Conversion of Aldehydes to Branched or Linear Ketones via Regiodivergent Rhodium-Catalyzed Vinyl Bromide Reductive Coupling-Redox Isomerization Mediated by Formate

Article abstract of DOI:10.1021/jacs.9b03113

A regiodivergent catalytic method for direct conversion of aldehydes to branched or linear alkyl ketones is described. Rhodium complexes modified by P^tBu₂Me catalyze formate-mediated aldehyde-vinyl bromide reductive coupling-redox isomerization to form branched ketones. Use of the less strongly coordinating ligand, PPh₃, promotes vinyl-to allylrhodium isomerization en route to linear ketones. This method bypasses the 3-step sequence often used to convert aldehydes to ketones involving the addition of pre-metalated reagents to Weinreb or morpholine amides.

Full text of DOI:10.1021/jacs.9b03113

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Conversion of Aldehydes to Branched or Linear Ketones via
Regiodivergent Rhodium-Catalyzed Vinyl Bromide Reductive
Coupling−Redox Isomerization Mediated by Formate
Robert A. Swyka,† William G. Shuler,† Brian J. Spinello, Wandi Zhang, Chunling Lan,
and Michael J. Krische*
Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States
S
* Supporting Information
ABSTRACT: A regiodivergent catalytic method for
direct conversion of aldehydes to branched or linear
alkyl ketones is described. Rhodium complexes modified
by PtBu2Me catalyze formate-mediated aldehyde−vinyl
bromide reductive coupling−redox isomerization to form
branched ketones. Use of the less strongly coordinating
ligand, PPh3, promotes vinyl- to allylrhodium isomer-
ization en route to linear ketones. This method bypasses
the 3-step sequence often used to convert aldehydes to
ketones involving the addition of pre-metalated reagents
to Weinreb or morpholine amides.
etones are of commercial significance across the
Kpharmaceutical, agrochemical, and flavor−fragrance in-
dustries. Convergent manufacturing routes to ketones from
aldehydes often rely on 3-step sequences involving the addition
of stoichiometric organometallic reagents to alkoxy-amides,1
such as the Weinreb amide2,3 or morpholine amides (Figure 1).4
Alternatively, 2-step ketone syntheses can be achieved through
the addition of vinylmetal reagents to aldehydes followed by
internal redox isomerization of the resulting allylic alcohols.5,6 In
Figure 1. Classical and contemporary strategies for the convergent
construction of linear or branched alkyl ketones.
connection with long-standing efforts to develop reductive C−C
couplings via transfer hydrogenation,7,8 we envisioned a direct
protocol for the conversion of aldehydes to ketones wherein
vinyl halide−carbonyl reductive coupling is followed by internal
redox isomerization. This transformation finds precedent in our
recently reported rhodium-catalyzed aryl halide−aldehyde
reductive coupling mediated by sodium formate,9,10 as well as
related redox-neutral aryl halide−aldehyde C−C couplings to
form aryl ketones.11 As described herein, our pursuit of this goal
has resulted in the development of a direct, regiodivergent12
vinyl bromide−aldehyde reductive coupling to form either linear
or branched ketone products.13−16
In an initial experiment, piperonal 1a (100 mol%) and 2-
bromopropene 2a (200 mol%) were exposed to NaO2CH (300
mol%) and Cs2CO3 (100 mol%) in the presence of the catalyst
assembled from Rh(acac)(CO)2 (5 mol%) and PtBu2Me (11
mol%) in DME (0.2 M) at 130 °C.9 The anticipated branched
ketone product 3a was formed in 45% yield after isolation by
flash column chromatography (Table 1, entry 1). A survey of
phosphine ligands was undertaken (Table 1, entries 1−10).
