Parameterization of phosphine ligands demonstrates enhancement of nickel catalysis via remote steric effects

Article abstract of DOI:10.1038/NCHEM.2741

The field of Ni-catalysed cross-coupling has seen rapid recent growth because of the low cost of Ni, its earth abundance, and its ability to promote unique cross-coupling reactions. Whereas advances in the related field of Pd-catalysed cross-coupling have been driven by ligand design, the development of ligands specifically for Ni has received minimal attention. Here, we disclose a class of phosphines that enable the Ni-catalysed Csp^3 Suzuki coupling of acetals with boronic acids to generate benzylic ethers, a reaction that failed with known ligands for Ni and designer phosphines for Pd. Using parameters to quantify phosphine steric and electronic properties together with regression statistical analysis, we identify a model for ligand success. The study suggests that effective phosphines feature remote steric hindrance, a concept that could guide future ligand design tailored to Ni. Our analysis also reveals that two classic descriptors for ligand steric environment - cone angle and % buried volume - are not equivalent, despite their treatment in the literature.

Full text of DOI:10.1038/NCHEM.2741

ARTICLES
PUBLISHED ONLINE: 6 MARCH 2017 | DOI: 10.1038/NCHEM.2741
Parameterization of phosphine ligands
demonstrates enhancement of nickel catalysis
via remote steric effects
Kevin Wu and Abigail G. Doyle
*
The field of Ni-catalysed cross-coupling has seen rapid recent growth because of the low cost of Ni, its earth abundance,
and its ability to promote unique cross-coupling reactions. Whereas advances in the related field of Pd-catalysed
cross-coupling have been driven by ligand design, the development of ligands specifically for Ni has received minimal
attention. Here, we disclose a class of phosphines that enable the Ni-catalysed Csp3 Suzuki coupling of acetals with
boronic acids to generate benzylic ethers, a reaction that failed with known ligands for Ni and designer phosphines
for Pd. Using parameters to quantify phosphine steric and electronic properties together with regression statistical
analysis, we identify a model for ligand success. The study suggests that effective phosphines feature remote steric
hindrance, a concept that could guide future ligand design tailored to Ni. Our analysis also reveals that two classic
descriptors for ligand steric environment—cone angle and % buried volume—are not equivalent, despite their treatment
in the literature.
ver the past 50 years, Pd-catalysed cross-coupling has partners17. In this context, our group reported Ni-catalysed Suzuki
evolved to become one of the most useful strategies for couplings of N,O-acetals and O,O-acetals that deliver 2-arylated
O
carbon–carbon (C–C) and C–heteroatom bond formation1. heterocycles using triphenylphosphine (PPh3) as a ligand18,19. A
The development of new ligands for Pd has been arguably the mechanistic study suggested a pathway involving boroxine-assisted
most important contributor to the advancement of these ionization of the acetals followed by Ni-catalysed coupling of the
methods, enabling reactions with a broad range of substrates resulting iminium or oxocarbenium ions20. Accordingly, we were
under mild and efficient conditions2–4. By contrast, the field of able to develop an asymmetric variant of the N,O-acetal coupling
nickel-catalysed cross-coupling has witnessed tremendous activity using a chiral phosphonite ligand for Ni (ref. 21). We recently con-
over the past two decades5, but minimal effort has been dedicated sidered whether this strategy could be expanded to offer a general
to the identification of new ligand sets (Fig. 1a)6–9. Furthermore, Csp3–C bond-forming approach to ether synthesis from a broad
phosphines developed for Pd catalysis have generally proven ineffec- range of readily available and stable acyclic and cyclic acetals in
tive for Ni (refs 10–12). According to the example set by Pd, the combination with boronic acids (Fig. 1b). This reaction would
design of new ligands for Ni should facilitate the refinement of exist- offer an expedient synthesis of benzylic ethers—highly valuable
ing methods and the identification of new chemical transform- pharmacophores in medicinal chemistry22—which are most commonly
ations. Here, we report the development of a new class of constructed by C–O bond formation.
