Glyoxal bis-hydrazones: A new family of nitrogen ligands for asymmetric catalysis

Article abstract of DOI:10.1039/b314249c

The introduction of C₂-symmetric dialkylamino substructures in chiral non-racemic glyoxal bis-hydrazones such as 9 appears as the key design element for this novel ligand class, as shown in the highly enantioselective copper(II)-catalyzed Diels

Full text of DOI:10.1039/b314249c

Glyoxal bis-hydrazones: a new family of nitrogen ligands for asymmetric
catalysis†
José M. Lassaletta,*a Manuel Alcarazoa and Rosario Fernándezb
a Instituto de Investigaciones Químicas, c/ Americo Vespuccio s/n, 41092 Seville, Spain.
E-mail: jmlassa@cica.es
b Departamento de Química Orgánica, Universidad de Sevilla, Apdo de Correos No. 553, 41071 Seville,
Spain. E-mail: ffernan@cica.es
Received (in Cambridge, UK) 10th November 2003, Accepted 3rd December 2003
First published as an Advance Article on the web 5th January 2004
The introduction of C2-symmetric dialkylamino substructures
in chiral non-racemic glyoxal bis-hydrazones such as 9 appears
as the key design element for this novel ligand class, as shown in
the highly enantioselective copper(II)-catalyzed Diels–Alder
reaction.
latest advances in the use of nitrogen-based chiral ligands have
been recently reviewed.1
During the last few years we have accumulated some knowledge
about the synthesis, reactivity and structural aspects of the
chemistry of N,N-dialkylhydrazones.2 These compounds, viewed
as N-dialkylamino imines, exhibit a higher thermal stability than N-
alkyl(aryl) derivatives as a result of the n ? p conjugation. The
behavior of the CNN bond is strongly dependent on the structure of
the amine moiety,2 which in turn controls the efficiency of the
conjugation and may incorporate structural elements able to
modulate the steric crowding around the coordination site. In
addition, a wide variety of chiral hydrazines are available from
inexpensive starting materials such as proline,3 carbohydrates,4
diketones,2e and others,5 while many others can be easily prepared
from chiral secondary amines by a nitrosation–reduction protocol.3
In summary, the electronic characteristics and structural variability
of hydrazones make these compounds an interesting class of
potentially useful ligands.
The design and synthesis of new families of chiral ligands
constitutes the starting task for the many particular pieces of
research that have contributed to the spectacular growth of
asymmetric catalysis during the last 30 years. Currently, there is a
growing interest in nitrogen-based ligands, which offer a much
higher structural variability and are easier to handle and recycle
than the widespread phosphorus-based ligands. In addition, most
nitrogen ligands are readily available, either from commercial
precursors or from the chiral pool (amines, amino acids, etc.). The
Despite these peculiarities, a literature survey revealed very few
examples of the use of chiral monohydrazones as ligands in
asymmetric catalysis,6 while, to the best of our knowledge, the use
of chiral bis-hydrazones as ligands in this context has no known
precedents. In this communication, we wish to report on the first
application of C2-symmetric bis-N,N-dialkylhydrazones as a new
class of efficient ligands in the enantioselective metal-catalyzed
Diels–Alder reaction.7
The well-known reaction of N-acryloyloxazolidinone 1 and
cyclopentadiene 2 was used as the model system. In a preliminary
survey, several proline-derived monohydrazones 3, as well as bis-
hydrazones 4 and 5, were used as multidentate ligands in
combination with several Lewis acids. Though the cycloaddition
reaction proceeded cleanly in all cases to afford the expected endo
cycloadduct 6, the observed enantioselectivities (0–18%) were
disappointing (Scheme 1).
The lack of selectivity was interpreted as the loss of a suitable
chiral environment around the metallic centre, an undesired process
that may take place after formation of the catalyst–substrate
complex by rotation around N–N bonds, as shown in Scheme 2 for
the bis-hydrazone type of ligand.
Scheme 1 Preliminary screening of new ligands.
In order to check the validity of this working hypothesis and to
eventually circumvent the undesired effect of the rotational
isomerism, we decided to prepare a second set of C2-symmetric bis-
hydrazones which, carrying in addition C2-symmetric substructures
in the two dialkylamino moieties, would a priori be able to provide
an adequate chiral environment while making it unnecessary to take
care regarding possible rotations around N–N bonds (Scheme 3).
Scheme 2 Rotational isomerism in catalyst–substrate complexes.
† Electronic supplementary information (ESI) available: experimental
procedures and spectral and analytical data for new compounds. See http:
//www.rsc.org/suppdata/cc/b3/b314249c/
Scheme 3 Ligands with inconsequential rotation around N–N bonds.
298
C h e m . C o m m u n . , 2 0 0 4 , 2 9 8 – 2 9 9
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

View Article Online
Therefore, novel hydrazines 7 and 8 were synthesized from the
corresponding diketones by oxazaborolidine-catalysed reduction,8
mesylation, and reaction with hydrazine. Their condensation with
glyoxal readily afforded the desired ligands 9 and 10 (Scheme 4),
and their Cu(OTf)2 1 : 1 complexes were used as the catalysts in the
chosen model reaction.
In both cases, cycloadduct 6 was formed with a significant
increase of enantioselectivities, thereby validating the suitability of
the strategy. As the highest induction was observed for ligand 9,
this result was further optimized to afford cycloadduct 6 in 90%
yield as a 98 : 2 endo : exo mixture and with 95% ee [(R,R)-endo)]
(Table 1, entry 1). These conditions were then applied to the
cycloaddition of 1 to other conjugated dienes such as cyclohex-
adiene 11, isoprene 12, 2,3-dimethyl-1,3-butadiene 13, and furan
14, affording high yields of the corresponding cycloadducts 15–18,
with good enantioselectivities in all cases (entries 2–5). Note-
worthy is that adducts 15 and 16 were obtained with complete
diastereo- and regioselectivity, respectively (entries 4 and 5). The
synthesis of ent-9 and its use in the model cycloaddition afforded
ent-6, thereby highlighting the availability of the desired enantio-
mer for each cycloadduct.
Scheme 4 Synthesis of ligands 9 and 10.
In conclusion, the inclusion of C2-symmetric dialkylamino
substructures in glyoxal bis-hydrazones is the key design element
resulting in the successful application of these compounds as novel
N-ligands for the enantioselective copper(II)-catalyzed Diels–Alder
cycloaddition. Both enantiomers of the required ligand are easily
available on a multigram scale in only three steps from 1,4-diph-
enylbutanedione. It is hoped that this new class of synthetic
nitrogen ligands will find applications in other catalytic organic
reactions.
At this point, it is worth mentioning that, even though the results
collected for the cyclic dienes 2 and 11 are similar to those obtained
with many other catalysts,9 the yields and selectivities achieved in
the cycloadditions to the more flexible dienes 12 and 13 appear as
a more interesting result, matching or exceeding those reported to
date.9b,c,10
We thank the DGICYT (grants PB 97/0747 and PPQ 2000-1341)
and the European Community (HPRN-CT-2001-00172), and the
Junta de Andalucía for financial support. M.A. thanks the
Ministerio de Educación y Ciencia for a predoctoral fellowship.
Table 1 Enantioselective Diels–Alder cycloadditions
Yield
Entry Diene L
T/°C (%)a Product
Confb dec eed
Notes and references
1 (a) F. Fache, E. Schulz, M. L. Tommasino and M. Lemaire, Chem. Rev.,
2000, 100, 2159; (b) A. Togni and L. M. Venanzi, Angew. Chem., Int.
Ed. Engl., 1994, 33, 497.
1
2
9
9
260 90
R,R
R,R
96 95
2 Nucleophilic reactivity: (a) R. Fernández and J. M. Lassaletta, Synlett,
2000, 1228; (b) R. Fernández, E. Martín-Zamora, C. Pareja and J. M.
Lassaletta, J. Org. Chem., 2001, 66, 5201; (c) J. Vázquez, A. Prieto, R.
Fernández, D. Enders and J. M. Lassaletta, Chem. Commun., 2002, 498;
. Imine-like reactivity: (d) R. Fernández, A. Ferrete, J. M. Lassaletta, J.
M. Llera and A. Monge, Angew. Chem., Int. Ed., 2000, 39, 2893; (e) R.
Fernández, A. Ferrete, J. M. Lassaletta, J. M. Llera and E. Martín-
Zamora, Angew. Chem., Int. Ed., 2002, 41, 832.
225 83
> 99 84
3 D. Enders, H. Kipphardt, P. Gerdes, L. J. Breña-Valle and V. Buhshan,
Bull. Soc. Chim. Belg., 1988, 97, 691.
4 (a) A. Defoin, A. Brouillard-Poichet and J. Streith, Helv. Chim. Acta,
1991, 74, 103; (b) D. Enders and J. Wiedeman, Synthesis, 1996,
1443.
5 (a) D. Enders, R. Maaßen and J. Runsink, Tetrahedron: Asymmetry,
1998, 2155 and references cited therein (b) Y. Yamamoto, Y. Hoshino,
Y. Fujimoto and J. Ohmoto, Synthesis, 1993, 298.
3
4
9
9
235 79d
235 89
R
R
—
—
92
92
6 (a) T. Mino, M. Shiotsuki, N. Yamamoto, T. Suenaga, M. Sakamoto, T.
Fujita and M. Yamashita, J. Org. Chem., 2001, 66, 1795; (b) T. Mino,
T. Ogawa and M. Yamashita, J. Organomet. Chem., 2003, 665, 122; (c)
D. Enders, R. Peters, R. Lochtman and J. Runsink, Eur. J. Org. Chem.,
2000, 2839.
7 (a) H. B. Kagan and O. Riant, Chem. Rev., 1992, 92, 1007; (b) E. J.
Corey, Angew. Chem., Int. Ed., 2002, 41, 1650.
8 D. J. Aldous, W. M. Dutton and P. G. Steel, Tetrahedron: Asymmetry,
2000, 11, 2455.
9 Selected recent examples: (a) D. A. Evans, S. J. Miller, T. Lectka and P.
von Matt, J. Am. Chem. Soc., 1999, 121, 7559; (b) D. A. Evans, D. M.
Barnes, J. S. Johnson, T. Lectka, P. von Matt, S. J. Miller, J. A. Murry,
R. D. Norcross, E. A. Shaughnessy and K. R. Campos, J. Am. Chem.
Soc., 1999, 121, 7559; (c) S. Kanemasa, Y. Oderaotoshi, S.-i.
Sakaguchi, H. Yamamoto, J. Tanaka, E. Wada and D. P. Curran, J. Am.
Chem. Soc., 1998, 120, 3074; (d) T. D. Owens, F. J. Hollander, A. G.
Oliver and J. A. Ellman, J. Am. Chem. Soc., 2001, 123, 1539.
10 S. Kobayashi, M. Araki and I. Hachiya, J. Org. Chem., 1994, 59,
3758.
5
6
9
250 88
R,R
74 96
2
ent-9 260 91
S,S
96 95
a Isolated yield. b Of major isomer. c Determined by HPLC in chiral
stationary phases. d A single regioisomer was detected by NMR and
HPLC.
C h e m . C o m m u n . , 2 0 0 4 , 2 9 8 – 2 9 9
299