Nickel-Catalyzed Addition of Aryl Bromides to Aldehydes to Form Hindered Secondary Alcohols

Article abstract of DOI:10.1021/jacs.8b13709

Transition-metal-catalyzed addition of aryl halides across carbonyls remains poorly developed, especially for aliphatic aldehydes and hindered substrate combinations. We report here that simple nickel complexes of bipyridine and PyBox can catalyze the addition of aryl halides to both aromatic and aliphatic aldehydes using zinc metal as the reducing agent. This convenient approach tolerates acidic functional groups that are not compatible with Grignard reactions, yet sterically hindered substrates still couple in high yield (33 examples, 70% average yield). Mechanistic studies show that an arylnickel, and not an arylzinc, adds efficiently to cyclohexanecarboxaldehyde, but only in the presence of a Lewis acid co-catalyst (ZnBr₂).

Full text of DOI:10.1021/jacs.8b13709

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Nickel-Catalyzed Addition of Aryl Bromides to Aldehydes To Form
Hindered Secondary Alcohols
Kevin J. Garcia, Michael M. Gilbert, and Daniel J. Weix*
Department of Chemistry, University of WisconsinMadison, Madison, Wisconsin 53706, United States
S
* Supporting Information
magnitude more abundant than aryl iodides (Scheme 1),10 but
their use in aldehyde arylation remains underdeveloped11−13
ABSTRACT: Transition-metal-catalyzed addition of aryl
halides across carbonyls remains poorly developed,
and a topic of current interest.14,15
especially for aliphatic aldehydes and hindered substrate
A major challenge for all of these reductive arylation
combinations. We report here that simple nickel
methods remains couplings with less reactive substrates. There
complexes of bipyridine and PyBox can catalyze the
are few examples of couplings with sterically hindered
addition of aryl halides to both aromatic and aliphatic
aldehydes16 and aryl halides.17 There are even fewer examples
aldehydes using zinc metal as the reducing agent. This
of coupling hindered aryl halides with aliphatic aldehydes,
convenient approach tolerates acidic functional groups
perhaps because aliphatic aldehydes are already deactivated
that are not compatible with Grignard reactions, yet
toward migratory insertion.18,19 We report here a solution to
sterically hindered substrates still couple in high yield (33
these challenging substrates as well as studies showing that the
examples, 70% average yield). Mechanistic studies show
key bond-forming step occurs by a 1,2-migratory insertion of
that an arylnickel, and not an arylzinc, adds efficiently to
cyclohexanecarboxaldehyde, but only in the presence of a
Lewis acid co-catalyst (ZnBr2).
arylnickel across the aldehyde.
Early experiments focused on coupling a branched aliphatic
aldehyde, cyclohexane carboxaldehyde, with a simple aryl
bromide, 4-bromoanisole, because no arylations of this type
were known. Confirming Cheng’s earlier report,13a we also
ross-coupling has revolutionized how molecules are
1
found that reactions with phosphine ligands gave a poor yield
Cmade. However, despite decades-old advancements in
(Table 1, entry 1). We next examined a variety of nitrogen
ligands, inspired by recent work by Fujihara and Martin with
activated carbonyls4 and Voskoboynikov’s positive results with
the rhodium-catalyzed addition of arylboronic acids to
aldehydes2,3 and the low functional-group compatibility of
organomagnesium and organolithium reagents, a recent
analysis of medicinal chemistry patents found that the
Grignard reaction remains among the most-used reactions.1b
This is in contrast to couplings with organic halides and
alkenes, where cross-coupling approaches have largely
supplanted other C−C bond-forming methods.1 This might
be because arylboron reagents require extra steps to synthesize,
often via reactive organometallic intermediates (Scheme 1).
