Alkynes as allylmetal equivalents in redox-triggered C-C couplings to primary alcohols: (Z)-homoallylic alcohols via ruthenium-catalyzed propargyl C-H oxidative addition

Article abstract of DOI:10.1021/ja505962w

The cationic ruthenium catalyst generated upon the acid-base reaction of H₂Ru(CO)(PPh₃)₃ and 2,4,6-(2-Pr) ₃PhSO₃H promotes the redox-triggered C-C coupling of 2-alkynes and primary alcohols to form (Z)-homoallylic alcohols with good to complete control of olefin geometry. Deuterium labeling studies, which reveal roughly equal isotopic compositions at the allylic and distal vinylic positions, along with other data, corroborate a catalytic mechanism involving ruthenium(0)-mediated allene-aldehyde oxidative coupling to form a transient oxaruthenacycle, an event that ultimately defines (Z)-olefin stereochemistry.

Full text of DOI:10.1021/ja505962w

Communication
pubs.acs.org/JACS
Open Access on 07/30/2015
Alkynes as Allylmetal Equivalents in Redox-Triggered C−C
Couplings to Primary Alcohols: (Z)‑Homoallylic Alcohols
via Ruthenium-Catalyzed Propargyl C−H Oxidative Addition
Boyoung Y. Park, Khoa D. Nguyen, Mani Raj Chaulagain, Venukrishnan Komanduri, and Michael J. Krische*
Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States
S
* Supporting Information
Scheme 1. 2-Alkynes as Allylmetal Equivalents in Redox-
ABSTRACT: The cationic ruthenium catalyst generated
Triggered C−C Couplings of Primary Alcohols
upon the acid−base reaction of H2Ru(CO)(PPh3)3 and
2,4,6-(2-Pr)3PhSO3H promotes the redox-triggered C−C
coupling of 2-alkynes and primary alcohols to form (Z)-
homoallylic alcohols with good to complete control of olefin
geometry. Deuterium labeling studies, which reveal roughly
equal isotopic compositions at the allylic and distal vinylic posi-
tions, along with other data, corroborate a catalytic mechanism
involving ruthenium(0)-mediated allene−aldehyde oxidative
coupling to form a transient oxaruthenacycle, an event that
ultimately defines (Z)-olefin stereochemistry.
llylative carbonyl additions represent a major class of C−C
A
bond formations that have found broad use in chemical syn-
thesis.1 The majority of methods rely upon use of preformed
allylmetal reagents or, as exemplified in Nozaki−Hiyama−
Kishi-type allylations, stoichiometric quantities of (organo)-
metallic reductant.2 By harnessing the native reducing capability
of alcohols, we have developed a broad, new class of redox-
triggered carbonyl allylations that bypass use of stoichiometric
(organo)metallic reagents (eq 1).3 In the course of our studies,
geometry (Scheme 1, eq 3). Mechanistic studies implicate inter-
vention of a novel alkylidene ruthenacyclopropane intermediate.
In initial experiments (Scheme 2), 2-butyne 1a and benzyl
alcohol 2d were exposed to our previously reported conditions
Scheme 2. Observation of (Z)-Allylation Pathways in
Ruthenium-Catalyzed C−C Couplings of Alkynes and
Primary Alcohols
Obora and Ishii reported a remarkable iridium-catalyzed C−C
coupling of 1-aryl-1-propynes to furnish branched products of
carbonyl allylation (Scheme 1, eq 2).4 Such branched products
of allylation are formed in related iridium-5a and ruthenium-
catalyzed5b C−C couplings of primary alcohols and allenes,
suggesting alkyne-to-allene isomerization is evident in this process.
These observations, in combination with our ongoing studies of
the ruthenium-catalyzed C−C coupling of alkynes and primary
alcohols or aldehydes to form allylic alcohols or enones,6 prompted
us to explore the use of alkynes as allyl donors7 under the condi-
tions of ruthenium catalysis. Here, we report that the cationic
ruthenium complexes generated through the acid−base reaction of
H2Ru(CO)(PPh3)3 and 2,4,6-(2-Pr)3PhSO3H catalyzes8 the redox-
triggered C−C coupling of alkynes and primary alcohols to furnish
(Z)-homoallylic alcohols with good to complete control of olefin
for ruthenium-catalyzed alcohol−alkyne C−C coupling to form
allylic alcohol Ia to determine whether trace quantities of allyla-
tion product were evident.6a The previously observed products
of vinylation, allylic alcohol Ia and enone dehydro-Ia, were
generated in 65% and 17% yield, respectively. Along with these
materials, careful analysis of the H NMR spectra of Ia did
indeed reveal trace quantities of (Z)-homoallylic alcohol IIa.
