Trineopentylphosphine: A conformationally flexible ligand for the coupling of sterically demanding substrates in the Buchwald-Hartwig amination and suzuki-miyaura reaction

Article abstract of DOI:10.1021/jo400435z

Trineopentylphosphine (TNpP) in combination with palladium provides a highly effective catalyst for the Buchwald-Hartwig coupling of sterically demanding aryl bromides and chlorides with sterically hindered aniline derivatives. Excellent yields are obtain

Full text of DOI:10.1021/jo400435z

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pubs.acs.org/joc
Trineopentylphosphine: A Conformationally Flexible Ligand for the
Coupling of Sterically Demanding Substrates in the Buchwald−
Hartwig Amination and Suzuki−Miyaura Reaction
Steven M. Raders, Jane N. Moore, Jacquelynn K. Parks, Ashley D. Miller, Thomas M. Leißing,
Steven P. Kelley, Robin D. Rogers, and Kevin H. Shaughnessy*
Department of Chemistry, The University of Alabama, Box 870336, Tuscaloosa, Alabama 35487-0336, United States
S
* Supporting Information
ABSTRACT: Trineopentylphosphine (TNpP) in combina-
tion with palladium provides a highly effective catalyst for the
Buchwald−Hartwig coupling of sterically demanding aryl
bromides and chlorides with sterically hindered aniline
derivatives. Excellent yields are obtained even when both
substrates include 2,6-diisopropyl substituents. Notably, the
reaction rate is inversely related to the steric demand of the
substrates. X-ray crystallographic structures of Pd(TNpP)2,
[Pd(4-t-Bu-C6H4)(TNpP)(μ-Br)]2, and [Pd(2-Me-C6H4)-
(TNpP)(μ-Br)]2 are reported. These structures suggest that the conformational flexibility of the TNpP ligand plays a key
role in allowing the catalyst to couple hindered substrates. The Pd/TNpP system also shows good activity for the Suzuki
coupling of hindered aryl bromides.
couplings.1a,b,7e,10 The commonly used organoboron reagents
INTRODUCTION
■
are typically insensitive to air and moisture, thermally stable,
Palladium-catalyzed carbon−carbon and carbon−heteroatom
bond-forming reactions are one of the most powerful
and tolerate a wide variety of functional groups.11 Although
efficient ligand-free catalyst systems have been reported,12 an
methodologies for the synthesis of natural products,
pharmaceuticals, and fine chemicals.1 Of the family of Pd-
ancillary ligand greatly enhances the efficiency of the catalyst.
Again, sterically demanding, electron-rich ligands, such as
catalyzed cross-coupling reactions, the Buchwald−Hartwig
dialkylarylphosphines,13 trialkylphosphines,5,14 and N-hetero-
amination and Suzuki−Miyaura cross-coupling reactions have
cyclic carbenes,7c,e have proven to be particularly useful.
been shown to be particularly useful for the synthesis of C−N
Despite significant study, there remains much to be learned
and C−C bonds, respectively. These reactions are favored
about the interplay of steric and electronic properties of the
ligands in these reactions.15 Recently, our group reported that
neopentylphosphines are effective ligands in a variety of
palladium-catalyzed cross-coupling reactions.16 Di(tert-butyl)-
neopentylphosphine (DTBNpP, Figure 1) provides catalysts
with comparable or improved activity for C−N and C−C bond-
forming reactions of aryl bromides to tri(tert-butyl)phosphine
(TTBP), while tert-butyldineopentylphosphine (TBDNpP) and
trineopentylphosphine (TNpP) give less active catalysts at
ambient temperature. The DTBNpP-based system gives a
because of their ease of operation and high degree of generality.
The Buchwald−Hartwig coupling of aryl halides or
pseudohalides with nitrogen nucleophiles is a powerful tool
for the synthesis of pharmaceuticals and agricultural materials.2
Typically, the Buchwald−Hartwig amination is preferred to
classical C−N bond-forming methodologies, such as nucleo-
philic aromatic substitution, reductive amination, and nitration
followed by reduction,3 and Cu-catalyzed amination reactions4
because of its high functional group tolerance, single-step
procedure, commercially available starting materials, and mild
reaction conditions. Sterically demanding, electron-rich ligands,
such as trialkylphosphines,5 dialkylarylphosphines (Buchwald
ligands),2c bicyclic triaminophosphines (Verkade’s super-
bases),6 N-heterocyclic carbenes,7 oxaphosphole ligands,8 and
chelating phosphines,9 have been shown to provide highly
efficient catalysts in the C−N bond formation.
