Asymmetric catalysis of hetero-ene reactions with tridentate Schiff base chromium(III) complexes

Article abstract of DOI:10.1021/ja025588j

Tridentate Schiff base chromium(III) complex 1 catalyzes the asymmetric hetero-ene reaction between aryl aldehydes and either 2-methoxypropene or 2-trimethylsilyloxypropene to provide a series of β-hydroxyenol ether products in high yields and enantiosele

Full text of DOI:10.1021/ja025588j

Published on Web 02/27/2002
Asymmetric Catalysis of Hetero-Ene Reactions with Tridentate Schiff Base
Chromium(III) Complexes
Rebecca T. Ruck and Eric N. Jacobsen*
HarVard UniVersity, Department of Chemistry and Chemical Biology, Cambridge, Massachusetts 02138
Received January 14, 2002
Scheme 1
Reactions between weakly nucleophilic and electrophilic partners
constitute interesting targets for asymmetric catalysis, particularly
in the context of synthetically valuable carbon-carbon bond-
forming processes. In this context, we discovered recently that chiral
tridentate Schiff base chromium(III) complexes catalyze highly
enantioselective and diastereoselective hetero-Diels-Alder (HDA)
reactions between simple aldehydes and only mildly nucleophilic
dienes.1 Mechanistic studies performed on this reaction indicate
that the role of the catalyst is simply that of Lewis acid activation
of aldehydes through single-point binding.2 This observation raises
Table 1. Ene Reaction of 2-methoxypropene with Aldehydes 2a-r
the possibility of a spectrum of other enantioselective reactions of
weak nucleophiles with aldehydes catalyzed by chiral CrIII com-
plexes. In this contribution, we describe the first evidence of the
generality of these catalysts, with the observation of highly selective
ene reactions between alkoxy- and silyloxyalkenes and aromatic
aldehydes.3,4 The â-hydroxyenol ether products formed in these
reactions are valuable chiral building blocks, useful as nucleophilic
partners in subsequent reactions or as direct precursors to â-hy-
droxyketone and â-hydroxyester derivatives (Scheme 1).
product
X
methoda
ee (%)
yield (%)e
time (h)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
H
B
A
A
B
B
B
B
A
A
B
B
A
A
A
A
A
A
A
88b
96b
86b
87b
94b
90b
89b
96b
84b
85c
95c
86d
84b
96b
90d
70d
92b
86b
82
97
94
78
41
50
26
98
97
78
75
80
92
89
85
88
96
82
40
20
36
40
40
40
40
20
36
40
40
36
40
20
36
36
20
20
2-Br
3-Br
4-Br
2-CH3
3-CH3
4-CH3
2-Cl
3-Cl
4-Cl
2-OCH3
3-CN
4-CN
2-NO2
3-NO2
4-NO2
2,4-Cl
2,6-Cl
Systematic optimization of the tridentate ligand framework and
counterion of the (Schiff base)Cr(III) complex led to the identifica-
tion of 1 as a highly enantioselective catalyst for the model ene
reaction between 2-methoxypropene and 2-bromobenzaldehyde.5
Catalyst 1 is prepared easily from commercially available compo-
nents, by condensation of 3,5-di-tert-butylsalicylaldehyde with cis-
1,2-aminoindanol, followed by reaction with CrCl2.6 The ene
reaction was found to proceed with highest enantioselectivities and
fastest rates in the presence of acetone or ethyl acetate as solvent
and added barium oxide as desiccant.7 Aging the catalyst for 5 h
at room temperature with desiccant prior to addition of 2-meth-
oxypropene and aldehyde at 4 °C led to a measurable improvement
in ee (up to 8% increase in the case of reactions with benzaldehyde).
With the optimized conditions outlined above in hand, a variety
of substituted benzaldehyde derivatives (2a-r) were examined in
asymmetric ene reactions with 2-methoxypropene (Table 1).
â-Hydroxyenol ether products 3a-r were obtained in 75-97%
isolated yield and 70-96% ee, with >85% ee obtained in the
majority of cases. The scope of this reaction was found not to be
limited to aromatic aldehyde derivatives, as n-hexanal underwent
conversion to the corresponding enol ether in 84% ee and 54%
yield. In all cases examined, crude product could be obtained in
nearly quantitative yield by filtration of the reaction mixtures
through a small pad of Celite. Material thus isolated was contami-
nated with catalyst, but could be used nonetheless in subsequent
reactions without deleterious effect (vide infra). Separation of
catalyst was accomplished by silica gel chromatography, leading
to the product yields listed in the table.8
a Reactions were carried out with 1.0 mmol of aldehyde and 2.09 mmol
(200 µL) 2-methoxypropene at 4 °C. Conditions A: 5 mol % catalyst, 5 h
pre-stir with 90% BaO (650 mg) and acetone (400 µL) at rt. B: 7.5 mol %
catalyst, 5 h pre-stir with 97% BaO (975 mg) and ethyl acetate (400 µL).
