Enantioselective conjugate addition of donor-acceptor hydrazones to α,β-unsaturated aldehydes through formal diaza-ene reaction: Access to 1,4-dicarbonyl compounds

Article abstract of DOI:10.1021/ja3041042

Donor-acceptor monosubstituted hydrazones participate as suitable reagents able to undergo an enantioselective formal diaza-ene reaction with α,β-unsaturated aldehydes under chiral secondary amine catalysis. This constitutes a new approach for the enantioselective conjugate addition of hydrazones to enals under metal-free conditions and leads to the formation of γ-hydrazono carboxylic acids after oxidation/[1,3]-H shift. The methodology is also useful for the synthesis of enantioenriched β-substituted α-keto-1,5-diesters by using the hydrazone moiety as a masked carbonyl group.

Full text of DOI:10.1021/ja3041042

Communication
pubs.acs.org/JACS
Enantioselective Conjugate Addition of Donor−Acceptor
Hydrazones to α,β-Unsaturated Aldehydes through Formal Diaza−
Ene Reaction: Access to 1,4-Dicarbonyl Compounds
Maitane Fernandez, Uxue Uria, Jose L. Vicario,* Efraím Reyes, and Luisa Carrillo
́
́
Departamento de Química Organica II, Facultad de Ciencia y Tecnología, Universidad del País Vasco/Euskal Herriko Unibertsitatea
(UPV/EHU), P.O. Box 644, E-48080 Bilbao, Spain
S
* Supporting Information
therefore opening the way to achieve enantiocontrol by using
a chiral secondary amine as the catalyst. In particular, we
thought of donor−acceptor hydrazones such as those shown in
Scheme 1 as potential acyl anion equivalents. The principles
ABSTRACT: Donor−acceptor monosubstituted hydra-
zones participate as suitable reagents able to undergo an
enantioselective formal diaza−ene reaction with α,β-
unsaturated aldehydes under chiral secondary amine
catalysis. This constitutes a new approach for the
enantioselective conjugate addition of hydrazones to
enals under metal-free conditions and leads to the
formation of γ-hydrazono carboxylic acids after oxida-
tion/[1,3]-H shift. The methodology is also useful for the
synthesis of enantioenriched β-substituted α-keto-1,5-
diesters by using the hydrazone moiety as a masked
carbonyl group.
Scheme 1. Donor−acceptor Monosubstituted Hydrazones as
Acyl Anion Equivalents in Enantioselective Conjugate
Addition under Iminium Activation
he discovery of new umpolung transformations in which
inversion of the natural reactivity pattern of a given
T
chemical reagent takes place during the overall process has
been an important field of research since Corey and Seebach
introduced the concept.1 In particular, conjugate addition of
acyl anion equivalents, the archetypical example of umpolung
reactivity, enables the preparation of 1,4-dicarbonyl com-
pounds, a molecular architecture that is difficult to access by
conventional methods. In this context, several approaches have
been devised using conveniently designed nucleophilic reagents
that, after the conjugate addition process takes place, are able to
deliver the final 1,4-dicarbonyl compound by unmasking the γ-
carbonyl group through a simple and high-yielding trans-
formation.2 In addition, if an enantiomerically enriched product
is desired, several catalytic enantioselective approaches have
been reported in the past few years, focused on the use of either
metal catalysis3 or organocatalysis.4 Alternatively, the enantio-
selective Stetter reaction using N-heterocyclic carbenes as
catalysts can be extremely efficient for the direct conjugate
addition of acyl anions,5 directly affording the final 1,4-
dicarbonyl adduct without the need for additional synthetic
steps to reveal the latent carbonyl functionality. However, this
reaction normally demands a highly electrophilic Michael
acceptor, such as a nitroalkene or an alkylidene malonate, in
order to proceed with high yield for the intermolecular
version.6
behind the reaction design rely on the ability of an N-
monosubstituted hydrazone to undergo a diaza−ene reaction
with a chiral α,β-unsaturated iminium ion intermediate that
operates as an activated Michael acceptor. This initial step
would deliver a γ-azoaldehyde adduct that, after a [1,3]-hydride
shift, would render a γ-hydrazono aldehyde product where the
hydrazone moiety could be considered as a latent carbonyl
functionality. Under this design, we anticipated that a donor−
acceptor hydrazone reagent would presumably fulfill the
requisites for becoming an active Michael donor in the
projected reaction under the typical neutral or slightly basic
conditions associated with iminium catalysis. In particular, it
was envisaged that the concurrent incorporation of an electron-
donating group (EDG) as the nitrogen substituent and an
electron-withdrawing group (EWG) as the substituent at the
azomethine carbon would enhance the reactivity of the
azomethine carbon atom toward its interaction with the
electrophilic β-carbon of the iminium ion, therefore resulting
in a highly productive situation.
