Cooperative dienamine/hydrogen-bonding catalysis: Enantioselective formal [2+2] cycloaddition of enals with nitroalkenes

Article abstract of DOI:10.1002/anie.201200269

Two can play this game: The title reaction is catalyzed by a chiral secondary amine in the presence of an achiral thiourea for the enantio- and diastereoselective synthesis of highly functionalized cyclobutanes (see scheme; TMS=trimethylsilyl). Mechanistically, two consecutive Michael reactions proceed through an unprecedented combination of an dienamine/iminium activation mode. Copyright

Full text of DOI:10.1002/anie.201200269

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Angewandte
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DOI: 10.1002/anie.201200269
Organocatalysis
Cooperative Dienamine/Hydrogen-Bonding Catalysis:
Enantioselective Formal [2+2] Cycloaddition of Enals with
Nitroalkenes**
Garazi Talavera, Efraꢀm Reyes, Jose L. Vicario,* and Luisa Carrillo
The cyclobutane scaffold is a structural motif incorporated
into a wide range of naturally occurring products, as well as
into transiently generated intermediates in primary and
secondary metabolism.[1] Moreover, the reactivity pattern
shown by cyclobutanes when exploiting ring strain as a driving
force to facilitate novel reactivity has also opened the way for
their use as intermediates in the synthesis of complex
molecules.[2] However, despite their interest, the development
of methodologies for the stereocontrolled synthesis of cyclo-
butanes has received little attention over the years.[3] In this
context, the [2+2] cycloaddition represents one of the most
straightforward approaches for the stereoselective construc-
tion of this structure with several reported and efficient
examples, which rely on the use of chiral ligands,[4] auxilia-
ries,[5] or Lewis acid catalysts.[6]
Within this context, we wondered if aminocatalysis could
contribute to this field by facing the challenge of setting up an
enantioselective version of a [2+2] cycloaddition reaction
between a,b-unsaturated aldehydes and nitroalkenes. We
were inspired by recent work by Seebach, Hayashi, and co-
workers,[7] and Blackmond and co-workers[8] (Scheme 1) in
which kinetic and structural studies of O-trimethylsilyl-
diphenylprolinol-catalyzed Michael addition of aldehydes to
nitroolefins led to the detection of an aminonitrocyclobutane
intermediate, which was identified as a resting state for the
catalyst. Taking this discovery into account, we hypothesized
that enolizable enals could undergo a similar reaction based
on the dienamine activation mode[9] where the catalyst would
be able to undergo turnover, thus furnishing a final nitro-
cyclobutane product. In fact, literature precedent exists for
the related [2+2] cycloaddition of enamines with electron-
poor alkenes, thus showing that this process can occur
spontaneously without the need of photochemical activa-
tion.[10] In contrast, there is also literature precedent which
shows that the reaction of nitroalkenes with enolizable a,b-
unsaturated aldehydes under dienamine catalysis leads to the
Scheme 1. a) Previous work: addition to nitroolefins throuh enamine
catalysis. b) Working hypothesis: formal [2+2] cycloaddition through
dienamine catalysis. TMS=trimethylsilyl.
exclusive formation of Michael-type adducts through the
selective a-functionalization of the dienamine intermediate
and therefore no opportunity arises for cyclobutane forma-
tion.[11]
Herein, we wish to present our initial results on a novel
chiral secondary amine catalyzed enantioselective formal
[2+2] cycloaddition of enolizable a,b-unsaturated aldehydes
with a-hydroxymethyl-substituted nitroalkenes which leads
to the formation of cyclobutanes in a single step (Scheme 2).
This reaction is in sharp contrast with previously published
work which, as already mentioned, shows the preference for
dienamine intermediates generated from enals to undergo
[*] G. Talavera, Prof. E. Reyes, Prof. J. L. Vicario, Prof. L. Carrillo
Departamento de Quꢀmica Orgꢁnica II, Facultad de Ciencia
y Tecnologꢀa, Universidad del Paꢀs Vasco/Euskal Herriko Unibert-
sitatea UPV/EHU, P.O. Box 644, 48080 Bilbao (Spain)
E-mail: joseluis.vicario@ehu.es
Homepage: http://www.ehu.es/GSA
[**] This research was supported by the Spanish MICINN (CTQ2011-
22790), the Basque Government (Grupos IT328-10 and fellowship
to G.T.) and UPV/EHU (UFI11/22)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200269.