b Ee determined by chiral GC on a Cyclodex-â column. c Ee determined
by chiral HPLC after hydrolysis to the hydroxyketone on a (R,R)-Whelk-
01 column. d Ee determined by chiral HPLC after ozonolysis to the ester
on a Chiralcel OD or Chiralpak AS column. e Isolated yield after silica gel
chromatography. f Absolute stereochemistry determined by hydrolysis of
3a to the hydroxyketone and comparison of optical rotation to known
literature value (ref 9).
The identity and position of the substitution on the benzaldehyde
ring is observed to have a significant impact on both the rate and
enantioselectivity of the reaction. Electron-deficient benzaldehydes
reacted smoothly within 40 h to provide the desired â-hydroxyenol
ether products. In contrast, electron-rich substrates such as o-, m-,
and p-tolualdehyde (Table 1, entries 3e-g) underwent reaction more
slowly, achieving 40-60% conversion during the same reaction
time. Ortho-substituted benzaldehyde derivatives displayed par-
* To whom correspondence may be sent. E-mail:
chemistry.harvard.edu.
jacobsen@
9
2882 VOL. 124, NO. 12, 2002 J. AM. CHEM. SOC.
10.1021/ja025588j CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
aryl aldehydes and both 2-methoxypropene and 2-trimethylsilyl-
oxypropene. Studies are currently underway to elucidate the
mechanism and scope of this new reaction.
Acknowledgment. This work was supported by the NIH (GM-
59316) and by a predoctoral fellowship from the National Science
Foundation and an ACS Division of Organic Chemistry Graduate
Fellowship sponsored by Albany Molecular Research, Inc. to R.T.R.
The X-ray crystal structure was solved by Dr. Richard Staples
(Harvard University).
Figure 1. X-ray crystal structure of catalyst 7.
Scheme 2
Supporting Information Available: Complete experimental pro-
cedures, chiral chromatographic analyses of racemic and enantiomeri-
cally enriched products, and crystallographic data for 7 (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) Dosseter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem., Int. Ed.
1999, 38, 2398-2400.
(2) The HDA reaction exhibits a first-order kinetic dependence on catalyst
and on diene, and saturation kinetics with respect to aldehyde. Ruck, R.
T.; Jacobsen, E. N., manuscript in preparation.
(3) For examples of asymmetric catalytic ene reactions of glyoxylate
derivatives, wherein two-point substrate binding is implicated, see:
Mikami, K.; Terada, M. ComprehensiVe Asymmetric Catalysis, Vol. III.;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds. Springer-Verlag:
Heidelberg, 1999; Chapter 32.
Scheme 3
(4) Carreira has described asymmetric titanium-catalyzed ene reactions
between 2-methoxypropene and propargylic aldehydes as well as certain
aliphatic aldehydes. However, unsatisfactory results were described for
benzaldehyde derivatives. Carreira, E. M.; Lee, W.; Singer, R. A. J. Am.
Chem. Soc. 1995, 117, 3649-3650.
(5) Ligands derived from a series of chiral â-amino alcohols and various 3,5-
disubstituted salicylaldehyde derivatives were evaluated. The 3-adamantyl
substituted catalyst identified as optimal for the HDA reaction (ref 1)
afforded 2-5% lower ee than 1 for a range of substrates. Catalysts bearing
noncoordinating counterions such as SbF6- afforded substantially lower
enantioselectivity than the corresponding chloride complexes, in contrast
to that which was observed in HDA reactions. Chiral (salen)CrCl
complexes were also found to be catalytically active in the ene reaction;
however poor (<30%) ee’s were obtained.
ticularly good reactivity and enantioselectivity relative to other
substituted derivatives (e.g., entry 3k, and comparison of entries
3b vs 3c or 3d and 3e vs 3f or 3 g). It is apparent that ortho
substituents serve to help define a particularly reactive CrIII‚aldehyde
complex wherein enantiofacial discrimination is enhanced, although
the bases for these effects are as yet not known.
The enantioenriched â-hydroxyenol ether products formed in the
ene reaction are easily transformed into aldol derivatives (Scheme
2). For example, the crude reaction mixture containing enol ether
3b was diluted with ether and filtered to remove the BaO.