With these precedents in mind and in connection with our
ongoing efforts to develop new organocatalytic reactions, we
decided to survey the possibility of carrying out the conjugate
addition of a suitable acyl anion equivalent to α,β-unsaturated
aldehydes by applying the iminium activation concept,7
Received: April 28, 2012
Published: July 9, 2012
© 2012 American Chemical Society
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It should be mentioned that there is one precedent in the
literature describing the use of disubstituted N,N-dialkylhy-
drazones derived from formaldehyde as Michael donors in the
conjugate addition to β,γ-unsaturated α-keto esters under chiral
Brønsted acid catalysis, furnishing moderate levels of
enantioselectivity.8 Monosubstituted hydrazones have also
been used by Scheidt under cooperative Mg(II)/NHC
catalysis,9 but in that case, they act as electrophiles, which is
the natural reactivity pattern expected for these azomethine
compounds. Thus, even though formaldehyde pyrrolidinyl
hydrazones have been employed as nucleophiles in several
transformations,10 there are no precedents showing their
behavior toward α,β-unsaturated aldehydes or ketones under
iminium activation. This is probably due to their predictable
tendency to undergo intramolecular condensation after
conjugate addition, rendering the corresponding aromatic N-
aminopyrrole derivatives.11 In addition, and to the best of our
knowledge, the application of this type of donor−acceptor
hydrazone in catalytic enantioselective diaza−ene-type reac-
tions is still unprecedented in the chemical literature,12 and
even the possibility of carrying out this reaction in an
asymmetric fashion under metal-free conditions is still
undocumented.
of diastereoisomers (entry 1) in a rather fast reaction (3 h
reaction time). However, even though the enantioselectivity
offered by this catalyst for the main diastereoisomer was
remarkably high (98% ee), the minor diastereoisomer was
isolated in only 10% ee. In this sense, and taking into
consideration that both diastereoisomers of 4a would converge
into a single product after the projected [1,3]-hydride shift
process, we next focused on searching for the best conditions to
obtain a highly enantioenriched material regardless the
diastereomeric proportion. We therefore tested the use of
catalyst 3b containing larger aryl groups, which delivered 4a in
a similar yield but with a significant improvement in the
enantioselectivity of the minor diastereoisomer (entry 2). We
next evaluated a family of related diarylprolinol catalysts
incorporating substituents of different sizes at the oxygen
atom (entries 3−5), observing that the use of O-methyl-
containing catalyst 3c provided poorer results in terms of both
yield and stereoselectivity (entry 3), whereas results similar to
those for the 3b-catalyzed reaction were obtained when the
steric bulk was slightly increased to triethylsilyl in 3d (entry 4
vs 2). Interestingly, the introduction of an even larger O-
trialkylsilyl group (catalyst 3e; entry 5) increased the
enantioselectivity for the minor diastereoisomer up to a
satisfactory 86% ee while maintaining a 98% ee for the major
diastereoisomer.