The Suzuki−Miyaura cross-coupling is an extensively studied
synthetic methodology for C−C bond formation owing to the
advantages of this reaction over other C−C bond-forming
reactions, such as the Negishi (organozinc), Kumada (organo-
magnesium), Hiyama (organosiloxane), and Stille (organotin)
Figure 1. Neopentylphosphine ligands.
Received: February 28, 2013
© XXXX American Chemical Society
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somewhat less active catalyst than TTBP for the coupling of
aryl chlorides, however.
benzene with 2,6-diisopropylaniline in good yield at 110 °C.8
There are few other examples of coupling similarly hindered
substrates.7d,22
The neopentyl group provides a different set of electronic
and steric effects than that of a tert-butyl group. The tert-butyl
substituent provides a fairly constant steric influence as it
rotates about the P−C bond. In contrast, the steric impact of
the neopentyl substituent varies significantly as the M−P−C−
C dihedral angle ranges from 0° (maximum steric effect) to
180° (minimal steric influence). Tolman estimated that TNpP
and TTBP had similar cone angles (180° and 182°,
respectively).17 These values were measured from the least
sterically demanding conformation for each ligand. Solid cone-
angles obtained from DFT-optimized, gas-phase Pd(PR3)
structures predicted that ligand cone angles increased with
the addition of neopentyl groups (TTBP (194°) < DTBNpP
(198°) < TBDNpP (210°) < TNpP (227°)).16a In these
calculated structures, the Pd−P−C−C dihedral angle of the
neopentyl substituents was small, resulting in the neopentyl
group exerting maximal steric influence. The solid-state
structure of Pd(DTBNpP)2 adopts a similar conformation in
which the Pd−P−C−C angle is 0.3(1)°.16c
Previously, our group compared the activity of catalysts
derived from the neopentylphosphine series (Figure 1) in the
Suzuki−Miyaura, Sonogashira, Heck, and Buchwald−Hartwig
cross-coupling reactions.16 It was determined that DTBNpP
provides the highest activity catalyst under mild conditions with
unhindered substrates, whereas the catalysts derived from
TBDNpP and TNpP afford lower activity. The DTBNpP/Pd
catalyst system provides low conversions with sterically
hindered substrates, however. Attempted coupling of 2-
bromo-m-xylene with phenylboronic acid gave no conversion
to product at room temperature or 80 °C.16b A subsequent
ligand screening for this reaction at 80 °C showed that the
catalyst derived from TNpP and Pd(OAc)2 gave an 87% yield
of 2,6-dimethylbiphenyl (eq 1). Based on the calculated steric
Electronically, the neopentyl substituent would be expected
to have a smaller inductive electron-donating effect than the
tert-butyl moiety. The CO stretching frequencies for trans-
L2Rh(CO)Cl complexes followed the trend TTBP < DTBNpP
< TBDNpP < TNpP, which was consistent with this
expectation.16a Calculated HOMO energy levels for the free
ligands showed that the HOMO energy level of the free ligand
increased going from TNpP to TTBP. In contrast, the HOMO
energy levels for the LPd(0) complexes, which are the
presumed catalytically active species, were similar for all four
ligands.
On the basis of these results, DTBNpP appeared to have
optimal steric and electronic properties for couplings of aryl
bromides, whereas TBDNpP and TNpP were perhaps too large
to form active catalysts. The lower activity of DTBNpP toward
aryl chlorides was tentatively attributed to the lower electron-
donating ability of DTBNpP compared to TTBP. Previous
results from our laboatory and others have indicated that steric
demand is the key factor in determining catalyst efficiency for
couplings of aryl bromides.15b,16a,18 Since the C−Cl bond is
stronger, more electron-rich palladium centers are required to
activate aryl chlorides, resulting in a stronger dependence on
electronic effects in coupling of aryl chlorides.
