Enolizable Ketones as Activators of Palladium(II) Precatalysts in Amine Arylation Reactions

Article abstract of DOI:10.1021/acscatal.0c00221

Enolizable ketones have been identified as effective activators for palladium(II) precatalysts in the coupling of aryl bromides and aniline. N-arylation reactions catalyzed by [(DTBNpP)PdCl₂]₂ (DTBNpP = (bis(tert-butyl)neopentylphosphine) and PEPPSI-IPr precatalysts are activated by the addition of acetone, mesityl oxide, and 3-pentanone. 3-Pentanone was the most effective activator. Mechanistic studies show that acetone, 3-pentanone, and mesityl oxide reduce [(DTBNpP)PdCl₂]₂ in the presence of NaO-t-Bu to Pd⁰(DTBNpP)₂

Full text of DOI:10.1021/acscatal.0c00221

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Article
Enolizable ketones as activators of palladium(II)
precatalysts in amine arylation reactions
Huaiyuan Hu, Ashley M. Gilliam, Fengrui Qu, and Kevin H. Shaughnessy
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c00221 • Publication Date (Web): 06 Mar 2020
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Enolizable Ketones as Activators of Palladium(II) Precatalysts in Amine Arylation
Reactions
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Huaiyuan Hu, Ashley M. Gilliam, Fengrui Qu, Kevin H. Shaughnessy*
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Department of Chemistry and Biochemistry, The University of Alabama, Box 870336,
Tuscaloosa, AL 35487-0336, USA
*Email: kshaughn@ua.edu
Abstract:
Enolizable ketones have been identified as effective activators for palladium(II)
precatalysts in the coupling of aryl bromides and aniline. N-Arylation reactions
catalyzed by [(DTBNpP)PdCl2]2 (DTBNpP = (di-(tert-butyl)neopentylphosphine) and
PEPPSI-IPR precatalysts are activated by the addition of acetone, mesityl oxide, and 3-
pentanone. 3-Pentanone was the most effective activator. Mechanistic studies show
that acetone, 3-pentanone, and mesityl oxide reduce [(DTBNpP)PdCl2]2 in the presence
of NaOt-Bu to Pd0(DTBNpP)2.
Keywords: cross-coupling, palladium, phosphine, N-heterocyclic carbene, amination,
precatalyst
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Introduction
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Palladium-catalyzed cross-coupling reactions have become ubiquitous methods for
the construction of C-C and C-heteroatom bonds in both academic and industrial
syntheses. Significant effort has been devoted to the development of optimized
supporting ligands that provide highly active catalysts across a broad range of
substrates, including sterically demanding trialkylphosphines,1 2-biarylphosphines,2
and N-heterocyclic carbenes.3 Many synthetic protocols rely on generating the active
catalyst species under the reaction conditions (in situ) through combination of a ligand,
or ligand precursor, and a palladium source. Although the choice of ligand often plays
a critical role in the success of a particular coupling reaction, recent research has shown
that the choice of catalyst precursor can also be critical in particularly challenging cross-
coupling reactions.4
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With current generation ligands, the active catalyst is a monodentate LPd(0)
species.5 The LPd(0) species is unstable and must be generated from catalyst
precursors, although it has been observed under catalytically relevant conditions.6 In
situ generation of the active species from a ligand and a palladium source in a 1:1 ratio
is a common strategy, but this approach provides limited control over the formation of
the LPd(0) complex. Improved performance can often be achieved by using a
palladium(0, I, or II) precatalyst containing one supporting ligand that will remain
bound upon activation and additional neutral or anionic ligands that will be lost during
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the activation process. Successful precatalysts include (LPd)2(µ-cod) (1),7 [((t-
Bu)3P)Pd(µ-X)]2 (2),8 (allyl)Pd(L)X (3-4),9 the Buchwald palladacycle precatalysts (5),10
and the PEPPSI complexes (6).3b,c,11
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Figure 1. Examples of palladium phosphine and NHC precatalysts
Palladium(0) precatalysts do not require reduction under the reaction conditions,
but are typically air-sensitive. Palladium(II) precatalysts are typically air stable, which
simplifies their handling. A palladium(II) precatalyst requires a reduction process to
form the active palladium(0) species, however. The palladium-allyl (3-4) and
palladacyclic catalysts (5) are designed to undergo base-promoted reductive elimination
under catalytic conditions to generate the LPd(0) species. In contrast, the PEPPSI
complexes do not contain ligands primed for reductive elimination upon exposure to
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base. The PEPPSI precatalyst can be reduced to Pd(0) under a variety of conditions
depending on the nature of the coupling partners. With organometallic coupling
partners, such as in a Negishi, Kumada, or Suzuki coupling, homocoupling of the
organometallic species provides the reduction route.12 In coupling with alkyl amines,
reduction can occur by β-hydride elimination of the coordinated amine. In the case of
aryl amine or thiolate coupling partners, these pathways are unavailable. Organ
showed that additives, such as Bu2Mg, morpholine, and KOi-Pr, activated the PEPPSI
precatalyst in the arylation of arylthiols.13 In the case of isopropoxide, acetone was
detected under the reaction conditions, which is consistent with an activation pathway
involve β-hydride elimination of a Pd-isopropoxide complex.14
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Our group has report the use of halide-bridged monophosphine palladium
complexes ([(R3P)PdCl2]2, PR3 = DTBNpP (7a), and TNpP (7b), Figure 1) as stable and
effective precatalysts for the Suzuki coupling reaction.15 Similar to the PEPPSI
precatalyst, complexes 7a-b require reduction to the LPd(0) species. Under Suzuki
coupling conditions, the arylboronic acid serves as the reductant. We sought to extend
the use of these precatalysts to the arylation of aniline derivatives. We expected that a
reducing additive would be necessary to activate precatalysts 7a-b. Here we report the
use of enolizable ketones as effective activators for 7a and the PEPPSI-IPr precatalysts in
the coupling of aryl bromides and aniline.