phosphines and demonstrate that these bench-stable ligands facili-
The coupling of benzaldehyde dimethyl acetal 1 with para-fluoro-
tate a Ni-catalysed Csp3 Suzuki coupling reaction that failed with phenyl boroxine was chosen as the model system for optimization
known ligand architectures for Ni and Pd. Quantitative molecular (Fig. 2a). This coupling was anticipated to be more challenging than
parameterization of these ligands and multivariate correlation our previously described Suzuki coupling of chromene acetals,
with reaction outcome are conducted13,14. These studies reveal that because the Csp3–O bond of chromene acetals experiences significant
two of the most frequently used parameters to describe ligand bond weakening due to conjugation, and addition of Ni to the benzo-
steric effects—cone angle and buried volume—are not equivalent, pyrylium delivers a stabilized π-allyl intermediate20, both not possible
despite their reported treatment in the literature15,16. Indeed, it is with simple acetals. Indeed, application of the previously identified
precisely their difference that provides an intuitive as well as quan- conditions using PPh3 L1 as ligand only yielded trace ether 2 at elev-
titative rationale for their success and for the failure of ligands devel- ated temperature. By contrast, use of tricyclohexylphosphine (PCy3,
oped for Pd. We expect that the new phosphines in this study will L2), one of the most common phosphines used for Ni-catalysed
find application in other Ni-catalysed coupling reactions. cross-coupling5,17, afforded modest amounts of product (29% yield).
Moreover, the insight gained from molecular parameterization More hindered trialkylphosphines (tert-butylphosphine, PtBu3, L3)
should serve as a general design principle for the identification of were ineffective, as were N-heterocyclic carbenes (L4). Alkyl arylpho-
new ligands tailored for Ni.
sphines, which possess intermediate steric hindrance and electronic
The field of Ni catalysis has recently witnessed rapid growth character to trialkylphosphines and triarylphosphines, were also eval-
owing to the base metal’s low cost and unique properties compared uated. Unsubstituted alkyl diarylphosphines (cyclohexyl diphenyl-
to its precious-metal sibling, Pd. One of the most significant contri- phosphine, PCyPh2 L9 and cyclopentyl diphenylphosphine,
butions of Ni catalysis to cross-coupling methodology has been PCypPh2 L11) were less effective than L2. However, PCy2Ph (L5)
enabling the use of substrates bearing abundant and relatively delivered similar yields to PCy3, as did the less hindered cyclopentyl
inert Csp2–O and Csp3–O bonds as electrophilic coupling variant PCyp2Ph (L8). More decorated versions of these ligand
Department of Chemistry, Princeton University, Princeton, New Jersey 08544, USA. e-mail: agdoyle@princeton.edu
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2741
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a
on a gram scale as air-stable solids that could be stored on the bench
for over a month without oxidation or decomposition.
Discovery
1970s
Method development
1980s 1990s
Pd
Ligand & catalyst design
We found that, within the alkyl diarylphosphine ((alkyl)PAr2)
platform, 2-substitution on the aryl groups was detrimental to reac-
tivity (L12), consistent with earlier observations using Buchwald
ligands L6 and L7. Ligands with electron-withdrawing groups at
the 3,5-positions were also ineffective (L15). In contrast, ligands
bearing bulky, electron-donating substituents (tBu) at the 3,5-pos-
itions (L13, L16) afforded improved reactivity over the parent
ligands (L9, L10), providing 67 and 68% yield of the desired ether
product, respectively. We questioned whether inclusion of larger
substituents at the 3,5-positions would further improve ligand per-
formance. The 2,4,6-tri-isopropylphenyl (TRIP) group has proven
of high utility in ligand and catalyst design as a very bulky substitu-
ent. For reasons of synthetic accessibility, we investigated modifi-
cation of the (alkyl)2PAr framework with this substituent.
Gratifyingly, the catalyst system using L17 demonstrated further
improvement, delivering 2 in 78% yield.
