Pd-Catalyzed Cross-Coupling of Hindered, Electron-Deficient Anilines with Bulky (Hetero)aryl Halides Using Biaryl Phosphorinane Ligands

Article abstract of DOI:10.1021/acscatal.0c04280

Biaryl phosphorinane ligands derived from addition of biaryl primary phosphines to trans,trans-dibenzylideneacetone (AlisonPhos and AliPhos) form highly active ligands for Pd-catalyzed coupling of hindered, electron-deficient anilines with hindered (heter

Full text of DOI:10.1021/acscatal.0c04280

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Pd-Catalyzed Cross-Coupling of Hindered, Electron-Deficient
Anilines with Bulky (Hetero)aryl Halides Using Biaryl Phosphorinane
Ligands
Alison M. Wilders, Jeremy Henle, Michael C. Haibach, Rafal Swiatowiec, Jeffrey Bien, Rodger F. Henry,
Shardrack O. Asare, Amanda L. Wall, and Shashank Shekhar*
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ABSTRACT: Biaryl phosphorinane ligands derived from addition of
biaryl primary phosphines to trans,trans-dibenzylideneacetone (Alison-
Phos and AliPhos) form highly active ligands for Pd-catalyzed coupling of
hindered, electron-deficient anilines with hindered (hetero)aryl halides, a
challenging class of C−N cross-coupling reaction with few precedents.
Broad substrate scope and functional group tolerance were observed
under the reaction conditions. Computational studies suggest that ligands
containing phenyl substituents provide greater activity through more
favorable aniline binding in the catalytic cycle in comparison to alkyl-
substituted phosphorinanes. A general and high-yielding procedure for the
synthesis of biaryl phosphorinanes by phospha-Michael addition of
primary biarylphosphines to 1,4-dien-3-ones in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), under relatively mild conditions (23−110
°C), is also described. HFIP as the solvent significantly accelerates the phospha-Michael addition, allowing the preparation of
previously inaccessible ligands and higher yields overall.
KEYWORDS: amination, phosphine ligands, cross-coupling, palladium, phospha-Michael addition
Recently, we reported that biaryl phosphorinanes are highly
effective ligands for Pd-catalyzed C−N and C−O cross-coupling
reactions.10,11 One of these ligands, VincePhos, was used in the
multikilogram scale synthesis of dasabuvir, an HCV polymerase
inhibitor.10b Herein, we report that the newly prepared biaryl
phosphorinanes AlisonPhos and AliPhos are highly effective
ligands for the Pd-catalyzed coupling of ortho- and ortho,ortho′-
substituted electron-deficient anilines (Hammett parameter (σ)
> 0.15) with hindered (hetero)aryl halides (Figure 1B). Many
functional groups are tolerated, and the substrate scope and
limitations are demonstrated with 100 examples. The ligands
AlisonPhos and AliPhos are easily prepared from the phospha-
Michael addition of air-stable primary biaryl phosphines with
readily available trans,trans-dibenzylideneacetone (dba). Com-
putational studies provide insight into the reactivity differences
observed between biaryl phosphorinanes derived from dba
versus previously described 1,1,5,5-tetraalkylpenta-1,4-dien-3-
ones.
INTRODUCTION
■
With the aid of the development of phosphine ligands, Pd-
catalyzed C−X (X = C, N, O) coupling reactions have become
an indispensable synthetic tool for both academic and industrial
laboratories.1 The development of new ligand scaffolds is
necessary to extend the scope of these reactions to increasingly
challenging substrate combinations, such as coupling of
hindered, electron-deficient anilines with hindered aryl halides
ArX (X = Cl, Br). Electron-deficient anilines are poorer
nucleophiles than electron-rich and -neutral anilines and are
more difficult to couple with ArX.2,3 Sterically hindered anilines
are also challenging to couple, particularly with ortho-substituted
aryl halides.3c,4 Thus, it is not surprising that no general method
is known for coupling hindered, electron-deficient anilines with
hindered ArX compounds (Figure 1A).5 Currently, there are few
isolated examples where ortho-substituted, electron-poor ani-
lines couple with ortho-substituted ArX.4,6 Two examples were
reported by Shaughnessy4b and one each by Buchwald2d and
Organ.2e Reactions of ortho-substituted ArX with ortho,ortho′-
disubstituted electron-poor anilines are even less prevalent.7
Also rare are reactions of ortho,ortho′-disubstituted ArX with
ortho-substituted, electron-poor anilines.8 This class of C−N
couplings is also not well precedented with Ni- and Cu-catalyzed
methods.6d,9
Received: October 5, 2020
Revised: November 24, 2020
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Figure 1. Reactions of hindered, electron-deficient anilines with hindered aryl halides.
