Carbonyl allylation in the absence of preformed allyl metal reagents: Reverse prenylation via iridium-catalyzed hydrogenative coupling of dimethylallene

Article abstract of DOI:10.1021/ja075971u

Iridium-catalyzed hydrogenation of dimethylallene in the presence of aromatic, heteroaromatic, and aliphatic carbonyl electrophiles 1a-12a delivers products of reverse prenylation 1b-12b. Reductive coupling of dimethyl allene to aldehyde 8a under an atmosphere of deuterium provides deuterio-8b. As revealed by 2H NMR analysis, deuterium incorporation is observed at the vinylic position (80% 2H). Unlike established methods for carbonyl allylation, the present protocol circumvents the use of stoichiometrically preformed organometallic reagents. Copyright

Full text of DOI:10.1021/ja075971u

Published on Web 09/27/2007
Carbonyl Allylation in the Absence of Preformed Allyl Metal Reagents:
Reverse Prenylation via Iridium-Catalyzed Hydrogenative Coupling of
Dimethylallene
Eduardas Skucas, John F. Bower, and Michael J. Krische*
UniVersity of Texas at Austin, Department of Chemistry and Biochemistry, Austin, Texas 78712
Received August 8, 2007; E-mail: mkrische@mail.utexas.edu
Nearly half a century ago, Mikhailov and Bubnov (1964) reported
the first carbonyl allylation employing an isolable preformed allyl
metal reagent, triallylborane.1a Twelve years later, Hosomi and
Sakurai (1976) reported that carbonyl compounds are subject to
allylation upon exposure to allylsilanes in the presence of Lewis
acids.1b,c These studies set the stage for enantioselective carbonyl
allylations employing chirally modified allyl metal reagents. The
first reagent of this type, reported by Hoffmann (1978),2a,b was an
allylborane derived from camphor. Subsequently, a host of chirally
modified allyl metal reagents for asymmetric carbonyl allylation
Figure 1. Iridium-catalyzed reductive coupling of dimethylallene to
were disclosed. These include reagents developed by Kumada
(1982),2c Brown (1983),2d Roush (1985),2e Reetz (1988),2f
Masamune (1989),2g Corey (1989),2h Seebach (1987),2i Duthaler
(1989),2j Panek (1991),2k and Leighton (2002).2l,m Catalytic enan-
tioselective carbonyl allylations have been achieved using chirally
modified Lewis acid catalysts, as described in seminal studies by
Umani-Ronchi (1993)3a and Keck (1993).3b Additionally, enantio-
selective carbonyl allylation may be catalyzed using chirally
modified Lewis bases, as revealed in elegant studies by Denmark
(1994).3c,d Other methods for catalytic carbonyl allylation involve
the reduction of metallo-π-allyls derived from allylic alcohols and
allylic carboxylates.4 Here, stoichiometric quantities of metal-based
terminal reductants, for example SmI2, SnCl2, and Et2Zn, are
required for catalytic turnover.5 Finally, carbonyl-ene processes
enable access to products of carbonyl allylation.6,7
aldehyde 8a under an atmosphere of deuterium.
found that catalysts derived from the cationic iridium complex
[Ir(cod)2]BARF (BARF ) B(3,5-(CF3)2C6H3)4) and the chelating
phosphine ligand BIPHEP promote the desired reaction. However,
using the parent allene, the initially formed homoallylic alcohol is
subject to over-reduction to furnish the product of carbonyl
propylation. For this reason, dimethylallene was selected as the
nucleophilic partner, as the anticipated product of carbonyl prenyl-
ation should be more resistant to over-reduction. To our delight,
iridium-catalyzed hydrogenation of dimethylallene in the presence
phenethyl glyoxalate 1a delivers the product of reVerse prenylation
in good isolated yield with only partial over-reduction of the
terminal alkene. An assay of various additives revealed that over-
reduction is completely suppressed for reactions conducted in DCE-
EtOAc (1:1) in the presence of the basic additive Li2CO3. Alternate
bases, for example KOAc, LiOH, Cs2CO3, i-Pr2NEt, were only
slightly less effective at suppressing over-reduction. Under these
conditions, diverse aldehydes undergo reverse prenylation in good
to excellent yield. One limitation of this first generation catalytic
system is that unactivated aliphatic aldehydes do not couple
efficiently. However, as established by the formation of 12b, for
electronically activated systems even ketone addition is possible
(Table 1).
Clearly, enormous effort has been devoted to the development
of carbonyl allylation methodologies.8 However, withstanding