On the basis of these postulates, we started our work by
surveying the viability of the projected transformation using the
reaction between enal 1a and hydrazone 2a as a representative
model system (Table 1). We first tested the performance of O-
Once the optimal catalyst had been identified, we directed
our efforts to improving the yield of the reaction, which was
achieved by working at a higher temperature, without this
affecting the enantioselectivity significantly (entry 6). Finally,
we also demonstrated that the reaction performed well with a
lower catalyst loading (10 mol %; entry 7), which resulted in
just a slight decrease in the yield while keeping identical levels
of stereoselection. These last conditions were therefore chosen
as the optimal ones for our reaction.14
Table 1. Screening for the Best Experimental Conditions
Using the Reaction of Enal 1a with Hydrazone 2a as a Model
a
System
Having established a robust experimental protocol for the
conjugate addition reaction, and in line with the overall reaction
design shown in Scheme 1, we next proceeded to study the
most appropriate conditions for inducing a [1,3]-hydride shift
process on the conjugate addition adduct 4a (Scheme 2).
b
c
d
entry
catalyst
T (°C)
yield (%)
dr
ee (%)
Scheme 2. Transformations Carried out on Aldehyde 4a
1
2
3
4
5
6
3a
3b
3c
3d
3e
3e
3e
4
51
63
20
66
64
83
79
70:30
70:30
70:30
70:30
70:30
70:30
70:30
98/10
95/78
74/12
96/75
98/86
96/84
96/84
4
4
4
4
r.t.
r.t.
e
7
a
Reaction conditions: 2.0 mmol of 1a, 1.0 mmol of 2a, and catalyst 3
(20 mol %) were stirred in toluene at the specified temperature for 2−
b
3 h. Yields of pure product as mixtures of diastereoisomers after flash
c
column chromatography. Diastereomeric ratios determined by NMR
d
analysis of the crude reaction mixtures. ee values for the major and
minor diastereoisomers respectively, as determined by chiral-sta-
e
tionary-phase HPLC analysis (see the Supporting Information). 10
mol % catalyst 3e was used.
trimethylsilyl (O-TMS)-substituted diphenylprolinol derivative
3a as a chiral secondary amine catalyst in toluene at 4 °C, which
are standard reaction conditions employed in other examples of
conjugate addition reactions under iminium activation.7,13 This
demonstrated the ability of the hydrazone reagent 2a to behave
as we anticipated in Scheme 1, leading to the formation of the
desired γ-azoaldehyde 4a in moderate yield as a 70:30 mixture
Treatment of the aldehyde with different Brønsted acids under
a variety of conditions led to the projected [1,3]-hydride shift
process smoothly, forming the desired γ-hydrazono aldehyde.
However, the isolated compound had a pronounced tendency
to undergo intramolecular hemiaminal formation and sub-
sequent dehydration, forming cyclic dihydropyridazine deriva-
tive 5a, albeit with retention of enantiopurity.
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Communication
a
To avoid this cyclization process, we decided to carry out the
oxidation of the aldehyde moiety. This proceeded simulta-
neously with the [1,3]-hydride shift process, affording the
desired γ-hydrazono carboxylic acid 6a in excellent yield
without erosion of enantiopurity (see Scheme 2). Alternatively,
dehydration after the acid-mediated [1,3]-hydride shift could be
avoided by using isopropyl alcohol as the solvent, leading to the
formation of 7a in good yield as a mixture of α- and β-anomers,
both of which were isolated with high enantiopurity. We also
surveyed the possibility of elaborating these adducts by
exploiting their aldehyde reactivity. In this sense, Wittig
reaction under standard conditions followed by addition of
trifluoroacetic acid (TFA) led to the formation of α,β-
unsaturated ε-hydrazono ester 8a in excellent yield and
retaining the ee of the starting material.