Scheme 1. Two-Step Procedure to Prepare Biaryl Phosphorinanes10a
phospha-Michael addition of primary biaryl phosphines (1) to
1,1,5,5-tetraalkylpenta-1,4-dien-3-ones (2) at 150−160 °C,
followed by ketalization of the resulting phosphinanones (3)
with ethylene glycol (Scheme 1).10a While many ligands were
prepared in good yields using this procedure, increasing the
RESULTS AND DISCUSSION
■
We are interested in evaluating biaryl phosphorinanes as ligands
for metal-catalyzed reactions.10 In order to rapidly prepare
newer ligands, an improved synthetic procedure was needed.
Biaryl phosphorinanes (4) were previously synthesized by the
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Figure 2. Optimization of reaction conditions for the formation of 3a. The x axis shows the combinations of additives and solvents that were tested.
The y axis shows the area % of 3a by HPLC analysis. Definitions: neat, no solvent; TsOH, p-toluenesulfonic acid; Thiourea, N,N′-bis[3,5-
bis(trifluoromethyl)phenyl]thiourea; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; TBD, triazabicyclodecene; TFE, 2,2,2-trifluoroethanol; HFIP,
1,1,1,3,3,3-hexafluoroisopropanol. Unless noted otherwise, all experiments were conducted with 1a (1 equiv), 2a (4 equiv), and additive (0.1 equiv) in
the solvent (10 mL/g of 1a) for 24 h at 150 °C (neat, toluene, DMF) or 110 °C (MeCN, TFE, HFIP). *The reaction corresponding to the green bar
was conducted with 1.2 equiv of 2a.
Figure 3. Scope of phospha-Michael addition with 2a−g. The crude yield based on HPLC is shown, unless otherwise noted. Legend: (a) reaction at
110 °C; (b) 1.5 equiv of dienone; (c) 2 equiv of dienone; (d) reaction at 80 °C; (e) isolated yield; (f) reaction at 23 °C, (g) reaction at 50 °C; (h) 2
equiv of 2g.
steric bulk on 1 and 2 led to diminished yields in the phospha-
Michael reaction, even at elevated reaction temperatures. For
example, 4a was isolated in only 18−20% yield and attempts to
prepare the more sterically encumbered phosphorinane 4b
failed altogether. Therefore, we sought a more general and
higher-yielding procedure to access biaryl phosphorinanes on
scale before exploring new cross-coupling reactions.
The effect of solvents (neat, toluene, DMF, acetonitrile) and
additives (acid, base, N,N′-bis[3,5-bis(trifluoromethyl)phenyl]-
thiourea) on the reaction of 1a with 2a was evaluated (Figure
2).10a,11,12 With all combinations, less than 16 area % of 3a by
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HPLC analysis was formed at 110−150 °C. Fluorinated
alcohols, such as 2,2,2-trifluoroethanol (TFE)13 and
HFIP,13c,14 have been shown to accelerate hetero-Michael
additions.15 While no improvement was observed in TFE, we
were pleased to find 3a was formed in >95 area % in HFIP at 110
°C. Clean conversion to 3a (89 area %) was retained even when
the amount of 2a was reduced to 1.2 equiv. On the basis of the
versatility of the phospha-Michael reaction,12a we expect this
method to be useful for preparing diversely functionalized
phosphorus-containing compounds.
