Direct, redox-neutral prenylation and geranylation of secondary carbinol C-H bonds: C4-regioselectivity in ruthenium-catalyzed C-C couplings of dienes to α-hydroxy esters

Article abstract of DOI:10.1021/ja3075049

The ruthenium catalyst generated in situ from Ru₃(CO) ₁₂ and tricyclohexylphosphine, PCy₃, promotes the redox-neutral C-C coupling of aryl-substituted α-hydroxy esters to isoprene and myrcene at the diene C4-position, resulting in direct carbinol C-H prenylation and geranylation, respectively. This process enables direct conversion of secondary to tertiary alcohols in the absence of stoichiometric byproducts or premetalated reagents, and is the first example of C4-regioselectivity in catalytic C-C couplings of 2-substituted dienes to carbonyl partners. Mechanistic studies corroborate a catalytic cycle involving diene-carbonyl oxidative coupling.

Full text of DOI:10.1021/ja3075049

Communication
pubs.acs.org/JACS
Direct, Redox-Neutral Prenylation and Geranylation of Secondary
Carbinol C−H Bonds: C4-Regioselectivity in Ruthenium-Catalyzed C−
C Couplings of Dienes to α‑Hydroxy Esters
Joyce C. Leung, Laina M. Geary, Te-Yu Chen, Jason R. Zbieg, and Michael J. Krische*
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712, United States
S
* Supporting Information
ABSTRACT: The ruthenium catalyst generated in situ
from Ru3(CO)12 and tricyclohexylphosphine, PCy3,
promotes the redox-neutral C−C coupling of aryl-
substituted α-hydroxy esters to isoprene and myrcene at
the diene C4-position, resulting in direct carbinol C−H
prenylation and geranylation, respectively. This process
enables direct conversion of secondary to tertiary alcohols
in the absence of stoichiometric byproducts or premeta-
lated reagents, and is the first example of C4-
regioselectivity in catalytic C−C couplings of 2-substituted
dienes to carbonyl partners. Mechanistic studies corrob-
orate a catalytic cycle involving diene−carbonyl oxidative
coupling.
Figure 1. Regioselectivity in intermolecular metal-catalyzed C−C
he ability to transform abundant feedstocks to value-
couplings of 2-substituted dienes to carbonyl partners. For catalytic
Tadded products in the absence of stoichiometric by-
intramolecular diene−aldehyde reductive couplings, see ref 10. For
catalyzed and noncatalyzed stoichiometric generation of allylmetal
species from dienes followed by carbonyl allylation, see refs 12−21.
products is a principal characteristic of a “process-relevant”
method.1 This attribute is exemplified by catalytic hydro-
genation, which is applied across all segments of the chemical
industry, including the manufacture of chiral pharmaceutical
C4-regioselectivity to form products of carbinol C−H
prenylation and geranylation, respectively (Figure 1).5−21
In preliminary experiments, a range of ruthenium and iridium
catalysts were assayed for their ability to promote the C−C
coupling of racemic ethyl mandelate 1a to isoprene 2a. These
attempts were completely unsuccessful or provided only trace
quantities C−C coupling product or the α-ketoester, oxo-1a.
Recently, however, Beller demonstrated that the catalyst
generated from Ru3(CO)12 and Cy2P(CH2)2PCy2 in tert-amyl
alcohol at 150 °C promotes the direct conversion of α-hydroxy
amides to α-amino amides through dehydrogenation of the
former.22 While these conditions did not translate directly to
the coupling of ethyl mandelate 1a and isoprene 2a (Table 1,
entry 1), simply changing the solvent to THF and increasing
the loading of ligand led to a 45% isolated yield of the n-
prenylated hydroxy ester 3a (Table 1, entry 2). Other bidentate
phosphine ligands such as ferrocene-derived ligands DPPF,
DiPPF, and BINAP-PCy2 were assayed under these conditions;
however, conversion to 3a was not observed (Table 1, entries
3−5). In contrast, use of the simple monodentate phosphine
ligand PCy3 (12 mol%) under these conditions led to a 59%
isolated yield of 3a (Table 1, entry 6). A comparable isolated
ingredients on scale2 and alkene hydroformylation,3 which may
be viewed as the prototypical C−C bond-forming hydro-
genation. As part of an effort aimed at the development of C−C
bond-forming hydrogenations beyond hydroformylation, we
have found that hydrogen transfer between primary alcohols
and π-unsaturated reactants generates organometal−aldehyde
pairs that combine to form products of carbonyl addition,
enabling a departure from stoichiometric organometallic
reagents in a range of CX (X = O, NR) additions.4
Although primary alcohols participate in transfer hydro-
genative C−C couplings to dienes5,6 and other π-unsaturated
reactants (allenes, enynes, alkynes and allylic acetates),4 to date,
secondary alcohols have proven uniformly unreactive, presum-
ably due to the relatively low electrophilicity of the transient
ketones that arise upon dehydrogenation. It was reasoned that
the transfer hydrogenative coupling of related α-hydroxy esters
and π-unsaturated reactants might be feasible, as the transient
α-ketoester esters are highly susceptible to nucleophilic
addition. However, dehydrogenation of α-hydroxy esters is