Results and Discussion
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Ketone activators in N-arylation reactions. We have previously reported that
DTBNpP in combination with Pd2(dba)3 (1 mol % Pd, 1:1 Pd/P) gives complete
conversion in the reaction of 4-bromoanisole and aniline in toluene with NaOt-Bu after
1 hour at room temperature.16 The ability of chloride dimer 7a to catalyze the arylation
of aniline was tested under the same conditions using 0.5 mol % 7a (1 mol % Pd, eq 1).
Little conversion was observed after 15 h at ambient temperature or 40 °C (Table 1,
entries 1-2). Complete conversion was achieved at 80 °C, however. The low activity of
7a at lower temperature was expected as there is not an efficient mechanism to convert
7a to a palladium(0) species. At 80 °C, catalyst activation does occur by an unknown
mechanism.
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Table 1. Effect of additives on the coupling of 4-bromoanisole and aniline catalyzed by
7aa
entry additive
T
(°C)
22
40
80
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yield
(%)b
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>99
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>99
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>99
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none
none
none
isopropanol
PhB(OH)2
acetone
acetone
3-pentanone
3-pentanone
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2,4-dimethyl-3-pentanone
2,4-dimethyl-3-pentanone
benzophenone
benzophenone
acetophenone
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>99
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acetophenone
propiophenone
propiophenone
isobutyrophenone
isobutyrophenone
mesityl oxide
mesityl oxide
a Conditions depicted in equation 1. b Yields determined by GC analysis of reaction
mixtures.
Additives that can serve as a reductant were explored to improve the activity of 7a
at lower temperatures. Isopropanol and phenylboronic acid both significantly
improved the reaction yield at 40 °C (entries 4-5). Surprisingly, acetone, which would
be formed upon reduction by isopropanol, gave complete conversion to product at 40
°C (entry 7) and a 42% yield at room temperature. With the success of acetone, other
ketones were tested. 3-Pentanone proved more effective than acetone giving nearly
complete conversion at room temperature (entry 8). The more hindered 2,4-dimethyl-3-
pentanone gave complete conversion at 40 °C, but was less effective than acetone or 3-
pentanone at room temperature. Benzophenone, which lacks an enolizable proton,
gave the same yields at room temperature or 40 °C (entries 12-13) as the additive-free
reactions (entries 1-2). Aryl alkyl ketones gave somewhat lower conversions compared
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to the symmetric dialkyl ketones, but followed the same trend (entries 14-19). Mesityl
oxide (4-methylpent-3-en-2-one), which would be the aldol condensation product
formed from acetone, also proved to be an effective activator (entries 21-22), giving
results comparable 3-pentanone.
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The ketone activators used in these reactions are potential substrates for α-arylation
reactions in competition with the desired N-arylation reaction. Small amounts of α-
arylated products (1-2%) were detected by GC in reactions using acetone, 3-pentanone,
acetophenone, and propiophenone as the activators. The larger relative concentration
of amine to ketone (12:1) and the increased coordinating ability of the amine results in a
preference for N-arylation over α-arylation.
To further evaluate the effectiveness of the ketone activators, reaction profiles were
determined for reactions activated by 3-pentanone, mesityl oxide, and acetone (Figure
2). At room temperature, 3-pentanone gave the highest initial reaction rate followed
closely by mesityl oxide. At room temperature, acetone gave only 12% conversion after
8 hours. At 40 °C, the reaction with acetone was slower than those with 3-pentanone or
mesityl oxide, but reached 80% conversion after 7 hours.
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Figure 2. Reaction profile for the reaction of 3-bromoanisole and aniline using 7a (0.5
mol %) under conditions of equation 1: 3-pentanone at 22 °C (purple triangle), mesityl
oxide at 22 °C (green diamond), acetone at 40 °C (red square), acetone at 22 °C (blue
circle).