2000s
2010s
Present
Discovery
Method development
Ni
R
PtBu3
Fu
tBu2P
R
iPr
PCy2
iPr
Pd
N
Major advances in
Pd-catalysed
cross-coupling
N
N
R
R
iPr
Beller
Buchwald
Hermann
TRIP
Phosphines
designed for Pd
iPr
Ni
The superior yields with L16 and L17 could be due to greater cat-
alyst stability, improved rates of reaction, or both. To probe this
question, NMR timepoint experiments were conducted to qualitat-
ively assess reaction progress with various ligands (Fig. 2b). Ligands
L16 and L17 exhibited greater rates than L2, thus suggesting these
ligands generate more active Ni catalysts. Furthermore, these time-
point studies illustrate that the catalyst system with L17 affords
superior yields to L16, despite having a lower initial rate and an
induction period.
mostly ineffective
PCyp2
New reactions
Greater efficiency
Expanded scope
Few efforts towards
Ni ligand development
iPr
iPr
Novel phosphine
b
OR
OR
Ar
Additive-free Suzuki coupling
from simple materials
Valuable benzylic ether
products
Ni, ligand
Ar–B(OR')2
OR
Next, we sought to understand what structural features of the new
ligands are responsible for their significantly improved rate and cata-
lyst stability. In particular, we sought to quantify the steric and elec-
tronic properties of these ligands using numerical parameters and
search for statistical correlations with reaction yield. The electronic
properties of the ligands were evaluated using the computationally
derived minimum electrostatic potential (Vmin) parameter, which cor-
relates with the Tolman electronic parameter23. No strong correlation
with yield was observed using Vmin alone (r2 = 0.18, Supplementary
Fig. 2); notably, L16 and L17 have only slightly greater Vmin values
than the parent scaffolds L6 and L4, respectively. The steric properties
of the ligands were also quantified and analysed. To achieve internal
consistency, all steric parameters were computed from molecular
mechanics models as opposed to using literature values
(Supplementary Section H). The first steric parameter examined was
Tolman’s cone angle metric15,24. Although the cone angle correlated
strongly with yield for a range of ligands (circles in Fig. 3a),
JohnPhos, XPhos, PtBu3 and L12 were notable outliers (triangles).
Another parameter often used to quantify ligand steric effects is
Figure 1 | Design of new ligands for Ni catalysis enables Suzuki coupling of
benzylic acetals. a, Ligand development in Pd versus Ni-catalysed cross-
coupling. Ligands engineered for Pd catalysis have facilitated many advances
in cross-coupling, including the discovery of altogether new transformations
and the refinement of existing methods such that they can be used for
large-scale synthesis. By contrast, minimal effort has been directed at ligand
design for Ni-catalysed cross-coupling, despite the opportunity it presents
for discovering novel reactions and for improving the efficiency of existing
methods. b, Ligand design for Suzuki coupling of acetals. The development
of a Ni-catalysed Suzuki coupling of acetals with readily available boronic
acids would facilitate the preparation of valuable ether products by C–C
bond formation. Application of known ligands for Ni and re-purposing
ligands designed for Pd to this transformation were both unsuccessful in this
regard, prompting the development and study of a new phosphine ligand
class for Ni.
architectures have been pioneered by the Buchwald laboratory for buried volume (%Vbur)
16,25. A qualitative trend readily became
Pd-catalysed couplings2. Unfortunately, members of this class, apparent with this parameter: ligands with large buried volumes are
such as JohnPhos L6 and XPhos L7, provided no detectable ineffective. The plot of %Vbur in Fig. 3a illustrates that a ligand
product. The low reactivity observed with ligands developed for Pd possessing a high buried volume is inactive, regardless of its cone
is not unique to this example and highlights the limitations of these angle (for example, JohnPhos, L12). Notably, cone angle and %Vbur
ligands when used with Ni (refs 10–12). Because Ni is smaller and have been considered as equivalent measures of ligand steric size
more nucleophilic than Pd, we questioned whether a novel ligand and used interchangeably in the literature16. The divergence in
framework designed specifically for this base metal could overcome the parameter–reactivity relationships shown in Fig. 3a provides
the limitations of current ligands and achieve efficient cross-coupling. a striking example showing how these two metrics are far from
Furthermore, we sought to obtain a rationale for the effect of equivalent (Fig. 3b). We sought to understand the origin of this
phosphine structure on reactivity to facilitate the development of discrepancy and how it translates to a structure-based insight into
other Ni-catalysed couplings and the discovery of additional ligand ligand effectiveness.
frameworks for Ni.
The difference between these two steric parameters can be
We focused our efforts on modification of the aryl alkylphos- appreciated through an understanding of the distinct methods
phine architecture, because the parent members of this class pro- each uses to describe ligand size. The buried volume metric empha-
vided modest reactivity and, unlike trialkylphosphines, this ligand sizes steric hindrance proximal to the metal by measuring the volume
scaffold is readily modifiable and tunable. A synthetic sequence occupied by the ligand in a sphere of defined radius (r = 3.5 Å,
that allowed facile access to these frameworks from readily available Fig. 3c). By contrast, the cone angle parameter measures a cone
starting materials was developed (Supplementary Section C). that encloses all groups of the ligand, regardless of how far they are
Notably, many of the new phosphines shown in Fig. 2a were isolated from the metal, and is therefore sensitive to ligand size, even at a
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2741
ARTICLES
angle are the ones that feature remote steric hindrance; they are rela-
tively unencumbered near the metal binding site but have large
groups distant from the metal. Given the smaller size of Ni relative
to Pd and the shorter Ni–P bond distance (2.05 versus 2.28 Å), it
makes intuitive sense that sterically hindered phosphines designed
for Pd catalysis would crowd a Ni centre, preventing critical substrate
or even ligand-binding events. In contrast, new ligands L16 and L17
probably permit coordination of reaction components to Ni while
still discouraging the binding of multiple ligand equivalents and pre-
venting bimetallic deactivation mechanisms26. Additional studies are
currently ongoing to investigate the specific influence ligands L16
and L17 impart on catalyst structure and activity.
a
Ni(cod)2 (15 mol%)
Ligand (30 mol%)
OMe
OMe
OMe
(p-F-PhBO)3 (0.6 equiv.)
Toluene, 60 °C, 16 h
F
1
2
PtBu3
PPh3
PCy3
IMes
L4
L1
<2% yield
L2
L3
29% yield
No product
No product
TRIP
Cy2P
Cy2P
Cyp2P
Cyp2P
Going further, a quantitative model to relate the cone angle and
%Vbur with yield was developed to explain the outliers and provide
quantitative support for the remote steric effect hypothesis
(Supplementary Section G). A positive correlation with cone angle
was observed, as well as an inverse correlation with the buried
volume (Fig. 3d). Taken together, these two terms are a mathemat-
ical representation of the remote steric effect concept. The function
can be visualized by plotting predicted versus measured yield
(Fig. 3d). A slope approaching one and a small intercept indicate
the model is accurate, while an r2 value of 0.96 demonstrates the
model’s precision. Notably, the model correctly accounts for the
entire scope of ligands tested in the study, including ligands with
high buried volume (JohnPhos, PtBu3), whereas they fell as outliers
in the simple yield versus cone angle correlation (Fig. 3a). Leave-
one-out cross-validation of the model was also performed. A Q2
value of 0.88 indicates that the model has potential predictive
ability on a new data set, a feature made more attractive given that
all of the ligand parameters are generated computationally rather
than obtained from experiment or literature. Indeed, a preliminary
evaluation suggests that the model can predict the performance of
ligands (Fig. 3d, squares) across a range of structures, including
two ligands possessing substituents not present in the training set
and a third ligand predicted and found to be active despite
its bearing a tert-butyl substituent that rendered all ligands in the
training set inactive.
Having arrived at an enabling ligand, the scope of boroxine
nucleophiles was then evaluated (Table 1). Both electron-deficient
(2,3) and electron-neutral (5) phenylboroxines afforded ethers in
good to excellent yields, whereas electron-rich phenylboroxines
(4) delivered modest reaction efficiency, presumably due to their
attenuated Lewis acidity20. Carbonyl-functionalized (6) and steri-
cally hindered (8) boroxines are competent coupling partners.
Furthermore, ligand L17 induces good reaction efficiency with
heterocyclic boroxines (9), as long as the heterocycle is not strongly
Lewis basic. Acetal scope investigations also revealed tolerance
for electronic and steric variation. Ortho-substitution on the benzal-
dehyde was well tolerated under the reaction conditions (10).
Both electron-rich (11) and electron-neutral (12) acetals were
also compatible; the former affords a synthetic alternative to the
limitation of using electron-rich aryl boroxines described
above. Unfortunately, electron-deficient acetals did not undergo
coupling. This result, taken together with the ineffectiveness of
electron-rich boroxines, is consistent with a mechanism involving
boronic acid-assisted ionization of the acetal followed by
oxidative addition to the resulting oxocarbenium intermediate20.
Notably, no over-arylation of the ether products to give tri-
arylalkanes is observed, even though Jarvo and Shi have reported
Ni-catalysed couplings of benzylic ethers related to the products
in Table 1 (refs 27,28).
R
TRIP
L5
24% yield
R = Ph L6 (JohnPhos)
No product
R = TRIP L7 (XPhos)
No product
L8
28% yield
L17
78% yield
Me
CypP
Me
tBuP
CyP
CypP
2
2
2
Me
2
L10
17% yield
L11
L12
No product
L9
10% yield
3% yield
tBu
tBu
R
17% yield
R = Me L14
CF3 L15
L13
67% yield
CypP
CyP
No product
68% yield
tBu L16
R
2
2
b
100
80
60
40
20
0
Ligand
PCy3
L16
L17
0
10
20
30
40
50
Time (h)
Figure 2 | Ligand evaluation and timepoint studies. a, Screen of existing
and novel phosphines for Ni. Ligand evaluation reveals that phosphines
bearing tertiary alkyl groups or ortho-substituted aryl groups are completely
ineffective. However, dialkylaryl [(alkyl)2PAr] and alkyldiaryl [(alkyl)PAr2]
phosphines with secondary alkyl substituents and 3,5-substituted aryl
groups are highly effective. IMes = 1,3-bis(2,4,6-trimethylphenyl)-
imidazolium. Yields determined by 19F NMR with 2-fluorobiphenyl as a
quantitative internal standard. b, Timepoint studies comparing the reaction
profile with L16, L17 and PCy3 (L2). Ligands L16 and L17 afford highly active
Ni catalysts in the Suzuki coupling; ligand L17 delivers the highest overall
yields, despite a slower initial rate of reaction. Reactions were conducted at
60 °C in toluene (0.06 M), 15 mol% Ni(cod)2 and 30 mol% of ligand.
cod = 1,5-cyclooctadiene.
More complex substrates, including exo- and endocyclic, biden-
distance. Because most ligands have operated in the first coordi- tate and hindered acetals, also underwent coupling to provide
nation sphere, a correlation between the two parameters has been several important structural motifs (Table 2). Products 17 and 19
observed; however, this correlation is not required by definition. are of particular interest because they represent the structural
Taken together, ligands with small buried volume and large cone cores of important pharmaceutical compounds29. Notably, phthalan
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2741
ARTICLES
a
b
90
200
190
180
170
160
150
140
130
120
110
100
90
XPhos
L17
80
70
60
50
40
30
20
10
0
θ > 150 and %Vbur < 35
L16
New steric regime
JohnPhos
CataXCium A
L17
%Vbur
L16
.
.
.
37
35
33
31
.
.
PCy3
PtBu3
Yield = 0.47+1.0(θ), r2 = 0.96
PCyp(Mes)2
θ =2.3+4.0(%Vbur), r2=0.89
PtBu3
JohnPhos
26 28 30 32 34 36 38 40 42 44 46 48 50
125 130 135 140 145 150 155 160 165 170 175
%Vbur
θ (deg)
Ligand parameter regression model
Yield = 0.24 + 0.82(θ ) − 0.67(%Vbur) − 0.084(Vmin) − 0.534(θ )(Vmin
d
c
)
90
80
70
60
50
40
30
20
10
0
%Vbur = % volume of sphere of
radius r occupied by ligand; any
group beyond r is not captured
L16
Cone angle (θ)
L17
P(CH2Cyp)(3,5-tBu2Ph)2
PtBu(3,5-tBu2Ph)2
θ = angle swept by cone that
encloses all ligand groups
P
Fixed distance
PCy(4-OMePh)2
Original data set
M
External predictions
PCyPh2
y = 1.1 + 0.96(x), r2 = 0.96
Remote steric hindrance =
high θ and low %Vbur
Radius (r)
Q2 = 0.88
JohnPhos
0
10
20
30
40
50
60
70
80
90
Measured yield
Figure 3 | Steric parameterization and analysis. a, Plot of yield versus cone angle (θ) and buried volume (%Vbur). A comparison of the ligand steric
parameters against reaction yield reveals that larger cone angle correlates with higher yield (circles), with the exception of ligands featuring high
buried volume (triangles). The regression equation only includes the circle data points. b, Plot of cone angle versus buried volume. Cone angle and
buried volume have previously been treated as equivalent measures of ligand steric environment, as illustrated by a 1:1 mapping of the two parameters
(circle data points). The regression equation only includes circle data points. The new phosphines prepared in this study (triangles) fall outside this
1:1 mapping, highlighting that these two terms are not equivalent, by definition. c, Definition of cone angle and buried volume. Both measure steric
encumbrance but with different distance dependencies. Buried volume only accounts for steric hindrance proximal to the metal whereas cone angle is
sensitive to ligand size at a distance. A ligand with a large cone angle and low %Vbur, such as those most successful in this new method, therefore
possesses remote steric hindrance. d, Plot of predicted yield versus actual yield. A quantitative model to relate cone angle, buried volume and Vmin to
yield was obtained by regression analysis. This model accounts for the entire scope of ligands tested in the study and features a mathematical representation
of the remote steric effect concept. We show that the model can predict the performance of ligands (green squares) that feature unique structural motifs
to those included in the ligand training set.
and dioxolane acetals 18 and 20, which were completely unreactive this same product class from acetals and aryl iodides using a
with PCy3, undergo C–C bond formation using L17 to afford stoichiometric reductant and a potent Lewis acid34. This reductive
α-arylated ethers 19 and 21 in good yield. The products 21 and approach failed with substituted acetals such as 22, 26, 28 and 30,
23 possess an alcohol tether capable of undergoing further functio- highlighting a major strategic advantage of this new method.
nalization, including serving as a directing group for additional Ni-
In conclusion, we have developed a novel class of aryl alkyl-
phosphines containing bulky groups at the 3,5-positions (L17)
catalysed coupling to give bioactive triarylmethane products30,31
.
Acetal 22 (1.3:1 d.r.) reacts to generate 23 in a 2:1 mixture of regioi- that confer high activity upon Ni catalysts for the Suzuki coupling
somers, with the major regioisomer (3.8:1 d.r.) derived from func- of benzylic acetals. Parameterization and modelling studies reveal
tionalization of the less substituted C–O bond. Compared with that the effectiveness of these ligands is a function of remote steric
the five-membered cyclic acetals 20 and 22, dioxane acetal 24 was hindrance, a structural concept relatively unexplored in ligand
less reactive. Perhaps most notably, acetals derived from sterically design. We reveal a divergence between the cone angle and
hindered alcohols (22, 26, 30) deliver products in excellent yield buried volume (%Vbur) parameters, two measures of steric size
that could not be easily obtained through most C–O bond- previously considered to be equivalent. Whereas %Vbur only
forming methods32. Although acid-catalysed approaches to these describes steric hindrance in the metal’s first coordination sphere,
products exist, they are typically limited to methyl ether formation cone angle captures it beyond the immediate proximity of the
from electron-rich or neutral benzhydrols and require strong acid metal. We show that the two can be used in conjunction to
and forcing conditions33. Furthermore, our laboratory previously develop a quantitative model for predicting ligand reactivity. We
described a reductive cross-coupling method for the synthesis of believe this new ligand architecture and the concept of remote
4
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2741
ARTICLES
Table 1 | Scope investigation.