Scheme 3. Scope of the Reaction
We next proceeded to extend the reaction, exploring other
α,β-unsaturated aldehydes with different substitution patterns
in order to determine the scope of the reaction and its
performance for the preparation of differently substituted γ-
hydrazono carboxylic acids. The results summarized in Scheme
3 show that the reaction proceeded satisfactorily in almost all
cases, furnishing adducts 4a−o in good yields, which were
further subjected to oxidation leading to γ-hydrazono carboxylic
acids 6a−o in excellent overall yields and enantioselectivities.
The reaction tolerates well the use of different β-substituted
enals containing alkyl chains of different length and size, and we
also observed that the yield of the process was only moderately
affected when the length of the chain was considerably
increased (compounds 6a−e). Aldehydes containing nonlinear
alkyl chains also performed well, providing excellent
enantioselectivities (compounds 6f and 6g), although with an
appreciable drop in isolated yield when the size of the
substituent was notably increased (i.e., compound 6g).
Furthermore, functionalized α,β-unsaturated aldehydes 1h−l
also performed well, furnishing the final adducts in good yields
with high enantiopurities. A particular situation appeared with
the case of δ-amino aldehyde 1l, which led to the formation of
the final adduct 4l as the corresponding hemiaminal, resulting
from intramolecular reaction between the aldehyde and the
pendant protected amine. This adduct showed a different
behavior during oxidation (see the Supporting Information for
details), leading to the formation of a bicyclic aminal structure
after the [1,3]-H shift process, from which suitable crystals for
X-ray analysis were obtained, allowing the determination of its
absolute stereostructure. This configuration was extended to all
the adducts 4a−p and is also in good agreement with the
expected stereochemical outcome described for other conjugate
addition reactions catalyzed by this type of O-silylated α,α-
diarylprolinol derivative.15 The reactivity of β-aryl-substituted
α,β-unsaturated aldehydes proved to be highly dependent on
the electronic nature of the aryl group. Aromatic enal 1n
incorporating an electron-withdrawing substituent performed
very well in the reaction, leading to 6n in good yield and
enantioselectivity, while cinnamaldehyde (1m) reacted very
slowly. On the other hand, isopropyl glyoxylate-based
hydrazone 2b could also be utilized, delivering the expected
adduct 6o in high yield and enantioselectivity. An important
validation of our strategy was to see the effect of changing the
electronic properties of the N-aryl group. In this sense, we
found out that N-phenyl-substituted hydrazone 2c furnished
the conjugate addition product 6p in 24% yield, although still
with excellent stereocontrol, while the related p-nitrophenyl-
substituted hydrazone 2d was unable to react with 1a under the
a
All of the reactions were carried out on a 1.00 mmol scale. Shown are
yields of pure products after flash column chromatography, dr values
determined by NMR analysis of the crude reaction mixtures, and ee
values determined by HPLC analysis (see the Supporting
b
c
Information). Reaction performed at 4 °C. 20 mol % catalyst
loading. An 80:20 mixture of diastereoisomers, each one as a 1:1
mixture of anomers, was obtained. Calculated for the bicyclic aminal
obtained after the [1,3]-H shift process (see the Supporting
d
e
f
Information). n.d. = not determined.
optimized reaction conditions. This is an indication of the
appropriateness of the aforementioned strategic design for the
hydrazone reagent.
Finally, having succeeded in the development of a general
method for the conjugate addition of hydrazones to enals, we
proceeded to find the appropriate conditions for transforming
the hydrazone into a carbonyl group (Scheme 4). After several
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Chem. Soc. Rev. 2000, 29, 359. (d) Marion, N.; Diez-Gonzalez, S.;
Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988.
(3) Linghu, X.; Potnik, J. R.; Johnson, J. S. J. Am. Chem. Soc. 2004,
126, 3070.
Scheme 4. Oxidative Cleavage of the Hydrazone Moiety
(4) For a review, see: (a) Bugaut, X.; Glorius, F. Chem. Soc. Rev.
2012, 41, 3511.
Aleman, J.; Milelli, A.; Kobbelgaard, S.; Jørgensen, K. A. J. Am. Chem.