1
Received: June 13, 2014
Published: July 30, 2014
© 2014 American Chemical Society
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Communication
Variation of the alkyne was explored as a potential means
of partitioning the vinylation and (Z)-allylation pathways. Upon
use of 4-methyl-2-pentyne 1c, the vinylation pathway was sup-
pressed and the product of (Z)-allylation 4d was formed in 29%
isolated yield as a 9:1 (Z:E) mixture of geometrical isomers.
Encouraged by this result, optimization of the (Z)-allylation path-
way was undertaken. Eventually, it was found that the
ruthenium(II) catalyst prepared in situ from the acid−base
reaction of H2Ru(CO)(PPh3)3 and 2,4,6-tri(2-propyl)-
phenylsulfonic acid hydrate8,9 (ArSO3)2Ru(CO)(PPh3)2 deliv-
ered the best results, providing the (Z)-homoallylic alcohol 4c
in 70% yield as a single geometrical isomer, as determined
richness of the transient aldehyde, yet 2-methoxy benzyl alcohol
2i provides a moderate yield of adduct 4i. Aliphatic alcohols
2j−2o provide moderate to good yields of the (Z)-homoallylic
alcohols 4j−4o. The coupling is effective for alcohols with
adjacent secondary, tertiary, and even quaternary carbon centers,
albeit with incomplete levels of (Z)-olefin stereocontrol. To
further probe the scope of this process, cyclohexyl-, tert-butyl-,
and 2-phenyl-2-propyl-substituted alkynes 1d−1f were surveyed.
Exposure of alkynes 1d−1f to alcohols 2c and 2j under standard
reaction conditions delivered the products of (Z)-allylation 4p−4r
and 4s−4u, respectively, in good yields with good levels of
(Z)-olefin stereocontrol (Table 2). Finally, as illustrated in the
1
by H NMR. Due to competing conventional alcohol−alkyne
transfer hydrogenation, 2-propanol (200 mol%) is required to
promote higher conversion. For the reaction of 4-methyl-2-
pentyne 1c and 4-bromobenzyl alcohol 2c conducted in the
absence of 2-propanol, the (Z)-homoallylic alcohol 4c is
obtained in roughly 40% isolated yield along with substantial
quantities of unreacted aldehyde 3c. 2-Propanol is postulated to
convert unreacted aldehyde back to the kinetically more reactive
primary alcohol, resetting the “redox trigger”.
Table 2. Redox-Triggered C−C Coupling of Alkynes 1d−1f
and Alcohols 2c and 2j To Form (Z)-Homoallylic Alcohols
4p−4u
a
Under these conditions, the reaction of 4-methyl-2-pentyne
1c with electron-deficient and electron-neutral benzylic alcohols
2a-2d and 2g-2i occurs smoothly to furnish the (Z)-homoallylic
alcohol 4a−4d and 4g−4i in moderate to good yield with com-
1
plete levels of olefin stereocontrol, as determined by H NMR
(Table 1). As illustrated in the coupling of benzylic alcohols 2e
and 2f, which incorporate 4-methyl and 4-methoxy substituents,
the efficiency of this process decreases with increasing electron
Table 1. Redox-Triggered C−C Coupling of Alkyne 1c and
a
Alcohols 2a−2o To Form (Z)-Homoallylic Alcohols 4a−4o
a
Yields are of material isolated by silica gel chromatography. See
Supporting Information for further experimental details.
reaction of 4-methyl-2-pentyne 1c and p-bromobenzaldehyde
3c, identical products of (Z)-allylation are accessible from the
aldehyde oxidation level under standard reaction conditions (eq 4).
Using the present catalyst system, less hindered 2-alkynes such as
2-pentyne react with alcohols through conventional transfer hydro-
genation pathways to form aldehyde products. Use of 3-alkynes
such as 1-cyclopentyl-1-butyne provides a 21% isolated yield of
C−C coupling product with excellent (Z)-stereoselectivity but as a
mixture of regio- and diastereomers.
To gain insight into the catalytic mechanism and the origins
of (Z)-olefin stereoselectivity, a series of deuterium labeling
studies were performed. In one experiment, the deuterium-
labeled alkyne, deteurio-1d, was employed as a reactant in the
absence of 2-propanol under otherwise standard conditions.
In a second experiment, the deuterium-labeled alcohol, deuterio-
2c, was employed as a reactant in the absence of 2-propanol.
Finally, the unlabeled alkyne 1d and alcohol 2c were reacted
a
Yields are of material isolated by silica gel chromatography. See
b
Supporting Information for further experimental details. H2Ru-
(CO)(PPh3)3 (7.5 mol%), 2,4,6-(2-Pr)3PhSO3H (21 mol%). Ru-
(O2CCF3)2(CO)(PPh3)2 (10 mol%), omit 2,4,6-(2-Pr)3PhSO3H.
c
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Communication
Scheme 3. Deuterium Labeling Studies and Proposed General Catalytic Mechanism Accounting for (Z)-Stereoselectivity and
a
the Roughly Equal Isotopic Compositions at Ha, Hc, and Hd in Different Labeling Experiments
a
The extent of 2H incorporation was determined using 1H and 2H NMR. For the deuterium labeling experiments, reactions were conducted under
standard conditions except for the indicated changes. See Supporting Information for further experimental details, including equations accounting for
the regioselectivity and extent of deuterium incorporation at positions Ha−He.
with d8-2-propanol. For each experiment, the pattern of deuterium
incorporation evident in the reaction product, deuterio-4p, was
1
2
determined by H and H NMR spectroscopy (Scheme 3).
Notably, the isotopic composition at the vinylic hydrogen Ha is
roughly equivalent to the isotopic composition of the allylic
hydrogens Hc and Hd for each experiment.
On the basis of these data, the indicated catalytic mechanism
was proposed (Scheme 3). The ruthenium bis-sulfonate
complex LnRuII(O3SAr)2 reacts with alcohol 2c to form the
ruthenium alkoxide I. β-Hydride elimination from alkoxide I pro-
vides the aldehyde 3c and the hydridoruthenium sulfonate II,
which upon loss of HO3SAr delivers the zerovalent ruthenium
complex III. Such alcohol mediated reductions of LnRuII(X)2 to
LnRu0 have been described.10 Propargyl C−H oxidative addition
from alkyne complex IV delivers the propargyl complex V, which
undergoes reductive elimination from the allenylruthenium
hydride VI (Path A)11 to provide the allene VII.12,13 Allene−
carbonyl oxidative coupling provides the oxaruthenacycle
VIII,14 defining the olefin (Z)-stereochemistry. Protonolytic
cleavage of the metallacycle delivers the (Z)-homoallylic alcohol 4p
and regenerates LnRuII(O3SAr)2 to close the catalytic cycle. Alter-
natively, the propargyl hydride complex V may hydrometallate
internally (Path B) to form the indicated alkylidine ruthenacyclo-
propane, which is a mesomeric form of VII-RuLn by virtue of
π-backbonding.15 Mechanisms involving intervention of homo-
propargylic alcohols were considered, but appear inconsistent with
the observed patterns of deuterium incorporation.
To challenge the veracity of this interpretation of the mecha-
nism, allene VII was subjected to standard coupling conditions
with alcohol 2c (eq 5) and aldehyde 3c (eq 6). In each experi-
ment, the product of (Z)-allylation 4p was formed in small
quantities along with a substantial amount of allene dimerization16
(possibly [2+2] cycloadducts)16b and hydrodimerization17 prod-
ucts (VII)2,18,19 which appear as a complex mixture of isomers as
determined by HRMS and GC-MS analysis (see Supporting
Information). Unreacted allene VII was not detected. Finally,
whereas reaction of alkyne 1c with alcohol 2c under standard
conditions provides the (Z)-homoallylic alcohol 4c in 70% yield
(Table 1), the same reaction conducted in the presence of allene
dimer/hydrodimer (VII)2 provides a 12% yield of 4c (eq 7).
Thus, competing allene dimerization and hydrodimerization not
only diverts material to alternate reaction products, but the allene
dimer/hydrodimer (VII)2 itself suppresses the (Z)-allylation path-
way, making reactions involving stoichiometric loadings of allene
VII intrinsically less efficient. These data suggest one important
feature of the present catalytic system is that the requisite allene
does not accumulate, but is generated transiently in a pairwise
fashion with the aldehyde. A low steady state concentration of
allene is important to suppress ruthenium-catalyzed allene
dimerization,16,18 hydrodimerization17 or thermally promoted allene
[2+2] cycloaddition,19 to produce dimers that poison the catalyst.
In summary, exposure of 2-alkynes and alcohols to the ruthenium
catalyst generated in situ upon the acid−base reaction of
H2Ru(CO)(PPh3)3 and 2,4,6-(2-Pr)3PhSO3H results in the
formation of (Z)-homoallylic alcohols with good to complete
control of olefin geometry. In a series of deuterium labeling
experiments, roughly equal isotopic composition is observed at the
allylic and distal vinylic positions of the product, corroborating a
catalytic mechanism wherein alkyne-to-allene isomerization precedes
allene−carbonyl oxidative coupling to form a geometrically defined
oxaruthenacycle. These studies contribute to the growing body of
redox-triggered alcohol C−C couplingsnew carbonyl addition
chemistry that extends beyond the use of premetalated reagents.3
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Journal of the American Chemical Society
Communication
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
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 Dorothy B. Banks graduate fellowship
program (B.Y.P.) are acknowledged for partial support of this
research
(16) For intermolecular ruthenium-catalyzed allene dimerization,
including [2+2] cycloaddition, see: (a) Yoshida, M.; Gotou, T.; Ihara,
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NOTE ADDED AFTER ASAP PUBLICATION
■
After this Communication was published ASAP on July 30,
2014, the list of authors was changed. The corrected version
was reposted August 6, 2014.
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