), 5.78
(dd, 1H, J=15.7 and 9.6 Hz), 6.49 (d, 1H, J=15.7 Hz), 6.84
(dd, 2H, J=6.8 and 2.0 Hz), 7.28 (dd, 2H, J=6.8 and
2.0 Hz), 9.88 (d, 1H, J=2.3 Hz); 13C NMR (100 MHz,
CDCl3): d=17.7, 21.7, 28.3, 40.5, 55.5, 58.3, 78.4, 114.2,
122.6, 127.9, 128.9, 134.3, 159.8, 204.4; FT-IR: n=2964, 2837,
1718, 1608, 1550, 1512, 1465, 1380, 1301, 1250, 1176, 1032,
973, 821 cmÀ1; HR-MS (ESI mode): m/z=309.1808, calculat-
ed for C16H25N2O4 [M+NH4]+: 309.1805.
4-en-1-ol (20)
To a solution of (2R,3R,E)-2-isopropyl-3-(nitromethyl)-5-
phenylpent-4-enal 4a (0,40 g, 1.53 mmol) in methanol
(6 mL) was added portions by portions NaBH4 (0.15 g,
3.83 mmol) at 08C. The reaction mixture was stirred during
two hours at 08C and was then hydrolyzed with a saturated
aqueous solution of NH4Cl. The resulting mixture was ex-
tracted with diethyl ether and with ethyl acetate. The com-
bined organic layers were then dried over Na2SO4, filtered,
concentrated under reduce pressure to give a yellow oil. The
crude product was purified by flash column chromatography
on silica gel (AcOEt/cyclohexane: 25/75) to provide a
1
yellow oil; yield: 0.68 g (99%). H NMR (400 MHz, CDCl3):
d=0.89 (d, 3H, J=7.0 Hz), 1.05 (d, 3H, J=7.0 Hz). 1.46 (m,
2H), 1.92 (m, 1H), 3.30 (m, 1H), 3.69 (dd, 1H, J=10.9 and
6.6 Hz), 3.86 (dd, 1H, J=10.9 and 2.3 Hz), 4.58 (dd, 1H, J=
12.1 and 10.5 Hz), 4.79 (dd, 1H, J=12.1 and 4.1 Hz), 6.08
(dd, 1H, J=15.7 and 9.1 Hz), 6.48 (d, 1H, J=15.7 Hz),
7.22–7.36 (m, 5H); 13C NMR (100 MHz, CDCl3): d=18.2,
686
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 667 – 695

Organocatalyzed Conjugate Addition of Carbonyl Compounds to Nitrodienes/Nitroenynes
21.9, 27.1, 44.0, 49.2, 60.9, 79.0, 126.5, 127.9, 128.7, 133.6,
136.6; HR-MS (ESI mode): m/z=281.1863, calculated for
C15H25N2O3 [M+NH4]+: 281.1859.
3.8 Hz), 4.42 (dd, 1H, J=12.6 and 9.3 Hz), 4.19 (qu, 2H),
3.48 (m, 1H), 2.57 (m, 1H), 2.03 (m, 1H), 1.29 (t, 3H, J=
7.0 Hz), 1.20 (d, 3H, J=7.0 Hz), 0.94 (d, 3H, J=7.0 Hz);
FT-IR: n=2963, 2875, 1717, 1656, 1554, 1466, 1448, 1373,
1271, 1177, 1033, 990, 705 cmÀ1.
ACHTUNGTRENNUNG
AHCTUNGTREG(NNNU R,E)-4-(Nitromethyl)-6-phenylhex-5-en-2-one (24)
According to known procedure[49] to
a solution of
To a solution [(1E,3E)-4-nitrobuta-1,3-dienyl]benzene 3a
(1.0 mmol), benzoic acid (0.23 mmol) and Jacobsenꢂs cata-
lyst VI (0.1 mmol) were added toluene (50 mL) followed by
the addition of acetone 2a (5.0 mmol). The resulting mixture
was stirred for 24 h. The crude product was purified by flash
column chromatography on silica gel (AcOEt/cyclohexane:
25/75) to provide a yellow oil; yield: 47 mg (88%). The
enantiomers were separated on SFC (OJ column: 2%-2-1-15
MeOH, 200 bar, 2 mLminÀ1, 308C); 1H NMR (400 MHz,
CDCl3): d=2.19 (s, 3H), 2.75 (d, 2H, J=6.6 Hz), 3.53 (m,
1H), 4.56 (m, 2H), 6,08 (dd, 1H, J=15.9 and 9.5), 6.53 (d,
1H, J=15.9 Hz), 7,23–7,34 (m, 5H); HR-MS (ESI mode):
m/z=234.1131, calculated for C13H15NO3 [M+H]+:
234.1124.
(2R,3R,E)-2-isopropyl-3-(nitromethyl)-5-phenylpent-4-en-1-
ol 20 (55 mg, 0.21 mmol) in 1.7 mL of CH2Cl2 cooled to
À788C was added PhSeCl (44 mg, 0.23 mmol) in one por-
tion. The mixture was stirred at À788C for 4 h and allowed
to warm to room temperature. Then solvent was removed
under reduced pressure and the residue was purified by
flash column chromatography on silica gel (AcOEt/cyclo-
hexane: 15/85) to provide a yellow oil; yield: 61 mg (69%).
1H NMR (400 MHz, CDCl3): d=0.76 (d, 3H, J=6.5 Hz),
0.78 (d, 3H, J=6.5 Hz), 1.29 (m, 1H), 1.63 (m, 1H), 3.01
(m, 1H), 3.37 (dd, 1H, J=10.8 and 8.6 Hz), 3.95 (t, 1H, J=
8.2 Hz), 4.21 (d, 1H, J=7.3 Hz), 4.33 (t, 1H, J=11.8 Hz),
4.44 (dd, 1H, J=12.6 and 4.0 Hz); 4.52 (dd, 1H, J=7.3 and
1.6 Hz), 7.18–7.42 (m, 10H); 13C NMR (100 MHz, CDCl3):
d=21.7, 21.8, 26.7, 42.6, 48.3, 52.0, 71.3, 75.0, 85.7, 127.5,
128.0, 128.4, 128.9, 129.1, 129.5, 135.1, 139.4.
AHCTUNGTREG(NNNU 3R,4R,E)-3-Hydroxy-4-(nitromethyl)-6-phenylhex-5-
en-2-one (25)
ACHTUNGTRENNUNG(1R,2R)-2-(Nitromethyl)cyclohex-3-enecarbaldehyde
To a solution of [(1E,3E)-4-nitrobuta-1,3-dienyl]benzene 3a
(0.34 mmol) and a-hydroxyacetone 2b (3.40 mmol) in
chloroform (3 mL) was added at 238C N-i-Pr-2,2’-bipyrroli-
dine II (0.06 mmol). Then the reaction mixture was stirred
at 238C during 4 days. The reaction mixture was then hydro-
lyzed with an aqueous saturated solution of NH4Cl and ex-
tracted three times with CH2Cl2. The combined organic
layers were dried over Na2SO4, filtered and finally concen-
trated under reduced pressure to be purified by flash
column chromatography on silica gel (AcOEt/cyclohexane:
25/75) to provide a yellow oil; yield: 76 mg (90%). The
enantiomers were separated on SFC (OJ column: 2%-2-1-15
MeOH, 200 bar, 2 mLminÀ1, 308C); 1H NMR (400 MHz,
CDCl3): d=2.35 (s, 3H), 3.46 (m, 1H), 3.61 (d, 1H, J=
3.8 Hz), 4.33 (m, 1H), 4.49 (d, 2H, J=6.8 Hz), 6.27 (d, 1H,
J=15.9 and 9.1 Hz), 6.63 (d, 1H, J=15.9 Hz), 7.26–7.40 (m,
5H); 13C NMR (100 MHz, CDCl3): d=26.8, 45.6, 75.7, 78.3,
124.4, 128.8, 128.8, 129.0, 135.4, 136.0, 208.0; HR-MS (ESI
mode): m/z=272.0890, calculated for C13H15NO4 [M+Na]+:
272,0893.
(22)
To a solution of (2S,3S,E)-2-(but-3-enyl)-3-(nitromethyl)-
hept-4-enal 12 (150 mg, 0.66 mmol) in toluene (70 mL) was
added the Grubbs second generation catalyst (28 mg,
0.03 mmol) at room temperature under a nitrogen atmos-
phere. The reaction mixture was heated at 708C during two
hours. The resulting reaction mixture was then filtered on
celite. The enantiomers were separated on chiral GC
(column: Hydrobex-B-6-TBDM: 60-0-1-170-20, 45 cm/s):
RT: 79.1 min (R,R), 79.4 min (S,S); 1H NMR (400 MHz,
CDCl3): d=1.73–1.82 (m, 1H), 1.99–2.06 (m, 1H), 2.12 (m,
2H), 2.55 (m, 1H), 3.33 (m, 1H), 4.43 (qd, 2H, J=14.9 and
6.8 Hz), 5.57 (m, 1H), 5.89 (m, 1H), 9.68 (s, 1H); 13C NMR
(100 MHz, CDCl3): d=20.5, 23.4, 33.3, 47.8, 78.1, 124.0,
130.7, 201.9; FT-IR: n=2930, 1716, 1549, 1434, 1378, 1266,
1171, 1068, 734, 702 cmÀ1.