Remarkably, use of PPh3 under otherwise identical conditions
led to a 48% yield of the linear ketone product 4a.13 The isolated
yield of linear ketone 4a was elevated to 77% yield upon use of
KO2CH (300 mol%) and K2CO3 (100 mol%) (Table 1, entry
12). Finally, by lowering the loading of K2CO3 (70 mol%), the
formation of a competing elimination side product, 5-(1-
butenyl)-1,3-benzodioxole, could be attenuated, enabling
formation of linear ketone 4a in 92% yield (Table 1, entry
13). Dry KO2CH (vide infra) and dry DME were required for
optimal isolated yields. Using PtBu2Me as ligand under these
conditions delivered the branched ketone 3a in 54% yield
(Table 1, entry 14), and at higher concentration (0.4 M) the
isolated yield of 3a was increased to 80% (Table 1, entry 15).
Notably, while optimal conditions for formation of the linear
and branched ketones 3a and 4a differ primarily on the basis of
ligand (Table 1, entries 13 vs 15), virtually complete partitioning
of these constitutionally isomeric products was observed (>40:1
1
isomeric ratios were observed by H NMR analysis of crude
reaction mixtures).
Received: March 21, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b03113
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
To evaluate reaction scope, optimal conditions identified for
the conversion of piperonal 1a to the constitutionally isomeric
branched and linear ketone products 3a and 4a were applied to
diverse aldehydes 1a−1r (Table 2). Aromatic aldehydes 1a−1k,
heteroaromatic aldehydes 1l−1m, and aliphatic aldehydes 1n−
1r were converted to the respective branched ketones 3a−3r or
linear ketones 4a−4r in generally good yields. With the
exception of branched ketone 3m, the chromatographically
isolated products appeared to be isomerically pure by 1H NMR
analysis. For 3m, delocalization of the pyrazole nitrogen might
deactivate the aldehyde toward insertion, providing a kinetic
window for competing branched-to-linear isomerization. For
optimal results, it was necessary to use freshly distilled DME and
KO2CH recrystallized from ethanol. The recrystallized KO2CH
was collected by filtration and washed with diethyl ether under
an inert atmosphere. If wet KO2CH is used, significant quantities
of aldehyde reduction and oxidative esterification are observed.
For reactions run on a 1 mmol scale, it was important to utilize a
narrow reaction vessel at low volume (10−20%).
Table 1. Selected Optimization Experiments in the Rhodium-
Catalyzed Reductive Coupling of 2-Bromopropene 2a with
Piperonal 1a To Form the Isomeric Ketones 3a and 4a
a
The feasibility of utilizing alternate vinyl bromides 2b and 2c
in regiodivergent reductive coupling−internal redox isomer-
ization was briefly investigated in reactions of piperonal 1a.
Under optimal conditions using PtBu2Me as ligand, the
anticipated branched ketones 3s and 3t were formed in good
yields (eq 1). However, when optimal conditions for formation
a
Yields are of chromatographically isolated isomerically pure (>20:1)
material. PtBu2Me·HBF4, PtBu3·HBF4, and PtBu2Ph (PhMe, 50 wt%)
were used. Bidentate ligands (5.5 mol%). See Supporting Information
for experimental details. K2CO3 (70 mol%). DME (0.4 M).
b
c
Table 2. Rhodium-Catalyzed Reductive Coupling−Internal Redox Isomerization of 2-Bromopropene 2a with Aldehydes 1a−1r
a
To Form the Branched Ketones 3a−3r or Linear Ketones 4a−4r
a
Standard conditions: Branched: aldehyde 1a−1r (100 mol%), 2-bromopropene (200 mol%), Rh(acac)(CO)2 (5 mol%), PtBu2Me·HBF4
(11 mol%), K2CO3 (70 mol%), KO2CH (300 mol%), DME (0.4 M), 130 °C. Linear: aldehyde 1a−1r (100 mol%), 2-bromopropene (200 mol%),
b
c
Rh(acac)(CO)2 (5 mol%), PPh3 (11 mol%), K2CO3 (70 mol%), KO2CH (300 mol%), DME (0.2 M), 130 °C. K2CO3 (30 mol%). K2CO3
d
e
omitted. DME (0.2 M), 130 °C. 120 °C. Yields are of chromatographically isolated material. As the isomeric ketone products are inseparable via
1
conventional flash chromatography, isomeric ratios were determined from H NMR analysis of isolated products.