A catalytic method for the direct addition of aryl halides to
aldehydes would be ideal, but relatively few couplings of this
type have been reported.4,5 The coupling of aryl iodides with
aldehydes in the presence of a reducing agent can be catalyzed
by Cr/Ni,6 Co,7 and Rh.8,9 Aryl bromides are an order of
Table 1. Aldehyde Arylation Optimization
entry
T (°C)
Zn (equiv)
L
yield (%)
1
2
3
4
5
6
7
80
80
80
80
60
60
60
2.5
2.5
2.5
2.5
1.5
1.5
1.5
L1
L3
L4
L6
L6
L7
L11
3
62
57
62
60
Scheme 1. Aldehyde Arylation Strategies
b
69 (64)
18
a
Reactions were run on 0.25 mmol scale in 1 mL of THF for 12 h.
Yields are corrected GC yields. For additional data on reactions with
b
L2, L5, and L8−L10, see the Supporting Information. Isolated yield
after column chromatography.
Received: December 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b13709
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Journal of the American Chemical Society
Communication
Scheme 2. Substrate Scope
a
Reactions were conducted on 0.5 mmol scale in 2 mL of THF for 12−16 h. Yields are isolated yields after chromatography on silica gel. X = Br for
b
all substrates unless otherwise noted. Isolated yield for a gram-scale reaction using standard glassware.
aromatic aldehydes.13d Many bidentate and tridentate ligands
provided secondary alcohol 23, but unsubstituted and alkyl-
substituted bipyridines provided the highest yield (Table 1,
entries 2−6). While we initially screened our reactions at 80
°C, we found that reactions conducted at 60 °C and with less
zinc provided nearly the same results (entries 4 and 5). The
side reaction that limits the yield of product 23 is pinacol
coupling of the aldehyde.20 The remaining aryl bromide is
converted into biaryl and hydrodehalogenated arene.
Adaptation of these conditions to benzaldehyde required
only a re-examination of the optimal ligands (Scheme 2). For
4-bromoanisole, 4,4′-di-tert-butyl-2,2′-bipyridine (L4) was
optimal (Scheme 2, product 1), but it only provided 17%
yield for ethyl 4-bromobenzoate (product 8). We found that
terpyridine ligands provided improved results and the
tetramethyl PyBox derivative L11 provided the highest yield
for this electron-poor aryl bromide (70% yield of 8).
The optimized conditions are applicable to a variety of
aldehydes and aryl bromides (Scheme 2). Notable features of
the scope are compatibility with both aromatic and aliphatic
aldehydes, tolerance for acidic functional groups (4, 5, 25,
27),21 and the ability to form hindered secondary alcohols
(15−22, 28−33).22 Finally, the chemistry is operationally
simple and scales well: 1.67 g of alcohol 29 was synthesized on
the benchtop using standard glassware without the need for
rigorous exclusion of oxygen.
These results are the state of the art for hindered secondary
alcohol synthesis without pre-formed organometallic reagents.
We could find no previous examples of coupling any aryl
bromide with a 2,6-disubsituted aldehyde (21, 22). Although a
few couplings with aliphatic aldehydes are known, it is notable
that no examples of 2° or 3° aldehydes have been reported
(23−33). Addition of hindered aryl groups, even to
unhindered aldehydes, is also challenging for published
B
DOI: 10.1021/jacs.8b13709
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Journal of the American Chemical Society
Communication
methods. As an extreme case, the only other examples of
coupling 2,4,6-triisopropylphenyl with aldehydes (as in 20 and
31) utilized aryllithium or arylmagnesium reagents. Finally, this
method could be used to form secondary alcohols from the
combination of hindered aryl bromides with hindered
aldehydes (20 and 28−33).
bromides is slowa catalytic reaction run without nickel does
not consume any 4-bromoanisole or cyclohexane carboxalde-
hydeand the Schlenk equilibrium to convert unreactive
ArZnBr into reactive Ar2Zn will be less favorable with added
ZnBr2. These results appear to rule out direct arylation via
diarylzinc reagents.
