Effect of aryl ligand identity on catalytic performance of trineopentylphosphine arylpalladium complexes in n-arylation reactions

Article abstract of DOI:10.1021/acs.organomet.0c00140

A series of air-stable [(Np₃P)Pd(Ar)Br]₂ (Np = neopentyl) and (Np₃P)Pd(Ar)(amine)Br complexes (amine = morpholine and isobutylamine) have been prepared and tested as precatalysts for the coupling of sterically demanding ar

Full text of DOI:10.1021/acs.organomet.0c00140

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Article
Effect of Aryl Ligand Identity on Catalytic Performance of
Trineopentylphosphine Arylpalladium Complexes in N‑Arylation
Reactions
Huaiyuan Hu, Corrie E. Burlas, Sabrina J. Curley, Tomasz Gruchala, Fengrui Qu,
and Kevin H. Shaughnessy*
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ABSTRACT: A series of air-stable [(Np3P)Pd(Ar)Br]2 (Np = neopentyl)
and (Np3P)Pd(Ar)(amine)Br complexes (amine = morpholine and
isobutylamine) have been prepared and tested as precatalysts for the
coupling of sterically demanding aryl bromides and aniline derivatives. The
complexes are more active than the catalyst generated in situ from
Pd2(dba)3 and PNp3. Increasing steric demand of the aryl group on
palladium correlates with increased catalyst activity. Reactions catalyzed by
[(Np3P)Pd(2,6-Me2C6H3)Br]2 occur efficiently at lower temperatures and
with similar or higher yields than those using Pd2(dba)3/PNp3. The amine
adducts give lower reaction rates and conversion to product than the
[(Np3P)Pd(Ar)Br]2 complexes. The lower activity of the amine adducts
appears to result from slow base-promoted reductive elimination to generate the catalytically active LPd(0) species.
Each of the precatalysts in Figure 1 lies off of the catalytic
cycle and must undergo one or more steps to generate the
catalytically active LPd(0) species. Catalyst activation can be
inefficient, resulting in low activity, off-cycle species. For
example, allylpalladium precatalysts (3) are prone to form
inactive μ-allylpalladium(I) dimer species.13 Alternatively, the
catalyst activation may release species that can potentially
inhibit the catalyst, such as the carbazole released by the G2
and G3 Buchwald palladacycles (5).8a A precatalyst that is on
the catalytic cycle, or in rapid equilibrium with an on-cycle
species, would potentially avoid these issues. In considering the
catalytic cycle for a Buchwald−Hartwig amine arylation
reaction, there are three stable species that are either on the
catalytic cycle or are catalytically viable off-cycle resting states:
the L2Pd0 species, the oxidative addition product ([LPd(Ar)-
X]n), and the amine adduct of the oxidative addition product
(Scheme 1).
INTRODUCTION
■
The development of catalysts for C−C and C−heteroatom
bond formation through the coupling of aryl halides with
nucleophiles has received extensive attention.1 Early work
primarily focused on identifying highly effective ligands, such
as trialkylphosphines,2 2-biarylphosphines,3 and N-heterocyclic
carbenes.4 These ligands are typically combined with palladium
sources, such as Pd(OAc)2 or Pd2(dba)3, under the reaction
conditions to generate active catalysts.
For these ligand classes, the active species is an unstable
LPd(0) species that is highly active toward oxidative addition.5
However, forming the catalyst in situ provides limited control
over the formation of the active species. In addition,
palladium(II) sources must undergo a two-electron reduction
to generate the active species. This issue is avoided with
Pd2(dba)3, but the released dba ligands can act as inhibitors of
the catalyst.6
In an effort to more efficiently generate the LPd(0) active
species, researchers have worked to develop palladium
precatalysts that are primed to form the active species under
catalytically relevant conditions.7 The optimal precatalyst
would have the desired 1:1 L/Pd ratio, be easily prepared
and air- and thermally stable, and undergo rapid conversion to
the LPd(0) species under catalytic conditions. Successful
examples of precatalysts include (LPd)2(μ-cod) (1),8 [((t-
Bu)3P)Pd(μ-X)]2 (2),9 (allyl)Pd(L)X (3 and 4),10 the
Buchwald palladacycle precatalysts (5),11 and the PEPPSI
complexes (6).4b,12 Of these, the palladium(II) precatalysts
(3−6) have been most widely used.
The L2Pd(0) species has been extensively used, but suffers
from an undesirable 2:1 L:Pd ratio, which can result in
decreased catalyst activity.14 In a mechanistic study of the Pd/
PNp3 (Np = neopentyl) catalyzed N-arylation reaction, we
Received: February 26, 2020
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dimer is an off-cycle complex that can readily enter the
catalytic cycle through equilibration with the 3-coordinate
species or direct dimer cleavage by the nucleophilic reagent
(Scheme 1). In the case of C−N coupling reactions, the amine
coordinates to the [LPd(Ar)X]n complex to give LPd(amine)-
(Ar)X, which is an isolable intermediate. Deprotonation of the
amine adduct and reductive elimination generates the LPd0
species. Therefore, the LPd(amine)(Ar)X complex represents
another possible stable precatalyst that could be used. The
amine adduct would only need to be deprotonated and
undergo reductive elimination to generate the LPd0 active
species. This is the activation pathway employed with the
Buchwald palladacycle precatalysts (5).8a
Coupling of hindered 2,6-di-ortho-substituted aryl halides
with hindered amines is often challenging with commonly used
ligands, such as tri-tert-butylphosphine or S-phos.19 Successful
examples of couplings to give highly hindered diaryl amines
have been achieved with N-heterocyclic carbene palladium
complexes,20 diketiminate palladium complexes,21 proazaphos-
phatrane-derived catalysts,22 and iminoproazaphosphatrane-
phosphine/Pd systems.23 We have previously shown that
trineopentylphosphine-supported catalysts are particularly
effective for the coupling of sterically demanding aryl halides.24
Here we report the use of air-stable complexes [(Np3P)Pd-
(Ar)Br]2 and (Np3P)Pd(Ar)(HNR2)Br (Np = neopentyl) as
catalysts for the coupling of sterically demanding aryl bromides
and aniline derivatives. We have explored how the aryl group
on palladium affects catalyst performance and the relative
activity of the [(Np3P)Pd(Ar)Br]2 and (Np3P)Pd(Ar)(HNR2)
Br complexes as catalyst sources.