Soc. 2008, 130, 12031. (c) Alba, A.-N.; Companyo, X.; Valero, G.;
For examples, see: (b) Cabrera, S.; Reyes, E.;
́
́
Moyano, A.; Rios, R. Chem.Eur. J. 2010, 16, 5354. (d) Jiang, H.;
Paixao, M. W.; Monge, D.; Jørgensen, K. A. J. Am. Chem. Soc. 2010,
132, 2775. (e) Alonso, B.; Reyes, E.; Carrillo, L.; Vicario, J. L.; Badía,
D. Chem.Eur. J. 2011, 17, 6048. (f) Uraguchi, D.; Ueki, Y.; Ooi, T.
Science 2009, 326, 20. (g) Uraguchi, D.; Ueki, Y.; Ooi, T. Chem. Sci.
2012, 3, 842. (h) Enders, D.; Bonten, M. H.; Raabe, G. Synlett 2007,
885.
(5) For leading reviews, see: (a) Vora, H. U.; Rovis, T. Aldrichimica
Acta 2011, 44, 3. (b) Enders, D.; Niemeyer, O.; Henseler, A. Chem.
Rev. 2007, 107, 5606.
(6) (a) Liu, Q.; Perreault, S.; Rovis, T. J. Am. Chem. Soc. 2008, 130,
14066. (b) Enders, D.; Han, J. Synthesis 2008, 3864. (c) Enders, D.;
Han, J.; Henseler, A. Chem. Commun. 2008, 3989. (d) DiRocco, D. A.;
Oberg, K. M.; Dalton, D. M.; Rovis, T. J. Am. Chem. Soc. 2009, 131,
10872. (e) DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc. 2011, 133,
10402. (f) Um, J. M.; DiRocco, D. A.; Noey, E. L.; Rovis, T.; Houk, K.
N. J. Am. Chem. Soc. 2011, 133, 11249. Also see: (g) Fang, X.; Chen,
X.; Lv, H.; Chi, Y. R. Angew. Chem., Int. Ed. 2011, 50, 11782.
(7) For reviews of iminium activation, see: (a) Vicario, J. L.; Reyes,
E.; Badía, D.; Carrillo, L. In Catalytic Asymmetric Conjugate Reactions;
unsuccessful attempts under different conditions for hydrolysis
or oxidative cleavage through ozonolysis, we found that the
hydrazone moiety could be cleanly and easily converted into
the corresponding ketone by phenyliodonium bis-
(trifluoroacetate) (PIFA)-mediated oxidative hydrolysis.16
Under the employed conditions, azolactone intermediates 9
were formed first by oxidation of the hydrazone followed by
intramolecular reaction with the carboxylic acid moiety. Next,
an ethanolysis/acid hydrolysis sequence provided the desired α-
keto-1,5-diesters 10. These conditions were employed for a set
of representative compounds 6, and we observed that in all
cases the reaction proceeded cleanly in excellent overall yields
without erosion of the enantiopurity of the starting materials.
In summary, we have shown that donor−acceptor
hydrazones such as 2 can participate in enantioselective
diaza−ene reactions with α,β-unsaturated aldehydes via
iminium activation in the presence of a chiral secondary
amine as the catalyst. The reaction leads to the formation of γ-
azoaldehydes, which are converted into enantiopure γ-
hydrazono carboxylic acids through an oxidation/[1,3]-hydride
shift sequence,. Moreover, we have also developed a procedure
for the conversion of these adducts into 1,4-dicarbonyl
compounds, resulting in a very efficient enantioselective
methodology for the indirect β-glyoxylation of enals using
monosubstituted hydrazones as masked acyl anion equiv-
alents.17
Cor
́
dova, A., Ed.; Wiley-VCH: Weinheim, Germany, 2010; pp 219−
294. (b) Erkkila, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107,
̈
5416. (c) Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39,
79. (d) MacMillan, D. W. C. Nature 2008, 455, 304. For pioneering
examples, see: (e) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2000, 122, 4243. (f) Yamaguchi, M.; Shiraishi, T.;
Hirama, M. Angew. Chem., Int. Ed. Engl. 1993, 32, 1176. (g) Kawara,
A.; Taguchi, T. Tetrahedron Lett. 1994, 35, 8805.