Although sterically demanding ligands provide high activity
catalysts for unhindered substrates, these catalysts often show
lower activity with sterically demanding substrates. For
example, coupling of 2,6-disubstituted aryl halides with 2,6-
disubstituted anilines is challenging for commonly used catalyst
systems based on tri-tert-butylphosphine or S-phos.8,19 2,6-
Dimethyl-substituted aryl bromides and chlorides have been
coupled with 2,6-disubstituted anilines (substituent = methyl,
isopropyl) in good yields using preformed N-heterocyclic
carbene palladium complexes,7d,20 diketiminate palladium
complexes,21 proazaphosphatrane-derived catalysts,6b and
iminoproazaphosphatrane-phosphine/Pd systems.22 Catalysts
derived from simple phosphines generally afford low
conversions or require high temperatures and/or high catalyst
loadings with these more challenging substrates,16a,19,23
although Nolan has reported an effective palladium-allyl
phosphine precatalyst for these couplings.24 Rodriguez and
Tang recently reported an oxaphosphole ligand that provides
active catalysts for the coupling of bromo-2,4,6-triisopropyl-
parameters for these ligands, it was surprising that TNpP gave a
more effective catalyst for coupling for hindered substrates than
DTBNpP. We hypothesized that the increased conformational
flexibility of TNpP compared to DTBNpP may allow it to
better accommodate sterically hindered substrates in the
coordination sphere.
Herein, we report the use of the conformationally flexible
trineopentylphosphine (TNpP) ligand in the Buchwald−
Hartwig amination and the Suzuki−Miyaura coupling of
sterically congested substrates. A wide variety of aryl bromides
and chlorides are coupled with mono- or di-ortho-substituted
aryl amines and boronic acids. The reported catalyst system
utilizes a simple, readily synthesized phosphine that can provide
an active catalyst in situ with a suitable palladium precursor. In
contrast to the air sensitivity of many simple trialkylphosphines,
such as TTBP or DTBNpP, TNpP shows no degradation in air
as a solid over a 9-day period or in solution over a period of 24
h.16b
RESULTS
■
Amination of Aryl Bromides. Catalysts derived from
DTBNpP and TNpP were compared in the coupling of a series
of aryl bromides and aniline derivatives with increasing steric
bulk (Table 1) to explore the tolerance of these catalysts for
sterically hindered substrates. The coupling of 4-bromotoluene
with 2,4,6-trimethylaniline was performed using 0.5 mol % of
Pd2(dba)3 and either 1 mol % of DTBNpP or 1 mol % of
TNpP at 80 °C in toluene for 2 h at 80 °C. Both catalyst
systems gave high conversions of the product (Table 1, entry
1). Using the more sterically demanding 2,6-diisopropylaniline
resulted in a significant decrease in the yield obtained using
DTBNpP, whereas the TNpP-derived catalyst again gave a high
yield of product (Table 1, entry 2). Using the more hindered 2-
bromo-m-xylene substrate resulted in a further decrease in yield
for the DTBNpP system in the coupling with 2,4,6-
trimethylaniline, whereas the TNpP-derived catalyst was again
unaffected by the increase in steric demand (Table 1, entry 3).
The catalyst derived from DTBNpP gave almost no product in
the coupling of 2-bromo-m-xylene with 2,6-diisopropylaniline.
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a
Table 1. Comparison Study of DTBNpP and TNpP
Table 2. Phosphine Screening in the Coupling of 1-Bromo-
2,4,6-triisopropylbenzene and 2,6-Diisopropylaniline
a
b
c,d
entry
PR3
θDFT (deg)
θT (deg)
yield (%)
1
2
3
4
5
6
7
8
9
TTBP
194
198
210
227
182
36
0
DTBNpP
TBDNpP
TNpP
4
180
170
132
100
100
3
PCy3
PBu3
177
173
t-Bu2PMe
PPh3
83
76
29
145
194
e
P(o-tol)3
214
a
Cone angle values determined from LDFT-optimized LPd(0)
structures.16a Cone angle values determined by Tolman.17 Reaction
conditions: 1-bromo-2,4,6-triisopropylbenzene (1.0 mmol), 2,6-
diisopropylaniline (1.2 mmol), Pd2(dba)3 (0.5 mol %), phosphine
(1.0 mol %), NaOt-Bu (1.5 mmol), toluene (2 mL), 80 °C, 1 h.
b
c
a
Reaction conditions: aryl bromide (1.0 mmol), amine (1.2 mmol),
d
e
Determined by GC analysis. Literature value.25
Pd2(dba)3 (0.5 mol %), phosphine (1.0 mol %), NaO-t-Bu (1.5
b
mmol), toluene (2 mL), 80 °C, 2 h. Determined by GC.
coupled with 2,6-diisoproplyaniline to obtain 96% of the
desired product in 1 h (2e). Using DTBNpP in place of TNpP
gave 2e in 44%, which is similar to that reported at room
temperature using the Pd/DTBNpP catalyst system.16a
Electron-rich aryl bromides were coupled with 2,6-diisoprop-
ylaniline in high product yields with short reaction times (2f,
2g, 2h, 2k). Interestingly, the reaction time increased by a
factor of 2 when there was no ortho substituent on the aryl
bromide (2f) compared to an ortho methyl group being
present (2g).