ACHTUNGTRENNUNG(4R,5R,E)-Ethyl 5-Formyl-6-methyl-4-(nitromethyl)-
hept-2-enoate (23)
To a solution of (2E,4E)-ethyl 5-nitropenta-2,4-dienoate 3f
(0.34 mmol) and isovaleraldehyde 1a (3.40 mmol) in chloro-
form (3 mL) was added at 238C (S)-(À)-(diphenyltrimethyl-
siloxymethyl)-pyrrolidine V (22 mg, 0.06 mmol). Then the
reaction mixture was stirred at 238C during 10 h. The reac-
tion mixture was then hydrolyzed with an aqueous saturated
solution of NH4Cl and extracted three times with CH2Cl2.
The combined organic layers were dried over Na2SO4, fil-
tered and finally concentrated under reduced pressure to be
purified by flash column chromatography on silica gel
(AcOEt/cyclohexane: 25/75) to provide a yellow oil; yield:
54 mg (93%). The enantiomers were separated on chiral GC
(column: Hydrodex B6 TBDMS: 110-0-1-170-15): RT:
(S)-2-[(S,E)-1-Nitro-4-phenylbut-3-en-2-yl)cyclo-
hexanone (26)
To a mixture of cyclohexanone 2c (0.35 mL, 3.4 mmol) and
[(1E,3E)-4-nitrobuta-1,3-dienyl)benzene
3a
(59 mg,
0.34 mmol) was added the aminal organocatalyst VII
(22 mg, 0.07 mmol). The reaction mixture was stirred at
238C during 14 h and then diluted in dichloromethane. Then
water was added and the organic layer was separated. The
aqueous layer was extracted two times with dichlorome-
thane. The combined organic layers were dried over
Na2SO4, filtered and finally concentrated under reduced
pressure to be purified by flash column chromatography on
silica gel (AcOEt/cyclohexane: 25/75) to provide a yellow
solid; yield: 78 mg (84%). The enantiomers were separated
on SFC (AD column: 2%-2-1-15 MeOH, 200 bar,
1
67.6 min (R,R), 69.5 min (S,S); H NMR (400 MHz, CDCl3):
d=9.84 (1H, d, J=1.5 Hz), 6.71 (dd, 1H, J=15.6 and
9.8 Hz), 5.98 (d, 1H, J=15.6 Hz), 4.53 (dd, 1H, J=12.6 and
Adv. Synth. Catal. 2010, 352, 667 – 695
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
687

Sꢀbastien Belot et al.
FULL PAPERS
1
2 mLminÀ1, 308C); 1H NMR (400 MHz, CDCl3): d=7.25–
7.36 (m, 5H), 5.99 (d, 1H, J=9.6 Hz), 6.02 (dd, 1H, J=15.7
and 9.6 Hz), 4.68 (dd, 1H, J=8.4 and 4.5 Hz), 4.58 (dd, 1H,
J=11.8 and 8.4 Hz), 3.36 (m, 1H), 2.55 (m, 1H), 2.41 (m,
1H), 2.41 (m, 1H), 2.18 (m, 1H), 2.09 (m, 1H), 1.90 (m,
1H), 1.65–1.71 (m, 2H), 1.45 (m, 1H); 13C NMR (100 MHz,
CDCl3): d=211.5, 136.3, 134.5, 128.7, 128.1, 126.6, 125.8,
78.2, 51.8, 42.8, 42.0, 32.7, 28.2, 25.2; HR-MS (ESI mode):
m/z=291,1703, calculated for C16H19NO3 [M+NH4]+:
291.1703.
yellow oil; yield: 0.16 g (22%); H NMR (400 MHz, CDCl3):
d=9.82 (d, 1H, J=4.3 Hz), 7.40–7.37 (m, 2H), 7.33–7.28 (m,
3H), 4.55 (m, 2H), 3.87 (m, 1H), 2.43 (m, 1H), 2.01 (m,
1H), 1.16 (d, 1H, J=6.8 Hz), 1.04 (d, 1H, J=6.5 Hz);
13C NMR (100 MHz, CDCl3): d=204.1, 131.9, 128.9, 128.5,
121.9, 86.7, 82.7, 76.9, 58.0, 30.2, 27.0, 20.7, 20.3; FT-IR: n=
3060, 2969, 1715, 1551, 1492, 1376, 1270, 728, 698 cmÀ1; HR-
MS (ESI mode): m/z=277.1557, calculated for C15H21NO3
[M+NH4]+: 277.1552.
AHCTUNGTREG(NNUN 2R,3S)-5-(4-Bromophenyl)-2-isopropyl-3-(nitro-
methyl)pent-4-ynal (27)
Organocatalyzed Michael Addition of Aldehyde to
Nitroenyne
From (E)-1-bromo-4-(4-nitrobut-3-en-1-ynyl)benzene 5b
and isovaleraldehyde 1a according to General Procedure 4
(18 h) to give a mixture of diastereoisomers (syn/anti: 97/3)
as a yellow solid. The crude product was purified by flash
column chromatography on silica gel (AcOEt/cyclohexane:
85/15) to provide a yellow solid; yield: 92 mg (80%). The
enantiomers were separated on chiral SFC (column OJ:
2%-2-1-15% MeOH, 200 bar, 2 mLminÀ1, 308C): RT:
General Procedure 4: To a solution of the corresponding ni-
troenyne (0.34 mmol) and aldehyde (3.40 mmol) in chloro-
form (3 mL) was added at À108C) (S)-(À)-(diphenyltrime-
thylsiloxymethyl)-pyrrolidine (11 mg, 0.03 mmol). Then the
reaction mixture was stirred at À108C and the evolution of
the reaction was monitored by TLC until completion. The
reaction mixture was then hydrolyzed with an aqueous satu-
rated solution of NH4Cl and extracted three times with
CH2Cl2. The combined organic layers were dried over
Na2SO4, filtered and finally concentrated under reduced
pressure to be purified by a flash column chromatography
on silica gel using a mixture of ethyl acetate and cyclohex-
ane as eluant.
1
5.91 min (S,R), 6.15 min (R,S); H NMR (400 MHz, CDCl3):
d=9.87 (d, 1H, J=1.0 Hz), 7.42 (d, 2H, J=8.4 Hz), 7.23 (d,
2H, J=8.4 Hz), 4.60 (dd, 1H, J=12.0 and 4.3 Hz), 4.49 (dd,
1H, J=12.0 and 8.0 Hz), 3.84 (m, 1H), 2.78 (m, 1H), 2.50
(m, 1H), 1.27 (d, 3H, J=7.3 Hz), 1.02 (d, 1H, J=6.8 Hz);
13C NMR (100 MHz, CDCl3): d=202.8, 133.3, 121.1, 123.0,
121.1, 85.7, 85.1, 77.2, 57.0, 29.8, 29.0, 21.5, 17.9; FT-IR: n=
2962, 2925, 2874, 1720, 1555, 1486, 1376, 1247, 1071, 1011,
824 cmÀ1; HR-MS (ESI mode): m/z=338.0396, calculated
for C15H17BrNO3 [M+H]+: 338.0392.
ACHTUNGTRENNUNG(2R,3S)-2-Isopropyl-3-(nitromethyl)-5-phenylpent-4-
ynal (6a)
From (E)-(4-nitrobut-3-en-1-ynyl)benzene 5a and isovaleral-
dehyde 1a according to General Procedure 4 (14 h) to give a
mixture of diastereomers (syn/anti: 93/7) as a yellow oil. The
crude product was purified by flash column chromatography
on silica gel (AcOEt/cyclohexane: 90/10) to provide a
yellow solid; yield: 73 mg (83%). The enantiomers were sep-
arated on chiral SFC (IC column : 2%-2-1-15% MeOH, 200
bar, 2 mLminÀ1, 308C): RT: 4.7 min (S,R), 5.6 min (R,S);
1H NMR (400 MHz, CDCl3): d=1.04 (d, 3H, J=6.8 Hz),
1.28 (d, 3H, J=7.1 Hz), 2.54 (m, 1H), 2.79 (m, 1H), 3.86
(m, 1H), 4.50 (dd, 1H, J=12.1 and 8.1 Hz), 4.61 (dd, 1H,
J=12.1 and 4.3 Hz), 7.31 (m, 3H), 7.39 (m, 2H), 9.89 (d,
1H, J=1.3 Hz); 13C NMR (100 MHz, CDCl3): d=18.0, 21.5,
29.0, 29.9, 58.0, 77.5, 84.4, 86.2, 122.3, 128.5, 128.8, 131.9,
203.1; FT-IR: n=3057, 2966, 1718, 1556, 1491, 1377, 1265,
726, 691 cmÀ1; HR-MS (ESI mode): m/z=277.1557, calculat-
ed for C15H21NO3 [M+NH4]+: 277.1552.
AHCTUNGTREG(NNUN 2R,3S)-2-Isopropyl-3-(nitromethyl)-5-[4-(trifluoro-
methyl)phenyl]pent-4-ynal (29)
From (E)-1-(4-nitrobut-3-en-1-ynyl)-4-(trifluoromethyl)ben-
zene 5d and isovaleraldehyde 1a according to General Pro-
cedure 4 (18 h) to give a mixture of diastereomers (syn/anti:
96/4) as a yellow oil. The crude product was purified by
flash column chromatography on silica gel (AcOEt/cyclo-
hexane: 85/15) to provide a yellow oil; yield: 96 mg (86%).