Figure 1. Examples of precatalysts that efficiently generate LPd(0)
and the precatalysts studied in this work.
Scheme 1. General Mechanism for Palladium-Catalyzed N-
Arylation Showing Potentially Isolable Complexes That
Could Serve as Precatalysts
RESULTS AND DISCUSSION
■
Oxidative addition complexes ([(Np3P)Pd(Ar)Br]2, 7a−c)
were synthesized from (cod)Pd(CH2TMS)2 under conditions
previously reported by our group (Scheme 2).15,25 Complexes
Scheme 2. Synthesis of Trineopentylphosphine
Arylpalladium Complexes
noted that palladium aryl species ([(PNp3)Pd(Ar)Br]2) were
dramatically more active than Pd(PNp3)2 for N-arylation
reactions.15 Buchwald reported the use of (AlPhos)Pd(Ar)X
(X = Br and OTf) precatalysts for the fluorination of aryl
bromides.16 Since these initial reports, [LPd(Ar)X]n complexes
have been shown to be significantly more active than catalysts
generated in situ or precatalysts 1−6 by a number of groups.17
The arylpalladium complex ([LPd(Ar)X]n) can be a stable
3-coordinate species (n = 1) or a halide bridged dimer (n = 2)
depending on the properties of the ligand, aryl group, and
halide.18 The [LPd(Ar)X]n precatalyst is converted to the
active LPd0 species by reaction with the nucleophilic coupling
partner followed by reductive elimination. The halide bridged
7a and 7b can also be made by reacting Pd(PNp3)2 with an
excess of the aryl bromide in toluene at 70 °C, but this method
does not work to prepare 7c.15 Complexes 7a−c were stored in
air, and no degradation was observed over the course of several
months. The aryl groups were chosen to have zero (7a), one
(7b), or two (7c) ortho substituents. Bromide-bridged dimeric
complexes 7a and 7c were converted to amine adducts by
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treatment with a secondary amine (morpholine) or a primary
amine (isobutylamine) in methylene chloride. Amine adducts
8c and 9c were recently reported by us.25 Complex 8a was
prepared in the same way in high yield. X-ray quality crystals of
8a were obtained (Figure 2), which showed the structure was
Figure 3. Reaction profiles for the coupling of 1-bromo-2,4,6-
triisopropylbenzene and 2,6-diisoproylaniline using precatalysts 7c
(solid line) or Pd2(dba)3/PNp3 (dotted line) as a function of
temperature (eq 1). Data points are the average of two independent
trials.
Figure 2. Thermal ellipsoid plot of 8a. Ellipsoids are drawn at the
50% level and hydrogens with the exception of the N−H hydrogen
have been omitted for clarity.
1
similar to that of 8c. H NMR analysis confirmed that the
amine coordinated as a neutral amine in all cases, rather than
as an anionic amido ligand. Complexes 8a, 8c, and 9c are also
air-stable solids that show no degradation when stored in
ambient conditions over several months.
The effectiveness of precatalyst 7c (0.5 mol %) was
compared to the catalyst generated from Pd2(dba)3 (0.5 mol
%) and PNp3 (1 mol %) for the coupling of 1-bromo-2,4,6-
triisopropylbenzene and 2,6-diisoproylaniline at 60, 36, and 22
°C (Figure 3). At 60 °C, complex 7c and the Pd2(dba)3/PNp3
The effect of the aryl group on palladium was then tested by
comparing the reaction profiles for arylpalladium complexes
7a−c. At 60 °C, over 90% conversion is obtained after 30 min
with precatalysts 7b and 7c (Figure 4), with the anisole
complex 7b giving a higher yield and faster rate. In contrast,
precatalyst 7a gave only 65% conversion after 30 min. At 36
°C, the trend was similar. Complexes 7b and 7c gave similar
reaction profiles (65% yield after 1 h), whereas conversion was
gave similar reaction profiles, but complex 7c gave a higher
conversion after 30 min (90 vs 62%). At 36 and 22 °C, the
reaction catalyzed by 7c gave a significantly higher initial rate
and overall conversion to product. The reactions catalyzed by
the Pd2(dba)3/PNp3 system showed an induction period prior
achieving maximum rate at both temperatures. We have
previously observed that the displacement of dba by PNp3 is
slow at room temperature.26 Therefore, the concentration of
active species early in the reaction is likely much higher using
7c than with the Pd2(dba)3/PNp3 system, particularly at lower
temperature. The dba ligand has also been shown to be an
inhibitor in cross-coupling reactions, which leads to slower
rates once the active species is formed.6
Figure 4. Reaction profiles for the coupling of 1-bromo-2,4,6-
triisopropylbenzene and 2,6-diisoproylaniline using precatalysts 7a−c
as a function of temperature (eq 1). Data points are the average of
two independent trials.