These conditions proved successful even with very sterically
hindered substrates. For example, 1-bromo-2,4,6-triisopropyl-
benzene was coupled with 2,6-diisopropylaniline to give (2l) in
97% yield after 1 h. The increase in reaction time can be
attributed to the steric hindrance of the bromide and amine.
Coupling 1-bromo-2,4,6-triisopropylbenzene with 2-tert-butyla-
niline to give 2m required a higher catalyst loading (4 mol %
Pd) for the reaction to reach completion. The extremely
sterically hindered 2,4,6-tri-tert-butylaniline could not be
coupled with any aryl bromide, including 4-bromotoluene.
This result suggests either that the amine cannot coordinate to
the palladium center or that reductive elimination is not
possible due to the steric congestion around the amine. 1-
Naphthylamine was coupled with 1-bromo-2,4,6-triisopropyl-
benzene using 2 mol % of Pd2(dba)3 and 4 mol % of TNpP
with a moderate yield of 53% (2n). When 1-naphthylamine was
coupled with other sterically hindered aryl bromides, high
yields were obtained, although longer reaction times were
required (2o, 2p). o-Anisidine was coupled with 2-bromo-m-
xylene in 82% yield (2s). By placing electron-withdrawing
groups on the aniline (such as sulfonamide or nitro groups),
higher palladium loading and longer reaction times are needed
(2t, 2u). In contrast to the successful formation of 2l using
PCy3 as the ligand, attempts to couple 1-bromo-2,4,6-
In contrast, TNpP gave the desired product in 95% yield
(Table 1, entry 4). These results show that the Pd/DTBNpP
catalyst system is sensitive to steric bulk around both the aryl
halide and amine substrate, while the catalyst derived from
TNpP is unaffected by the steric demand in these substrates.
To further explore the effect of ligand structure on the
coupling of hindered substrates, a range of phosphines were
used in the coupling of 1-bromo-2,4,6-triisopropylbenzene with
2,6-diisopropylaniline (Table 2). The commonly used TTBP
ligand gave 36% conversion after 1 h. As expected on the basis
of the results in Table 1, the DTBNpP-derived catalyst system
gave no conversion to the desired product. TBDNpP gave only
a 4% conversion after 1 h. TNpP gave 100% conversion of the
desired product even with these very hindered substrates. Based
on these results, other phosphines ligands were explored in this
reaction. The catalyst system using tricyclohexylphosphine
(PCy3) also gave a nearly quantitative conversion to the diaryl
amine product. The less hindered n-Bu3P gave poor conversion.
A good conversion (83%) was obtained with t-Bu2PMe.
Triphenylphosphine also gave a moderately active catalyst,
whereas the more hindered P(o-tol)3 gave a low conversion to
product. On the basis of these results, there is not a clear
correlation between cone angle values and catalyst efficiency in
this reaction.
Reaction Scope. With these pleasing results, the Pd/TNpP
catalyst system was subjected to a variety of sterically
demanding aryl bromides with a range of sterically hindered
anilines, and the results are shown in Table 3. The coupling of
2-bromo-m-xylene and bromomesitylene with 2,6-dimethylani-
line gave the tetra-o-methyl-substituted diaryl amines in high
yields in 1 h (2a, 2b). Interestingly, when 2,6-diisopropylaniline
was used as the coupling partner, complete conversion occurred
with a shorter reaction time (2c, 2d). 4-Bromotoluene was
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a,b
Table 3. Pd2(dba)3/TNpP-Catalyzed Coupling of Aryl Bromides
a
Reaction conditions: aryl bromide (1.0 mmol), amine (1.2 mmol), Pd2(dba)3 (0.5 mol %), phosphine (1.0 mol %), NaO-t-Bu (1.5 mmol), toluene
b
c
d
e
(2 mL), 80 °C. Isolated yields (average of three runs). 1 mol % of DTBNpP used. Pd2(dba)3 (2 mol %), TNpP (4 mol %). Pd2(dba)3 (1 mol %),
TNpP (2 mol %).
triisopropylbenzene with 2-tert-butylaniline or 1-naphthylamine
to give 2m and 2n, respectively, with Pd2(dba)3 (2 mol
%)/PCy3 (4 mol %) gave low conversion to the desired
product (<50%) and significant formation of 2,4,6-triisopro-
pylbenzene.
