Dual function catalysts. Dehydrogenation and asymmetric intramolecular Diels-Alder cycloaddition of N-hydroxy formate esters and hydroxamic acids: Evidence for a ruthenium-acylnitroso intermediate

Article abstract of DOI:10.1021/ja050059b

The chiral ruthenium salen complex, 13b, functions as an efficient catalyst for the sequential oxidation and asymmetric Diels-Alder cycloaddition of hydroxamic acids and N-hydroxy formate esters. This result provides evidence for the formation of a ruthen

Full text of DOI:10.1021/ja050059b

Published on Web 02/26/2005
Dual Function Catalysts. Dehydrogenation and Asymmetric Intramolecular
Diels-Alder Cycloaddition of N-Hydroxy Formate Esters and Hydroxamic
Acids: Evidence for a Ruthenium-Acylnitroso Intermediate
Chun P. Chow and Kenneth J. Shea*
Department of Chemistry, 516 Rowland Hall, UniVersity of California, IrVine, California 92697-2025
Received January 5, 2005; E-mail: kjshea@uci.edu
Significant progress has been made in the design of asymmetric
catalysts for the Diels-Alder reaction.1 In all cases that we are
aware of, cycloaddition occurs upon treatment of a stable Diels-
Alder precursor with a chiral Lewis acid catalyst. There are,
however, many important Diels-Alder precursors that are not stable
entities but rather are reactive intermediates that are generated in
situ in the presence of a diene trap. Inducing asymmetry in these
cycloadditions presents an interesting challenge. We report a dual
function catalyst that serves to generate the reactive Diels-Alder
precursor as well as to induce asymmetry in the subsequent cyclo-
addition step. This represents the first example of a strategy of this
type and extends the potential utility of these important reactions.
The results establish mechanistic support for formation of a complex
between the reactive Diels-Alder intermediate and the catalyst.
Cycloadditions of aryl and acyl nitroso groups have played a
key role in heterocycle synthesis.2 More recently, asymmetric
variants of these reactions have received attention. For example,
Yamamoto reported an asymmetric catalyst for the Diels-Alder
cycloaddition of 2-methyl-5-nitroso pyridine with dienes.3 The acyl
nitroso group (i.e., 2), on the other hand, is a reactive intermediate.
It is generated in situ and has a relatively short lifetime in the
presence of dienes.4 Miller5 and others6 have developed stoichio-
metric asymmetric cycloadditions of acyl nitroso derivatives by
incorporating a chiral auxiliary in the acyl nitroso precursor.
Regarding efforts to develop catalysts for these reactions, the
recent work of Whiting7 and Iwasa8 are noteworthy. In particular,
the Whiting group reported that complexes of ruthenium(II) catalyze
the oxidation of tert-butyl-N-hydroxy formate (4) to the corre-
sponding nitroso formate 5 using tert-butyl hydroperoxide (TBHP)
as the stoichiometric oxidant.7 Reactions run in the presence of
cyclohexadiene (CHD) resulted in moderate yield of cycloadduct
6. Although an asymmetric ruthenium-salen catalyst was also
found to be an effective oxidation catalyst, products of the
bimolecular Diels-Alder reaction with CHD as the diene trap were,
in all cases, racemic.9 A very low enantiomeric excess was noted
with PROPHOS. The experiment raises an intriguing question; is
it feasible to develop a catalyst that functions both as an oxidant
and as an effective asymmetric catalyst for the subsequent cycload-
dition reaction? The expectation of asymmetry is predicated on the
assumption that following oxidation, the cycloaddition takes place
while the acyl nitroso intermediate remains associated with the spent
ruthenium oxidation catalyst.
If one could adopt the ruthenium-catalyzed oxidation protocol,
the intramolecular version of the cycloaddition might have a higher
probability to take place while the intermediate is still in the
coordination sphere of the ruthenium. To examine the influence of
intramolecularity, several type 2 Diels-Alder precursors were
synthesized.10,11 Both hydroxamic acid 7 and N-hydroxy formate
ester 10 undergo intramolecular Diels-Alder cycloaddition upon
oxidation with stoichiometric tetrabutylammonium periodate. Im-
portantly, the enantiomers of the racemic products, cycloadducts 9
and 12, could be separated by chiral HPLC.
To evaluate the performance of ruthenium catalysts, chiral salen
ligands based on (+)-1,2-diaminocyclohexane were prepared and
converted to their Ru(II) complexes upon treatment with RuCl2-
(PPh3)3.12 A standard protocol was used to assess catalyst perfor-
mance. The procedure involves treatment of 1 equiv of hydroxamic
acid (or N-hydroxy formate ester) with 1 equiv of TBHP in the
presence of 0.1 mol % of ruthenium catalyst in CH2Cl2. The reaction
was allowed to proceed for 1 h at room temperature. Bimolecular
reactions with precursors 1 and 4 were run in the presence of 1 M
CHD. The rate of background oxidation was less than 4% after 1