Hydrolysis of 3b was performed by treatment with 2 N HCl,
affording â-hydroxyketone 4 in 97% isolated yield and with no
measurable racemization.10 Alternatively, the filtered reaction solu-
tion containing 3b was diluted with methanol and subjected to
ozonolysis at -78 °C. The resultant ozonide was quenched with
dimethyl sulfide, and â-hydroxyester 5 was obtained in 94% isolated
yield.11
The scope of the ene methodology was extended successfully
to the use of silyl enol ethers.12 Reaction of 2-trimethylsilyloxy-
propene with either benzaldehyde (2a) or 2-bromobenzaldehyde
(2b) proceeded smoothly to generate â-hydroxysilylenol ethers 6a
and 6b, respectively, with no observable silyl transfer (Scheme 3).13
A small volume of 2,6-lutidine was added to each of these reactions
to serve as an acid scavenger, and no pre-stir was necessary to
achieve the optimal enantioselectivity. The â-hydroxysilylenol ether
products of these reactions are interesting chiral building blocks
for subsequent aldol-type reactions.
A crystal structure of catalyst 7 (Figure 1), prepared from 3-tert-
butyl-5-bromosalicyladehyde and aminoindanol, provides valuable
information to begin mechanistic analysis of the ene reaction.14 The
X-ray data reveal a dimeric structure bearing two ligands and two
CrIII centers bridged through the indane-bound oxygens. Each
molecule of chromium also is bound to an axially positioned
chloride ion and water molecule.15 We propose that the role of the
pre-stir is to remove one molecule of bound water from the catalyst
dimer, thus providing an open coordination site for binding of
aldehyde.16
(6) Complete experimental details are provided as Supporting Information.
(7) Reactions employing ethyl acetate as solvent afforded slightly lower
enantioselectivities (1-4%) than those carried out in acetone. However,
ethyl acetate proved preferable for electron-rich aldehydes, as these
underwent side reactions with acetone. The role of BaO as a desiccant
rather than as an acid scavenger is supported by the observation that added
bases such as 2,6-lutidine bore no effect on the reaction outcome.
(8) Lower-than-quantitative isolated yields result from partial decomposition
of â-hydroxyenol ether products upon exposure to silica gel. For certain
reactions, (e.g. leading to 3e-3 g via “Conditions B”) the modest yields
reflect incomplete conversion of the starting aldehyde.
(9) Rho, H. S. Synth. Commun. 1997, 27, 3887-3893.
(10) This ene reaction-hydrolysis sequence is equivalent to a direct aldol
reaction between an aldehyde and acetone. For examples of acetone direct
aldol reactions, see: (a) Trost, B. M.; Silcoff, E. R.; Ito, H. Org. Lett.
2001, 3, 2587-2590. (b) List, B.; Lerner, R. A.; Barbas, C. A., III J. Am.
Chem. Soc. 2000, 122, 2395-2396. (c) Yoshikawa, N.; Yamada, Y. M.
A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168-
4178.
(11) This ene reaction-ozonolysis sequence is equivalent to a traditional
Mukaiyama aldol reaction between an aldehyde and the silylketene acetal
of methyl acetate. For examples, see: Carreira, E. M. ComprehensiVe
Asymmetric Catalysis III; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.
Springer-Verlag: Heidelberg, 1999; Chapter 29.1.
(12) (a) Mikami, K. et al. Tetrahedron Lett. 1997, 38, 579-582. (b) Mikami,
K.; Matsukawa, S. J. Am. Chem. Soc. 1993, 115, 7039-7040.
(13) Failure to observe silyl transfer with trimethylsilyloxy-substituted ene
reactants is consistent with a concerted pathway for this reaction. Shoda,
H.; Nakamura, T.; Tanino, K.; Kuwajima, I. Tetrahedron Lett. 1993, 34,
6281-6284.
(14) CrIII complex 7 is also catalytically active in the ene reaction, but it displays
slightly lower enantioselectivity than 1.
(15) Full crystallographic data are provided as Supporting Information.
(16) The removal of water from the catalyst is an energetically difficult process
as a result of the strong driving force for CrIII to maintain a hexacoordinate
ligand environment (Huheey, J. E.; Keiter, E. A.; Keiter, R. L. Inorganic
Chemistry; Harper Collins College Publishers: New York, 1993.) The
mildly Lewis basic solvents employed in this reaction presumably assist
in the displacement of water from the catalyst. Use of less polar,
noncoordinating solvents such as CH2Cl2 result in poorer reactivity and
enantioselectivity in the ene reaction. Ene reactions with 2-trimethyl-
silyloxypropene do not require aging of catalyst with drying agent, the
likely result of catalyst-bound water reacting rapidly with excess starting
silyl enol ether.
We have shown that tridentate Schiff base chromium(III)
complex 1 efficiently catalyzes the asymmetric ene reaction between
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