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much slower for the phenyl-substituted complex 7a. At room
temperature all three complexes gave low conversions, but
again ortho-substituted complexes 7b and 7c gave a higher
conversion than 7a.
Amine adducts 8a,c and 9c were then tested under the same
conditions as complexes 7a−c (eq 1). At 60 °C, the palladium
complexes with 2,6-dimethylphenyl ligands (8c and 9c) gave
significantly higher reaction rates than that of the phenyl
complex (8a) (Figure 5). The isobutyl amine complex (9c)
Figure 6. Comparison of aryl palladium precatalysts 7a and 7c and
their amine adducts (8a and 8c) in the coupling of 1-bromo-2,4,6-
triisopropylbenzene and 2,6-diisoproylaniline (eq 1). Data points are
the average of two independent trials.
(10j−l). Coupling with 2-aminoanthracene gave only a 45%
yield.
A modest yield of 10n (45%) was achieved in the coupling
of 1-bromo-2,6-dimethylbenzene with diisopropyl amine at
100 °C. Branched secondary amines represent a significant
challenge in amine arylation reactions.27 To our knowledge,
this represents the first example of a palladium-catalyzed
coupling of a secondary amine having α-carbon branches at
both nitrogen substituents with an ortho-substituted aryl
halide. The only catalytic coupling reactions to produce these
types of hindered N,N-dialkylaniline derivatives involve the
copper-catalyzed electrophilic amination of organozinc or
boron reagents with O-benzoyl hydroxylamines.28
Complex 7c provides comparable or higher reactions yields,
while using lower reaction temperatures than the catalyst
derived from Pd2(dba)3/PNp3. The reactions catalyzed by 7c
were accomplished at 40 °C, compared to 80 °C for reactions
using a combination of Pd2(dba)3 and PNp3.24a Precatalyst 7c
gave higher yields in many cases. For example, products 10b
and 10c were obtained in 86 and 83% yield, respectively, using
the catalyst derived in situ from Pd2(dba)3 and PNp3. In other
cases, such as 10d and 10h, the yields were the same under
both systems, although the in situ catalyst system required
higher temperatures to achieve those yields.
Catalyst Activation. Previous mechanistic studies of the
Pd/PNp3 catalyst system have shown that [(PNp3)Pd(Ar)Br]
complexes react with aniline in the presence of NaOt-Bu at 80
°C to form Pd(PNp3)2 and ArNHPh within a few minutes
(Scheme 1).15 Because of the fast rate, we have not been able
to obtain kinetics for the reaction of complexes 7a−c with
aniline and base. Reductive elimination of aryl bromides has
been observed with sterically demanding ligands, such as P(t-
Bu)3.29 We have seen no evidence of this behavior with PNp3
and think that is unlikely to occur under catalytic conditions.
Assuming that complexes 7a−c initiate the catalytic cycle by
reaction with amine and base followed by reductive elimination
to (PNp3)Pd0 (Scheme 1), the identity of the aryl group
Figure 5. Reaction profiles for the coupling of 1-bromo-2,4,6-
triisopropylbenzene and 2,6-diisoproylaniline using precatalysts 8a,c
and 9c as a function of temperature (eq 1). Data points are the
average of two independent trials.
gave a comparable initial rate to the morpholine adduct (8c),
but it became inactive after about 30 min at about 45%
conversion. Morpholine complex 8c retained activity during
the reaction and gave a higher overall conversion (60%).
Notably, the rate of conversion and yield of the amine adducts
(8a,c and 9c) are significantly lower than for halide-bridged
dimers 7a and 7c (Figure 6). At 36 and 22 °C, amine adducts
8a,c and 9c gave low conversions with catalyst deactivation
occurring rapidly.
Arylpalladium complex 7c was applied to the coupling of a
range of sterically demanding aryl bromides and amines at 40
°C (Scheme 3). Sterically demanding aryl bromides and
amines are challenging substrates for most catalyst systems but
are well-tolerated by the PNp3/Pd system.24 Excellent yields
(93−95%) were obtained in the coupling of 2-substituted aryl
bromides with 2,6-diisopropylaniline. Less hindered 3- and 4-
substituted aryl bromides also gave excellent yields, with the
exception of 4-bromobenzonitrile (11g, 36%). Nitriles are
competitive ligands for palladium and often lead to low yields.
Tetra-ortho-isopropyl-substituted product 11h was obtained in
97% yield. In comparison, the Pd2(dba)3/PNp3 catalyst system
gave a similar yield but required that the reaction be run at 80
°C.24a However, 1-bromo-2,6-dimethoxybenzene gave only a
54% yield with 2,6-diisopropylaniline (10i). The lower yield is
likely due to the increased electron density of the
dimethoxyarene. Coupling of 1-bromo-2,6-dimethylbenzene
with 2-substituted aniline derivatives also gave high yields
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Scheme 3. Coupling of Hindered Aryl Bromides and
Amines Using Precatalyst 7c
Scheme 4. Base Activation of Precatalyst 8a
a
The reaction of complex 8a (17 μM) and NaOt-Bu (43 μM)
at room temperature in C6D6 showed a single resonance at 9.1
ppm in the 31P NMR spectrum after 1 min (Figure S41). This
peak does not correspond with the peak for 8a (7.8 ppm),
although the 1H NMR spectrum is similar to that of 8a (Figure
S40). Notably, the N−H proton is observed in the same place
as 8a, which would suggest the new peak is not the
deprotonated amide complex (11). The new peak also is not
palladacycle 14 (37 ppm). It is possible that the addition of
NaOt-Bu results in a shift of the resonance for 8a due to an
increase in the ionic strength of the solution. Alternatively, the
new peak may be due to t-butoxide displacing bromide in the
complex. After 5 min, the peak at 9.1 ppm had partially
converted to give a 20% yield of (PNp3)2Pd (13) (Figure S43).