Excited by this simple and high-yielding procedure, we
explored the scope of phospha-Michael addition in HFIP
(Figure 3). The phosphinanones 3a−q were observed in
excellent yield. The intermediates 3a−g, derived from additions
to 2a,b, were not isolated and were converted directly to the
corresponding phosphorinanes 4a−g (eq 1).16 Gratifyingly, 4a,c
20%.10a While we had failed to prepare 4b previously, it was now
isolated in 40% yield.17
The phosphinanones 3h−q, derived from addition to
dienones 2c−g, were isolated in high yield with less than 5%
of the uncyclized monoaddition intermediates left at 24 h.18
A
lower reaction temperature (23−50 °C) was suitable for bis-
addition to dienones 2c−f, while the bulkier dienone 2g
required a higher temperature (110 °C) to reach acceptable
conversions. The reaction with dienone 2c formed 3i in nearly
1:1 dr.12f In the reactions with dba (2f), the meso isomer was the
major product formed (3l−p), in most cases with >95:5
selectivity.19 The acid-catalyzed reaction of phenylphosphine
(PhPH2) with 2f was previously studied, and it was determined
that the rac isomer is the kinetic product while the meso isomer is
the thermodynamic product.12f Under analogous conditions,20
both meso and rac isomers were observed in a 3:2 ratio for 3n and
3:1 for 3o,p. Thus, the thermodynamic products are formed at a
much faster rate in HFIP, which results in the higher isolated
yield of the major isomer. Only a single diastereomer was
observed in the reaction with 2e. The phosphinanones 3i−p
were converted to phosphorinanes 4i−p as shown in eq 1. The
solid-state structure of 4p shows the meso isomer with the phenyl
groups in the equatorial position of the phosphacycle (Figure 3).
Ketalization of 3h,q was unsuccessful.21 Instead, ligands 4h,q
were prepared by converting the carbonyl group to methyl ether
(eq 2). All primary biaryl phosphines, except that needed to
prepare 3m, are air-stable solids and are conveniently handled
on the bench.
Having access to 4a−q in gram quantities, we evaluated these
ligands in the Pd-catalyzed coupling of hindered, electron-
deficient anilines with hindered (hetero)aryl halides. The
reaction of an ortho-substituted aryl bromide (5) with an
electron-deficient, ortho-substituted aniline (6) in 1,4-dioxane at
90 °C was chosen as a model reaction to identify an optimal
ligand for this challenging class of C−N coupling reactions
(Figure 4). Surprisingly, ligands with aryl substituents on the
phosphacycle (4l−q) formed the coupled product 7 in higher
were isolated in 78 and 65% yields, respectively, over two steps,
which is significantly higher than our earlier report of 18−
Figure 4. Ligand screening for Pd-catalyzed amination. The y axis is the assay yield of 7 in the crude reaction mixture by HPLC analysis using an
internal standard, and the x axis is the list of ligands. Reactions were conducted with 5 (2.0 μmol), 6 (2.4 μmol), base (4.0 mmol), Pd2(dba)3 (2.5 mol
%), NaOtBu (10 mol %), and 4a−h,j (5.5 mol %) or 4i,k−q (11 mol %) in 1,4-dioxane (60 μL) at 100 °C. Pd2(dba)3, the ligand, and NaOtBu were
prestirred in 1,4-dioxane at 80 °C for 30 min prior to the addition of 5, 6, and base.10a
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Figure 5. Substrate scope. Unless noted otherwise, all reactions were conducted with (hetero)aryl halide (1 equiv), aniline (1.2 equiv), Pd2(dba)3
(0.25 mol %), AlisonPhos (1.1 mol %), NaOtBu (1 mol %), and K3PO4 (2 equiv) in 1,4-dioxane (0.8 M) at 90 °C for 18 h. Pd2(dba)3, the ligand, and
NaOtBu were prestirred in 1,4-dioxane at 80 °C for 30 min prior to the addition of the substrates. The assay yield of the product in the reaction mixture,
determined by HPLC, is reported. The isolated yield is shown in parentheses. Legend: (a) 1.2 equiv of sodium trifluoroacetate was added; (b) AliPhos
was used; (c) tBuOH was used as the reaction solvent.
yields in comparison to analogous ligands with alkyl
substituents. For example, ligands 4g,o, which share a biaryl
backbone, produced 7 in 12 and 82% assay yields by HPLC,
respectively. Curiously, even the bulky ligand 4q, expected to be
less effective for coupling hindered partners, was superior to the
analogues derived from alkyl dienones (4a,d).
Although a high yield of 7 (>80% assay yield) was observed in
the presence of 2.5 mol % of Pd2(dba)3 with several ligands,
conducting the reaction at a lower loading of Pd identified 4o
(AlisonPhos) as the most effective ligand (Table S1). With only
0.25 mol % of Pd2(dba)3 and 0.5 mol % of AlisonPhos, 7 was
observed in 89% assay yield at 90 °C.
Initially, the reactions of electron-rich aryl chlorides (12 and
13) did not work well under the standard conditions. Electron-
rich electrophiles are known to be challenging coupling partners
for electron-poor anilines.2e Presumably, the electron-rich ArCl
forms the less electrophilic oxidative addition intermediate
LPdII(Ar)(Cl) in comparison to those formed from electron-
poor and -neutral ArCl. Hindered, electron-poor anilines likely
do not coordinate effectively to the more electron rich metal
center.2b We hypothesized that the addition of a chloride
scavenger will generate a more electrophilic oxidative addition
intermediate and promote coordination of aniline to Pd(II).
Indeed, addition of sodium trifluoroacetate (NaTFA)24
significantly improved the reactions of 12 and 13.
Broad substrate scope was observed for coupling of ortho-
substituted, electron-deficient anilines with ortho-substituted
electrophiles (7−16, Figure 5). Aryl bromides (7, 8, and 14) and
chlorides (9−13) were both suitable electrophiles and formed
the coupled products in excellent yields in the presence of only
0.25 mol % of Pd2(dba)3. Heteroaryl chlorides also formed the
coupled products (10, 15, and 16) in high yields. A variety of
commonly encountered functional groups such as amide, CF3,
ester, acetyl, nitrile, aldehyde, OCHF2, and OCF3 were well
tolerated. The reaction displayed excellent selectivity for the N-
arylated product in the presence of a hydroxyl group; however,
the N-arylated product was found to cyclize to the
pyridoquinazolinone (10) under the reaction conditions.22,23
The reactions of ortho-substituted nitro anilines also
improved upon modification of the standard reaction con-
ditions. For example, only 75 HPLC peak area % of 14 was
observed in the presence of AlisonPhos. We hypothesized that 2-
methyl-4-nitroaniline, a highly electron-poor nucleophile, was
likely slower to coordinate to the putative oxidative addition
complex (AlisonPhos)PdII(Ar)(X) in comparison to the
aforementioned anilines. We reasoned that a less-hindered
ligand would promote binding of this aniline to Pd. To our
delight, 4n (AliPhos) enabled the coupling of 2-methyl-4-
nitroaniline with a hindered aryl bromide (14) and two
heteroaryl chlorides (15 and 16) in higher yields than were
observed with AlisonPhos.
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Figure 6. High-throughput evaluation ofsubstrate scope for the coupling of (a) ortho,ortho′-disubstituted ArCl with ortho-substituted anilines and (b)
ortho,ortho′-disubstituted anilines with ortho-substituted ArCl. All reactions were conducted with (hetero)aryl halide (1 equiv), aniline (1.2 equiv),
Pd2(dba)3 (1.5 mol %), AliPhos (6.6 mol %), NaOtBu (6 mol %), NaTFA (1.2 equiv), and K3PO4 (2 equiv) in 1,4-dioxane (0.5 M) at 100 °C for 18 h.
Pd2(dba)3, the ligand, and NaOtBu were prestirred in 1,4-dioxane at 80 °C for 30 min prior to the addition of the substrates. Products were identified
by LCMS. The values depicted in each cell are area % values of the desired products in the crude HPLC chromatogram of the reaction. Legend: (#)
hydrolyzed product included in yield; (*) reactions were run in tBuOH.
AliPhos was also an effective ligand for coupling the more
challenging substrate combination, ortho,ortho′-disubstituted
aryl chlorides and ortho-substituted anilines, forming 17−21 in
excellent yields (88−99%), although a higher loading of
Pd2(dba)3 (1.0−1.5 mol %) was required. Impressively, a
heteroaryl chloride, 3-chloro-2,4-dimethoxypyridine, could even
be coupled with a nitro aniline (20).
Next, reactions of ortho,ortho′-disubstituted, electron-defi-
cient anilines and ortho-substituted (hetero)aryl chlorides were
evaluated. Pd2(dba)3 (1.0−1.5 mol %) and AliPhos formed the
coupled products in good to excellent yields in reactions with
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a
Table 1. Calculated ΔG Values for Catalytic Steps
ligand
X
ΔGox
ΔGbind
ΔGdepro
ΔGred
4g
4g
4o
4o
Cl
Br
Cl
Br
−22.8
−28.3
−22.1
−27.0
13.3
13.0
3.6
−7.5
−2.5
−1.5
4.2
−10.6
−10.6
−7.5
2.0
−7.5
a
All values given in kcal/mol.
a
Table 2. Gibbs Free Energy Values for Two-Step Aniline Binding Process
b
c
d
ligand
X
ΔGdesat
ΔGbind,Ib‑II
ΔGbind
4g
4g
4o
4o
Cl
Br
Cl
Br
14.9
13.8
7.6
−1.7
−0.8
−3.9
−5.0
13.3
13.0
3.6
7.0
2.0
a
b
All values given in kcal/mol. Change in Gibbs free energy value for forming a three-coordinate Pd complex from the four-coordinate oxidative
addition complex. Change in Gibbs free energy value for aniline binding to the three-coordinate Pd complex. Overall change in Gibbs free energy
for aniline binding to the oxidative addition complex.
c
d
anilines containing one ortho-methyl and one electron-with-
drawing ortho-substituent (22−28). In addition to electron-rich
(22 and 23) and electron-poor aryl chlorides (24−26), a five-
membered heteroaryl chloride was also found to be a suitable
electrophile (28). To our delight, anilines containing two
electron-withdrawing ortho-substituents, which are extremely
poor nucleophiles, were also effectively coupled in good yield
(29−33). Unfortunately, the reaction of ortho,ortho′-disubsti-
tuted aryl chlorides with ortho,ortho′-disubstituted anilines
remains a limitation (34 and 35).
To further explore the utility of our methodology, a “one-pot,
multisubstrate screening strategy”25 was adopted by evaluating
two arrays of challenging coupling partners (6 electrophiles × 6
nucleophiles, AliPhos/Pd as catalyst) in a high-throughput
experiment (Figure 6a,b).10a The products were identified by
LCMS, and yields are given in HPLC peak area %. The reactions
of ortho,ortho′-disubstituted aryl chlorides with ortho-substi-
tuted anilines gave moderate to excellent area % values of the
coupled products for most combinations (Figure 6a). A low area
% of the coupled products was observed for reactions with 4-
chloro-3,5-dimethylpyridine, likely resulting from inhibition by
pyridine. In contrast, 51−95 area % of the coupled products was
observed for reactions with 3-chloro-2,4-dimethoxypyridine.
Moderate to excellent area % values of the coupled products
were also observed for the reactions of ortho,ortho′-disubstituted
anilines with ortho-substituted aryl chlorides in most combina-
tions (Figure 6b). Even anilines with two highly electron-
withdrawing substituents (CF3, CN, NO2) formed the coupled
products in synthetically useful yields. Surprisingly, 2,6-bis-
(trifluoromethyl)benzenamine was not effectively coupled with
any of the electrophiles tested. For electrophiles which were
known to be susceptible to hydrodechlorination in the substrate
scope, reactions were run in both 1,4-dioxane and tBuOH. The
reaction with the higher area % of the coupled products is
shown.
We were curious about the greater effectiveness of biaryl
phosphorinanes derived from aryl dienones in comparison to
those derived from alkyl dienones in the C−N coupling
reactions described above (Figure 4). The initial rate of reaction
with AlisonPhos was independent of the concentration of ArCl
and the identity of ArX (X = Cl, Br) but was dependent on the
concentration of aniline (Table S2). On the basis of these
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results, transmetalation (i.e., aniline binding and deprotonation)
is likely the slowest step in the catalytic cycle.26
Table 3. Selected Calculated Bond Distances in the Oxidative
Addition Complexes (I)
a
A computational study was undertaken to compare
AlisonPhos (4o) with 4g, ligands sharing a common biaryl
backbone but having different phosphacycle substitution.
Previous reports involving C−N coupling have noted that the
formation of the N-bound Pd complex and the energy required
to do so are indicative of catalyst performance.27 With that in
mind, the ΔG values were calculated for each step of the catalytic
cycle: oxidative addition (ΔGox), aniline binding (ΔGbind),
deprotonation (ΔGdepro), and reductive elimination (ΔGred)
(Table 1). 1-Bromo-2-methylbenzene, 1-chloro-2-methylben-
zene, and aniline 6 were chosen as representative substrate
combinations for calculations. Ground state geometries were
optimized using DFT (B3LYP-D3/LANL2DZ/6-31G**), with
thermal corrections calculated at the same level of theory.