B
DOI: 10.1021/jacs.9b03113
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Journal of the American Chemical Society
Communication
Scheme 1. General Catalytic Mechanism Accounting for Regiodivergence in the Rhodium-Catalyzed Aldehyde Reductive
Coupling of 2-Bromopropene 2a To Form Isomeric Ketones 3a−3r and 4a−4r
of the linear products using PPh3 as ligand were applied, the
linear ketones were not obtained in isomerically pure form. This
limitation was easily overcome through use of the isomeric
terminal vinyl bromides iso-2b and iso-2c, which deliver the
constitutionally isomeric linear ketones 4s and 4t, albeit in
modest yield (eq 2).
To gain insight into the catalytic cycle, a series of deuterium
labeling experiments were performed (eqs 3−6). Exposure of
aldehyde deuterio-1a to 2-bromopropene 2a under standard
conditions favoring formation of the branched regioisomer
delivers deuterio-3a, which incorporates a single deuterium atom
(>95% 2H) at the methyl group of the isopropyl ketone (eq 3).
As deuterio-3a is postulated to arise via isomerization of the
corresponding allylic alcohol deuterio-iso-3a, the latter com-
pound was subjected to standard conditions favoring formation
of the branched regioisomer (eq 4). In this case, deuterium was
donor ligand PtBu2Me, aldehyde insertion occurs to form a
rhodium alkoxide.18 The bromide moiety of the kinetic rhodium
alkoxide can react with KO2CH to form a hydride, which upon
O−H reductive elimination19 delivers the allylic alcohol and,
therefrom, the branched ketone. Alternatively, the kinetic
rhodium alkoxide can undergo β-hydride elimination to form
an enone, which undergoes conjugate reduction to form the
branched ketone (not shown). For the weak σ-donor ligand
PPh3, phosphine dissociation at the stage of the vinylrhodium-
(III) intermediate triggers β-hydride elimination to form a
transient allene, which upon hydrometalation delivers an
allylrhodium(III) species.13 Aldehyde insertion delivers a
homoallylic rhodium alkoxide,18 which is ultimately converted
to the linear ketone. Coupling products were not formed in
reactions using other weakly coordinating monodentate ligands,
for example, P(OPh)3, P(C6F5)3, or P(2-Fur)3.
2
incorporated at both the methyl group (92% H) and the
2
methine moieties (8% H) of the isopropyl ketone. Similarly,
deuterio-1a and the homoallylic alcohol deuterio-iso-4a were
exposed to standard conditions favoring formation of the linear
regioisomer (eqs 5 and 6). The resulting n-propyl ketones
deuterio-4a and deuterio-4a′ display similar but non-identical
patterns of deuterium incorporation. These data corroborate
allylic and homoallylic alcohols as reactive intermediates en route
to the branched and linear ketone products, respectively. The
non-identical patterns of deuterium incorporation between
deuterio-3a vs deuterio-3a′ and deuterio-4a vs deuterio-4a′ suggest
that redox isomerization may occur in part from the kinetic
rhodium alkoxide.
Based on the collective data, the catalytic cycle shown in
Scheme 1 is proposed. Vinyl bromide oxidative addition forms
the indicated vinylrhodium(III) species.17 For the strong σ-
In summary, we report a catalytic method enabling direct
conversion of aldehydes to alkyl ketones20−22 and establish
conditions for regiodivergent access to either the branched or
C
DOI: 10.1021/jacs.9b03113
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Journal of the American Chemical Society
Communication
(7) For selected reviews on transfer hydrogenative reductive coupling,
see: (a) Iida, H.; Krische, M. J. Catalytic Reductive Coupling of Alkenes
and Alkynes to Carbonyl Compounds and Imines Mediated by
Hydrogen. Top. Curr. Chem. 2007, 279, 77−104. (b) Hassan, A.;
Krische, M. J. Unlocking Hydrogenation for C−C Bond Formation: A
Brief Overview of Enantioselective Methods. Org. Process Res. Dev.
2011, 15, 1236−1242. (c) Moran, J.; Krische, M. J. Formation of C-C
Bonds via Ruthenium Catalyzed Transfer Hydrogenation. Pure Appl.