Table 4. TNpP/Pd2(dba)3-Catalyzed Coupling of Aryl
Chlorides
a,b
Pd/TNpP-Catalyzed Amination of Aryl Chlorides.
Good to excellent yields for aminations of sterically hindered
aryl chlorides were obtained using the Pd2(dba)3/TNpP
catalyst system. As was previously shown, higher temperature
and higher catalyst loadings were needed to fully convert aryl
chlorides to their desired products compared to aryl
bromides.16a Using the Pd2(dba)3/TNpP system, aryl chlorides
with no or one ortho-substituent were coupled with 2,6-
diisopropylaniline at 100 °C using 0.5 mol % of Pd2(dba)3 and
1.0 mol % of TNpP (Table 4). The electron-rich 4-
chloroanisole and 2-chloroanisole gave 83% and 97%,
respectively (3a, 3b). As with aryl bromides, more sterically
hindered substrates reacted faster than unhindered examples. 4-
Chloroanisole required 24 h reach completion in the coupling
with 2,6-diisopropylaniline, whereas only 12 and 13 h were
required with 2-chloroanisole and 2-chlorotoluene, respectively.
Di-ortho-substituted aryl chlorides, such as 2-chloro-m-xylene,
required that the palladium loading be increased to 2 mol % to
obtain high yields of the desired diaryl amine (3d−h), however.
Tri-ortho-substituted products (3f and 3h) were obtained in
good yields with only 1 mol % of palladium. Increasing the
palladium loading to 2 mol % allowed for complete conversions
with yields above 90% for the coupled diaryl amines (3f−h),
however.
a
Reaction conditions: aryl chloride (1.0 mmol), amine (1.2 mmol),
Pd2(dba)3 (0.5 mol %), phosphine (1.0 mol %), NaO-t-Bu (1.5
mmol), toluene (2 mL), 100 °C. Isolated yields (average of three
runs). Pd2(dba)3 (1 mol %), TNpP (2 mol %).
b
c
TNpP/Pd2(dba)3 Coupling of 9-Bromoanthracene. To
further explore the scope of the Pd2(dba)3/TNpP system, 9-
bromoanthracene was coupled with 2,6-diisopropylaniline. Full
conversion of 9-bromoanthracene occurred, but the isolated
product was determined to be the anthraquinone monoimine
(5a) rather than the expected 9-arylaminoanthracene. Oxidized
product 5a was isolated in 91% yield (Table 5). The
anthraquinone monoimine product was also isolated when
2,6-dimethylaniline was used as the coupling partner (4b).
When aniline was used as the coupling partner, the 9-
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Suzuki−Miyaura Cross-Coupling. With the success of the
TNpP system in the synthesis of hindered diarylamines, we
focused our attention on the synthesis of hindered biaryls using
the Suzuki coupling. Using TNpP as the ligand; the base,
solvent, palladium source, and temperature were varied to
obtain the optimal conditions for the Suzuki−Miyaura reaction.
Both Pd(OAc)2 (1 mol %) and Pd2(dba)3 (0.5 mol %) in
combination with TNpP (1 mol %) gave comparable results in
the reaction between bromomesitylene and o-tolylboronic acid
in the presence of sodium carbonate in 1:1 THF/H2O at 25 °C.
Sodium carbonate was found to be the most efficient base when
compared with cesium carbonate, cesium fluoride, and
potassium fluoride. While previous publications by our group
have indicated that TNpP requires elevated temperatures,16a
the coupling of bromomesitylene and o-tolylboronic acid gave
moderate conversion at ambient temperature. Varying the
temperature in reactions using catalysts formed from 1:1 and
1:2 Pd to ligand ratios with 1 mol % Pd indicated that 50 °C is
the most effective temperature for this reaction with lower
catalytic activity observed at higher and lower temperatures
(Table 6).