Single-point energies were calculated using DFT (B3LYP-D3/
LANL2DZ/6-311++G**/COSMO-SMD(dioxane)) and had
thermal corrections applied.
complex
P−Pd
Pd−X
ipso C−Pd
I-4g-Cl
I-4g-Br
I-4o-Cl
I-4o-Br
2.42
2.43
2.32
2.33
2.38
2.56
2.38
2.56
2.62
2.63
2.67
2.67
a
Distances reported in units of angstroms (Å) taken from optimized
geometries.
The ΔGox values for forming the oxidative addition complexes
I-4g-Br, I-4o-Br and I-4g-Cl, I-4o-Cl are comparable,
respectively. However, a large difference in ΔGbind is observed.
The binding of aniline to I-4g-Br is 11 kcal/mol less favorable
than to I-4o-Br, and binding to I-4g-Cl is 10 kcal/mol less
favorable than to I-4o-Cl.28 The oxidative addition complexes
show endergonic binding to aniline, suggesting relatively low
equilibrium concentrations of the aniline-bound Pd complexes;
the calculated Keq values are ∼10−10 for I-4g-Br and I-4g-Cl and
∼10−3 for I-4o-Br and I-4o-Cl (see the Supporting Information
for calculations). Although both deprotonation and reductive
elimination steps are thermodynamically favored for 4g-bound
Pd complexes, 4o forms a superior catalyst. The higher
effectiveness of 4o is likely due to the calculated ∼107 higher
effective concentration of the aniline-bound Pd complexes II-
4o-Br and II-4o-Cl in comparison to II-4g-Br and II-4g-Cl.
To further understand the difference in ΔGbind, the
coordination of aniline to the oxidative addition complex as a
two-step process was investigated: first, the formation of a three-
coordinate complex from the oxidative addition complex, and
second, the binding of aniline to this coordinatively unsaturated
complex to form the aniline-bound complex (Table 2).
Formation of the three-coordinate complex is less energetically
unfavorable for 4o than for 4g (ΔGdesat). Aniline binding to the
three-coordinate complex is favored for 4o over 4g
(ΔGbind, Ib‑II). Further analysis of the oxidative addition
complexes shows that the P−Pd bond length is shorter in I-
4o-Br and I-4o-Cl than in I-4g-Br and I-4g-Cl (Table 3), and
the interaction between the ipso carbon of the biaryl backbone
and Pd is weaker (evidenced by a slightly longer C−Pd distance
in 4o-bound complexes). Contrary to expectation, this suggests
that 4o is more electron-donating than 4g. The reduced steric
bulk of 4o allows for better coordination of the phosphorus atom
to Pd, which produces an apparent increase in electron donation
over 4g (Table S30).29 These steric and electronic factors
stabilize the three-coordinate complex of 4o, leading to the
lower energetic cost for desaturation in comparison to 4g.
More favorable aniline binding to the 4o-bound three-
coordinate complex over the 4g-bound complex also results
from the decreased steric bulk of 4o. Steric interactions between
the biaryl backbone and phosphorinane substituents of 4g
destabilize both the three-coordinate intermediate (Ib-4g-Br)
and the aniline-bound complex (II-4g-Br). Ib-4g-Br shows
significant hindrance of the Pd atom that is not present in Ib-4o-
Br, which likely inhibits aniline coordination (Figure 7). In
summary, the more favorable ΔGbind value for 4o in comparison
Figure 7. (left) Three-coordinate complex Ib-4o-Br, in a view along the
Pd−(o-tolyl) bond. (right) Three-coordinate complex Ib-4g-Br, in a
view along the Pd−(o-tolyl) bond. Pd atoms are shown in teal. Both the
dimethylamino and methoxy subunits of 4g are in closer proximity to
the aniline coordination site in the ground state geometry.
to that for 4g arises from (1) increased electron donation from
4o to the Pd center and (2) decreased steric hindrance in the
three-coordinate and aniline-bound Pd complexes of 4o.
CONCLUSION
■
In summary, we have developed a general and high-yielding
procedure for the synthesis of biaryl phosphorinanes by the
double phospha-Michael addition of primary biaryl phosphines
to 1,4-dien-3-ones under relatively mild conditions. HFIP was
found to be a uniquely effective solvent for the phospha-Michael
addition. Unlike previous reports where at least 4 equiv of
dienone was required at elevated temperatures (150−160 °C),
only 1.2−2.0 equiv of the dienone at 23−110 °C was sufficient.