Chem. 2012, 84, 1729−1739. (d) Ketcham, J. M.; Shin, I.;
Montgomery, T. P.; Krische, M. J. Catalytic Enantioselective CH
Functionalization of Alcohols by Redox-Triggered Carbonyl Addition:
Borrowing Hydrogen, Returning Carbon. Angew. Chem., Int. Ed. 2014,
53, 9142−9150. (e) Nguyen, K. D.; Park, B. Y.; Luong, T.; Sato, H.;
Garza, V. J.; Krische, M. J. Metal-catalyzed reductive coupling of olefin-
derived nucleophiles: Reinventing carbonyl addition. Science 2016, 354,
aah5133. (f) Kim, S. W.; Zhang, W.; Krische, M. J. Catalytic
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Mediated Hydrogen Transfer: Merging the Chemistry of Grignard and
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linear ketone isomers. Specifically, using the rhodium catalyst
modified by PtBu2Me, vinyl halide−aldehyde reductive coupling
mediated by formate is followed by redox isomerization of the
resulting allylic alcohol to form branched ketone products. In
contrast, use of a less strongly coordinating ligand, Ph3P,
promotes vinyl- to allylrhodium isomerization en route to linear
ketones. This method bypasses the 3-step sequence often used
to convert aldehydes to ketones involving the addition of
stoichiometric organometallic reagents to Weinreb or morpho-
line amides.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b03113.
■
S
Experimental procedures and spectral data (PDF)
(8) For general reviews on carbonyl reductive coupling, see:
(a) Moragas, T.; Correa, A.; Martin, R. Metal-Catalyzed Reductive
Coupling Reactions of Organic Halides with Carbonyl-Type
Compounds. Chem. - Eur. J. 2014, 20, 8242−8258. (b) Holmes, M.;
Schwartz, L. A.; Krische, M. J. Intermolecular Metal-Catalyzed
Reductive Coupling of Dienes, Allenes, and Enynes with Carbonyl
Compounds and Imines. Chem. Rev. 2018, 118, 6026−6052.
(9) Swyka, R. A.; Zhang, W.; Richardson, J.; Ruble, J. C.; Krische, M. J.
Rhodium-Catalyzed Aldehyde Arylation via Formate-Mediated Trans-
fer Hydrogenation: Beyond Metallic Reductants in Grignard/Nozaki−
Hiyami−Kishi-Type Addition. J. Am. Chem. Soc. 2019, 141, 1828−
1832.
AUTHOR INFORMATION
Corresponding Author
*mkrische@mail.utexas.edu
ORCID
■
Michael J. Krische: 0000-0001-8418-9709
Author Contributions
†R.A.S. and W.G.S. contributed equally.
Notes
The authors declare no competing financial interest.
(10) For a related aryl halide−carbonyl reductive cyclization mediated
by elemental hydrogen, see: Shin, I.; Ramgren, S. D.; Krische, M. J.
Reductive Cyclization of Halo-Ketones to form 3-hydroxy-2-oxindoles
via Palladium Catalyzed Hydrogenation: a Hydrogen-mediated
Grignard Addition. Tetrahedron 2015, 71, 5776−5780.
ACKNOWLEDGMENTS
■
The authors thank the Robert A. Welch Foundation (F-0038)
and the NIH-NIGMS (RO1-GM069445) for support. Eli Lilly
and Company is acknowledged for LIFA postdoctoral fellowship
funding (R.A.S.).
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(17) For studies on the oxidative addition of aryl and vinyl halides to
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Aryl Bromides: Aryl−Br and Phosphine Ligand C−H Activation. Chem.
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Chelation-Assisted Carbon-Halogen Bond Activation by a Rhodium(I)
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Chaplin, A. B.; Weller, A. S. Dihydrogen Loss from a 14-Electron
Rhodium(III) Bis-Phosphine Dihydride To Give a Rhodium(I)
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Organometallics 2008, 27, 2918−2921. (e) Bisphosphine complexes:
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E
DOI: 10.1021/jacs.9b03113
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX