Enantioselective reductive coupling of 1,3-enynes to heterocyclic aromatic aldehydes and ketones via rhodium-catalyzed asymmetric hydrogenation: Mechanistic insight into the role of Bronsted acid additives

Article abstract of DOI:10.1021/ja0673027

Hydrogenation of 1,3-enynes 1a-e in the presence of heterocyclic aromatic aldehydes and ketones using chirally modified cationic rhodium precatalysts results in reductive coupling to afford dienylated α-hydroxy heteroarenes 2-23 with exceptional levels of

Full text of DOI:10.1021/ja0673027

Published on Web 12/09/2006
Enantioselective Reductive Coupling of 1,3-Enynes to Heterocyclic Aromatic
Aldehydes and Ketones via Rhodium-Catalyzed Asymmetric Hydrogenation:
Mechanistic Insight into the Role of Brønsted Acid Additives
Venukrishnan Komanduri and Michael J. Krische*
Department of Chemistry and Biochemistry, UniVersity of Texas at Austin, Austin, Texas 78712
Received October 11, 2006; E-mail: mkrische@mail.utexas.edu
Table 1. Enantioselective Hydrogen-Mediated Coupling of
Although alkene hydroformylation represents the largest volume
application of homogeneous metal catalysis,1 systematic efforts
toward the development of hydrogen-mediated C-C bond forma-
tions that extend beyond couplings to carbon monoxide have been
absent from the literature, withstanding recent work from our
laboratory.2,3 Through the use of cationic rhodium precatalysts, the
hydrogen-mediated reductive coupling of conjugated enones,2a-d,k
dienes,2e enynes,2f,j,l,n and diynes2g,o to carbonyl and imine2j partners
has been devised. Further, hydrogenation of 1,6-diynes, 1,6-
enynes,2h,i and 1,6-alkynals2m was found to provide products of
reductive carbocyclization. These studies rank among the first
examples of hydrogen-mediated C-C bond formation that proceed
in the absence of carbon monoxide.3
1,3-Enynes to Heterocyclic Aromatic Aldehydes and Ketonesa
Recently, we found that Brønsted acid co-catalysts greatly
enhance both rate and conversion in hydrogen-mediated alkyne-
carbonyl coupling reactions.2l However, all hydrogen-mediated
alkyne couplings developed to date require vicinal dicarbonyl
partners. It was postulated that heterocyclic aromatic aldehydes and
ketones that are isoelectronic with respect to the vicinal dicarbonyl
motif might be viable electrophilic partners. Here, we disclose that
hydrogenation of conjugated enynes in the presence of such
heterocyclic aromatic aldehydes and ketones using chirally modified
rhodium catalysts enables direct formation of carbonyl addition
products with exceptional levels of asymmetric induction and
regiocontrol.4-6 Further, upon use of the Akiyama-Terada-type
phosphoric acid derived from BINOL as the Brønsted acid
co-catalyst,7,8 highly optically enriched products of C-C coupling
are obtained using an achiral rhodium catalyst.
Our initial studies focused on the reductive coupling of enyne
1a to 2-pyridinecarboxaldehyde (100 mol %). Gratifyingly, hydro-
genation of these two compounds at 40 °C using a cationic rhodium
catalyst modified by (R)-Tol-BINAP provides the reductive coupling
product 2 in 91% isolated yield and 92% ee. Isomeric 3- and
4-pyridinecarboxaldehydes do not participate in the coupling. These
conditions were applied to the reductive coupling of diverse
heterocyclic aromatic aldehydes to enynes 1a-e (Table 1). In cases
where the (R)-Tol-BINAP-modified catalyst provides insufficient
levels of asymmetric induction, catalysts ligated by (R)-xylyl-
WALPHOS were found to confer high levels of optical enrichment.
Notably, coupling proceeds efficiently in the presence of multiple
Lewis basic nitrogen atoms (7, 13) and sulfur atoms (11, 14).
Further, as demonstrated by the formation of 18-23, heterocyclic
aromatic ketones are efficient coupling partners (Table 1). Absolute
stereochemical assignments are based upon single-crystal X-ray
diffraction analysis of the carbamate derived upon reaction of
coupling product 2 with the isocyanate derived from phenylalanine
methyl ester. Finally, the diene side chain of the coupling products
may be selectively transformed, providing access to a variety of
functional group arrays (Table 2). To gain further insight into the
catalytic mechanism and, in particular, the role of the Brønsted
acid co-catalyst, the reductive coupling of enyne 1a to 2-pyridin-
a Cited yields are of isolated material and represent the average of two
runs. Yields indicated parenthetically are based upon recovered starting
material. All reactions simply employ hydrogen balloons and typically
require less than 3 h to reach completion. See Supporting Information for
detailed experimental procedures. b Reaction was run at 65 °C. c Reaction
was performed at 4 mol % catalyst loadings. d The opposite sense of
asymmetric induction is observed upon use of (R)-Tol-BINAP and (R)-
xylyl-WALPHOS. The indicated enantiomers represent the major enanti-
omers obtained using (R)-Tol-BINAP as ligand.9
ecarboxaldehyde was performed using an achiral rhodium catalyst
in the presence of substoichiometric quantities of the Akiyama-
9
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J. AM. CHEM. SOC. 2006, 128, 16448-16449
10.1021/ja0673027 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Elaboration of Coupling Products 2 and 8a
GM69445) for partial support of this research. Professor Benjamin
List is thanked for the donation of the chiral phosphoric acid.
Umicore is thanked for the donation of Rh(COD)2OTf.
Supporting Information Available: Spectral data for all new
compounds, along with HPLC traces of racemic and optically enriched
coupling products. Single-crystal X-ray diffraction data for of the
carbamate derived upon reaction of coupling product 2 with the
isocyanate derived from phenylalanine methyl ester. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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a Cited yields are of pure isolated material and represent the average of
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b Yield based on recovered starting material.
Scheme 1. Plausible Catalytic Mechanism as Supported by the
Effect of Chiral Brønsted Acid Catalyst and 2H-Labeling
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Terada-type phosphoric acid derived from BINOL.7,8 Remarkably,
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Reductive coupling of enyne 1a to 2-pyridinecarboxaldehyde
under a deuterium atmosphere provides, after isolation by silica
gel chromatography, deuterio-2. The collective data suggest a
catalytic mechanism in which association of the Brønsted acid to
2-pyridinecarboxaldehyde precedes oxidative coupling with the
conjugated enyne to form an oxarhodacyclic intermediate. Deute-
riolytic cleavage of the metallacycle via σ bond metathesis, which
likely occurs through a six-centered transition structure,9 releases
the Brønsted acid co-catalyst and delivers a cationic Rh(III)(vinyl)-
(deuteride), which reductively eliminates to form the deuterio-2,
along with the starting cationic rhodium complex to complete the
catalytic cycle.
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Acknowledgment. Acknowledgment is made to the Welch
Foundation, Johnson & Johnson, and the NIH-NIGMS (RO1-
JA0673027
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