Several phosphorinanes (4a,c,d,j), known to be effective for C−
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N and C−O cross-coupling reactions, were isolated in excellent
yields on a gram scale. Previously inaccessible, bulky biaryl
phosphorinanes, such as 4b, could also be readily prepared. Our
new method provides rapid access to valuable ligands, and
several new ligands were prepared on a gram scale.30
Michael C. Haibach − Process Research and Development,
AbbVie Inc., North Chicago, Illinois 60064, United States
Rafal Swiatowiec − Process Research and Development, AbbVie
Inc., North Chicago, Illinois 60064, United States
Jeffrey Bien − Process Research and Development, AbbVie Inc.,
North Chicago, Illinois 60064, United States
Rodger F. Henry − Process Research and Development, AbbVie
Inc., North Chicago, Illinois 60064, United States
Shardrack O. Asare − Analytical Research and Development,
AbbVie Inc., North Chicago, Illinois 60064, United States
Amanda L. Wall − Analytical Research and Development,
AbbVie Inc., North Chicago, Illinois 60064, United States
The biaryl phosphorinanes derived from readily available dba,
AlisonPhos (4o) and AliPhos (4n), are highly effective ligands
for Pd-catalyzed couplings of hindered, electron-deficient
anilines with hindered (hetero)aryl bromides and chlorides. A
broad scope was demonstrated for the following substrate
combinations: ortho-substituted aryl halides with ortho-sub-
stituted anilines, ortho,ortho′-disubstituted aryl halides with
ortho-substituted anilines, and ortho-substituted aryl halides with
ortho,ortho′-disubstituted anilines. Even electron-rich aryl
chlorides, typically attenuated electrophiles for coupling with
hindered anilines, were found to be suitable coupling partners.
Only the coupling of ortho,ortho′-disubstituted anilines and
ortho,ortho′-disubstituted aryl halides was unsuccessful under
the reported conditions.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.0c04280
Notes
The authors declare the following competing financial
interest(s): All authors are AbbVie employees and may own
AbbVie stocks.
Computational studies provide insight into the higher
effectiveness of biaryl phosphorinanes derived from phospha-
Michael addition to aryl dienones (4o) in comparison to those
from addition to alkyl dienones (4g). Coordination of hindered,
electron-deficient anilines to the oxidative addition intermediate
((L)PdII(Ar)(X)), prior to deprotonation and reductive
elimination, was found to be the key step in enabling the
reaction. The aniline coordination proceeds via a two-step
process: first, the four-coordinate (L)PdII(Ar)(X) intermediate,
containing Pd−P and Pd−Cipso interactions, converts into a
three-coordinate (L)PdII(Ar)(X) intermediate that lacks the
Pd−Cipso interaction, and second, aniline coordinates to the
three-coordinate Pd(II) intermediate. Formation of the three-
coordinate complex is less energetically unfavorable for 4o than
for 4g, and coordination of aniline is more favored to three-
coordinate(4o)PdII(Ar)(X) than to (4g)PdII(Ar)(X). The net
result is that while coordination of aniline to (L)PdII(Ar)(X)
was endergonic for both 4o and 4g, coordination to (4o)-
PdII(Ar)(X) was calculated to be ∼10 kcal/mol less unfavorable,
which supports the higher effectiveness of 4o.
ACKNOWLEDGMENTS
■
This publication was sponsored by AbbVie. AbbVie contributed
to the design, study conduct, and financial support for this
research. AbbVie participated in the interpretation of data,
writing, reviewing, and approving the publication. We thank Dr.
Michael Clift at AbbVie for helpful discussions.
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.0c04280.
Compiled CN experiments (PDF)
Solid-state structures (CIF)
Experimental procedures and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Shashank Shekhar − Process Research and Development,
AbbVie Inc., North Chicago, Illinois 60064, United States;
orcid.org/0000-0002-1903-5380;
Email: Shashank.shekhar@abbvie.com
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Authors
Alison M. Wilders − Process Research and Development,
AbbVie Inc., North Chicago, Illinois 60064, United States
Jeremy Henle − Process Research and Development, AbbVie
Inc., North Chicago, Illinois 60064, United States;
orcid.org/0000-0001-9045-1726
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(17) See Figure S2 for a discussion on the potential role of HFIP in
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intermediate (3q-mono) was observed.
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was confirmed by 1H NMR.
(20) 20 mol % TsOH·H2O, MeCN, 80 °C, 16 h.
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