The results in Table 1 and Figure 2 show that the presence of at least one α-proton is
necessary to achieve high conversion. The best results were obtained with ethyl ketones
having two α-protons (3-pentanone and propiophenone), followed by methyl ketones
(acetone and acetophenone). Isopropyl ketones were less effective than acetone, yet did
have an activating effect. The branched ketones may be less effective as activators due
to the increased steric hindrance at the α-position. Mesityl oxide has a similar activating
effect to 3-pentanone, despite being a methyl ketone.
To determine the optimal loading of ketone activator, the reaction of 4-bromoanisole
and aniline catalyzed by 7a (0.5 mol %) was performed at room temperature with 3-
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pentanone loadings ranging from 2–20 mol % relative to 4-bromoanisole, which
corresponds to 2–20 equivalents relative to palladium. The rate of conversion increased
on going from 2 to 8 mol % 3-pentanone (Figure S18, Supporting Information). After 3
hours, the reaction with 2 mol % 3-pentanone had reached 49% conversion, whereas the
reaction with 8 mol % had reached 87% conversion (Figure 3). Reactions with 8–14
mol% 3-pentanone had nearly identical reaction profiles (Figure S18). Further
increasing the 3-pentanone loading to 20 mol%, resulted in slower conversion (48%
after 3 hours). After 18 hours, the reactions with 5–14 mol % 3-pentanone gave
complete conversion, whereas a 70% conversion was achieved with 2 mol % ketone and
an 80% conversion with 20 mol % ketone.
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Figure 3. Average yield (3 trials) after 3 hours for the reaction 4-bromoanisole and
aniline catalyzed by 7a (0.5 mol %) using NaOt-Bu in toluene at room temperature as a
function of 3-pentanone loading.
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These results show that precatalyst 7a requires at least 5 mol% 3-pentanone to be
efficiently activated. Little change in reaction rate is seen between 5 and 14 mol%
ketone, but the catalyst is inhibited at a 20 mol% loading. Although the reaction rate is
slower with a 20 mol% loading of ketone, the reaction still selectively produced the
desired amine product. No significant (>1-2%) byproducts are seen by GC in these
reactions. The cause of the inhibition at high ketone loading with precatalyst 7a
remains unclear, but is not due to competitive arylation of the ketone.
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The use of ketone activators with 7a was tested in the coupling of aniline with a
small set of aryl bromides (Scheme 1). Reactions with 3-pentanone (condition A) and
mesityl oxide (condition C) were performed at room temperature, whereas those with
acetone (condition B) were carried out at 40 °C. High yields were obtained under all
three conditions with 4-bromotoluene, 1-bromo-4-fluorobenzene, N,N-dimethyl 4-
bromoaniline, and 4-bromoacetophenone. These substrates encompass electron-rich
and electron-deficient examples. Low yields were obtained with 4-bromobenzonitrile
and 4-bromophenol. Although electron deficient, 4-bromobenzonitrile can compete
with the phosphine ligands to coordinate to palladium. 4-Bromophenol is
deprotonated under the reaction conditions to give a very electron-rich 4-
bromophenoxide substrate.
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Scheme 1. Coupling of aryl bromides catalyzed by 7a using ketone activators.
Condition A: 3-pentanone, 22 °C; Condition B: acetone, 40 °C; Condition C: mesityl
oxide, 22 °C. Yields determined by GC.
The PEPPSI precatalyst family has a monomeric (NHC)PdCl2(3-chloropyridine)
structure in which the pyridine ligand can be displaced under the reaction conditions to
reveal the (NHC)Pd(0) active species.3b,c,11 No examples of phosphine analogs of the
PEPPSI catalysts have been reported. Our group previously reported the structure of
(DTBNpP)PdCl2(4-picoline),15 but had not explored the catalytic activity of these types
of complexes. Aniline (8a-b) and 3-chloropyridine (9a-b) complexes were readily
prepared by reacting the nitrogen ligand with dimers 7a or 7b in methylene chloride
(Scheme 2).
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Scheme 2. Synthesis of nitrogen ligand adducts of 7a-b.
The synthesis and crystal structure of 8b has been previously reported by us.17 X-
ray quality crystals of 9b were obtained by slow evaporation from a benzene solution.
Complex 9b adopts a square planar structure with the 3-chloropyridine ligand trans to
the TNpP ligand that is structurally similar to that of other (TNpP)PdCl2(amine)
adducts that we have characterized (Figure 4).17 The structure of 9b has the same Pd-N
bond length as the PEPPSI-IPr complex,18 but the palladium square plane is somewhat
more distorted to accommodate the TNpP ligand.