Scheme 2. One-step synthesis of cyclobutanes by [2+2] cycloaddition/
hemiacetalization under dienamine catalysis.
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a functionalization with nitroalkenes.[11] It should also be
pointed out that there is only one literature precedent dealing
with an enantioselective intermolecular [2+2] cycloaddition
between enals and electron-rich alkenes which proceeds
under iminium catalysis,[12] and the dienamine route pre-
sented herein is still an unexplored approach[13] which is also
a complementary methodology to reported example, as it
allows the [2+2] cyclocondensation of enals with an electron-
poor alkene. In addition, this new process leads to the
formation of cyclobutanes that are not obviously accessible
using other methods.
at a lower temperature led to 3a with an excellent ee value,
but in much lower yield (entry 6). With the aim of improving
this latter parameter, we next considered the possibility of
a dual activation approach for both the aldehyde and the
nitroalkene by using the combination of the amine catalyst 4a
and the achiral thiourea 5a, which was expected to engage in
selective hydrogen bonding with the nitroalkene.[14] When we
used this catalyst combination, the yield increased to 70%
without affecting the enantioselectivity (entry 7), and an even
better result was obtained when thiourea 5b was employed
(entry 13).
We started our study by surveying the best reaction
conditions for the transformation using the reaction of the
enal 1a with nitroalkene 2a as a model system (Table 1). We
Having established the best protocol for the reaction, we
next surveyed the scope of this transformation with respect to
the a,b-unsaturated aldehydes and nitroolefins. As summar-
ized in Table 2, the reaction behaved well in all cases tested
Table 1: Screening for the best experimental conditions using the
reaction of aldehyde 1a and nitroalkene 2a as a model system.[a]
Table 2: Scope of the reaction.[a]
Entry
3
R1
R2
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3 f
3g
3h
3i
Ph
Ph
Ph
Ph
Ph
86
88
77
73
72
91
91
90
67
69
52
38
91
92
92
89
95
94
94
94
92
94
94
85
4-MeC6H4
4-FC6H4
2-thienyl
Ph
4-MeC6H4
4-FC6H4
4-MeOC6H4
Ph
Entry
4
Co-catalyst
Solvent
T [8C]
Yield [%][b]
ee [%][c]
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
2-thienyl
Ph
1
2
3
4
5
6
7
8
4a
4b
4a
4a
4a
4a
4a
4a
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
5a
CHCl3
CHCl3
toluene
THF
4
4
4
4
4
À20
À20
À20
59
0
56
<5
<5
47
74
–
86
n.d.
n.d.
90
91
91
9
10
11
12
3j
3k
3l
4-MeC6H4
Ph
Et
EtOH
toluene
toluene
toluene
70
86
5b
[a] All reactions carried out on 0.35 mmol scale of 1a. [b] Yield of pure
product as a 1:1 mixture of a and b anomers (NMR analysis) after
column chromatography. [c] Determined by HPLC analysis of the
corresponding lactone.
[a] Reaction conditions: 1a (0.35 mmol), 2a (0.52 mmol), catalyst 4
(20%), and co-catalyst (20%) were stirred in the specified solvent and
temperature for 72 h. [b] Yield of pure product as a 1:1 mixture of a and
b anomers after column chromatography. [c] Determined by HPLC
analysis of the corresponding lactone. n.d.=not determined, THF=
tetrahydrofuran.