Ar1
TRIP
Ni(cod)2 (15 mol%)
L17 (30 mol%)
OMe
OMe
OMe
B
O
B
O
B
Cyp2P
Ar2
Acetal
Ar2
Ar1
Ar1
O
Toluene, 70 °C, 16 h
Ar1
TRIP
Aryl boroxine
(0.6 equiv.)
Ether
OMe
L17
OMe
OMe
OMe
OMe Me
OMe
OMe
O
OMe
O
Me
Ph
Ph
Ph
Ph
Ph
Me
Ph
Ph
OEt
Ph
CF3
F
OMe
Me
Me
2
3
4
5
9
6
7
8
82% yield
89% yield
26% yield
56% yield
91% yield
55% yield
57% yield
77% yield*
OMe
OMe
OMe
OMe
OMe
OEt
O
O
O
OMe
CF3 MeO
CF3
F
CF3
CF3
CF3
CF3
10
59% yield
11
61% yield
12
73% yield
13
86% yield
14
73% yield
15
70% yield†
A range of aryl boroxines undergo cross-coupling with dimethyl acetals derived from benzaldehydes. Yields shown are isolated yields. *Run at 60 °C. †2-furan diethyl acetal used.
Table 2 | Scope investigation with more complex acetal substrates.
Ar1
TRIP
TRIP
Ni(cod)2 (15 mol%)
L17 (30 mol%)
OR
OR
OR
B
O
B
O
B
Cyp2P
Acetal
Ar2
Ar2
Ar1
O
Toluene, 70 °C, 16 h
Ar1
CF3
F3C
Acetal
Aryl boroxine
(0.6 equiv.)
Ether
L17
Acetal
Product
Acetal
Product
Acetal
O
Product
Product
OH
O
O
O
Ph
O
OH
O
Ph
Ar1
O
O
Ar1
O
Ar1
Ph
Ph
Ar1
Ph
Ph
OCH2Ph
Ph
O
Ph
OMe
16
17
78% yield
20
21
68% yield
24
25
34% yield
28
29
54% yield
w/PCy3: no product
Me
Me
O
t-Bu
O
t-Bu
Ar1
Oi-Pr
Oi-Pr
Oi-Pr
OH
O
O
O
O
Ph
OCH2t-Bu
Ph
Ph
Ph
Ar1
OMe
Ar1
Ph
O
Ph
Ar1
18
19
67% yield
w/PCy3: no product
23
26
27
82% yield
30
31
85% yield
22*
60% yield†
Several exocyclic and endocyclic acetals undergo C–C bond formation to afford valuable cyclic and acyclic ethers. Access to sterically hindered ethers is also possible using this method. In the cases examined,
the new phosphine framework is exclusively effective. PCy3, a ligand that delivered low but measurable yield in the model reaction, is completely inactive, highlighting the impact of ligand development on
reaction discovery. Yields shown are isolated yields. *1.3:1 mixture of diastereomers. †Run at 85 °C; isolated as a 2:1 mixture of regioisomers (major regioisomer shown).
steric hindrance will lead to significant advances in both Ni catalysis
and ligand design.
References
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2741
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The authors acknowledge financial support from NIGMS (R01 GM100985). The authors
also thank M.S. Sigman (University of Utah) for helpful suggestions on this manuscript and
B. Shields, T. Graham (Merck) and D. Ahneman for discussions.
Author contributions
K.W. and A.G.D. conceived the work. K.W. performed and analysed the experiments and
calculations. K.W. and A.G.D. designed the experiments, analysed the data and co-wrote
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Additional information
Supplementary information and chemical compound information are available in
the online version of the paper. Reprints and permissions information is available online
at www.nature.com/reprints. Correspondence and requests for materials should be addressed
to A.G.D.
24. Hartwig, J. F. Organotransition Metal Chemistry: From Bonding to Catalysis
(University Science, 2010).
Competing financial interests
The authors declare no competing financial interests.
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