(8) Herrera, R. P.; Monge, D.; Martín-Zamora, E.; Fernandez, R.;
Lassaletta, J. M. Org. Lett. 2007, 9, 3303.
(9) Raup, D. E. R.; Cardinal-David, B.; Holte, D.; Scheidt, K. A. Nat.
Chem. 2010, 2, 766.
(10) For pioneering reports, see: (a) Lassaletta, J. M.; Fernandez, R.
Tetrahedron Lett. 1992, 33, 3691. (b) Lassaletta, J. M.; Fernandez, R.;
Martín-Zamora, E.; Diez, E. J. Am. Chem. Soc. 1996, 118, 7002. For
other examples, see: (c) Hashimoto, T.; Hirose, M.; Maruoka, K. J.
Am. Chem. Soc. 2008, 130, 7556. (d) Dixon, D. J.; Tillman, A. L. Synlett
2005, 2635. (e) Rueping, M.; Sugiono, E.; Theissmann, T.; Kuenkel,
A.; Kockritz, A.; Pews-Davtyan, A.; Nemati, N.; Beller, M. Org. Lett.
2007, 9, 1065. For a review, see ref 2a.
(11) (a) Lerche, H.; Severin, T. Synthesis 1978, 687. (b) Severin, T.;
Adam, R.; Lerche, H. Chem. Ber. 1975, 108, 1756.
(12) There is one precedent regarding the use of metalated N-tert-
butylhydrazones as Michael donors with crotonates. See: Baldwin, J.
E.; Adlington, R. M.; Bottaro, J. C.; Kolhe, J. N.; Perry, M. W. D.; Jain,
A. U. Tetrahedron 1986, 42, 4223.
ASSOCIATED CONTENT
■
S
* Supporting Information
Characterization of all new compounds, copies of H and 13C
1
NMR spectra and HPLC traces, and crystal structure data
(CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
joseluis.vicario@ehu.es.
■
Notes
The authors declare no competing financial interest.
(13) Tests of a set of different solvents showed toluene to be the
most efficient one in terms of both conversion and stereoselectivity.
(14) Incorporation of either Brønsted acids (such as PhCO2H) or
bases (DABCO, DBU) was also tested while carrying out the reaction
screening. However, these did not lead to any improvement.
(15) Nielsen, M.; Worgull, D.; Zweifel, T.; Gschwend, B.; Bertelsen,
S.; Jørgensen, K. A. Chem. Commun. 2011, 47, 632.
ACKNOWLEDGMENTS
■
The authors thank the Spanish MICINN (CTQ2011-22790),
the Basque Government (IT328-10 and fellowships to M.F.
and U.U.), and UPV/EHU (UFI QOSYC 11/22) for financial
support. Membership in the COST Action CM0905 is also
acknowledged.
(16) Barton, D. H. R.; Jaszberenyi, J. C.; Liu, W.; Shinada, T.
Tetrahedron 1996, 52, 14673.
REFERENCES
■
(17) For an example of a catalytic enantioselective β-glyoxylation of
alkylidene α-ketoamides under NHC catalysis, see: Liu, Q.; Rovis, T.
Org. Lett. 2009, 11, 2856. Also see refs 4h and 6a.
(1) (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239.
(b) Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231. (c) Corey, E.
J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1965, 4, 1075.
(2) For reviews, see: (a) Brehme, R.; Enders, D.; Fernandez, R.;
Lassaletta, J. M. Eur. J. Org. Chem. 2007, 5629. (b) Johnson, J. S.
Angew. Chem., Int. Ed. 2004, 43, 1326. (c) Enders, D.; Shilvock, J. P.
11875
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