Rhodium-Catalyzed Aldehyde Arylation via Formate-Mediated Transfer Hydrogenation: Beyond Metallic Reductants in Grignard/Nozaki-Hiyami-Kishi-Type Addition

Article abstract of DOI:10.1021/jacs.8b13652

The first intermolecular carbonyl arylations via transfer hydrogenative reductive coupling are described. Using rhodium catalysts modified by ^tBu₂PMe, sodium formate-mediated reductive coupling of aryl iodides with aldehydes occurs in a chemoselective fashion in the presence of protic functional groups and lower halides. This work expands the emerging paradigm of transfer hydrogenative coupling as an alternative to pre-formed carbanions or metallic reductants in C=X addition.

Full text of DOI:10.1021/jacs.8b13652

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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Rhodium-Catalyzed Aldehyde Arylation via Formate-Mediated
Transfer Hydrogenation: Beyond Metallic Reductants in Grignard/
Nozaki−Hiyami−Kishi-Type Addition
Robert A. Swyka,†,∥ Wandi Zhang,†,∥ Jeffery Richardson,‡ J. Craig Ruble,§ and Michael J. Krische*,†
†Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States
‡Discovery Chemistry Research and Technologies, Eli Lilly and Company Limited, Erl Wood Manor, Windlesham, Surrey GU20
6PH, United Kingdom
§Discovery Chemistry Research and Technologies, Eli Lilly and Company, Indianapolis, Indiana 46285, United States
S
* Supporting Information
ABSTRACT: The first intermolecular carbonyl arylations
via transfer hydrogenative reductive coupling are
described. Using rhodium catalysts modified by tBu2PMe,
sodium formate-mediated reductive coupling of aryl
iodides with aldehydes occurs in a chemoselective fashion
in the presence of protic functional groups and lower
halides. This work expands the emerging paradigm of
transfer hydrogenative coupling as an alternative to pre-
formed carbanions or metallic reductants in CX
addition.
ince the seminal work of Butlerov (1863),1a,b Reformatsky
1c
and Grignard (1900),1d the use of pre-formed
S(1887),
organometallic reagents in carbonyl addition has remained a
cornerstone of chemical synthesis.2 Countless protocols for the
addition of non-stabilized carbanions and their equivalents
(e.g., arylboron reagents)3f,g to carbonyl compounds and
imines now exist, including enantioselective methods.3 Never-
theless, the requisite organometallic nucleophiles complicate
large-volume applications due to issues of safety, the frequent
Figure 1. Classical carbonyl arylation and related catalytic reductive
couplings.
requirement of cryogenic conditions, and the separation/
disposal of metallic byproducts. While metal-catalyzed
reductive coupling represents an alternative to discrete
organometallic reagents in carbonyl addition, the terminal
reductants often utilized in such processes are metallic (Zn,
Mn), toxic (CrCl2), pyrophoric (BEt3, ZnEt2, AlMe3), or
expensive/mass-intensive (R3SiH).4 Using hydrogen, 2-prop-
anol, and formic acid, which are relatively benign, inexpensive,
low-molecular-weight reductants, diverse catalytic enantiose-
lective carbonyl and imine reductive coupling reactions were
developed in our laboratory,4b,d,e,g,i,l including aldol addition-
s,5a vinylations,5b allylations,4l,5c−e and propargylations.4l,5f,g
Here, we report the first examples of intermolecular carbonyl
arylation via metal-catalyzed transfer hydrogenation, representing
the first intermolecular carbonyl−aryl halide reductive couplings
beyond metallic reductants (Figure 1).6,7
via hydrogenation or transfer hydrogenation have not been
described, almost certainly due to competing hydrogenolysis of
the aryl halide.10 Despite this lack of precedent, a hydrogen-
mediated Grignard-type cyclization was recently developed in
our laboratory.11 While these conditions were not applicable to
intermolecular carbonyl reductive couplings, related redox-
neutral aryl halide−aldehyde couplings to form ketone
products have been reported.12 In these processes, Ar−X
oxidative addition is followed by carbonyl insertion to form a
metal alkoxide, which upon β-hydride elimination and H−X
reductive elimination returns the metal to its low-valent form.
It was posited that interception of the metal alkoxide derived
upon carbonyl arylation by 2-propanol or a formate salt might
enable reductive arylation to form secondary alcohol products.
Aside from the Nozaki−Hiyami−Kishi reaction,6,7 surpris-
ingly few intermolecular metal-catalyzed aryl halide−aldehyde
reductive couplings have been reported, all of which are
mediated by elemental zinc8 (or an Mn−Cr alloy)8c or are
conducted electrochemically.9 Reductive aldehyde arylations
Received: December 21, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b13652
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 1. Selected Optimization Experiments in the
Rhodium-Catalyzed Transfer Hydrogenative Aldehyde
Arylation
Table 2. Rhodium-Catalyzed Transfer Hydrogenative
Coupling of Aldehydes 1a−1u and Aryl Iodides 2a−2u To
a
a
Form Products of Reductive Arylation, 3a−3u
a
Yields are of material isolated by silica gel chromatography.
tBu2PMe·HBF4 was employed as ligand precursor. PtBu3 was used
as a 1.0 M solution in toluene. Lithium formate was used as the
monohydrate. The loading of bidentate ligands was 5.5 mol%. The
loading of dimeric rhodium pre-catalysts was 2.5 mol%. See
Supporting Information for further experimental details. Reaction