Complete conversion to Pd(PNp3)2 occurred after 14 h
(Figure S45). The 1H NMR spectrum shows that the
morpholine ligand was completely converted to N-phenyl
morpholine (Figure S44). Repeating the reaction with a 10:1
ratio of NaOt-Bu (170 μM) to 8a (10 μM) showed conversion
of 8a to Pd(PNp3)2 over the course of an hour (Figures S46−
S50) along with formation of a small amount of palladacycle
14 as a byproduct.
Complex 8c (12.0 ppm) underwent a similar slow
conversion to (Np3P)2Pd(0), although a number of
unidentified palladium(II) species were present throughout
the reaction (Figures S51−S56). After 40 min, 23% conversion
to (Np3P)2Pd(0) had occurred. After 1 h, the reaction had
progressed to 31% conversion. Complex 9c (16.9 ppm) did
not form (Np3P)2Pd(0) under these conditions. After 20 min,
complex 9c was completely converted to a new complex with a
chemical shift of −6.7 ppm (Figure S57), but no further
change occurred over the next 80 min (Figure S58). Attempts
to isolate or further characterize the species at −6.7 ppm were
unsuccessful.
a
Reaction performed at 100 °C. Reaction times were not optimized.
Isolated yields, except for yields in parentheses, which were
determined by GC analysis.
should not affect the reaction after this initial process.
Therefore, differences in the effectiveness of these precatalysts
are presumably due to differences in the rate and/or efficiency
of generating the (PNp3)Pd0 active species. It is unclear how
the identity of the aryl group on palladium affects this process.
Amine coordination would be expected to be more favorable
with less hindered aryl groups.25 Reductive elimination from
7c would also be expected to be slower than for 7a or 7b due
to the increased steric demand of the 2,6-dimethylphenyl
ligand.30
The amine adducts would be expected to be deprotonated
by base to give a palladium amido intermediate (11) that
would undergo reductive elimination of the aryl amine to
generate the active (Np3P)Pd0 species (12, Scheme 4). In the
absence of aryl halide, 12 would disproportionate to 13 and
Pd0. A possible side reaction would be metalation of the PNp3
ligand in 8a with elimination of arene and dissociation of
morpholine to give palladacycle 14 (Y = Br).15 Elimination of
arene or morpholine could also potentially occur from 11 to
give palladacycle 14 (Y = phenyl or morpholido).
The amine adducts (8a,c and 9c) undergo base-promoted
reductive elimination at rates that are slow compared to the
catalytic reaction. The observed rates are much slower than
those reported for other LPd(Ar)(amine)X complexes.31 The
reason for the slow reductive elimination is unclear, although it
is consistent with the lower coupling efficiency for these
complexes compared to the halide-bridged dimers (7a−c).
However, the reactivity of the amine adducts with base does
not correlate with their catalyst performance. Complexes 8c
and 9c give conversion rates and turnover numbers higher than
those of 8a, although both are less efficient than [(PNp3)Pd-
(Ar)Br]2 complexes 7a−c. In contrast, complexes 8c and 9c
E
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give base-promoted formation of Pd(PNp3)2 slower than does
8a.
CONCLUSIONS
■
Trineopentylphosphine arylpalladium halide complexes have
been shown to be effective catalysts for the coupling of
sterically hindered aryl bromides and anilines. Aryl palladium
complex 7c shows an increased coupling rate compared to the
catalyst generated in situ from Pd2(dba)3 and PNp3. The
coupling rate shows a positive correlation between the steric
demand of the palladium-bound aryl group and the coupling
rate. Mono- and di-ortho-substituted arylpalladium complexes
7b and 7c give higher rates and overall conversion than the
phenylpalladium complex (7a). Amine adducts give slower
reaction rates than the halide-bridge dimer precatalysts (7a−
c). Analysis of the reaction of the amine adducts with NaOt-Bu
show that the base-promoted reductive elimination is
unexpectedly slow for these complexes. This result suggests
that deprotonation and reductive elimination of the alkyl
amine adducts occurs more slowly than the reaction of
complexes 7a−c with aniline and base to generate the LPd(0)
active species. Thermodynamically disfavored displacement of
the amine by the aniline substrate may be required to activate
the amine adducts. This work shows that the structure of the
palladium-bound aryl group does have a measurable effect on
catalyst performance.
The reason for this apparent contradiction is unclear, but it
should be noted that under the catalytic conditions the aniline
substrate is present in large excess relative to the catalyst
species (120 equiv). Aniline binds much more weakly to the
(PNp3)Pd(Ar)Br fragment than morpholine or isobutyl amine
(Scheme 5a). Reaction of [(PNp3)Pd(Ar)Br]2 with 20 equiv of
Scheme 5. Amine Binding Equilibria and Plausible
a
Activation Route to Complexes 7a−c
EXPERIMENTAL SECTION
■
General Procedures and Materials. Reagents were purchased
from commercial suppliers and used as received, except as noted.
Toluene was refluxed over sodium for an hour and freshly distilled
before use. Pentane was dried over CaH2, distilled, and degassed by
three freeze−pump−thaw cycles prior to use. PNp3,32 (cod)Pd-
(CH2TMS)2,33 7c,15 8c,25 and 9c25 were prepared following reported
methods. Reactions were conducted under nitrogen using double-
manifold inert-atmosphere techniques, unless noted otherwise. All the
GC samples were measured using a Shimadzu GC-2014 Gas
Chromatograph using a 10 °C/min increasing rate from 150 to 250
a
(a) Amine binding equilibria and (b) a plausible activation route for
amine adduct complexes 8a,c and 9c.