h in all cases.
Consistent with the report by Whiting, O-tert-butyl-N-hydroxy
formate (4) is oxidized by 13a to yield (racemic) CHD cycloadduct
6 (74% yield). The intramolecular N-hydroxy formate ester precur-
sor 10 was also oxidized by 13a to give cycloadduct 12 in 64%
yield. Importantly, chiral HPLC indicated a slight enantiomeric
excess (9% ee) in the cycloadduct. Although the magnitude of the
enrichment was quite low, the result has important mechanistic
implications. For any level of asymmetric induction to occur, some
component of the cycloaddition of the acyl nitroso intermediate
11 must have taken place within the coordination sphere of the
chiral ruthenium catalyst. It has been proposed that reaction of 13a
with TBHP results in formation of the active oxidant, a Ru(IV)
oxo species 14.7 The preceding results permit refinement of this
mechanism (Scheme 1). Dehydrogenation of 10 by 14 produces a
geminate pair comprised of the spent oxidant, the Ru(II) byproduct,
and the nitroso formate intermediate 11 (complex 15 in Scheme
1). Some fraction of the Diels-Alder cycloaddition takes place
within complex 15 prior to the dissociation and/or reoxidation of
the ruthenium by TBHP. The stability and lifetime of complex 15,
therefore, is critical for the asymmetric Diels-Alder reaction.
9
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J. AM. CHEM. SOC. 2005, 127, 3678-3679
10.1021/ja050059b CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Proposed Mechanism for the Asymmetric Formation of
Oxazinolactam 12
Scheme 2. Proposed Mechanism for the Dehydrogenation and
Cycloaddition of N-Hydroxy Formate Esters
a bimolecular cycloaddition that would be competitive with the
bimolecular reoxidation of Ru(II).
Acknowledgment. This research was supported in part by a
grant from the NIH. C.P.C. thanks Xerox Corporation for the Xerox
Technical Minority Scholarships, and the UC Regents for a
dissertation fellowship.
A more Lewis acidic catalyst could produce a stronger oxidant
and perhaps stabilize complex 15. Indeed, improved yields and
higher enantiomeric excesses were found with electron-withdrawing
substituents at positions R1 and R2 in 13. (Supporting Information).
The most effective substitution pattern was the dinitro derivative
13b (R1, R2 ) NO2). This complex is a competent catalyst both
for the oxidation of hydroxamic acid 1 (48% yield of cycloadduct
3 with 1 M CHD) as well as for the oxidation of hydroxamic acid
7 (66% yield of cycloadduct 9). More importantly, the dinitro
catalyst 13b delivers cycloadduct 12 in 43% ee.
Supporting Information Available: Experimental information,
including the preparation of compounds 3, 6, 7, 9, 10, 12, and 13. This
material is available free of charge via the Internet at http://pubs.acs.org.
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Possible explanations for the modest enantioselectivity include
breakdown of complex 15 prior to cycloaddition by dissociation
of the acyl nitroso intermediate or reoxidation by TBHP to 14 and/
or cycloaddition within the complex with an intrinsically low
enantioselectivity. Focusing on the competing reoxidation step, we
note that the lifetime of 15 is dependent on the rate of reoxidation,
a bimolecular reaction. Suppression of this bimolecular reaction
might be achieved by decreasing the overall concentration.
Incremental dilution to 7.2 × 10-2 M showed increase in
chemical yield up to 82%. A parallel trend in enantioselectivity
was observed with decreasing concentration. The optimum forma-
tion of cycloadduct 12 was achieved at 7.2 × 10-2 M. These
conditions also resulted in improved enantioselectivity (71%). The
enantioselectivity was further enhanced (75% ee) by lowering the
temperature to 15 °C. Continued decrease in reaction concentration
resulted in reduced yield.
Further refinement of the mechanism is now warranted (Scheme
2). Ru(IV) oxo complexes are known dehydrogenation reagents.13,14
Hydrogen transfer is expected to produce a Ru(II) hydrate.15 The
Ru hydrate can bind the nitroso formate intermediate by a hydrogen
bond (15a) or it can undergo ligand replacement to produce 15b.
(The H-bonded complex would be the first intermediate in the ligand
exchange.)16 There is ample precedent for facile exchange at Ru-
(II) centers16 as well as for Ru(II) nitroso complexes.17 Coordination
of the acyl formate in 15a and/or 15b is expected to catalyze the
Diels-Alder cycloaddition in light of recent experimental evidence
regarding the acceleration of R-acetoxynitroso cycloadditions by
Lewis acids.18 Cycloaddition from either intermediate (15a,b) could
account for the observed asymmetry (Scheme 2).
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The low (or no) enantioselectivity for the intermolecular reaction
is consistent with the proposal since the Diels-Alder step involves
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