The enantiomers were partly separated on chiral SFC after
reduction into the corresponding alcohol (NaBH4,10 equiv.,
and ethanol, 1 mL in a one-pot procedure) either (column
AD: 2%-2-1-15% MeOH, 200 bar, 2 mLminÀ1, 308C): RT:
7.57 min (S,R), 8.12 min (R,S) or (column AD: 2%-2-1-15%
MeOH, 200 bar, 2 mLminÀ1, 458C): RT: 7.21 min (S,R),
7.59 min (R,S); 1H NMR (400 MHz, CDCl3): d=9.89 (d,
1H, J=0.8 Hz), 7.56 (d, 2H, J=8.4 Hz), 7.49 (d, 2H, J=
8.1 Hz), 4.63 (dd, 1H, J=12.1 and 4.3 Hz), 4.51 (dd, 1H, J=
12.1 and 7.8 Hz), 3.87 (m, 1H), 2.82 (m, 1H), 2.52 (m, 1H),
1.30 (d, 3H, J=7.3 Hz), 1.04 (d, 1H, J=6.8 Hz); 13C NMR
(100 MHz, CDCl3): d=202.7, 164.0, 132.2, 125.4, 125.4, 87.1,
84.9, 77.4, 57.0, 29.9, 29.1, 21.5, 18.0; HR-MS (ESI mode):
m/z=328.1155, calculated for C16H17F3NO3 [M+H]+:
328.1161.
ACHTUNGTRENNUNG(2S,3S)-2-Isopropyl-3-(nitromethyl)-5-phenylpent-4-
ynal (6a)
To a solution of (S)-(À)-(diphenyltrimethylsiloxymethyl)-
pyrrolidine V (93 mg, 0.29 mmol) and (E)-(4-nitrobut-3-en-
1-ynyl)benzene 3a (0.50 g, 2.86 mmol) in chloroform
(25 mL) was added isovaleraldehyde 1a (3.1 mL,
28.60 mmol) at 238C. The reaction mixture was stirred at
238C during 4 h and was then extracted three times with di-
chloromethane. The combined organic layers were dried
over Na2SO4, filtered and finally concentrated under reduce
pressure to give a mixture of diastereomers (syn/anti: 65/35)
as a yellow oil. Purification by a flash column chromatogra-
phy on silica gel (AcOEt/cyclohexane: 10/90) provided a
AHCTUNGTREG(NNUN 2R,3S)-2-Isopropyl-3-(nitromethyl)-5-(m-tolyl)pent-
4-ynal (30)
From (E)-1-methyl-3-(4-nitrobut-3-en-1-ynyl)benzene 5e
and isovaleraldehyde 1a according to General Procedure 4
(18 h) to give a mixture of diastereomers (syn/anti: 96/4) as
688
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Adv. Synth. Catal. 2010, 352, 667 – 695

Organocatalyzed Conjugate Addition of Carbonyl Compounds to Nitrodienes/Nitroenynes
a yellow oil. The crude product was purified by flash
column chromatography on silica gel (AcOEt/cyclohexane:
85/15) to provide a yellow oil: yield: 76 mg (82%). The
enantiomers were separated on chiral SFC (column IC: 0%-
6-1-15% MeOH, 200 bar, 2 mLminÀ1, 308C): RT: 12.3 min
6.8 Hz); 13C NMR (100 MHz, CDCl3): d=203.4, 95.3, 73.4,
57.3, 30.9, 29.2, 28.7, 21.3, 18.0.
AHCTUNGTREG(NNUN 2R,3S)-2-Methyl-3-(nitromethyl)-5-phenylpent-4-ynal
(34)
1
(S,R), 12.8 min (R,S); H NMR (400 MHz, CDCl3): d=9.89
From (E)-(4-nitrobut-3-en-1-ynyl)benzene 5a and propional-
dehyde 2b according to General Procedure 4 at À258C
(14 h) to give a mixture of diastereomers (syn/anti: 93/7) as
a yellow oil. The crude product was purified by flash
column chromatography on silica gel (AcOEt/cyclohexane:
90/10) to provide a yellow solid; yield: 64 mg (81%). The
enantiomers were separated on chiral SFC (OD column:
2%-2-1-15% MeOH, 200 bar, 2 mLminÀ1, 308C): RT:
7.0 min (S,R), 8.0 min (R,S); 1H NMR (400 MHz, CDCl3):
d=9.7 (s, 1H), 7.29–7.39 (m, 5H), 4.61–4.66 (m, 2H), 3.98
(m, 1H), 2.72 (m, 1H), 1.38 (d, 3H, J=7.3 Hz); 13C NMR
(100 MHz, CDCl3): d=201.1, 131.9, 128.9, 128.5, 122.0, 86.5,
83.2, 76.4, 46.7, 31.6, 10.7.
(d, 1H, J=1.3 Hz), 7.19 (m, 3H), 7.14 (m, 1H), 4.61 (dd,
1H, J=12.1 and 4.6 Hz), 4.49 (dd, 1H, J=12.1 and 7.8 Hz),
3.86 (m, 1H), 2.78 (m, 1H), 2.54 (m, 1H), 2.32 (s, 3H), 1.28
(d, 3H, J=7.1 Hz), 1.04 (d, 1H, J=6.8 Hz); 13C NMR
(100 MHz, CDCl3): d=203.1, 138.2, 132.5, 129.7, 129.0,
128.3, 122.0, 86.4 , 83.9, 77.4, 57.2, 29.9, 29.0, 21.5, 21.3, 17.9;
HR-MS (ESI mode): m/z=274.1448, calculated for
C16H20NO3 [M+H]+: 274.1443.
ACHTUNGTRENNUNG(2R,3S)-2-Isopropyl-3-(nitromethyl)-5-(thiophen-3-
yl)pent-4-ynal (31)
From (E)-3-(4-nitrobut-3-en-1-ynyl)thiophene 5f and isova-
leraldehyde 1a according to General Procedure 4 (18 h) to
give a mixture of diastereomers (syn/anti: 96/4) as a yellow
oil. The crude product was purified by flash column chroma-
tography on silica gel (AcOEt/cyclohexane: 85/15) to pro-
vide a yellow oil; yield: 82 mg (91%). The enantiomers were
separated on chiral SFC (column IC: 2%-2-1-15% MeOH,
200 bar, 2 mLminÀ1, 308C): RT: 5.40 min (S,R), 6.25 min
AHCTUNGTREG(NNNU 2R,3S)-3-(Nitromethyl)-5-phenyl-2-propylpent-4-yn-
1-ol (35)
From (E)-(4-nitrobut-3-en-1-ynyl)benzene 5a and n-valeral-
dehyde 1c according to General Procedure 4 at À258C
(14 h). In-situ reduction into the corresponding alcohol
(NaBH4, 10 equiv., and ethanol, 1 mL in a one-pot proce-
dure) gave a mixture of diastereomers (syn/anti: 93/7) as a
yellow oil. The crude product was purified by flash column
chromatography on silica gel (AcOEt/cyclohexane: 75/25) to
provide a yellow solid; yield: 81 mg (91%). The enantiomers
were separated on chiral SFC (IC column: 2%-2-1-15%
MeOH, 200 bar, 2 mLminÀ1, 308C): RT: 10.6 min (S,R),
10.9 min (R,S); 1H NMR (400 MHz, CDCl3): d=7.44 (m,
2H), 7.34 (m, 3H), 4.71 (dd, 1H, J=12.3 and 8.9 Hz), 4.71
(dd, 1H, J=12.4 and 6.5 Hz), 3.88 (m, 2H), 3.73 (m, 1H),
1.84 (bm, 2H), 1.51 (m, 3H), 1.38 (m, 1H), 1.00 (t, 3H, J=
7.0 Hz); 13C NMR (100 MHz, CDCl3): d=131.9, 128.5,
128.4, 122.6, 85.4, 77.5, 63.4, 42.1, 33.3, 30.0, 20.7, 14.4.
1
(R,S); H NMR (400 MHz, CDCl3): d=9.88 (s, 1H), 7.41 (t,
1H, J=1.0 Hz), 7.25 (m, 1H), 7.05 (dd, 1H, J=5.0 and
1.0 Hz), 4.59 (dd, 1H, J=12.1 and 4.3 Hz), 4.49 (dd, 1H, J=
12.1 and 7.8 Hz), 3.84 (m, 1H), 2.77 (m, 1H), 2.52 (m, 1H),
1.27 (d, 3H, J=7.1 Hz), 1.02 (d, 1H, J=6.8 Hz); 13C NMR
(100 MHz, CDCl3): d=203.0, 130.0, 129.4, 125.5, 121.3, 84.0,
81.3, 77.3, 57.1, 29.9, 29.0, 21.5, 17.9; HR-MS (ESI mode):
m/z=266.0859, calculated for C13H16NO3S [M+H]+:
266.0851.
ACHTUNGTRENNUNG(2R,3S)-2-Isopropyl-3-(nitromethyl)dec-4-ynal (32)
From (E)-1-nitronon-1-en-3-yne 5g and isovaleraldehyde 1a
according to General Procedure 4 (14 h) to give a mixture of
diastereomers (syn/anti: 84/16) as an orange oil. The crude
product was purified by flash column chromatography on
silica gel (AcOEt/cyclohexane: 90/10) to provide an orange
oil; yield: 72 mg (84%). The enantiomers were separated on
chiral GC (column Hydrobex-B-6-TBDM: 60-1-170,
50 cm/s): RT: 104.1 min (R,S), 104.3 min (S,R).
(R)-2-[(S)-1-Nitro-4-phenylbut-3-yn-2-yl]heptan-1-ol
(36)
From (E)-(4-nitrobut-3-en-1-ynyl)benzene 5a and heptanal
1d according to General Procedure 4 at À258C (14 h). In-
situ reduction into the corresponding alcohol (NaBH4,
10 equiv., and ethanol, 1 mL in a one-pot procedure) gave a
mixture of diastereomers (syn/anti: 99/1) as a yellow oil. The
crude product was purified by flash column chromatography
on silica gel (AcOEt/cyclohexane: 75/52) to provide a
yellow solid; yield: 88 mg (89%). The enantiomers were sep-
arated on chiral SFC (IC column: 2%-2-1-15% MeOH, 200
bar, 2 mLminÀ1, 308C); 1H NMR (400 MHz, CDCl3): d=
7.38 (m, 2H), 7.29 (m, 3H), 4.65 (dd, 1H, J=12.4 and
9.1 Hz), 4.58 (dd, 1H, J=12.4 and 6.3 Hz), 3.86 (m, 2H),
3.69 (m, 1H), 1.78 (m, 1H), 1.75 (bs, 1H), 1.45 (m, 3H),
1.30 (m, 5H), 0.90 (t, 3H, J=6.8 Hz); 13C NMR (100 MHz,
CDCl3): d=131.9, 128.5, 128.4, 122.6, 85.4, 85.4, 77.5, 63.4,
42.4, 33.4, 32.1, 27.7, 27.2, 22.6, 14.1.
ACHTUNGTRENNUNG(2R,3S)-2-Isopropyl-6,6-dimethyl-3-(nitromethyl)hept-
4-ynal (33)
From (E)-5,5-dimethyl-1-nitrohex-1-en-3-yne 5h and isova-
leraldehyde 1a according to General Procedure 4 at À258C
(18 h) to give a mixture of diastereomers (syn/anti: 96/4) as
a yellow oil. The crude product was purified by flash
column chromatography on silica gel (AcOEt/cyclohexane:
90/10) to provide a yellow oil; yield: 82 mg (91%). The
enantiomers were separated on chiral GC (column Chirasil-
Dex-CB: 80-1-170-5, 30 cm/s): RT: 55.5 min (R,S), 57.0 min
(S,R); 1H NMR (400 MHz, CDCl3): d=9.79 (d, 1H, J=
1.5 Hz), 4.44 (dd, 1H, J=11.8 and 4.5 Hz), 4.33 (dd, 1H, J=
12.0 and 7.5 Hz), 3.54 (m, 1H), 2.55 (m, 1H), 2.37 (m, 1H),
1.18 (d, 3H, J=7.2 Hz), 1.21 (s, 9H), 0.93 (d, 1H, J=
Adv. Synth. Catal. 2010, 352, 667 – 695
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689

Sꢀbastien Belot et al.
FULL PAPERS
1.63 (m, 1H), 1.08 (d, 3H, J=6.9 Hz), 1.01 (d, 3H, J=
6.9 Hz); 13C NMR (100 MHz, CDCl3): d=131.8, 128.5,
128.4, 122.7, 86.8, 85.1, 77.9, 61.0, 48.5, 33.3, 26.9, 21.9, 19.1;
FT-IR: n=3416, 2964, 2930, 2876, 1552, 1490, 1443, 1379,
1104, 1040, 756, 691 cmÀ1; HR-MS (ESI mode): m/z=
305.1621, calculated for C15H19NO3 [M]+: 305.1627.
(R)-2-[(S)-1-Nitro-4-phenylbut-3-yn-2-yl]nonan-1-ol
(37)
From (E)-(4-nitrobut-3-en-1-ynyl)benzene 5a and nonanal
1e according to General Procedure 4 at À258C (14 h). In-
situ reduction into the corresponding alcohol (NaBH4,
10 equiv., and ethanol, 1 mL in a one-pot procedure) gave a
mixture of diastereomers (syn/anti: 99/1) as a yellow oil. The
crude product was purified by flash column chromatography
on silica gel (AcOEt/cyclohexane: 75/25) to provide a
yellow solid; yield: 102 mg (95%). The enantiomers were
separated on chiral SFC (IC column: 2%-2-1-15% MeOH,
200 bar, 2 mLminÀ1, 308C); 1H NMR (400 MHz, CDCl3):
d=7.38 (m, 2H), 7.28 (m, 3H), 4.64 (dd, 1H, J=12.4 and
8.8 Hz), 4.58 (dd, 1H, J=12.4 and 6.3 Hz), 3.85 (m, 2H),
3.67 (m, 1H), 2.05 (bs, 1H), 1.76 (m, 1H), 1.56 (m, 3H),
1.45 (3H), 1.27 (6H), 0.88 (t, 3H, J=6.3 Hz); 13C NMR
(100 MHz, CDCl3): d=131.8, 128.5, 128.4, 122.6, 85.4, 85.3,
77.5, 63.2, 42.4, 33.3, 32.9, 32.0, 27.8, 27.6, 25.8, 22.7, 14.2.
AHCTUNGTRENNG(UN 3R,4R,Z)-2-Benzylidene-4-isopropyl-3-
(nitromethyl)tetrahydrofuran (40)
To a solution of (2R,3S)-2-isopropyl-3-(nitromethyl)-5-phe-
nylpent-4-yn-1-ol 39 (60 mg, 0.23 mmol) in ethanol (2 mL)
at 238C were successively added p-TsOH (4 mg, 0.02 mmol),
AuClPPh3 (6 mg, 0.01 mmol) and AgBF4 (2 mg, 0.01 mmol).
The resulting heterogeneous reaction mixture was stirred
for 30 min at room temperature. Then it was hydrolyzed
with water and extracted with CH2Cl2. The combined organ-
ic layers were dried over Na2SO4, filtered and finally con-
centrated under reduced pressure to be purified by a flash
column chromatography on silica gel (AcOEt/cyclohexane:
10/90) to provide white crystals; yield: 51 mg (85%).
1H NMR (400 MHz, benzene): d=7.70 (d, 2H, J=7.5 Hz),
7.23 (t, 2H, J=7.5 Hz), 7.04 (t, 1H, J=7.5 Hz), 5.20 (s, 1H),
3.69 (m, 3H), 3.20 (m, 2H), 1.46 (m, 1H), 0.73 (m, 1H),
0.45 (d, 3H, J=6.5 Hz), 0.32 (d, 3H, J=6.5 Hz); 13C NMR
(100 MHz, CDCl3): d=155.7, 136.2, 127.8, 127.6, 125.6, 99.7,
73.7 , 72.1, 46.5, 42.9, 25.3, 21.0, 19.8; FT-IR: n=2961, 2923,
1774, 1692, 1553, 1452, 1379, 1278, 1262, 1177, 1020,
699 cmÀ1; HR-MS (ESI mode): m/z=261.1353, calculated
for C15H19NO3 [M]+: 261.1359.
(S)-2-[(R)-1-Nitro-4-phenylbut-3-yn-2-yl]cyclo-
hexanone (38)
To a mixture of cyclohexanone 2c (0.35 mL, 3,4 mmol) and
(E)-(4-nitrobut-3-en-1-ynyl)benzene 5a (59 mg, 0.34 mmol)
was added the aminal organocatalyst (22 mg, 0.07 mmol).
The reaction mixture was stirred at 238C during 14 h and
then diluted in dichloromethane. Then water was added and
the organic layer was separated. The aqueous layer was ex-
tracted two times with dichloromethane. The combined or-
ganic layers were dried over Na2SO4, filtered and finally
concentrated under reduced pressure to be purified by flash
column chromatography on silica gel (AcOEt/cyclohexane:
25/75) to provide a yellow solid; yield: 75 mg (89%). The
enantiomers were separated on SFC (AD column: 5%-2-1-
15 MeOH, 200 bar, 2 mLminÀ1, 308C): RT: 7.7 min (S,R),
8.8 min (R,S); 1H NMR (400 MHz, CDCl3): d=7.38 (m,
2H), 7.29 (m, 3H), 4.71 (dd, 1H, J=12.3 and 5.5 Hz), 4.59
(dd, 1H, J=12.3 and 7.3 Hz), 3.83 (q, 1H), 2.64 (m, 1H),
2.55 (m, 1H), 2.48 (m, 1H), 2.37 (m, 1H), 2.15 (m, 1H),
1.98 (m, 1H), 1.76–1.60 (m, 3H); 13C NMR (100 MHz,
CDCl3): d=210.3, 131.9, 128.6, 128.4, 122.5, 85.8, 85.0, 77.2,
50.8, 42.6, 36.0, 32.6, 31.5, 28.2, 25.3; HR-MS (ESI mode):
m/z=271.1200, calculated for C16H17NO3 [M+H]+:
271.1203.
Gold-Catalyzed Tandem Acetalization/Cycloiso-
merization
General Procedure 5: To a solution of the corresponding
adduct 6a (0.23 mmol), synthesized through the organocata-
lytic step, in chloroform stabilized with amylene (2 mL), was
added at 08C successively the corresponding alcohol
(0.28 mmol), p-TsOH (4 mg, 0.02 mmol), AuClPPh3 (6 mg,
0.01 mmol) and AgBF4 (2 mg, 0.01 mmol). The resulting het-
erogeneous reaction mixture was stirred for 1–2 h. Then it
was hydrolyzed with water and extracted with CH2Cl2. The
combined organic layers were dried over Na2SO4, filtered
and finally concentrated under reduced pressure to be puri-
fied by a flash column chromatography on silica gel using a
mixture of ethyl acetate and cyclohexane as eluant.
ACHTUNGTRENNUNG(2R,3S)-2-Isopropyl-3-(nitromethyl)-5-phenylpent-4-
yn-1-ol (39)
(3R,4R,5S,Z)-2-Benzylidene-5-ethoxy-4-isopropyl-3-
(nitromethyl)tetrahydrofuran (42)
To a solution of (2R,3S)-2-isopropyl-3-(nitromethyl)-5-phe-
nylpent-4-ynal 6a (100 mg, 0.43 mmol) in methanol (1 mL)
was added portions by portions NaBH4 (25 mg, 0.64 mmol,
1.3 equiv.) at 08C. The reaction mixture was stirred during
one hour at 08C and was then hydrolyzed with a saturated
aqueous solution of NH4Cl. The resulting mixture was ex-
tracted with diethyl ether and with ethyl acetate. The com-
bined organic layers were then dried over Na2SO4, filtered,
concentrated under reduce pressure to give a yellow oil. The
crude product was purified by flash column chromatography
on silica gel (AcOEt/cyclohexane: 25/75) to provide a
From (2R,3S)-2-isopropyl-3-(nitromethyl)-5-phenylpent-4-
ynal 6a and ethanol according to General Procedure 5 (1
hour) to give a mixture of diastereoisomers (trans/cis: 97/3)
as a yellow oil. The crude product was purified by flash
column chromatography on silica gel (AcOEt/cyclohexane:
1
10/90) to provide a yellow oil; yield: 63 mg (90%). H NMR
(400 MHz, benzene): d=7.68 (d, 2H, J=7.5 Hz), 7.24 (t,
2H, J=7.5 Hz), 7.05 (t, 1H, J=7.5 Hz), 5.46 (s, 1H), 4.76
(d, 1H, J=3.8 Hz), 4.51 (dd, 1H, J=12.3 and 10.8 Hz), 4.03
(dd, 1H, J=12.3 and 3.5 Hz), 3.45 (m, 1H), 3.34 (m, 1H),
3.03 (m, 1H), 1.30–1.26 (m, 2H), 0.83 (t, 3H, J=7.0 Hz),
0.62 (d, 3H, J=5.8 Hz), 0.57 (d, 3H, J=6.0 Hz); 13C NMR
(100 MHz, benzene): d=155.5, 136.4, 128.6, 128.6, 126.1,
1
yellow oil; yield: 82 mg (81%). H NMR (400 MHz, CDCl3):
d=7.38 (m, 2H), 7.28 (m, 3H), 4.71 (d. 2H, J=7.6 Hz), 4.00
(dd, 1H, J=10.8 and 2.8 Hz), 3.82 (m, 2H), 2.08 (m, 1H),
690
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Adv. Synth. Catal. 2010, 352, 667 – 695

Organocatalyzed Conjugate Addition of Carbonyl Compounds to Nitrodienes/Nitroenynes
105.3, 102.0, 76.7, 64.2, 51.7, 41.8, 23.6, 20.9, 20.6, 15.0; FT-
IR: n=2966, 2933, 2874, 1675, 1551, 1449, 1377, 1348, 1299,
1165, 1126, 1104, 975, 934, 825, 754, 694 cmÀ1; HR-MS (ESI
mode): m/z=306.1715, calculated for C17H24NO4 [M+H]+:
306.1705.
1362, 1126, 1104, 1042, 980, 932, 754, 694 cmÀ1; HR-MS (ESI
mode): m/z=292.1557, calculated for C16H22NO4 [M+H]+:
292.1548.
(3R,4R,5S,Z)-2-Benzylidene-5-isopropoxy-4-iso-
propyl-3-(nitromethyl)tetrahydrofuran (44)
(3R,4R,5R,Z)-2-Benzylidene-5-ethoxy-4-isopropyl-3-
(nitromethyl)tetrahydrofuran (42)
From (2R,3S)-2-isopropyl-3-(nitromethyl)-5-phenylpent-4-
ynal 6a and 2-propanol according to General Procedure 5 (2
hour) to give a mixture of diastereoisomers (trans/cis: 97/3)
as a yellow oil. The crude product was purified by flash
column chromatography on silica gel (AcOEt/cyclohexane:
From (2R,3S)-2-isopropyl-3-(nitromethyl)-5-phenylpent-4-
ynal 6a and ethanol according to General Procedure 5 but in
THF instead of chloroform (4 h) to give a mixture of diaste-
reoisomers (trans/cis: 74/26) as a yellow oil. The crude prod-
uct was purified by flash column chromatography on silica
gel (AcOEt/cyclohexane: 15/85) to provide the expected
diastereoisomer; yield: 13 mg (18%). 1H NMR (400 MHz,
benzene): d=7.70 (d, 2H, J=7.8 Hz), 7.28 (t, 2H, J=
7.5 Hz), 7.07 (t, 1H, J=7.5 Hz), 4.96 (s, 1H), 4.90 (d, 1H,
J=2.8 Hz), 3.84–3.80 (m, 2H), 3.71–3.65 (m, 2H), 3.24 (m,
1H), 2.09 (m, 1H), 1.24–1.1.18 (m, 1H), 1.00 (t, 3H, J=
7.0 Hz), 0.59 (d, 3H, J=6.5 Hz), 0.57 (d, 3H, J=6.8 Hz);
13C NMR (100 MHz, benzene): d=153.9, 136.4, 128.2, 127.9,
126.0, 106.8, 99.6, 73.6, 64.5, 50.7, 42.2, 25.2, 21.9, 18.5, 15.2;
HR-MS (ESI mode): m/z=306.1713, calculated for
C17H24NO4 [M+H]+: 306.1705.
1
10/90) to provide a yellow oil; yield: 65 mg (88%). H NMR
(400 MHz, benzene): d=7.68 (d, 2H, J=7.5 Hz), 7.24 (t,
2H, J=7.5 Hz), 7.05 (t, 1H, J=7.5 Hz), 5.45 (s, 1H), 4.89
(d, 1H, J=4.0 Hz), 4.56 (dd, 1H, J=12.6 and 10.8 Hz), 4.05
(dd, 1H, J=12.8 and 3.8 Hz), 3.40 (m, 1H), 3.35 (m, 1H),
1.34–1.22 (m, 2H), 0.94 (d, 3H, J=6.3 Hz), 0.82 (d, 3H, J=
6.3 Hz), 0.62 (d, 3H, J=6.0 Hz), 0.58 (d, 3H, J=6.0 Hz);
13C NMR (100 MHz, benzene): d=155.6, 136.5, 128.6, 126.0,
103.8, 101.8, 76.8, 70.8, 51.7, 42.0, 23.6, 23.5, 21.4, 20.9, 20.5;
FT-IR: n=2966, 2874, 1674, 1552, 1493, 1449, 1379, 1370,
1119, 1100, 978, 935, 825, 753, 694 cmÀ1; HR-MS (ESI
mode): m/z=320.1866, calculated for C18H26O4N [M+H]+:
320.1861.
(3S,4S,5S,Z)-2-Benzylidene-5-ethoxy-4-isopropyl-3-
(nitromethyl)tetrahydrofuran (42)
(3R,4R,5S,Z)-2-Benzylidene-4-isopropyl-3-(nitro-
methyl)-5-propoxytetrahydrofuran (44)
From
(2S,3S)-2-isopropyl-3-(nitromethyl)-5-phenylpent-4-
From (2R,3S)-2-isopropyl-3-(nitromethyl)-5-phenylpent-4-
ynal 6a and propanol according to General Procedure 5 (1
hour) to give a mixture of diastereoisomers (trans/cis: 97/3)
as a yellow oil. The crude product was purified by flash
column chromatography on silica gel (AcOEt/cyclohexane:
ynal 6a and ethanol according to General Procedure 5 (1
hour) to give a mixture of diastereoisomers (trans/cis: 97/3)
as a yellow oil. The crude product was purified by flash
column chromatography on silica gel (AcOEt/cyclohexane:
1
1
12/88) to provide a yellow oil; yield: 59 mg (84%). H NMR
10/90) to provide a yellow oil; yield: 67 mg (91%). H NMR
(400 MHz, benzene): d=7.69 (d, 2H, J=7.2 Hz), 7.29 (t,
2H, J=7.6 HZ), 7.08 (t, 1H, J=7.3 Hz), 5.07 (s, 1H), 4.98
(s, 1H), 4.43 (dd, 1H, J=12.8 and 10.3 Hz), 4.02 (dd, 1H,
J=13.0 and 5.5 Hz), 3.53 (m, 1H), 3.18 (m, 1H), 3.12 (m,
1H), 1.82 (d, 1H, J=6.3 Hz), 1.34 (m, 1H), 0.91 (t, 3H, J=
7.0 Hz), 0.68 (d, 3H, J=6.8 Hz), 0.67 (d, 3H, J=6.8 Hz);
13C NMR (100 MHz, benzene): d=154.9, 136.5, 128.7, 128.3,
126.1, 108.9, 101.7, 79.2, 64.2, 53.0, 43.9, 29.0, 19.5, 19.5, 15.1;
HR-MS (ESI mode): m/z=306.1710, calculated for
C17H24NO4 [M+H]+: 306.1705.
(400 MHz, benzene): d=7.68 (d, 2H, J=7.5 Hz), 7.24 (t,
2H, J=7.5 Hz), 7.05 (t, 1H, J=7.3 Hz), 5.45 (s, 1H), 4.77
(d, 1H, J=4.0 Hz), 4.52 (dd, 1H, J=12.8 and 11.0 Hz), 4.03
(dd, 1H, J=12.6 and 3.8 Hz), 3.44 (m, 1H), 3.35 (m, 1H),
2.94 (m, 1H), 1.31–1.22 (m, 2H), 0.69 (t, 3H, J=7.3 Hz),
0.63 (d, 3H, J=5.8 Hz), 0.58 (d, 3H, J=6.0 Hz); 13C NMR
(100 MHz, benzene): d=155.5, 136.4, 128.6, 128.6, 126.1,
105.7, 101.9, 76.7, 70.5, 51.8, 41.8, 23.7, 23.0, 20.9, 20.7, 10.8;
FT-IR: n=2971, 2871, 1676, 1554, 1449, 1378, 1112, 980, 754,
694 cmÀ1; HR-MS (ESI mode): m/z=342.1661, calculated
for C18H25NO4Na [M+Na]+: 342.1675.
(3R,4R,5S,Z)-2-Benzylidene-4-isopropyl-5-methoxy-3-
(nitromethyl)tetrahydrofuran (43)
(3R,4R,5S,Z)-2-Benzylidene-4-isopropyl-5-(2-methyl-
allyloxy)-3-(nitromethyl)tetrahydrofuran (46)
From (2R,3S)-2-isopropyl-3-(nitromethyl)-5-phenylpent-4-
ynal 6a and methanol according to General Procedure 5 (1
hour) to give a mixture of diastereoisomers (trans/cis: 97/3)
as a yellow oil. The crude product was purified by flash
column chromatography on silica gel (AcOEt/cyclohexane:
From (2R,3S)-2-isopropyl-3-(nitromethyl)-5-phenylpent-4-
ynal 6a and methallyl alcohol according to General Proce-
dure 5 (1 hour) to give a mixture of diastereoisomers (trans/
cis: 96/4) as a yellow oil. The crude product was purified by
flash column chromatography on silica gel (AcOEt/cyclo-
hexane: 10/90) to provide a yellow oil; yield: 61 mg (80%).
1H NMR (400 MHz, benzene): d=7.67 (d, 2H, J=7.3 Hz),
7.24 (t, 2H, J=7.5 Hz), 7.05 (t, 1H, J=7.3 Hz), 5.45 (s, 1H),
4.82 (m, 2H), 4.77 (s, 1H), 4.52 (dd, 1H, J=12.5 and
11.0 Hz), 4.03 (dd, 1H, J=12.8 and 3.8 Hz), 3.88 (d, 1H, J=
12.3 Hz), 3.54 (d, 1H, J=12.3 Hz), 3.35 (m, 1H), 1.49 (s,
3H), 1.32 (m, 2H), 0.64 (t, 3H, J=5.5 Hz), 0.58 (d, 3H, J=
6.0 Hz); 13C NMR (100 MHz, benzene): 155.4, 141.4, 136.3,
1
10/90) to provide a yellow oil; yield: 58 mg (86%). H NMR
(400 MHz, benzene): d=7.67 (d, 2H, J=7.6 Hz), 7.24 (t,
2H, J=7.5 Hz), 7.06 (t, 1H, J=7.5 Hz), 5.45 (s, 1H), 4.60
(d, 1H, J=3.8 Hz), 4.45 (dd, 1H, J=12.5 and 10.8 Hz), 4.02
(dd, 1H, J=12.8 and 3.8 Hz), 3.32 (m, 1H), 2.91 (s, 3H),
1.31–1.22 (m, 2H), 0.61 (d, 3H, J=5.8 Hz), 0.56 (d, 3H, J=
5.8 Hz); 13C NMR (100 MHz, benzene): d=155.4, 136.4,
128.7, 128.6, 126.1, 106.7, 102.1, 76.7, 55.5, 51.7, 41.7, 23.6,
20.9, 20.7; FT-IR: n=2961, 2932, 1675, 1550, 1448, 1379,
Adv. Synth. Catal. 2010, 352, 667 – 695
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
691

Sꢀbastien Belot et al.
FULL PAPERS
128.7, 128.6, 126.2, 112.7, 105.1, 102.2, 76.7, 72.6, 51.9, 41.8,
2.69 (m, 1H), 1.28–1.23 (m, 1H), 1.17–1.09 (m, 1H), 0.97 (d,
3H, J=7.0 Hz), 0.52 (d, 3H, J=6.08 Hz), 0.42 (d, 3H, J=
6.0 Hz); 13C NMR (100 MHz, benzene): d=155.5, 144.2,
136.4, 128.7, 128.6, 128.6, 127.5, 126.7, 126.1, 106.0, 102.1,
76.5, 74.8, 51.9, 41.7, 40.1, 23.7, 20.9, 20.5, 18.2; FT-IR: n=
2967, 2930, 2872, 1676, 1552, 1494, 1450, 1379, 1112, 978,
756, 695 cmÀ1; HR-MS (ESI mode): m/z=418.2006, calculat-
ed for C24H29O4NNa [M+Na]+: 418.1988.
23.7, 20.9, 20.7, 19.6; FT-IR: n=3024, 2961, 2874, 1675,
1551, 1449, 1378, 1126, 1101, 974, 928, 826, 754, 694 cmÀ1
;
HR-MS (ESI mode): m/z=354.1685, calculated for
C19H25NO4Na [M+Na]+: 354.1675.
(3R,4R,5S,Z)-2-Benzylidene-5-(benzyloxy)-4-iso-
propyl-3-(nitromethyl)tetrahydrofuran (47)
From (2R,3S)-2-isopropyl-3-(nitromethyl)-5-phenylpent-4-
ynal 6a and benzyl alcohol according to General Procedure
5 (2 h) to give a mixture of diastereoisomers (trans/cis: 96/4)
as a yellow oil. The crude product was purified by flash
column chromatography on silica gel (AcOEt/cyclohexane:
(3R,4R,5S,Z)-2-Benzylidene-5-(4-chlorobenzyloxy)-4-
isopropyl-3-(nitromethyl)tetrahydrofuran (50)
From (2R,3S)-2-isopropyl-3-(nitromethyl)-5-phenylpent-4-
ynal 6a and 4-chlorobenzyl alcohol according to General
Procedure 5 (1 hour) to give a mixture of diastereoisomers
(trans/cis: 97/3) as a yellow oil. The crude product was puri-
fied by flash column chromatography on silica gel (AcOEt/
cyclohexane: 10/90) to provide a white solid; yield: 72 mg
1
10/90) to provide a yellow oil; yield: 69 mg (90%). H NMR
(400 MHz, benzene): d=7.69 (d, 2H, J=7.3 Hz), 7.26 (t,
2H, J=7.6 Hz), 7.16–7.07 (m, 6H), 5.48 (s, 1H), 4.87 (d,
1H, J=4.2 Hz), 4.51 (m, 2H), 4.10 (d, 1H, J=11.8 Hz), 3.95
(dd, 1H, J=12.6 and 3.5 Hz), 3.33 (m, 1H), 1.34–1.20 (m,
2H), 0.59 (d, 3H, J=6.0 Hz), 0.54 (d, 3H, J=6.3 Hz);
13C NMR (100 MHz, benzene): d=155.4, 137.3, 136.3, 128.7,
128.6, 128.4, 128.3, 126.2, 104.6, 102.3, 76.7, 70.4, 51.8, 41.8,
23.6, 20.8, 20.7; FT-IR: n=2973, 2934, 2870, 1677, 1553,
1380, 1115, 980, 931, 743, 694 cmÀ1; HR-MS (ESI mode):
m/z=368.1869, calculated for C22H26NO4 [M+H]+:
368.1862.
1
(78%). H NMR (300 MHz, benzene): d=7.65 (d, 2H, J=
7.4 Hz), 7.27 (t, 2H, J=7.6 Hz), 7.07 (d, 3H, J=8.2 HZ),
6.76 (d, 2H, J=8.2 Hz), 5.48 (s, 1H), 4.78 (d, 1H, J=
4.3 Hz), 4.44 (dd, 1H, J=12.5 and 11.0 Hz), 4.29 (d, 1H, J=
11.7 Hz), 3.97–3.90 (m, 2H), 3.33 (m, 1H), 1.34–1.20 (m,
2H), 0.55 (t, 6H, J=6.0 Hz); 13C NMR (75 MHz, benzene):
d=155.1, 136.2, 135.8, 134.2, 129.7, 128.9, 128.7, 128.6, 126.3,
104.7, 102.5, 76.6, 69.6, 51.8, 41.7, 23.6, 20.8, 20.7; FT-IR: n=
2972, 2872, 1672, 1553, 1381, 1110, 983, 935, 743, 694 cmÀ1
;
HR-MS (ESI mode): m/z=402.1467, calculated for
C22H25ClNO4 [M+H]+: 402.1472. [a]2D0: À198.58 (c 1.13, 99%
ee, CHCl3).
(3R,4R,5S,Z)-2-Benzylidene-5-(cyclohexyloxy)-4-iso-
propyl-3-(nitromethyl)tetrahydrofuran (48)
From (2R,3S)-2-isopropyl-3-(nitromethyl)-5-phenylpent-4-
ynal 6a and cyclohexanol according to General Procedure 5
(2 h) to give a mixture of diastereoisomers (trans/cis: 92/8)
as a yellow oil. The crude product was purified by flash
column chromatography on silica gel (AcOEt/cyclohexane:
X-Ray Analysis
CCDC 737010.[39] Data were collected on a STOE IPDS II
diffractometer at 180 K using Mo radiation. The crystal is
orthorhombic, with space-group P212121 and unit cell param-
eters a=12.2013(7) ꢄ, b=12.5543 (7) ꢄ, c=13.3320(10) ꢄ.
32843 reflections were measured of which 6093 are unique
(Rint =0.073 after face-indexed integration absorption cor-
rection with Tmin =0.798 Tmax =0.953) and 3601 reflections
have I>2.0s(I). Full-matrix least square refinement on F2
using 3718 reflections yielded the final agreement factors of
R=0.033, wR=0.058, S=0.97. The H atoms positions were
determined geometrically and were constrained to ride on
the atom they are bonded to. The Flack parameter refined
to 0.01(6).
1
10/90) to provide a yellow oil; yield: 64 mg (77%). H NMR
(400 MHz, benzene): d=7.68 (d, 2H, J=7.3 Hz), 7.23 (t,
2H, J=7.5 Hz), 7.03 (t, 1H, J=7.5 Hz), 5.46 (s, 1H), 4.97
(d, 1H, J=3.8 Hz), 4.63 (dd, 1H, J=12.5 and 11.0 Hz), 4.07
(dd, 1H, J=12.8 and 3.8 Hz), 3.39 (m, 2H), 1.63 (m, 1H),
1.49 (m, 3H), 1.29 (m, 4H), 1.05 (m, 4H), 0.66 (d, 3H, J=
5.8 Hz), 0.60 (d, 3H, J=6.0 Hz); 13C NMR (100 MHz, ben-
zene): d=155.6, 136.6, 128.6, 128.6, 126.0, 104.0, 101.8, 76.9,
76.3, 51.9, 42.1, 33.5, 31.7, 25.8, 23.8, 23.7, 20.9, 20.7; FT-IR:
n=2931, 2859, 1675, 1553, 1492, 1449, 1378, 1118, 1102, 979,
949, 928, 754, 694 cmÀ1
; HR-MS (ESI mode): m/z=
382.2016, calculated for C21H29O4NNa [M+Na]+: 382.1994.
One Pot Organocatalyzed Michael Addition and
Gold-Catalyzed Tandem Acetalization/Cyclo-
isomerization
(3R,4R,5S,Z)-2-Benzylidene-4-isopropyl-3-(nitro-
methyl)-5-[(S)-2-phenylpropoxy]tetrahydrofuran (49)
From (2R,3S)-2-isopropyl-3-(nitromethyl)-5-phenylpent-4-
ynal 6a and (2S)-2-phenylpropan-1-ol according to General
Procedure 5 (2 hour) to give a mixture of diastereoisomers
(trans/cis: 96/4) as a yellow oil. The crude product was puri-
fied by flash column chromatography on silica gel (AcOEt/
cyclohexane: 10/90) to provide a yellow oil; yield: 77 mg
General Procedure 6: To a solution of the nitroenyne
(0.23 mmol) and aldehyde (2.30 mmol) in amylene-stabilized
chloroform (2 mL) was added at À108C (S)-(À)-(diphenyl-
trimethylsiloxymethyl)-pyrrolidine (8 mg, 0.02 mmol). Then
the reaction mixture was stirred at À108C and the evolution
of the reaction was monitored by TLC until completion.
Then the alcohol (0.28 mmol), p-TsOH (10 mg, 0.06 mmol),
AuClPPh3 (6 mg, 0.01 mmol) and AgBF4 (2 mg, 0.01 mmol)
were successively added at À108C. The resulting heteroge-
neous reaction mixture was stirred for 3–5 h at À108C. Then
it was hydrolyzed with water and extracted with CH2Cl2.
The combined organic layers were dried over Na2SO4, fil-
1
(90%). H NMR (400 MHz, benzene): d=7.70 (d, 2H, J=
7.2 Hz), 7.24 (t, 2H, J=7.8 Hz), 7.14 (d, 2H, J=7.5 Hz),
7.06 (t, 2H, J=7.0 Hz), 6.95 (d, 2H, J=7.2 Hz), 5.46 (s,
1H), 4.72 (d, 1H, J=4.5 Hz), 4.42 (dd, 1H, J=12.8 and
11.0 Hz), 3.97 (dd, 1H, J=12.8 and 3.8 Hz), 3.62 (dd, 1H,
J=9.3 and 6.3 Hz), 3.33 (m, 1H), 3.12 (t, 1H, J=8.0 Hz),
692
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 667 – 695

Organocatalyzed Conjugate Addition of Carbonyl Compounds to Nitrodienes/Nitroenynes
tered and finally concentrated under reduced pressure to be
purified by a flash column chromatography on silica gel
using a mixture of ethyl acetate and cyclohexane as eluant.
FT-IR: n=2966, 2874, 1674, 1552, 1493, 1449, 1379, 1370,
1119, 1100, 978, 935, 825, 753, 694 cmÀ1; HR-MS (ESI
mode): m/z=320.1866, calculated for C18H26O4N [M+H]+:
320.1861.
(3R,4R,5S,Z)-2-Benzylidene-5-ethoxy-4-isopropyl-3-
(nitromethyl)tetrahydrofuran (42)
(3R,4R,5S,Z)-2-(4-Bromobenzylidene)-5-ethoxy-4-
isopropyl-3-(nitromethyl)tetrahydrofuran (52)
From (E)-(4-nitrobut-3-en-1-ynyl)benzene 5a, isovaleralde-
hyde 1a and ethanol according to General Procedure 6 to
give a mixture of diastereoisomers (trans/cis: 92/8) as a
yellow oil. The crude product was purified by flash column
chromatography on silica gel (AcOEt/cyclohexane: 10/90) to
From (E)-1-bromo-4-(4-nitrobut-3-en-1-ynyl)benzene 5b,
isovaleraldeyde 1a and ethanol according from General Pro-
cedure 6 to give a mixture of diastereoisomers (trans/cis: 97/
3) as a yellow oil. The crude product was purified by flash
column chromatography on silica gel (AcOEt/cyclohexane:
provide
a
yellow oil; yield: 56 mg (80%). 1H NMR
1
(400 MHz, benzene): d=7.68 (d, 2H, J=7.5 Hz), 7.24 (t,
2H, J=7.5 Hz), 7.05 (t, 1H, J=7.5 Hz), 5.46 (s, 1H), 4.76
(d, 1H, J=3.8 Hz), 4.51 (dd, 1H, J=12.3 and 10.8 Hz), 4.03
(dd, 1H, J=12.3 and 3.5 Hz), 3.45 (m, 1H), 3.34 (m, 1H),
3.03 (m, 1H), 1.30–1.26 (m, 2H), 0.83 (t, 3H, J=7.0 Hz),
0.62 (d, 3H, J=5.8 Hz), 0.57 (d, 3H, J=6.0 Hz); 13C NMR
(100 MHz, benzene): d=155.5, 136.4, 128.6, 128.6, 126.1,
105.3, 102.0, 76.7, 64.2, 51.7, 41.8, 23.6, 20.9 , 20.6, 15.0; FT-
IR: n=2966, 2933, 2874, 1675, 1551, 1449, 1377, 1348, 1299,
1165, 1126, 1104, 975, 934, 825, 754, 694 cmÀ1; HR-MS (ESI
mode): m/z=306.1715, calculated for C17H24NO4 [M+H]+:
306.1705.
10/90) to provide a yellow oil; yield: 76 mg (86%). H NMR
(400 MHz, benzene): d=7.42 (d, 2H, J=8.8 Hz), 7.39 (d,
2H, J=8.8 Hz), 5.33 (s, 1H), 4.77 (d, 1H, J=3.8 Hz), 4.53
(dd, 1H, J=12.8 and 11.0 Hz), 4.05 (dd, 1H, J=12.8 and
3.8 Hz), 3.47 (m, 1H), 3.36 (m, 1H), 3.07 (m, 1H), 1.33–1.28
(m, 2H), 0.89 (t, 3H, J=7.0 Hz), 0.68 (d, 3H, J=5.8 Hz),
0.63 (d, 3H, J=5.8 Hz); 13C NMR (100 MHz, benzene): d=
156.#, 135.3, 131.6, 130.1, 119.6, 105.5, 100.7, 76.5, 64.4, 51.6,
41.8, 23.6, 20.8, 20.6, 15.0; FT-IR: n=2974, 2932, 2871, 1674,
1553, 1488, 1379, 1110, 974, 934, 843 cmÀ1; HR-MS (ESI
mode): m/z=384.0799, calculated for C17H23BrNO3 [M+
H]+: 384.0810.
(3R,4R,5S,Z)-2-Benzylidene-4-isopropyl-5-methoxy-3- (2S,3R,4R,Z)-2-Ethoxy-3-isopropyl-5-(4-methoxy-
(nitromethyl)tetrahydrofuran (43)
benzylidene)-4-(nitromethyl)tetrahydrofuran (53)
From (E)-(4-nitrobut-3-en-1-ynyl)benzene 5a, isovaleralde-
hyde 1a and methanol according to General Procedure 6 to
give a mixture of diastereoisomers (93/7) as a yellow oil.