carbonyl-ene processes,6,7 the aforementioned protocols invariably
employ stoichiometric quantities of preformed allyl metal reagents1-3
or metallic reductants,4,5 mandating stoichiometric generation of
metallic byproducts.
Hydrogen-mediated reductive coupling offers a byproduct-free
alternative to stoichiometrically preformed organometallic reagents
in an ever increasing range of CdX (X ) O, NR) addition
processes.9 It was postulated that the allyl metal species arising
transiently upon allene hydrogenation10 may be subject to capture
by exogenous carbonyl electrophiles to furnish products of carbonyl
allylation. Precedent for such a transformation was rendered
tenuous, as intermolecular allene-carbonyl reductive coupling
under the conditions of nickel catalysis using silane as terminal
reductant provides products of carbonyl vinylation via coupling to
the central allenic carbon atom.11 The regiochemistry required for
homoallyl alcohol formation had only been observed in multi-
component reaction of allenes and aldehydes with halo- or metallo-
arenes.12,13 To date, simple catalytic reductiVe allene-carbonyl
coupling to furnish homoallylic alcohols has not been achieVed.
Here, we report that iridium catalyzed hydrogenation14 of dimeth-
ylallene in the presence of carbonyl electrophiles delivers products
of carbonyl allylation, specifically, products of reverse prenylation.
In our initial studies, a range of rhodium and iridium catalysts
were assayed for their ability to catalyze the hydrogenative coupling
of gaseous allene to various carbonyl electrophiles. Here, it was
A plausible general catalytic mechanism involves allene hydro-
metallation to provide the primary σ-allyl iridium complex I, which
engages the carbonyl partner in a closed six-centered transition
structure II. Carbonyl addition with allylic inversion accounts for
the formation of reverse prenylated adducts. Hydrogenolytic
cleavage of the resulting iridium alkoxide III delivers deuterio-8b
with concomitant regeneration of Ir(H)(Ln) to close the cycle. To
corroborate the proposed mechanism, dimethylallene was coupled
to aldehyde 8a under an atmosphere of deuterium (Figure 1). As
revealed by 2H NMR analysis, the total amount of deuterium
incorporated into deuterio-8b is 80%. It should be emphasized that
mechanisms involving allene-aldehyde oxidative coupling are
potentially operative and cannot be excluded on the basis of
available data. Studies focused on uncovering the origins of
incomplete deuterium incorporation are in progress. One possible
explanation invokes â-hydride elimination from the tertiary σ-allyl
haptomer of the iridium allyl to form isoprene.
Carbonyl allylation is employed extensively in organic synthesis.8
Yet, withstanding carbonyl-ene processes,6,7 prevailing protocols
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J. AM. CHEM. SOC. 2007, 129, 12678-12679
10.1021/ja075971u CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Reverse Prenylation via Iridium-Catalyzed Hydrogenative
Supporting Information Available: Experimental procedures and
spectral data for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Coupling of Dimethylallene to Carbonyl Compoundsa
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a In all cases, cited yields are of isolated material. Standard conditions
employ 1 equiv of aldehyde and 4 equiv of allene using 5 mol % loading
of precatalyst. For substrates 2a, 7a, 9a, and 12a, 8 equiv allene and 10
mol % loading of precatalyst were used (see Supporting Information for
detailed experimental procedures).
b
invariably employ stoichiometric quantities of preformed allyl metal
reagents1-3 or metallic reductants.4,5 The preliminary studies
reported herein reveal that carbonyl allylation, specifically reverse
prenylation, may be achieved simply by hydrogenating dimethyl-
allene in the presence of carbonyl electrophiles, representing a
departure from the use of stoichiometric organometallic reagents
in carbonyl allylation. Future studies will focus on the development
of related hydrogenative protocols for carbonyl allylation and
crotylation.
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Acknowledgment. Acknowledgment is made to Johnson &
Johnson, Merck, and the NIH-NIGMS (Grant RO1-GM069445) for
partial support of this research.
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