Conversion of Primary Alcohols and Butadiene to Branched Ketones via Merged Transfer Hydrogenative Carbonyl Addition-Redox Isomerization Catalyzed by Rhodium

Article abstract of DOI:10.1021/jacs.1c07230

The first examples of rhodium-catalyzed carbonyl addition via hydrogen autotransfer are described, as illustrated in tandem butadiene-mediated carbonyl addition-redox isomerizations that directly convert primary alcohols to isobutyl ketones. Related reductive coupling-redox isomerizations of aldehyde reactants mediated by sodium formate also are reported. A double-labeling crossover experiment reveals that the rhodium alkoxide obtained upon carbonyl addition enacts redox isomerization without dissociation of rhodium at any intervening stage.

Full text of DOI:10.1021/jacs.1c07230

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Conversion of Primary Alcohols and Butadiene to Branched Ketones
via Merged Transfer Hydrogenative Carbonyl Addition−Redox
Isomerization Catalyzed by Rhodium
Brian J. Spinello, Jessica Wu, Yoon Cho, and Michael J. Krische*
Cite This: J. Am. Chem. Soc. 2021, 143, 13507−13512
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ABSTRACT: The first examples of rhodium-catalyzed carbonyl addition via hydrogen autotransfer are described, as illustrated in
tandem butadiene-mediated carbonyl addition−redox isomerizations that directly convert primary alcohols to isobutyl ketones.
Related reductive coupling−redox isomerizations of aldehyde reactants mediated by sodium formate also are reported. A double-
labeling crossover experiment reveals that the rhodium alkoxide obtained upon carbonyl addition enacts redox isomerization without
dissociation of rhodium at any intervening stage.
etal-catalyzed carbonyl reductive coupling has emerged
1
Mas an important method for C−C bond formation.
These processes unlock the possibility of replacing stoichio-
metric organometallic reagents with safer and more tractable
pro-nucleophiles, including abundant π-unsaturated feed-
stocks2 such as α-olefins,3 styrene,4 acetylene,5 and butadiene.6
Despite the promise of this approach, catalytic reactions of this
type often require reductants that are not ideal (Mn, Zn, Et3B,
Et2Zn, and HSiR3).1 Consequently, work from our laboratory
has focused on the use of feedstock reductants (H2, 2-PrOH,
and HCO2H) in metal-catalyzed carbonyl reductive cou-
pling.7,8c Additionally, we have developed a unique class of
hydrogen autotransfer processes in which alcohols serve dually
as reductants and carbonyl pro-electrophiles, thus enabling
direct conversion of lower alcohols to higher alcohols.7,8c
Given the commercial significance of ketones across diverse
chemical industries, and the fact that classical methods for their
convergent construction rely on premetalated reagents,9,10
efforts were made to exploit hydrogen transfer in metal-
catalyzed ketone syntheses beyond premetalated reagents or
metallic reductants (Figure 1). Preexisting methods of this type
include hydroacylation (which typically requires β-chelating
groups to suppress decarbonylation),11,12 “oxa-Heck” reactions
(which are restricted to aryl transfer),13−15 two reports of the
reductive coupling of styrenes with anhydrides,4a,c and, finally,
recently reported formate-mediated reductive coupling−redox
isomerizations of aldehydes and vinyl halides16a or triflates.16b
Here, we report a method for the direct redox−neutral
Figure 1. Classical vs catalytic methods for convergent ketone
construction.
conversion of primary benzylic or aliphatic alcohols and
butadiene (12 × 106 tons/year) to branched ketones via
merged transfer hydrogenative carbonyl addition−redox
isomerization.17−20 These processes represent the first
Received: July 12, 2021
Published: August 20, 2021
examples of rhodium-catalyzed carbonyl addition via hydrogen
autotransfer.7,8c
In an initial experiment, 3-methoxybenzyl alcohol 1a (100
mol%) and butadiene 2a (500 mol%) were exposed to K2CO3
(20 mol%) in the presence of the catalyst derived from
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The yield of 3a was further improved to 87% by increasing the
loading of K2CO3 (50 mol%) (Table 1, entry 6). Deviation
from the latter conditions did not enhance the yield of 3a
(Table 1, entries 7−11). In particular, omission of K2CO3
resulted in a significantly lower yield of 3a (Table 1, entry 7).
The importance of base is also reflected by the sensitivity of
the catalyst system toward adventitious moisture. Whereas
reactions run in “wet” PhCl enable formation of 3a in 87%
yield (Table 1, entry 6), use of “anhydrous” PhCl as solvent
resulted in a 58% yield of 3a (not shown). A sample of both
“wet” and “anhydrous” PhCl was subjected to Karl Fischer
titration, revealing “anhydrous” PhCl contained 61.1 ppm
water, whereas “wet” PhCl contained 138 ppm water.
Deliberate use of water as an additive or cosolvent, however,
led to low isolated yields of 3a. We speculate that adventitious
water solubilizes K2CO3, but excess moisture may lead to
formation of hydroxy-bridged rhodium dimers, which were
demonstrated to be catalytically inactive.
Table 1. Selected Optimization Experiments in the Tandem
Rhodium-Catalyzed Transfer Hydrogenative Coupling−
a
Redox Isomerization of Alcohol 1a with Butadiene 2a
To evaluate reaction scope, optimal conditions for the
conversion of 1a to branched ketone 3a were applied to
diverse benzylic alcohols 1a−1r (Scheme 1). Transfer
hydrogenative carbonyl addition−redox isomerization to
form adducts containing electronically diverse aromatic (3a−
3l) and heteroaromatic (3m−3r) rings occurred efficiently.
This includes compounds containing furan (3m), benzothio-
phene (3n), indole (3o), pyridine (3q), and pyrimidine (3r)
substructures. Application of these conditions to aliphatic
alcohols led to low isolated yields of the corresponding
ketones. Following additional optimization (see the Supporting
Information for details), it was found that the catalyst
assembled in situ from Rh(cod)2OTf (7.5 mol%) and P(p-F-
Ph)3 (18 mol%) delivered 3s in 75% yield. These conditions
a
Yields are of material isolated by silica gel chromatography. The
loading of dimeric rhodium precatalysts was 2.5 mol%. See the
Supporting Information for experimental details.
Rh(acac)(CO)2 (5 mol%) and PPh3 (11 mol%) in PhCl (0.2
M) at 130 °C.16 The desired branched ketone 3a was isolated
by flash column chromatography in 13% yield along with a
substantial quantity of unreacted alcohol 1a (Table 1, entry 1).
It was postulated that a cationic rhodium catalyst might
facilitate β-hydride elimination of the transient rhodium
alkoxide. Indeed, upon evaluation of different rhodium
precatalysts (Table 1, entries 1−5), a 70% isolated yield of
F
3a was obtained by using Rh(cod)2BAr4 (Table 1, entry 5).
Scheme 1. Rhodium-Catalyzed Tandem Transfer Hydrogenative Coupling−Redox Isomerization of Primary Alcohols 1a−1x
a
with Butadiene 2a to Form Isobutyl Ketones 3a−3x
a
b
Yields are of material isolated by silica gel chromatography. See the Supporting Information for experimental details. Conditions A: alcohol (100
c
F
mol%), butadiene (500 mol%), Rh(cod)2BAr4 (5 mol%), PPh3 (11 mol%), K2CO3 (50 mol%), PhCl (0.2 M), 130 °C. Conditions B: alcohol
d
(100 mol%), butadiene (500 mol%), Rh(cod)2OTf (7.5 mol%), P(p-F-Ph)3 (18 mol%), K2CO3 (70 mol%), PhCl (0.2 M), 130 °C. Butadiene
e
f
g
h
(800 mol%). K2CO3 (30 mol%). K2CO3 (70 mol%). K2CO3 (90 mol%). Rh(cod)2OTf (10 mol%), P(p-F-Ph)3 (24 mol%).
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enabled conversion of aliphatic alcohols 1t−1x to branched
ketones 3t−3x in good isolated yields. Under the present
conditions, butadiene is a superior partner for C−C coupling.
As illustrated by the conversion of alcohol 1a with isoprene 2b
to deliver sec-isoamyl ketone 4a (eq 1), the coupling of higher
Scheme 3. Deuterium-Labeling Studies and Double-
Labeling Crossover Experiment
a
dienes is possible. However, attempted reactions of more
complex dienes (myrcene, 2-phenylbutadiene, 1,3-cyclohexa-
diene, and 1,3-pentadiene) using this first-generation catalytic
system resulted in low conversion to the targeted ketone
products (10−15% yield).
Whereas reactions that convert primary alcohols 1a−1x to
isobutyl ketones 3a−3x are redox-neutral processes involving
hydrogen autotransfer, the conversion of aldehyde reactants to
isobutyl ketones would represent a reductive process. As
documented in the review literature,1i only a single method for
rhodium-catalyzed reductive coupling of acyclic dienes with
unactivated aldehydes has been reported, which utilizes Et3B (a
pyrophoric liquid) as reductant.20 The development of a
diene−aldehyde reductive coupling−redox isomerization
mediated by abundant feedstock reductants (H2, 2-PrOH,
and NaO2CH) would be more desirable.2 To our delight, it
was found that exposure of aldehydes dehydro-1a, dehydro-1g,
and dehydro-1s to butadiene 2a under standard conditions in
the presence of sodium formate (500 mol%) enabled
formation of the corresponding isobutyl ketones 3a, 3g, and
3s in good yield (Scheme 2).
a
The structural assignment of all deuterated compounds are based on
1H NMR, 2H NMR, and HRMS analyses. 100% 2H refers to
incorporation of a single deuterium atom at the indicated position.
See the Supporting Information for experimental details.
2
was transferred to the β-carbon (20% H at Hβ), the γ-carbon
(95% H at Hγ), and the α-methyl carbon (27% H at HMe).
Deuterium was not observed at the α-carbon (0% H at Hα).
As branched homoallylic alcohols are putative intermediates in
the formation of the isobutyl ketones 3a−3x, iso-deuterio-3a
was subjected to standard reaction conditions in the absence of
butadiene (to mitigate deuterium loss). The anticipated
isobutyl ketone deuterio-3a′ was obtained, which incorporates
deuterium at the β-carbon (43% 2H at Hβ), the γ-carbon (10%
2H at Hγ), and the α-methyl carbon (42% 2H at HMe) but not
2
2
2
To gain insight into the catalytic mechanism, deuterium
labeling experiments were performed (Scheme 3). Exposure of
d2-3-methoxybenzyl alcohol, deuterio-1a, to standard reaction
conditions provides the isobutyl ketone deuterio-3a. Deuterium
Scheme 2. Rhodium-Catalyzed Tandem Formate-Mediated
Reductive Coupling−Redox Isomerization of Aldehydes
dehydro-1a, dehydro-1g, and dehydro-1s with Butadiene 2a to
a
2
Form Isobutyl Ketones 3a, 3g, and 3s
at the α-carbon (0% H at Hα). The absence of deuterium at
the α-carbon is due to protonation of a transient rhodium(I)
enolate (that arises via hydrometalation of an intermediate
enone) by primary alcohol reactant or secondary alcohol
product. Whereas 71% total deuterium transfer was observed
in the initial deuterium labeling experiment, 95% total
deuterium transfer was observed in the latter experiment,
which is conducted in the absence of butadiene. Indeed, it was
found that the extent of deuterium transfer was dependent
upon the loading of butadiene (not shown). Finally, a double-
labeling crossover experiment was conducted in which the
homoallylic alcohols iso-deuterio-3a and iso-3i were exposed to
standard reaction conditions in the absence of butadiene.
Crossover of deuterium or hydrogen into the resulting ketones
deuterio-3a″ and 3i′ is not observed. The collective data
suggest that both formation of the allylrhodium intermediate
from butadiene and internal redox isomerization17,18 occur via
rapid, reversible, and nonregioselective hydrometalation events
and that the kinetic rhodium alkoxide enacts redox−isomer-
ization without dissociation of rhodium at any intervening
stage.
a
Yields are of material isolated by silica gel chromatography. See the
Supporting Information for experimental details.
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a
Scheme 4. General Catalytic Mechanism for Transfer Hydrogenative Carbonyl Addition
a
As corroborated by deuterium labeling studies, dissociation of rhodium does not occur at any stage of the redox isomerization event.
A general catalytic mechanism consistent with the results of
deuterium labeling has been proposed (Scheme 4). Entry into
the catalytic cycle via formation of a rhodium(I) alkoxide is
followed by β-hydride elimination to generate an aldehyde and
a rhodium(I) hydride. Hydrorhodation of butadiene delivers a
nucleophilic allylrhodium(I) species that participates in
aldehyde addition to form a branched homoallylic rhodium(I)
alkoxide. This homoallylic rhodium(I) alkoxide affects redox
isomerization17,18 through a series of β-hydride elimination
hydrorhodation events to provide a rhodium enolate, which
upon exchange with reactant alcohol releases the isobutyl
ketone and regenerates the primary rhodium(I) alkoxide to
close the catalytic cycle. As established by the double-labeling
crossover experiment (Scheme 3), dissociation of rhodium
does not occur at any stage during the course of redox
isomerization.
In summary, we report the first examples of rhodium-
catalyzed carbonyl addition via hydrogen autotransfer, as
illustrated in tandem carbonyl addition−redox isomerizations
that directly convert primary alcohols and butadiene to
isobutyl ketones. Additionally, related aldehyde−butadiene
reductive couplings to form isobutyl ketones are achieved
using formate as the terminal hydrogen source. These studies
contribute to a growing class of atom-efficient processes that
convert abundant chemical feedstocks to value added products
in the absence of premetalated reagents or metallic
reductants.2,21
Jessica Wu − Department of Chemistry, University of Texas at
Austin, Austin, Texas 78712, United States
Yoon Cho − Department of Chemistry, University of Texas at
Austin, Austin, Texas 78712, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c07230
Author Contributions
J.W. and Y.C. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Robert A. Welch Foundation (F-0038) and the NIH-
NIGMS (RO1-GM069445) are acknowledged for partial
support of this research.
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■
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c07230.
Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Michael J. Krische − Department of Chemistry, University of
Texas at Austin, Austin, Texas 78712, United States;
Email: mkrische@mail.utexas.edu
Authors
Brian J. Spinello − Department of Chemistry, University of
Texas at Austin, Austin, Texas 78712, United States
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