°C. NMR spectra were obtained on a Bruker 500 MHz spectrometer.
̈
31P NMR spectra were acquired under gated decoupling mode at fixed
scans through the length of experiment with the aid of an automated
data collection program
aniline results in no observable adduct formation (K < 10−5).25
The binding constant would be expected to be even lower for
the sterically demanding aniline derivatives used in this study.
In contrast, morpholine and isobutylamine react stoichiometri-
cally with 7a−c to give the amine adduct (K > 104). Despite
the unfavorable equilibrium for displacement of an alkyl amine
by aniline, the much larger concentration of aniline may allow
for a small equilibrium concentration of the aniline adduct to
form. Deprotonation and reductive elimination of the aniline
adduct is fast,15 whereas deprotonation and reductive
elimination of amine adducts 8 and 9 is slow. Therefore,
displacement of the amine by aniline may be necessary to form
the active species (Scheme 5b). This process may compete
with formation of catalytically inactive palladacycle 14. Further
mechanistic study of this system is ongoing.
In our studies of the Pd/PNp3 system, we observed that
coupling reactions of aniline occurred with slower rates and
lower conversion than when 2,6-diisopropylaniline was used as
the amine nucleophile.15 We proposed that aniline promoted
the conversion of the active palladium catalyst to inactive
palladacycle 14 at a faster rate than the more hindered aniline
substrates. Reactions catalyzed by alkylamine adducts 8a,c and
9c show catalyst deactivation occurring within 30−60 min.
The more basic alkyl amine may facilitate palladacycle
formation in competition with the formation of the (PNp3)Pd0
active species, ultimately resulting in catalyst deactivation.
Further studies to understand this process are ongoing.
[(PNp3)Pd(C6H5)Br]2 (7a). The target complex was prepared
according to the reported synthesis of 7c.15 Trineopentylphosphine
(120 mg, 0.492 mmol) and bromobenzene (153.9 μL, 1.476 mmol)
were combined in 12 mL of pentane in a two neck flask under N2
protection. Freshly made (cod)Pd(CH2TMS)2 (190 mg, 0.488
mmol) was added under N2 counter flow. The reagent mixture was
stirred at 22 °C for 14 h. The resulting mixture was concentrated to
about 1 mL. The gray solids were filtered and washed with pentane.
The gray solids were collected and dissolved in 5 mL of methylene
chloride and filtered through Celite. The filtrate was collected, and the
volatiles were removed to provide an air-stable white solid (160 mg,
64%). 1H NMR (500 MHz, C6D6, 295 K): δ 7.72 (br, 2H), 7.06 (br,
2H), 6.91 (br, 1H), 1.72 (d, J = 10.5 Hz, 6H), 1.22 (brs, 27H). 13C
NMR (125 MHz, C6D6, 295 K): δ 152.9, 135.8, 123.4, 108.0, 40.2 (d,
J
C−P = 20 Hz), 33.5, 32.6. 31P{1H} NMR (202.5 MHz, C6D6, 295 K):
δ 7.9. Elemental analysis: calcd for C42H76Br2P2Pd2: C, 49.67; H,
7.54; N, 0. Found: C, 50.56; H, 7.72; N, 0.0.
[(PNp3)Pd(2-MeOC6H4)Br]2 (7b). Trineopentylphosphine (100
mg, 0.410 mmol), 2-bromoanisole (160 μL, 1.285 mmol), (cod)Pd-
(CH2TMS)2 (160 mg, 0.411 mmol), and pentane were reacted by the
same method as 7a to give an air-stable yellow solid (80 mg, 36%). 1H
NMR (500 MHz, C6D6, 295 K): δ 7.79 (br, 1H), 6.99 (m, 1H), 6.89
(m, 1H), 6.49 (d, J = 8.2 Hz, 1H), 3.98 (s, 3H), 1.76 (brs, 6H), 1.29
(br, 27H). 13C NMR (125 MHz, C6D6, 295 K): δ 162.1 (d, JC−P
12.5 Hz), 141.4, 138.2 (d, JC−P = 13.8 Hz), 126.0, 122.4 (d, JC−P
=
=
3.75 Hz), 112.4 (d, JC−P = 25 Hz), 56.5 (d, JC−P = 11.3 Hz), 41.3
(brs), 34.7, 34.0. 31P{1H} NMR (202.5 MHz, C6D6, 295 K): δ 11.21,
F
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pubs.acs.org/Organometallics
Article
11.17, 9.75, 9.69 (stereoisomeric mixture: 1:1:0.2:0.2). Elemental
analysis: calcd for C44H80Br2O2P2Pd2: C, 49.13; H, 7.50; N, 0. Found:
C, 48.93; H, 7.53; N, 0.0.
128.7, 127.6, 127.4, 127.2, 124.0, 117.6, 111.6, 28.6, 24.7, 23.1.
HRMS: m/z calcd for C24H27N (M+) 329.2144. Found 329.2147.