Given the large improvement in reactivity with sterically
hindered substrates compared to previous reports, it would be
beneficial to understand the mechanism. Five potential
mechanisms have strong precedent in the literature: (1) 1,2-
migratory insertion of an arylnickel(II) intermediate across the
aldehyde;13a,19 (2) 1,2-migratory insertion of an arylnickel(I)
intermediate across the aldehyde; (3) in situ formation of a
diarylzinc reagent23 that could react with the aldehyde;24 (4)
in situ formation of a radical from the aldehyde with
subsequent capture by arylnickel and reductive elimination;9,15
and (5) reaction of a (L)NiII(μ2-aldehyde) species with
arylzinc and subsequent reductive elimination.25 For a
bisphosphine nickel system, Cheng had suggested migratory
insertion via nickel(II) based upon the finding that a mixture
of Ni(cod)2 with L1, benzaldehyde, and bromoanisole only
formed alcohol product when zinc bromide was present.13a
Considering the differences in ligand and reactivity observed, it
was not clear if this hypothesis could be extended to our
system.
Second, we considered transmetalation of arylzinc reagents
with (L)NiII(μ2-aldehyde), followed by reductive elimination.
Reaction of pre-formed (L3)Ni0(cod) with aldehyde, followed
by 4-methoxyphenylzinc bromide formed no addition product
(Scheme 3). This rules out the intermediacy of (L3)NiII(μ2-
aldehyde) species.
Third, pre-formed (L3)NiII(2-cumyl)Br (37) only reacts
with cyclohexane carboxaldehyde to form product 29 in the
presence of zinc bromide (Scheme 4). This is consistent with
a
Scheme 4. Stoichiometric Reactions of (L)NiII(Ar)Br
A series of studies appears to rule out three of these
mechanisms and point to migratory insertion of arylnickel
across the aldehyde (Scheme 3). First, we found that arylzinc
Scheme 3. Reactivity of Arylzinc Bromide
a
Reactions were run at 0.0125 M in [Ni] in THF at 60 °C for 12 h.
Yield is corrected GC yield. See Supporting Information for additional
experiments and full details.
arylnickel(II) 1,2-migratory insertion. The role of ZnBr2 could
be to abstract a halide from 37 to form [(L)NiII(Ar)]ZnBr3,23b
accelerate migratory insertion via σ-coordination of the
carbonyl oxygen, or both. Finally, these conditions are not
consistent with formation of an alkyl radical from the aldehyde
because arylnickel(II) 37 is not sufficiently reducing.
To examine the possibility that reduction of 37 is
accelerated by abstraction of bromide by ZnBr2, we also
examined the addition of a strong single-electron reductant
that would not have a strong halide affinity or be able to form
an arylmetal reagent, Cp*2Co.26 This reaction resulted in no
product formation, in sharp contrast with the studies of
Fujihara with similar arylnickel(II) complexes and CO2.4a
When Cp*2Co and ZnBr2 were both added to the reaction of
(L3)NiII(2-cumyl)Br with cyclohexane carboxaldehyde, prod-
uct was formed, but in diminished yield compared to the
reaction without reductant. While we cannot rule out the
intermediacy of arylnickel(I), at this time we think an
arylnickel(II) is more likely.
a
Reaction conducted at 0.18 M ArZnBr with a 1:1 ratio of ArZnBr/
b
CyCHO. Reaction conducted with a 1:1:1 ratio of [Ni]/CyCHO/
ArZnBr.
Based upon these experiments, we propose the mechanism
in Scheme 5. Reduction of the nickel pre-catalyst forms 38, and
oxidative addition of Ar−Br forms 39. The pinacol side
product appears to arise from 38 because it was formed in
larger amounts in experiments that started with nickel(0) or in
experiments that generated nickel(0) in situ (Scheme 3 and
Supporting Information). Arylnickel(II) 39 interacts with
ZnBr2 and aldehyde to form a reactive intermediate, here
depicted with zinc coordination to the aldehyde as 40. 1,2-
reagents react slowly with cyclohexane carboxaldehyde to form
product 23 (20% yield after 24 h). We do not think that this
process is important in catalytic reactions because the amount
of product formed is diminished further when catalytic
(L3)NiBr2 is present (10% yield of 23 with equal amounts
of bianisole). The amount of diarylzinc present in solution
would likely be low because direct insertion of zinc into aryl
C
DOI: 10.1021/jacs.8b13709
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Journal of the American Chemical Society
Communication
Rochester), Melodie Christensen (Merck), who conducted
preliminary studies with phosphine ligands that led to this
work, Kai Kang (Univ. of Wisconsin−Madison) for the
synthesis of the arylnickel(II) complex, and Matthew J.
Goldfogel (Univ. of Wisconsin−Madison) for the synthesis
of a reductant used in mechanistic studies. We also thank
Chiral Technologies (Joe Barendt) for the donation of achiral
SFC columns used in this work.
Scheme 5. Proposed Mechanism
REFERENCES
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b13709.
Detailed procedures, additional optimization data, and
full characterization data (PDF)
AUTHOR INFORMATION
(6) (a) Furstner, A.; Shi, N. Nozaki−Hiyama−Kishi Reactions
̈
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Nickel(II) Chloride and Palladium(II) Acetate on Chromium(II)-
Mediated Coupling Reaction of Iodo Olefins with Aldehydes. J. Am.
Chem. Soc. 1986, 108, 5644−5646.
Corresponding Author
*dweix@wisc.edu
ORCID
Kevin J. Garcia: 0000-0002-7656-959X
Daniel J. Weix: 0000-0002-9552-3378
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Research reported in this publication was supported by the
University of Wisconsin-Madison and the National Institute of
General Medical Sciences of the National Institutes of Health
under award numbers T32GM008505 (K.J.G.) and
S10OD020022 (UW Chemistry Instrumentation Center).
The authors are indebted to Jill A. Caputo (Univ. of
D
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Journal of the American Chemical Society
Communication
(10) For Ar−X, X = B(OH)2, 8525; X = Zn, Mg, Li, or Cu, 2812; X
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from aldehyde reduction and product oxidation to ketone.
(21) Acidic functional groups presented a challenge for Rh-catalyzed
arylation (product 4 was formed in only 27% yield).8
(22) At this time, reactions with substrates that contain a ketone
provide lower yields (product 34 in the Supporting Information, 14%
yield). In addition, ethyl 4-bromobenzoate and N-Boc-5-bromoindole
provided low yields with cyclohexane carboxaldehyde (products 35
and 36 in the Supporting Information).
̂
́
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(16) Rh-catalyzed arylation with PhI tolerated 2-substituted
aldehydes reasonably well (2-iodotoluene, 70%; naphthaldehyde,
57%; o-anisaldehyde, 63% yield).8 Few examples of hindered
aldehydes have been reported for nickel-catalyzed arylation: 2,4-
dimethoxybenzaldehyde (12% yield)13a and 2,4,5-trimethoxybenzal-
dehyde (93%)13d have been coupled with PhBr.
(28) For a concurrent study on rhodium-catalyzed arylation that
does not require a metal reducing agent, see: Swyka, R. A.; Zhang, W.;
Richardson, J.; Ruble, J. C.; Krische, M. J. Rhodium-Catalyzed
Aldehyde Arylation via Formate-Mediated Transfer Hydrogenation:
Beyond Metallic Reductants in Grignard-NHK-Type Addition. J. Am.
Chem. Soc. 2019, DOI: 10.1021/jacs.8b13652.
(17) Rh-catalyzed arylation with PhCHO does not tolerate a 2-
iodotoluene (trace product).8 Nickel-catalyzed arylation is more
tolerant for couplings with PhCHO but varies with the catalyst used.
For example, bromomesitylene was coupled in 98% yield,13d but the
same substrate failed in an earlier study.13a
(18) Few couplings with aliphatic aldehydes have been reported.
The only hindered examples are the nickel-catalyzed coupling of
methyl 2-bromobenzoic acid ester with heptanal (38% yield) and
butanal (24% yield)13b and the Rh-catalyzed coupling of 2-
phenylpropionaldehyde with iodobenzene (62% yield).8
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