The crude product was purified by flash column chromatog-
raphy on silica gel (AcOEt/cyclohexane: 10/90) to provide a
yellow oil; yield: 54 mg (81%). 1H NMR (400 MHz, ben-
zene): d=7.67 (d, 2H, J=7.6 Hz), 7.24 (t, 2H, J=7.5 Hz),
7.06 (t, 1H, J=7.5 Hz), 5.45 (s, 1H), 4.60 (d, 1H, J=
3.8 Hz), 4.45 (dd, 1H, J=12.5 and 10.8 Hz), 4.02 (dd, 1H,
J=12.8 and 3.8 Hz), 3.32 (m, 1H), 2.91 (s, 3H), 1.31–1.22
(m, 2H), 0.61 (d, 3H, J=5.8 Hz), 0.56 (d, 3H, J=5.8 Hz);
13C NMR (100 MHz, benzene): d=155.4, 136.4, 128.7, 128.6,
126.1, 106.7, 102.1, 76.7, 55.5, 51.7, 41.7, 23.6, 20.9, 20.7; FT-
IR: n=2961, 2932, 1675, 1550, 1448, 1379, 1362, 1126, 1104,
1042, 980, 932, 754, 694 cmÀ1; HR-MS (ESI mode): m/z=
292.1557, calculated for C16H22NO4 [M+H]+: 292.1548.
From (E)-1-methoxy-4-(4-nitrobut-3-en-1-ynyl)benzene 5c,
isovaleraldeyde 1a and ethanol according from General Pro-
cedure 6 to give a mixture of diastereoisomers (trans/cis: 91/
9) as a yellow oil. The crude product was purified by flash
column chromatography on silica gel (AcOEt/cyclohexane:
1
10/90) to provide a yellow oil; yield: 59 mg (77%); H NMR
(400 MHz, benzene): d=7.65 (d, 2H, J=8.4 Hz), 7.39 (d,
2H, J=8.4 Hz), 5.48 (s, 1H), 4.77 (d, 1H, J=4.0 Hz), 4.54
(dd, 1H, J=12.6 and 10.8 Hz), 4.04 (dd, 1H, J=12.9 and
3.8 Hz), 3.49 (m, 1H), 3.38 (m, 1H), 3.32 (s, 3H), 3.05 (m,
1H), 1.33–1.28 (m, 2H), 0.85 (t, 3H, J=7.1 Hz), 0.63 (d,
3H, J=5.8 H7z), 0.63 (d, 3H, J=6.0 Hz); 13C NMR
(100 MHz, benzene): d=158.4, 153.7, 129.9, 129.2, 114.1,
105.1, 101.6, 76.8, 64.1, 54.8, 51.9, 41.8, 23.7, 20.9, 20.7, 15.1;
HR-MS (ESI mode): m/z=336.1821, calculated for
C18H26NO5 [M+H]+: 336.1811.
(3R,4R,5S,Z)-2-Benzylidene-5-isopropoxy-4-iso-
propyl-3-(nitromethyl)tetrahydrofuran (44)
(2S,3R,4R,Z)-2-Ethoxy-3-isopropyl-4-(nitromethyl)-5-
[4-(trifluoromethyl)benzylidene]tetrahydrofuran (54)
From (E)-(4-nitrobut-3-en-1-ynyl)benzene 5a, isovaleralde-
hyde and 2-propanol according to General Procedure 6 to
give a mixture of diastereoisomers (trans/cis: 88/12) as a
yellow oil. The crude product was purified by flash column
chromatography on silica gel (AcOEt/cyclohexane: 10/90) to
From (E)-1-(4-nitrobut-3-en-1-ynyl)-4-(trifluoromethyl)-ben-
zene 5d, isovaleraldeyde 1a and ethanol according from
General Procedure 6 to give a mixture of diastereoisomers
(trans/cis: 97/3) as a yellow oil. The crude product was puri-
fied by flash column chromatography on silica gel (AcOEt/
cyclohexane: 10/90) to provide a yellow oil; yield: 72 mg
provide
a
yellow oil; yield: 58 mg (79%). 1H NMR
1
(400 MHz, benzene): d=7.68 (d, 2H, J=7.5 Hz), 7.24 (t,
2H, J=7.5 Hz), 7.05 (t, 1H, J=7.5 HZ), 5.45 (s, 1H), 4.89
(d, 1H, J=4.0 Hz), 4.56 (dd, 1H, J=12.6 and 10.8 Hz), 4.05
(dd, 1H, J=12.8 and 3.8 Hz), 3.40 (m, 1H), 3.35 (m, 1H),
1.34–1.22 (m, 2H), 0.94 (d, 3H, J=6.3 Hz), 0.82 (d, 3H, J=
6.3 Hz), 0.62 (d, 3H, J=6.0 Hz), 0.58 (d, 3H, J=6.0 Hz);
13C NMR (100 MHz, benzene): d=155.6, 136.5, 128.6, 126.0,
103.8, 101.8, 76.8, 70.8, 51.7, 42.0, 23.6, 23.5, 21.4, 20.9, 20.5;
(84%). H NMR (400 MHz, benzene): d=7.42 (d, 2H, J=
8.8 Hz), 7.39 (d, 2H, J=8.8 Hz), 5.33 (s, 1H), 4.77 (d, 1H,
J=3.8 Hz), 4.53 (dd, 1H, J=12.8 and 11.0 Hz), 4.05 (dd,
1H, J=12.8 and 3.8 Hz), 3.47 (m, 1H), 3.36 (m, 1H), 3.07
(m, 1H), 1.33–1.28 (m, 2H), 0.89 (t, 3H, J=7.0 Hz), 0.68 (d,
3H, J=5.8 Hz), 0.63 (d, 3H, J=5.8 Hz); 13C NMR
(100 MHz, benzene): d=156.3, 135.3, 131.6, 130.1, 119.6,
105.5, 100.7, 76.5, 64.4, 51.6, 41.8, 23.6, 20.8, 20.6, 15.0; HR-
Adv. Synth. Catal. 2010, 352, 667 – 695
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Sꢀbastien Belot et al.
FULL PAPERS
MS (ESI mode): m/z=374.1583, calculated for C18H23F3NO4
[M+H]+: 374.1579.
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9) as a yellow oil. The crude product was purified by flash
column chromatography on silica gel (AcOEt/cyclohexane:
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1
10/90) to provide a yellow oil; yield: 62 mg (86%). H NMR
(400 MHz, benzene): d=7.71 (d, 1H, J=7.8 Hz), 7.39 (s,
1H), 7.24 (t, 1H, J=7.6 Hz), 6.92 (d, 1H, J=7.3 Hz), 5.49
(s, 1H), 4.77 (d, 1H, J=4.0 Hz), 4.53 (dd, 1H, J=12.6 and
10.9 Hz), 4.02 (dd, 1H, J=12.6 and 3.8 Hz), 3.48 (m, 1H),
3.37 (m, 1H), 3.32 (s, 3H), 3.04 (m, 1H), 2.19 (s, 3H), 1.33–
1.27 (m, 2H), 0.83 (t, 3H, J=7.1 Hz), 0.61 (d, 3H, J=
5.8 Hz), 0.56 (d, 3H, J=6.0 Hz); 13C NMR (100 MHz, ben-
zene): d=155.3, 137.7, 136.4, 129.6, 128.5, 127.0, 105.3,
102.2, 76.8, 64.2, 51.7, 41.9, 23.7, 21.6, 20.9, 20.6, 15.0; HR-
MS (ESI mode): m/z=320.1857, calculated for C18H26NO4
[M+H]+: 320.1862.
(2S,3R,4R,Z)-2-Ethoxy-3-isopropyl-4-(nitromethyl)-5-
(thiophen-3-ylmethylene)tetrahydrofuran (56)
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From (E)-3-(4-nitrobut-3-en-1-ynyl)thiophene 5f, isovaleral-
deyde 1a and ethanol according from General Procedure 6
to give a mixture of diastereoisomers (trans/cis: 89/11) as a
yellow oil. The crude product was purified by flash column
chromatography on silica gel (AcOEt/cyclohexane: 7/93) to
provide
a
yellow oil; yield: 54 mg (77%). 1H NMR
(400 MHz, benzene): d=7.27 (m, 2H), 6.93 (dd, 2H, J=5.0
and 3.3 Hz), 5.53 (s, 1H), 4.72 (d, 1H, J=3.3 Hz), 4.49 (dd,
1H, J=12.6 and 11.1 Hz), 4.00 (dd, 1H, J=12.6 and
3.6 Hz), 3.42 (m, 1H), 3.33 (m, 1H), 3.01 (m, 1H), 1.33–1.23
(m, 2H), 0.83 (t, 3H, J=7.1 Hz), 0.61 (d, 3H, J=5.8 Hz),
0.55 (d, 3H, J=6.1 Hz); 13C NMR (100 MHz, benzene): d=
154.8, 137.3, 129.1, 124.9, 121.9, 105.3, 97.2, 77.0, 64.5, 52.4,
41.4, 24.0, 21.2, 21.0, 15.4; HR-MS (ESI mode): m/z=
312.1275, calculated for C15H22NO4S [M+H]+: 312.1270.
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Acknowledgements
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J. Org. Chem. 2008, 73, 8337.
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We thank the European Community (Marie Curie Early
Stage Researcher Training, MEST-CT-2005-019780). We also
thank Dr. Jeremy Prodger and Dr. Gerry Rassias from GSK
(Stevenage, UK) both for the correction of the manuscript
and fruitful discussions.
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695