N-(2,6-Diisopropylphenyl)naphthalen-1-amine (10d).24a Using
the general procedure, 1-bromonaphthalene (207 mg, 1.00 mmol)
and 2,6-diisopropylaniline (226 μL, 1.20 mmol) were coupled using
0.5 mol % 7c at 40 °C to give the product as a white solid (282 mg,
(PNp3)Pd(morpholine)(Ph)Br (8a). The target compound was
prepared according to the reported synthesis of 8c.25 [(PNp3)Pd-
(C6H5)Br]2 (7a, 67.6 mg, 0.067 mmol) was dissolved in methylene
chloride (8 mL) under nitrogen. Morpholine (13.0 μL, 0.150 mmol)
was added into the solution. After stirring for 1 h, the volatiles were
removed to provide an air-stable white solid (75 mg, 95%) that was
1
93%). H NMR (500 MHz, CDCl3): δ 8.22−8.24 (m, 1H), 8.00−
8.01 (m, 1H), 7.64−7.68 (m, 2H), 7.48−7.51 (m, 1H), 7.42−7.44
(m, 3H), 7.35 (t, J = 7.8 Hz, 1H), 6.37 (d, J = 7.5 Hz, 1H), 5.90 (s,
1H), 3.34 (sept, J = 6.8 Hz, 2H), 1.36 (d, J = 6.9 Hz, 6H), 1.27 (d, J =
6.9 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ 147.2, 143.6, 135.8,
134.7, 129.0, 127.4, 126.8, 126.0, 125.2, 124.2, 123.5, 120.2, 118.3,
107.2, 28.4, 25.0, 23.4. HRMS: m/z calcd for C22H25N (M+)
303.1987. Found 303.1982.
N-(2,6-Diisopropylphenyl)benzo[d][1,3]dioxol-5-amine (10e).
Using the general procedure, 1-bromo-3,4-(methylenedioxy)benzene
(120.4 μL, 1.00 mmol) and 2,6-diisopropylaniline (226.3 μL, 1.20
mmol) were coupled using 0.5 mol % 7c at 40 °C to give the product
as a light yellow solid (276.3 mg, 93%). 1H NMR (500 MHz,
CD3CN): δ 7.23 (m, 3H), 6.59 (d, J = 8.1 Hz, 1H), 6.10 (d, J = 5 Hz,
1H), 5.80 (s, 2H), 5.78 (d, J = 5.8 Hz, 1H), 5.75 (s, 1H), 3.17 (m,
2H), 1.12 (d, J = 6.5 Hz, 12H). 13C NMR (125 MHz, CD3CN): δ
149.4, 148.7, 145.7, 140.2, 137.0, 128.1, 124.8, 118.3, 109.4, 104.9,
101.6, 96.3, 28.9, 24.1. HRMS: m/z calcd for C19H23NO2 (M+)
297.1729. Found 297.1725.
1
analytically pure. H NMR (500 MHz, C6D6, 295 K): δ 7.56 (d, J =
8.8 Hz, 2 H), 7.07(t, J = 7.4 Hz, 2H), 6.98 (t, J = 7.2 Hz, 1H), 3.53
(brs, 1H), 3.11 (d, J = 11.3 Hz, 2H), 2.60 (m, 6H), 1.99 (d, J = 9.9
Hz, 6H), 1.30(s, 27H). 13C NMR (125 MHz, C6D6, 295 K): δ 158.0,
135.2, 123.8, 67.7, 48.7, 40.5 (d, JC−P = 23.8 Hz), 33.6, 32.8. 31P{1H}
NMR (202.5 MHz, C6D6, 295 K): δ 7.8. Elemental analysis: calcd for
C25H47BrNOPPd: C, 50.47; H, 7.96; N, 2.35. Found: C, 50.57; H,
7.96; N, 2.33.
Crystallographic Structure Determination of 8a. A suitable
crystal of 8a was selected and mounted on a Mitgen cryoloop in a
random orientation on a XtaLAB Synergy R, DW system, HyPix
diffractometer. The crystal was kept at 101(2) K during data
collection. Using Olex2,34 the structure was solved with the ShelXT35
structure solution program using Intrinsic Phasing and refined with
ShelXL36 refinement package using Least Squares minimization using
either Olex234 or ShelXle37 or both.
N-(4-Fluorophenyl)-2,6-diisopropylaniline (10f). Using the gen-
eral procedure, 1-bromo-4-fluorobenzene (109.9 μL, 1.00 mmol) and
2,6-diisopropylaniline (226 μL, 1.20 mmol) were coupled using 0.5
mol % 7c at 40 °C to give the product as a red brown oil (251.3 mg,
93%). 1H NMR (500 MHz, CD3CN): δ 7.24 (m, 3H), 6.87 (t, J = 8.6
Hz, 2H), 6.39 (m, 2H), 5.89 (s, 1H), 3.15 (d, J = 6.9 Hz, 2H), 1.11
(d, J = 6.7 Hz, 12H). 13C NMR (125 MHz, CD3CN): δ 157.3, 148.8,
146.4, 136.6, 128.3, 124.8, 116.4 (d, JC−F = 22.5 Hz), 114.21 (d, JC−F
= 7.5 Hz), 29.0, 24.0. HRMS: m/z calcd for C18H22FN (M+)
271.1736. Found 271.1733.
General Procedure for Buchwald−Hartwig Amination. The
palladium precatalyst (0.5 mol %) was measured into a 5 mL screw-
capped vial in air. The vial with a stirring bar was placed into a
nitrogen-filled glovebox. NaOt-Bu (1.5 equiv) was added to the vial.
The vial was sealed with a Teflon septum and taken out of the
glovebox. The aryl halide (1 mmol), arylamine (1.2 equiv), and 4 mL
of toluene were added, and the reaction was placed in an oil bath
preheated to 40 °C. After the reaction had reached completion as
judged by GC; the reaction mixture was dissolved in ethyl acetate and
filtered through a plug of silica gel. After drying, the crude reaction
mixture was purified by flash chromatography on silica gel (0.5−10%
EtOAc/hexane) to obtain pure product.