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Figure 4. Thermal ellipsoid plot (50% probability) of the molecular structure of 9b. Hydrogen
atoms and disorder are omitted for clarity. Selected bond distances (Å) and angles (°): Pd1-P1
2.2571(3), Pd1-N1 2.1349(9), Pd-Clave 2.307, Cl1-Pd1-N1 88.48(1), N1-Pd1-Cl2 89.12(2), Cl2-
P1-P1 93.78(1), P1-Pd1-Cl1 88.70(2).
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Complexes 8a-b and 9a-b were tested in the coupling of bromobenzene and aniline
in comparison to the halide dimers 7a-b at 22 °C (Table 2). In the absence of ketone
activator, less than 10% yield was observed for all precatalysts. With 3-pentanone (10
mol %), all three DTBNpP-derived precatalysts (7a, 8a, and 9a) gave quantitative
conversion to product. The TNpP-derived catalysts were less effective. Previous
studies have shown that TNpP-derived catalysts generally required higher
temperatures than those derived from DTBNpP.19 3-Chloropyridine-derived complex
9b provided higher yields than 7b, whereas aniline complex 8b was less effective.
Table 2. Amine adducts as precatalysts for N-arylation reactions
yield Ph2NH (%)
entr precataly
condition
condition
y
1
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3
4
st
Aa
4
Bb
7a
8a
9a
7b
>99
6
5
>99
>99
0.3
19
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8b
9b
0.3
0.2
12
27
a Condition A: precatalyst (1 mol % Pd), phenyl bromide (1 mmol), aniline (1.2
7
8
9
mmol), NaOt-Bu (1.5 mmol), toluene, 22 °C, 3 h. b Condition B: Same as condition A
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with the addition of 3-pentanone (0.1 mmol).
Ketone arylation. Enolate arylation products were observed as minor byproducts in
the ketone-activated amination reactions. Based on these results, precatalyst 7a was
expected to be an effective precatalyst for the arylation of ketones in the absence of
other activators. Coupling of 4-bromoanisole with acetophenone and propiophenone
gave over 50% conversion to the α-arylated products after 1 hour and complete
conversion to product after 5 hours (eq 2). Complex 7a showed comparable activity to
the catalyst generated in situ from Pd(OAc)2 and DTBNpP.20
Ketone activation of the PEPPSI-IPr precatalyst. The PEPPSI family of precatalysts
developed by Organ (6, Figure 1) effectively catalyze a wide range of C-C and C-
heteroatom coupling reactions.3b,c Similar to complex 7a, the PEPPSI precatalysts must
undergo reduction to form the active palladium(0) species. The ability of ketones to
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promote the coupling of 4-bromoanisole and aniline using the PEPPSI-IPr precatalyst
was tested (eq 3). In the absence of any additive, low yields were obtained in the
coupling of 3-bromoanisole and aniline using PEPPSI-IPr from room temperature to 60
°C (Table 3, entries 1-3). Significantly higher yields were obtained by the addition of 3-
pentanone (entries 4-5), although the yields at room temperature and 40 °C were lower
than those obtained with precatalyst 7a. Increasing the temperature to 60 °C and the 3-
pentanone loading to 29 mol % increased the yield to 80% (entry 7). The higher ketone
loading increased the amount of α-arylated byproducts to 5%. Mesityl oxide also
improved the yield of product, but was less effective than 3-pentanone (entries 8-9).
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Table 3. Effect of 3-pentanone in activation of PEPPSI-IPr precatalysta
entry additive
temp
(°C)
22
40
60
22
40
60
60
yield
(%)b
0
1
2
3
4
5
6
7
8
9
none
none
none
3-pentanone
3-pentanone
3-pentanonec
3-pentanoned
mesityl oxide
mesityl oxide
7
14
14
61
71
80
4
22
40
43
a Conditions depicted in equation 3. b Yields determined by GC analysis of reaction
c
mixtures. 22 mol % 3-pentanone d 29 mol % 3-pentone
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The PEPPSI-IPr precatalyst was used in the coupling of a series of aryl bromides and
aniline using 22 mol % 3-pentanone at 60 °C (Scheme 3). 4-Bromoanisole gave 71%
conversion to product under these conditions. Aryl bromides with ortho-substituents
gave complete conversion to product under these conditions and high isolated yields.
Even in the presence of a relatively high concentration of 3-pentanone, high selectivity
for the N-arylation reaction occurs. The PEPPSI-IPr/3-pentanone system is much more
efficient with the ortho-substituted aryl bromides than unhindered cases. Complete
conversion of 2-bromotoluene was achieved at room temperature in the presence of 3-
pentanone compared to 3% yield in the absence of the ketone activator. In contrast,
only 14% conversion to product was achieved at room temperature with 4-
bromoanisole under the same conditions.
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Scheme 3. 3-Pentanone-activated coupling of aryl bromides and aniline using
5
6
7
a
PEPPSI-IPr. Isolated yields, except yields in parentheses (GC yields). Reaction
8
9
performed at room temperature.