challenging from both thermodynamic and kinetic standpoints.
Here, we report that the ruthenium catalyst generated from
Ru3(CO)12 and tricyclohexylphosphine promotes efficient
redox-neutral C−C coupling of aryl-substituted α-hydroxy
esters 1a−1f to isoprene 2a and myrcene 2b with unique diene
Received: July 30, 2012
Published: September 17, 2012
© 2012 American Chemical Society
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Communication
good yield as single regioisomers. Alkyl-substituted α-hydroxy
esters such as ethyl lactate provide low isolated yields of C−C
coupling product using this first generation catalyst. However,
analogous coupling reactions of aryl-substituted α-hydroxy
esters 1a−1f with myrcene 2b were successful, delivering
products of geranylation 4a−4f with complete control of olefin
geometry (Table 3). Thus, direct secondary carbinol C−H
Table 1. Selected Optimization Experiments in the C−C
a
Coupling of α-Hydroxy Ester 1a to Isoprene 2a
Table 3. Geranylation of α-Hydroxy Esters 1a−1f via
Ruthenium-Catalyzed Hydrohydroxyalkylation of Myrcene
a
2b
a
Yields are of material isolated by silica gel chromatography. See
b
Supporting Information for further details. Cy2P(CH2)2PCy2 (6 mol
%). Cy3P (18 mol%).
c
yield of 3a could be obtained at 130 °C by extending the
reaction time (Table 1, entry 7). At this stage, different solvents
were evaluated (Table 1, entries 8−10). By conducting the
reaction in toluene, the n-prenylated product 3a was obtained
in 68% isolated yield (Table 1, entry 10). Variation of ligand
loading did not improve the isolated yield of 3a (Table 1, entry
11), nor did changes in concentration (Table 1, entries 12, 13).
However, by decreasing reaction time and increasing the
loading of isoprene (500 mol%), a 75% isolated yield of the n-
prenylated product 3a was obtained (Table 1, entry 15).
Under these optimal conditions, the redox-neutral C−C
coupling of aryl-substituted α-hydroxy esters 1a−1f and
isoprene 2a was explored (Table 2). In each case, the
corresponding n-prenylated products 3a−3f were isolated in
Table 2. Prenylation of α-Hydroxy Esters 1a−1f via
a
As described for Table 2. See Supporting Information for further
Ruthenium-Catalyzed Hydrohydroxyalkylation of Isoprene
b
a
details. Myrcene 2b (400 mol%).
2a
prenylation and geranylation is achieved under redox-neutral
conditions in the absence of stoichiometric byproducts or
premetalated reagents.23 Reactions using 2,3-dimethylbuta-
diene, 1,3-pentadiene, and 3-methyl-1,3-pentadiene were
attempted under standard conditions, but only trace quantities
of product were observed.
To probe the catalytic mechanism and gain insight into the
origins of regioselectivity, deuterated rac-ethyl mandelate,
deuterio-1a, was exposed to isoprene 2a under standard
conditions for redox-neutral C−C coupling (eq 1). Notably,
a
Yields are of material isolated by silica gel chromatography. See
b
Supporting Information for further details. Isoprene 2a (600 mol%).
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Communication
Scheme 1. Plausible Catalytic Mechanism for the Redox-Neutral C−C Coupling of deuterio-1a to Isoprene 2a
the n-prenylated adduct deuterio-1a incorporates deuterium
exclusively at the cis-methyl group of the n-prenyl moiety (2H
50%). Incomplete deuterium incorporation may be attributed
to the reversible transfer of hydrogen between deuterio-1a and
isoprene, as corroborated by deuterium loss in recovered
oxidative coupling. Direct prenylations and geranylations of
secondary carbinol C−H bonds employing isoprene and
myrcene, respectively, should facilitate access to diverse
terpenoid natural products.
2
deuterio-1a (2H 54%). The regioselectivity and extent of H
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
incorporation were evaluated using 1H and 2H NMR
spectroscopy. Also, recovered from this reaction in 9% yield
is the α-ketoester, oxo-1a. Indeed, for many of the reactions
reported in Tables 2 and 3 small quantities of the
corresponding the α-ketoesters can be observed by thin layer
chromatography or isolated by flash silica gel chromatography
(typically <5% yield).
The regioselectivity of C−C coupling and deuterium
incorporation is consistent with the indicated catalytic cycle,
which involves diene−carbonyl oxidative coupling (Scheme 1).
To further challenge this mechanistic hypothesis, the redox-
neutral coupling of rac-ethyl mandelate 1a and butadiene 2c
was performed under standard conditions. The product of C−
C coupling 5a is formed as (Z)-stereoisomer, which is
consistent with the proposed oxidative coupling mechanism
(eq 2).
S
AUTHOR INFORMATION
Corresponding Author
mkrische@mail.utexas.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Robert A. Welch Foundation (F-0038), the NIH-NIGMS
(RO1-GM069445), and the Government of Canada’s Banting
Postdoctoral Fellowship Program (L.M.G.) are acknowledged
for partial support of this research. Shih-Tien Chen is
acknowledged for skillful technical assistance.
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