was conducted without Cs2CO3. 75 °C in DME or 130 °C in
diglyme. 2a (150 mol%).
b
c
d
With this strategy in mind, piperonal 1a (100 mol%) and 4-
iodotoluene 2a (200 mol%) were exposed to 2-propanol or
sodium formate in the presence of diverse palladium or
rhodium complexes. Using the catalyst derived from Rh(acac)-
(CO)2 (5 mol%) and PCy3 (11 mol%) with NaO2CH (300
mol%) as reductant and Cs2CO3 (100 mol%) as base in
dioxane (0.2 M) at 130 °C, the desired reductive coupling
product 3a was formed in 12% isolated yield (Table 1, entry
1). A range of other ligands were evaluated under these
conditions (Table 1, entries 1−8). It was found that the
catalyst formed in situ from Rh(acac)(CO)2 (5 mol%) and
tBu2PMe (11 mol%) delivered the benzhydryl alcohol 3a in
40% isolated yield (Table 1, entry 8). Increased efficiencies
were observed for reactions conducted in tert-amyl alcohol
(Table 1, entry 9) and dimethoxyethane (Table 1, entry 10),
which provided 64% and 72% isolated yields of 3a,
respectively. Deviation from the latter conditions did not
improve the yield of 3a (Table 1, entries 11−20). Lower
loadings of NaO2CH or 2a decreased the isolated yield of 3a.
NHC-modified rhodium complexes did not promote reductive
coupling.8g
a
All reactions were performed on a 0.20 mmol scale. Yield of material
isolated by silica gel chromatography. See Supporting Information for
further experimental details. [RhCl(CO)2]2 (2.5 mol%) was used.
b
3b, 3f, 3j, 3o, and 3p, aryl iodides may be activated in the
presence of aryl chlorides and bromides. Additionally, as
illustrated by the formation of 3c−3e, 3h, 3j−3l, 3n, and 3o,
fluorine-containing functional groups are tolerated. Notably, 2-
fluoro- and 2-chloro-containing 1-iodobenzenes 2l and 2o
were converted to adducts 3l and 3o, respectively, without
competing aryne formation.13 The formation of products 3g, 3i
and 3s, which incorporate alcohol, carbamate, and sulfonamide
groups, respectively, demonstrates the tolerance of acidic OH-
and NH-containing functional groups. Adducts 3e, 3h, and 3o,
which incorporate aromatic N-heterocycles, are formed
efficiently, as are adducts 3i and 3m, which contain methyl
sulfide and methyl ester moieties. The tolerance of ortho-
substituted iodides, as demonstrated by the formation of
adducts 3c, 3e, 3j−3l, 3n−3p, 3r, and 3tin particular the
formation of adduct 3c, derived from an ortho,ortho-
To evaluate reaction scope, optimal conditions identified for
the formation of 3a were applied to aldehydes 1a−1u and aryl
iodides 2a−2u (Table 2). Both aromatic (1a−1p) and
aliphatic aldehydes (1q−1u) underwent reductive coupling
efficiently, and diverse functional groups, including those that
are incompatible with main-group organometallic reagents,
were tolerated. As illustrated in the formation of compounds
B
DOI: 10.1021/jacs.8b13652
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
In summary, we report the first example of reductive
carbonyl arylation using a non-metallic reductant, sodium
formate. This process is non-cryogenic and can be applied in
the presence of functional groups that are typically not
compatible with traditional main-group organometallic re-
agents. This work, along with other hydrogen-transfer-
mediated carbonyl reductive couplings developed in our
laboratory, defines a departure from the use of pre-metalated
reagents in chemical synthesis. Future studies will focus on
development of related transfer hydrogenative couplings of
vinylic and saturated alkyl halides.
Scheme 1. Proposed Catalytic Mechanism for Rhodium-
Catalyzed Transfer Hydrogenative Arylation Mediated by
Formate
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b13652.
■
S
Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
*mkrische@mail.utexas.edu
■
ORCID
Jeffery Richardson: 0000-0002-4450-3828
Michael J. Krische: 0000-0001-8418-9709
Author Contributions
∥R.A.S. and W.Z. contributed equally.
Notes
disubstituted mesityl iodideis also notable. Finally, linear
and branched aliphatic aldehydes were converted to adducts
3q−3u without competing aldol dimerization. The primary
side reactions observed are reduction of the aldehyde,
dehydrohalogenation, or reductive dimerization of the aryl
iodide and ketone formation.12
To gain insight into the catalytic cycle, deuterium labeling
experiments were undertaken (eqs 1 and 2 in Scheme 1).
Exposure of the aldehyde deuterio-1a to 4-iodotoluene 2a
under standard reaction conditions resulted in the formation of
deuterio-3a, which completely retains deuterium at the carbinol
position (>95:5 2H) (eq 1). In a second experiment, aldehyde
1a and 4-iodotoluene 2a were subjected to standard reaction
conditions using NaO2CD (eq 2). The product 3a did not
incorporate deuterium. These results refute intervention of
ketone intermediates that might arise via β-hydride elimination
from the rhodium alkoxide derived upon carbonyl insertion
into the aryl−rhodium bond.14 Exposure of aryl ketones to the
standard reaction conditions results in only trace quantities of
carbonyl reduction product.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Robert A. Welch Foundation (F-0038) and the NIH-
NIGMS (RO1-GM069445) are acknowledged for generous
financial support. Eli Lilly and Company is acknowledged for
LIFA postdoctoral fellowship funding (R.A.S.).
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E
DOI: 10.1021/jacs.8b13652
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