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Mechanism of ketone activation. Ketones have not previously been shown to be
able to activate palladium(II) precatalysts in cross-coupling reactions, to our knowledge.
To better understand this process, the reaction of precatalyst 7a with ketones under a
variety of conditions was analyzed by 31P NMR spectroscopy. Treatment of 7a with
acetone in toluene resulted in no change in the 31P NMR spectrum over 13 hours
(Scheme 4). When 7a was reacted with NaOt-Bu in toluene, complete conversion to
palladacycle 10 occurred within 10 minutes. We have previously observed the base
promoted metalation of 7a to be rapid in the absence of other reactants.15 When 7a was
treated with acetone and NaOt-Bu in toluene, the only phosphorus species observed
after 10 minutes was free DTBNpP. No change was observed over the course of 14
hours. When this reaction was repeated at 40 °C, a 3:1 mixture of free DTBNpP and
Pd0(DTBNpP)2 (12) was observed. Over the course of 2.5 hours, the remaining free
DTBNpP was converted to complex 12. The results show that in the presence of acetone
and NaOt-Bu, the DTBNpP ligand is rapidly displaced to form a phosphorus-free
palladium species (11) with an unknown structure. At 40 °C, this species slowly forms
Pd0(DTBNpP)2 without any other phosphorus byproducts. Notably, palladacycle 10 is
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not formed in the presence of acetone, which suggests that the conversion of 7a to 11 is
much faster than base-promoted ligand metalation to give 10. Under the catalytic
reaction conditions (4-bromoanisole, aniline, NaOt-Bu, acetone, and toluene), only free
DTBNpP is observed from 10 minutes through 13 hours at both 22 and 40 °C. In the 40
°C reaction, complete conversion of the aryl bromide occurs after 2.5 hours.
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Scheme 4. Reaction of precatalyst 7a with reaction components
The reaction of 7a with 3-pentanone and mesityl oxide was explored in a similar
fashion. No reaction is seen with 7a and 3-pentanone. In the presence of NaOt-Bu and
3-pentanone, complete conversion to Pd(DTBNpP)2 (12) occurs within 10 minutes,
without formation of palladacycle 10. Unlike acetone, no free DTBNpP is observed. In
contrast, under the full catalytic conditions, only free DTBNpP is seen during the course
of the coupling reaction as was the case for acetone. Mesityl oxide is also unreactive
with 7a in the absence of base, but gives clean conversion to 12 in the presence of NaOt-
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Bu. In the mesityl oxide-promoted coupling reaction, only complex 12 is observed after
10 minutes, with no further change in the 31P NMR spectrum over several hours.
These studies show that the tested ketones are capable of reducing 7a to
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palladium(0) complex 12. This reaction occurs slowly in the case of acetone, through a
phosphine-free palladium intermediate. In the cases of 3-pentanone and mesityl oxide,
this reduction occurs rapidly (< 10 minutes) at room temperature without observing
free phosphine. It is possible that these reactions also proceed through intermediate 11,
but that the resulting intermediate rapidly is converted to palladium(0) complex 12.
The efficiency of the catalytic reaction correlates with rapid formation of 12 in the
presence of ketone and base. Both 3-pentanone and mesityl oxide are effective
activators of precatalyst 7a, whereas acetone is less effective at ambient temperature and
provides a less active catalyst at 40 °C. Although the rapid formation of 12 correlates
with efficient catalysis, complex 12 is not seen under catalytic conditions when 3-
pentanone is used as the activator. It is possible that the formation of 12 in the absence
of aryl bromide and aniline indicates efficient Pd(0) formation, but that under the
catalytic condition the amine or other ligands are coordinated to the active species. In
contrast to these results, we do observe either 12 or the oxidative addition product
derived from 12 ([(DTBNpP)Pd(Ar)Br]2) under Suzuki coupling conditions.15
Analysis of the reaction of 7a with 3-pentanone (4 equiv) and NaOt-Bu (20 equiv) by
1H NMR spectroscopy showed a broad peak at approximately 4 ppm. This resonance is
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consistent with an O-bound metal enolate,21 although it is not possible to determine if
the coordinated metal is sodium, palladium, or a mixture of the two. No other new
resonances consistent with possible byproducts of the palladium reduction reaction
were observed.
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The nature of the phosphine-free palladium complex (11) is unknown. We
hypothesize that complex 11 may be a [Pd(enolate)2]n or [ClPd(enolate)]n species. This
species then would undergo a reductive process to form Pd(0), which can recoordinate
the phosphine ligands. A plausible mechanism in the case of 3-pentanone would
formation of a C-bound palladium enolate followed by β-hydride elimination (Scheme
5, Path A). This sequence has been proposed for the palladium-catalyzed oxidation of
ketones to α,β-unsaturated ketones.22 An alternative possibility available to methyl
ketones would be reductive elimination from a dienolate complex (Path B). Oxidative
coupling of enolates by one electron oxidants, such as ferrocenium,23 TiCl4,24 and
CuCl2,25 have been reported, but to our knowledge there are no examples of enolate
homocoupling by a reductive elimination process using palladium.