when g-aryl-substituted a,b-unsaturated aldehydes were
employed, regardless of the electronic nature of the g sub-
stituent. In this sense, both the electron-rich (1b) and
electron-poor (1c) aryl-substituted enals reacted efficiently
with a-hydroxymethylnitrostyrene (2a) to furnish the corre-
sponding bicyclic adducts 3b and 3c, respectively, in good
yields and excellent enantioselectivities (entries 2 and 3). The
g-heteroaryl-substituted enal 1d also performed well in the
reaction with 2a, thus delivering 3d in good yield and
enantioselectivity (entry 4). Regarding the nitrostyrene
reagent we evaluated the use of the 2a and other derivatives
incorporating electron-donating or electron-withdrawing sub-
stituents at the aryl moiety, and, in all cases the reaction also
proceeded with similar levels of chemical efficiency and
stereocontrol (entries 5–11). We also evaluated the use of a b-
alkyl-substituted a,b-unsaturated aldehyde such as 2-hexenal
(1 f), which led to the formation of the desired cyclobutane
adduct with a somewhat lower yield, but still with good levels
of stereocontrol (entry 12). This final experiment also points
toward the ability of the g-aryl substituent on the enal
initially tested the performance of catalyst 4a under standard
reaction conditions, which involve the use of benzoic acid as
Brønsted acid co-catalyst in CHCl3 at 48C (entry 1). Under
these reaction conditions, the adduct 3a was isolated in
moderate yield with a promising 74% ee. Importantly, NMR
analysis of the crude reaction mixture indicated that 3a had
been formed as a 1:1 mixture of a and b anomers. No other
diastereoisomers could be detected, which indicated that the
formal [2+2] cycloaddition process also had taken place with
complete diastereocontrol. Increasing the steric bulk at the
aryl moieties of the diarylprolinol catalyst (entry 2) did not
result in any significant improvement. We next evaluated the
influence of the solvent by adopting 4a as the most efficient
catalyst, and observed that running the reaction in toluene led
to a slight increase in the enantioselectivity (entry 3), whereas
other more polar solvents were incompatible with this
transformation (entries 4 and 5). We also found that working
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reagents 1a–e to stabilize the dienamine intermediate by
extending the conjugated system, which facilitates the reac-
tion. Finally, it should noted that, as it happened in the model
reaction, the formation of the cyclobutane scaffold took place
in all cases with complete diastereoselection, and only the
expected a and b anomers, resulting from the formation of the
hemiacetal moiety, were observed; no other diastereoisomer
was detected in the NMR spectra of the crude reaction
mixtures.
Considering that the cyclobutane adducts 3a–l had been
obtained as mixtures of anomers, we decided to carry out their
oxidation to the corresponding lactones for the purpose of
better characterization, thus obtaining bicyclic adducts 6a–l in
excellent yields and as single diastereoisomers (Scheme 3).
Scheme 4. Proposed reaction mechanism.
In summary, we have presented an efficient methodology
for the enantio- and diastereoselective synthesis of substi-
tuted cyclobutanes by direct reaction of enolizable a,b-
unsaturated aldehydes and a-hydroxymethylnitrostyrenes
using a chiral secondary amine and an achiral thiourea as
a catalytic couple. The success of the reaction relies on the
dual activation of both the enal and the nitroalkene reagents
by the two catalysts, the former being engaged in a cascade
Michael/Michael reaction through activation by the amine
catalyst and the latter being activated by the thiourea through
hydrogen bonding. This is the first example of a cascade
reaction involving the dienamine/iminium manifold and also
a good example of the great potential offered by the
combination of the different organocatalytic activation mech-
anisms, which can lead to the discovery of new transforma-
tions and novel reactivity patterns.
Scheme 3. Oxidation of compounds 3a–l and survey of transforma-
tions carried out on compound 6a. PCC=pyridium chlorochromate.
We could also grow a crystal of compound 6a suitable for X-
ray analysis,[15] and established unambiguously the absolute
configuration of the products 3 and 6. In addition, we also
decided to explore some possible transformations of the
obtained bicyclic adducts to illustrate their potential applica-
tion as chiral building blocks in organic synthesis (Scheme 3).
For example, using lactone 6a as a model substrate, we
quantitatively obtained the tetrasubstituted cyclobutane 7a
by base-promoted methanolysis. We have also carried out the
reduction of the nitro group under standard reaction con-
ditions to give the corresponding amine 8a in good yield.
We propose a catalytic cycle (Scheme 4) which starts with
the activation of the enal by the amine catalyst 4a through
dienamine formation, and then generation of the cyclobutane
ring is proposed to most likely occur by means of a stepwise
Michael/Michael process, in which the dienamine undergoes
a conjugate addition at its g-carbon atom with the nitroalkene
2 and a subsequent intramolecular reaction of the generated
nitronate intermediate with the remaining a,b-unsaturated
iminium ion moiety. Once this cascade takes place, an
enamine intermediate is formed which undergoes hydrolysis,
thus releasing the catalyst and delivering the final adduct 3
after an hemiacetalization process. The thiourea co-catalyst is
proposed to be involved in the activation of the nitroalkene in
the initial Michael reaction, although it can also participate in
the stabilization of the nitronate intermediate during the
subsequent intramolecular Michael reaction. Similarly, the
formation of the final adducts as stable hemiacetal derivatives
is also believed to play a crucial role,[16] thereby providing
a thermodynamic driving force for the reaction to proceed to
completion.
Received: January 11, 2012
Published online: March 16, 2012
Keywords: asymmetric synthesis · carbocycles · cycloadditions ·
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Michael addition · organocatalysis
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