N-(2,6-Diisopropylphenyl)-2,4,6-triisopropylaniline (10h).39
Using the general procedure, 1-bromo-2,4,6-triisopropylbenzene
(253 μL, 1.00 mmol) and 2,6-diisopropylaniline (226 μL, 1.20
mmol) were coupled using 0.5 mol % 7c at 40 °C to give the product
as clear, colorless crystals (341 mg, 97%). 1H NMR (500 MHz,
CDCl3): δ 7.27 (d, J = 7.6 Hz, 2H), 7.15−7.18 (m, 3H), 4.99 (s, 1H),
3.24−3.38 (m, 4H), 3.07 (sept, J = 6.7 Hz, 1H), 1.45 (dd, J = 6.9, 0.8
Hz, 6H), 1.45 (d, J = 7.1 Hz, 12H), 1.39 (d, J = 7.1 Hz, 12H). 13C
NMR (125 MHz, CDCl3): δ 143.8, 141.9, 141.2, 140.1, 138.3, 124.0,
122.3, 121.8, 34.2, 28.1, 27.9, 24.5, 23.9, 23.8. HRMS: m/z calcd for
C24H27N (M+) 379.3239. Found 379.3241.
N-(2-Tolyl)-2,6-diisopropylaniline (10a).38 Using the general
procedure, 2-bromotoluene (120 μL, 1.00 mmol) and 2,6-
diisopropylaniline (226 μL, 1.20 mmol) were coupled using 0.5 mol
1
% 7c at 40 °C to give the product as brown oil (254 mg, 95%). H
NMR (500 MHz, CD3CN): δ 7.26 (m, 3H), 7.09 (d, J = 7.0 Hz, 1H),
6.87 (t, J = 7.4 Hz, 1H), 6.57 (t, J = 7.1 Hz, 1H), 5.93 (d, J = 8.0 Hz,
1H), 5.46 (s, 1H), 3.10 (sept, J = 3.10 Hz, 2H), 2.30 (s, 3H), 1.16
(dd, J = 35.5, 6.5 Hz, 12H). 13C NMR (125 MHz, CD3CN): δ 148.8,
147.5, 136.8, 131.1, 128.2, 127.6, 124.7, 122.4, 118.3, 111.6, 29.0,
24.7, 23.4, 18.0. HRMS: m/z calcd for C24H27N (M+) 267.1987.
Found 267.1984.
N-(2,6-Diisopropylphenyl)-2,6-dimethoxyaniline (10i). Using the
general procedure, 1,3-dimethoxy-2-bromobenzene (217.06 mg, 1.00
mmol) and 2,6-diisopropylaniline (226.3 μL, 1.20 mmol) were
coupled using 0.5 mol % 7c at 40 °C to give the product as a brown
oil (168.4 mg, 54%). 1H NMR (500 MHz, CD3CN): δ 7.15 (m, 1H),
7.10 (d, J = 7.9 H, 2H), 6.68 (m, 1H), 6.58 (d, J = 8.3 Hz, 2H), 5.54
(s, 1H), 3.56 (s, 6H), 3.33 (sept, J = 6.8 Hz, 2H), 1.09 (d, J = 6.9 Hz,
12H). 13C NMR (125 MHz, CD3CN): δ 149.4, 148.0, 140.6, 129.2,
128.9, 126.7, 123.3, 118.3, 107.0, 56.8, 28.9, 23.8. HRMS: m/z calcd
for C20H27NO2 (M+) 313.2042. Found 313.2038.
N-(2-Methoxyphenyl)-2,6-diisopropylaniline (10b).19a Using the
general procedure, 2-bromoanisole (125 μL, 1.00 mmol) and 2,6-
diisopropylaniline (226 μL, 1.20 mmol) were coupled using 0.5 mol
% 7c at 40 °C to give the product as a clear, colorless oil (269 mg,
1
95%). H NMR (500 MHz, CDCl3): δ 7.42−7.45 (m, 1H), 7.37−
7.38 (m, 2H), 6.99 (dd, J = 7.6, 1.1 Hz, 1H), 6.80−6.89 (m, 2H), 6.29
(dd, J = 7.6, 1.6 Hz, 1H), 5.80 (s, 1H), 4.75 (s, 3H), 3.34 (sept, J =
6.8 Hz, 2H), 1.30 (d, J = 6.9 Hz, 12H). 13C NMR (125 MHz,
CDCl3): δ 147.8, 146.2, 138.1, 135.6, 127.3, 123.9, 121.3, 117.0,
111.2, 110.0, 55.8, 28.4, 24.1. HRMS: m/z calcd for C19H25NO (M+)