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Scheme 5. Possible reduction pathways from a Pd(II)-bound enolate
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6
7
8
9
The β-hydride elimination pathway should result in the formation of 1-penten-3-one
from 3-pentanone or 1-phenyl-2-penten-1-one from propiophenone. Analysis of the
reduction of palladium by 3-pentanone (4 equivalents) and NaOt-Bu (20 equiv) shows
no evidence of the β-hydride elimination products by 1H NMR spectroscopy or GC-MS
analysis. The expected products of enolate homocoupling, for example hexane-2,5-
dione from acetone, have also not been observed by GC-MS or 1H NMR analysis.
Therefore, the mechanism by which complex 7a is reduced to palladium(0) in the
presence of ketones and base remains unclear.
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Amination reactions activated by acetone and 3-pentanone appear to involve a
phosphine-free species (11) as the potential active catalyst. To determine whether the
phosphine is necessary, (MeCN)2PdCl2 was explored as a precatalyst (Table 4). Using
(MeCN)2PdCl2 in place of 7a with acetone (40 °C) or 3-pentanone (22 °C) gave no
conversion to product. When DTBNpP was used in combination with (MeCN)2PdCl2,
no yield was obtained at 22 °C in the absence of ketone activator. Addition of acetone at
40 °C gave a modest yield of the arylated product, but the (MeCN)2PdCl2/DTBNpP
catalyst system was less effective than 7a. The use of 3-pentanone with
(MeCN)2PdCl2/DTBNpP at room temperature gave no conversion. It appears that the
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prior coordination of DTBNpP to the palladium is critical to the success of the
precatalyst under these conditions.
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Table 4. Aniline arylation using (MeCN)2PdCl2 as the precatalysta
entry ligand
additive
acetone
3-pentanone
T (°C) yield (%)
1
40
22
22
40
22
0
0
0
35
0
none
2
3
4
5
none
DTBNpP none
DTBNpP acetone
DTBNpP 3-pentanone
a Reaction conditions: 4-bromoanisole (1 mmol), aniline (1.2 mmol), NaOt-Bu (1.5
mmol), (MeCN)2PdCl2 (0.01 mmol), DTBNpP (0 or 0.01 mmol), ketone (0.1 mmol), in
toluene at the indicated temperature. Yields were determined by GC analysis.
Conclusion
Enolizable ketones have been demonstrated to be effective activators of
palladium(II) precatalysts in the arylation of aniline using both phosphine and NHC-
derived precatalyst species. 3-Pentanone was identified as the most effective activator.
Mechanistic studies indicate that palladium(II) complex 7a is reduced to palladium(0) in
the presence of ketone and base. The rate of the reduction correlates with the activity of
the catalyst formed upon ketone activation. 3-Pentanone and mesityl oxide, which give
rapid conversion to palladium(0) complex 12 also provide the most active 7a-derived
catalysts. Acetone gives slow reduction of 7a to 12 and also provides a less active
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catalyst. The mechanism of the reduction process remains unclear, however. We
hypothesize that a palladium enolate species is the key intermediate. In the case of 3-
pentanone, a likely activation pathway would be β-hydride elimination to give a
palladium-hydride that could be deprotonated to afford the palladium(0) active species.
The expected byproducts of this pathway have not been observed, however. Therefore,
an as yet undetermined mechanism is possible . Efforts to determine the reduction
mechanism are ongoing.
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Experimental
General Procedure. Reagents were purchased from commercial suppliers and used
as received, except as noted. [(DTBNpP)PdCl2]2 (7a),15 [(TNpP)PdCl2]2 (7b),15 and
(TNpP)Pd(aniline)Cl2 (8b)17 were prepared according to previously reported methods.
Toluene was refluxed over sodium for an hour and freshly distilled before use.
Reactions were conducted under nitrogen double-manifold inert-atmosphere
techniques, unless noted otherwise. GC analysis was performed using a Shimadzu gas
chromatograph (GC-2014) outfitted with a Alltech EC-5 column (30 m X 0.32 mm ID X
0.25 μm film thickness) and FID detector. Chromatograms were run with an initial
oven temperature of 150 °C increasing to 250 °C at a rate of 10 °C/min. NMR spectra
were obtained on a Brüker 500 MHz spectrometer. 31P NMR spectra were acquired
using gated decoupling mode.
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General procedure for ketone-activated N-arylation reactions. A screw-capped
vial with 7a (0.5 mol%) was put into the glovebox. NaOt-Bu (1.5 equiv) was added. The
vial was sealed with a septum cap and taken out of the glove box. Aryl halide (1 mmol),
ketone (10 mol%), aniline (1.2 mmol), and toluene (3 ml) were added and the reaction
was stirred at room temperature or placed in an oil bath preheated to the desired
temperature. After 15 h, the reactions were analyzed by GC.
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(DTBNpP)Pd(aniline)Cl2 (8a). [(DTBNpP)PdCl2]2 (7a, 100 mg, 0.128 mmol) was
dissolved in methylene chloride (8 mL). Then aniline (35.1 μL, 0.384 mmol) was added
into the solution. After stirring for one hour, the volatiles were removed under vacuum
to provide 8a as an air-stable orange solid (116.7 mg, 94%).1H NMR (500 MHz, C6D6, 295
K): δ 7.28 (d, J = 7.8 Hz, 2H), 6.96 (t, J = 7.8 Hz, 2H), 6.82 (t, J = 7.3 Hz, 1H), 3.90 (s, 2H),
2.08 (d, J = 12.8 Hz, 2H), 1.43 (d, J = 12.8 Hz, 18H), 1.33 (s, 9 H), 13C NMR (125 MHz,
C6D6, 295 K): δ 140.95, 124.72, 121.36, 107.98, 37.23 (d, JC-P = 6.4 Hz), 34.26 (d, JC-P = 25.2
Hz), 33.59 (d, JC-P = 6.4 Hz), 31.21 (d, JC-P = 4.3 Hz), 30.86(d, JC-P = 4.3 Hz). 31P{1H} NMR
(202.5 MHz, C6D6, 295 K): δ 63.0.
(DTBNpP)Pd(3-chloropyridine)Cl2 (9a). [(DTBNpP)PdCl2]2 (7a, 100 mg, 0.128
mmol) was dissolved in methylene chloride (8 mL) under nitrogen. Then 3-
chloropyridine (36.5 μL, 0.384 mmol) was added to the solution. After stirring for one
hour, the volatiles were removed under vacuum to provide 9a as an air-stable orange
solid (120.2 mg, 93%).1H NMR (500 MHz, C6D6, 295 K): δ 9.11 (s, 1H), 8.71 (s, 1H), 6.55
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(d, J = 7.3 Hz, 1H), 6.02 (s, 1H), 2.28 (d, J = 12.8 Hz, 2H), 1.59 (d, J = 12.8 Hz , 18H), 1.50
(s, 9 H), 13C NMR (125 MHz, C6D6, 295 K): δ 150.57, 149.51, 137.15, 131.97, 124.27, 37.86
(d, JC-P = 6.4 Hz), 34.48 (d, JC-P = 25.2 Hz), 33.81 (d, JC-P = 6.4 Hz), 31.351 (d, JC-P = 4.3 Hz),
31.16(d, JC-P = 4.3 Hz). 31P{1H} NMR (202.5 MHz, C6D6, 295 K): δ 62.0.
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(TNpP)Pd(3-chloropyridine)Cl2 (9b). [(TNpP)PdCl2]2 (7b, 100 mg, 0.119 mmol) was
dissolved in methylene chloride (8 mL). Then 3-chloropyridine (33.9 μL, 0.357 mmol)
was added into the solution. After stirring for one hour, the volatiles were removed
under vacuum to provide 9b as an air-stable orange solid (119.3 mg, 94%). Orange
single crystals were formed after slow evaporation of a benzene solution. 1H NMR (500
MHz, C6D6, 295 K): δ 9.33 (s, 1H), 8.96 (s, 1H), 6.56 (d, J = 7.3 Hz, 1H), 6.04 (s, 1H), 3.82
(s, 2H), 2.35 (d, J = 12.8 Hz, 6H), 1.35 (s, 27 H), 13C NMR (125 MHz, C6D6, 295 K): δ
150.66, 149.65, 137.41, 132.34, 124.54, 39.15 (d, JC-P = 25.2 Hz), 33.41 (d, JC-P = 6.4 Hz), 32.64
(d, JC-P = 4.3 Hz). 31P{1H} NMR (202.5 MHz, C6D6, 295 K): δ 15.28.
Crystallographic analysis of 9b. A suitable crystal of 9b 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
Olex2,26 the structure was solved with the ShelXT27 structure solution program using
Intrinsic Phasing and refined with ShelXL28 refinement package using Least Squares
minimization using either Olex226 or ShelXle29 or both. The structure was found to have
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a rotational disorder on one of the neopentyl ligand. Atoms on the two moieties were
restrained to have similar geometries (SAME).
7
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9
General procedure for the PEPPSI-IPr-catalyzed amination. PEPPSI-IPr (3.4 mg, 5
μmol) was added to a 3 dram glass vial with a stir bar. The vial was transferred into a
nitrogen glove box, where, NaO-t-Bu (144 mg,1.50 mmol) was added. The vial was
sealed with rubber septum cap and removed from the glove box. The remaining
reagents were added to a vial in the following order via syringe: dry toluene (3.5 mL),
aryl bromide (1.0 mmol), 3-pentanone (23 μL, 0.22 mmol), and aniline (110 μL, 1.20
mmol). The vials were placed in a preheated oil bath at the desired temperature and
allowed to stir for 24 hrs. The reaction mixture was quenched with aqueous ammonium
chloride and extracted three times with ethyl acetate (ca 25 mL). The combined organic
phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure.
The crude products were purified via silica gel chromatography eluting with hexane.
N-Phenyl-2-toluidine.30 2-Bromotoluene (120.4 μL, 1.0 mmol) was coupled with
aniline according to the general procedure. GC analysis indicated complete conversion.
The reaction mixture was worked up as described in the general procedure. The crude
product was purified by column chromatography to afford the product as an oil (148.6
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1
mg, 87%). H NMR (CDCl3, 500 MHz) δ 7.24–7.21 (m, 3H), 7.17 (m, 1H), 7.11 (t, J = 7.8
Hz, 1H), 6.94–6.91 (m, 3H), 6.90–6.86 (m, 1H), 5.34 (brs, 1H), 2.22 (s, 3H). 13C NMR
(CDCl3, 126 MHz) δ 144.0, 141.2, 130.9, 129.3, 128.3, 126.7, 122.0, 120.4, 118.8, 117.4, 17.8.
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N-Phenyl 2,6-dimethylaniline.30 2-Bromo-1,3-dimethylbenzene (133 μL, 1.0 mmol)
was coupled with aniline according to the general procedure. GC analysis indicated
95% conversion. The reaction mixture was worked up as described in the general
procedure. The crude product was purified by column chromatography to afford the
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product as an oil (167.5 mg, 91%). H NMR (CDCl3, 500 MHz) δ 7.21–7.10 (m, 5H), 6.78
(tt, J = 7.3 Hz, 1.0 Hz, 1H), 6.55-6.53 (m, 2H), 5.21 (brs, 1H), 2.25 (s, 6H). 13C NMR
(CDCl3, 126 MHz) δ 146.3, 138.2, 135.9, 129.2, 128.5, 125.8, 118.1, 113.5, 18.3.
N-Phenyl 2-isopropylaniline.31 1-Bromo-2-isopropylbenzene (153 μL, 1.0 mmol)
was coupled with aniline according to the general procedure. GC analysis indicated
complete conversion. The reaction mixture was worked up as described in the general
procedure. The crude product was purified by column chromatography to afford the
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product as an oil (184.6 mg, 93%). H NMR (CDCl3, 500 MHz) δ 7.31 (dd, J = 7.7, 1.4 Hz,
1H), 7.24–7.19 (m, 3H), 7.13 (dt, J = 7.6, 1.6 Hz, 1H), 7.06 (dt, J = 7.5, 1.2, 1H), 6.87–6.82
(m, 3H), 5.40 (brs, 1H), 3.15 (sept, J = 6.9 Hz, 1H), 1.24 (d, J = 7.0 Hz, 6H). 13C NMR
(CDCl3, 126 MHz) δ 145.3, 140.6, 139.5, 129.2, 126.4, 126.0, 123.5, 121.9, 119.7, 116.4, 27.6,
23.0.
N-Phenyl 2,4,6-triisopropylaniline.32 1-Bromo-2,4,6-triisopropylbenzene (153 μL,
1.0 mmol) was coupled with aniline according to the general procedure. GC analysis
indicated complete conversion. The reaction mixture was worked up as described in the
general procedure. The crude product was purified by column chromatography to
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afford the product as an oil (228.1 mg, 95%). H NMR (CDCl3, 500 MHz) δ 7.18 (t, J = 7.3
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Hz, 2H), 7.12 (s, 2H), 6.74 (tt, J = 7.3, 1.0 Hz, 1H), 6.54 (d, J = 8.3 Hz, 2H), 5.09 (brs, 1H),
3.25 (sept, J = 6.9 Hz, 2H), 2.99 (sept, J = 6.9 Hz, 1H), 1.35 (d, J = 6.9 Hz, 6H), 1.20 (d, J =
6.9 Hz, 12H). 13C NMR (CDCl3, 126 MHz) δ 148.4, 147.4, 147.2, 132.7, 129.1, 121.7, 117.3,
112.8, 34.2, 28.2, 24.1, 23.9.
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Supporting Information
Supporting information is available free of charge at https://xxxx
NMR spectra of isolated compounds, X-ray characterization details, reaction
profile as a function of ketone loading (PDF)
Accession Codes
CCDC 1978602 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, by
emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
336033.
Acknowledgements. H.H. acknowledges support of his post-doctoral associate
position from the College of Arts & Sciences, The University of Alabama. The structure
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of 9b was obtained on an X-ray diffractometer purchased with support from NSF (CHE
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MRI 1828078). Johnson-Matthey is acknowledged for donation of palladium salts.
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