283.1936. Found 283.1940.
N-(2-Methoxyphenyl)-2,6-dimethylaniline (10j).40 Using the
general procedure, 2-bromo-m-xylene (133 μL, 1.00 mmol) and o-
anisidine (135 μL, 1.20 mmol) were coupled using 0.5 mol % 7c at 40
1
°C to give the product as a white solid (209.1 mg, 92%). H NMR
N-(2,6-Diisopropylphenyl)-[1,1′-biphenyl]-2-amine (10c).24a
Using the general procedure, 2-bromobiphenyl (172 μL, 1.00
mmol) and 2,6-diisopropylaniline (226 μL, 1.20 mmol) were coupled
using 0.5 mol % 7c at 40 °C to give the product as a white solid
(234.5 mg, 93%). 1H NMR (500 MHz, CDCl3): δ 7.75 (d, J = 7.4 Hz,
2H), 7.65 (t, J = 7.6 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.42−7.45 (m,
1H), 7.33−7.38 (m, 3H), 7.23 (dt, J = 7.8, 1.0 Hz, 1H), 6.94 (t, J =
7.4 Hz, 1H), 6.41 (d, J = 8.2 Hz, 1H), 5.42, (s, 1H), 3.63 (sept, J = 6.6
Hz, 2H), 1.34 (d, J = 6.9 Hz, 6H), 1.25 (d, J = 6.8 Hz, 6H). 13C NMR
(125 MHz, CDCl3): δ 147.6, 145.0, 139.7, 135.7, 130.3, 129.5, 129.2,
(500 MHz, CDCl3): δ 7.22−7.23 (m, 2H), 7.16−7.19 (m, 1H), 6.96
(dd, J = 7.4, 1.8 Hz, 1H), 6.80−6.85 (m, 2H), 6.25 (dd, J = 7.5, 2.1
Hz, 1H), 5.76 (s, 1H), 4.03 (s, 3H), 2.32 (s, 6H). 13C NMR (125
MHz, CDCl3): δ 146.9, 138.6, 136.3, 136.2, 128.6, 125.9, 121.3,
117.4, 111.2, 110.0, 55.8, 18.4. HRMS: m/z calcd for C15H17NO
(M+) 227.1310. Found 227.1307.
N-(2-(tert-Butyl)phenyl)-2,6-dimethylaniline (10k).24a Using the
general procedure, 2-bromo-m-xylene (133 μL, 1.00 mmol) and 2-
tert-butylaniline (187 μL, 1.20 mmol) were coupled using 0.5 mol %
1
7c at 40 °C to give the product as a white solid (228 mg, 90%). H
G
https://dx.doi.org/10.1021/acs.organomet.0c00140
Organometallics XXXX, XXX, XXX−XXX

Organometallics
pubs.acs.org/Organometallics
Article
NMR (500 MHz, CDCl3): δ 7.49 (dd, J = 7.8, 1.4 Hz, 1H), 7.27−
7.29 (m, 2H), 7.20−7.23 (m, 1H), 7.09−7.12 (m, 1H), 6.91 (dt, J =
8.2, 1.1 Hz, 1H), 6.39 (dd, J = 8.0, 1.1 Hz, 1H), 5.49 (s, 1H), 2.34 (s,
6H), 1.72 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 144.1, 139.2,
135.3, 134.2, 128.8, 127.1, 126.6, 125.4, 118.7, 114.0, 34.7, 30.1, 18.8.
HRMS: m/z calcd for C18H23N (M+) 253.1830. Found 253.1837.
N-(2,6-Dimethylphenyl)naphthalen-1-amine (10l).41 Using the
general procedure, 2-bromo-m-xylene (133 μL, 1.00 mmol) and 1-
naphthylamine (172 mg, 1.20 mmol) were coupled using 0.5 mol %
Fengrui Qu − Department of Chemistry & Biochemistry, The
University of Alabama, Tuscaloosa, Alabama 35487, United
States; orcid.org/0000-0002-9975-2573
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.organomet.0c00140
Notes
The authors declare no competing financial interest.
1
7c at 40 °C to give the product as a white solid (215 mg, 87%). H
NMR (500 MHz, CDCl3): δ 8.20−8.22 (m, 1H), 8.00−8.01 (m, 1H),
7.64−7.68 (m, 2H), 7.47 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 8.0 Hz,
1H), 7.33−7.35 (m, 2H), 7.27−7.30 (m, 1H), 6.43 (d, J = 7.5 Hz,
1H), 5.84 (s, 1H), 2.37 (s, 6H). 13C NMR (125 MHz, CDCl3): δ
141.4, 138.9, 135.4, 134.8, 128.9, 128.8, 126.7, 126.0, 125.7, 125.2,
124.2, 120.5, 119.0, 107.4, 18.3. HRMS: m/z calcd for C18H17N (M+)
247.1361. Found 247.1360.
ACKNOWLEDGMENTS
■
H.H. acknowledges support of his postdoctoral associate
position from the College of Arts & Sciences, The University
of Alabama. The structure of 8a was obtained on an X-ray
diffractometer purchased with support from NSF (CHE MRI
1828078). Johnson-Matthey is acknowledged for donation of
palladium salts.
N-(2,6-Dimethylphenyl)anthracen-2-amine (10m). Using the
general procedure, 2-bromo-m-xylene (133 μL, 1.00 mmol) and 2-
aminoanthracene (232 mg, 1.20 mmol) were coupled using 0.5 mol %
7c at 40 °C to give the product as an earth gray powder (134 mg,
REFERENCES
1
■
45%). H NMR (500 MHz, CD3CN): δ 8.30 (s, 1H), 7.96 (s, 1H),
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6.9 Hz, 2H), 7.19 (m, 4H), 6.42 (s, 1H), 6.32 (s, 1H), 2.23 (s, 6H).
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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/acs.organomet.0c00140.
NMR spectra of isolated compounds, NMR spectra from
catalyst activation studies (PDF)
Accession Codes
CCDC 1983639 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
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Corresponding Author
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Email: kshaughn@ua.edu
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Authors
Huaiyuan Hu − Department of Chemistry & Biochemistry, The
University of Alabama, Tuscaloosa, Alabama 35487, United
States
Corrie E. Burlas − Department of Chemistry & Biochemistry,
The University of Alabama, Tuscaloosa, Alabama 35487,
United States
Sabrina J. Curley − Department of Chemistry & Biochemistry,
The University of Alabama, Tuscaloosa, Alabama 35487,
United States
Tomasz Gruchala − Department of Chemistry & Biochemistry,
The University of Alabama, Tuscaloosa, Alabama 35487,
United States
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