Table 5. TNpP/Pd2(dba)3-Catalyzed Coupling of 9-
Bromoanthracene
a,b
Table 6. Optimization of the Palladium/TNpP-Catalyzed
a
Suzuki−Miyaura Cross Coupling
a
Reaction conditions: 9-bromoanthracene (1.0 mmol), amine (1.2
mmol), Pd2(dba)3 (0.5 mol %), phosphine (1.0 mol %), NaO-t-Bu
b
(1.5 mmol), toluene (2 mL), 80 °C. Isolated yields (average of three
c
runs). Pd2(dba)3 (1 mol %), TNpP (2 mol %).
b
palladium source
Pd(OAc)2
Pd:TNpP ratio
1:1
T (°C)
yield (%)
25
40
64
69
84
77
69
68
67
70
56
55
71
78
56
55
60
77
72
71
61
phenylaminoanthracene product (4c) was obtained in 87%
yield as the only product using 1 mol % of Pd2(dba)3. The 9-
aminoanthracene products were also obtained with mono-
ortho-substituted anilines (4d and 4e) 9-Aminoanthracenes are
known to undergo oxidation to the imine quinone form when
treated with oxidants or, in some cases, upon air oxidation.26 9-
Arylaminoanthracenes are typically stable in air, however,
presumably because of delocalization of the amine lone pair
into the aryl substituent. Based on this precedent, we
hypothesized that compounds 5a and 5b formed by oxidation
of the 9-arylaminoanthracene analogues. Treatment of aniline
product 4c under the reaction conditions for 24 h resulted in
no oxidation, which suggested that the oxidation occurs upon
exposure to air during workup. Next, the reaction of 9-
bromoanthracene and 2,6-diisopropylaniline was performed
under rigorously air-free conditions. The crude product was
recovered without exposure to air and was shown to contain N-
(2,6-diisopropylphenyl)-9-aminoanthracene (4a) and none of
50
60
80
100
25
1:2
0.5:1
0.5:2
50
80
100
25
Pd2(dba)3
50
80
100
25
50
60
80
100
the monoimine anthraquinone form (5a) as determined by 13
C
a
Reaction conditions: bromomesitylene (1.0 mmol), phenylboronic
acid (1.1 mmol), palladium (1 mol %), TNpP (1−2 mol %) Na2CO3
(1.1 mmol) in water/THF (1:1, 2 mL). Yield determined by GC
NMR. Upon exposure to air, amines 4a and 4b underwent slow
oxidation to give 5a and 5b. Complete oxidation occurred
during purification by flash silica gel chromatography. The
initial yellow amine product band turned to a bright red color
as it was eluted. Therefore, amines 4a and 4b are formed under
the coupling conditions followed by air oxidation to 5a or 5b.
The increased air sensitivity of the hindered 9-amino-
anthracenes (4a and 4b) may be due to the decreased
resonance delocalization of the nitrogen lone pair onto the aryl
ring because the 2,6-disubstituted aryl substituent is forced to
be roughly perpendicular to the 9-aminoanthracene unit.
b
analysis.
With optimized conditions in hand for the Pd(OAc)2/TNpP
system, the series of neopentylphosphine ligands and TTBP
were compared in the coupling of bromomesitylene and o-
tolylboronic acid. The catalyst derived from TTBP gave a
nearly quantitative yield (98%, Table 7). Among the neo-
pentylphosphines, TNpP gave the highest conversion to
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The optimized conditions were used for a range of substrates,
shown in the Table 8. Moderately hindered aryl bromides were
readily coupled with minimally hindered aryl boronic acids.
Bromomesitylene gave good yields in couplings with phenyl-
boronic acid (6a) and 2,4-difluorophenylboronic acid (6l). A
lower yield was obtained when o-tolylboronic acid was used
(6b). Good yields were obtained in the coupling of o-
tolylboronic acid with 1-bromo-2-isopropylbenzene (6f), 2-
bromobiphenyl (6g), and 1-bromonaphthalene (6h). The very
hindered 1-bromo-2,4,6-triisopropylbenzene substrate gave low
yields, even with phenylboronic acid. The Pd/TNpP catalyst
was more sensitive to steric bulk on the boronic acid than on
the aryl bromide (6c). Attempted synthesis of 6b by coupling
2-bromotoluene and mesitylboronic acid gave only a 17% yield
at 100 °C. The TNpP-derived catalyst appears to be particularly
sensitive to sterically hindered boronic acid substrates in the
transmetalation or reductive elimination steps.
Unlike the amination reaction, the Pd(OAc)2/TNpP catalyst
gave low conversions with aryl chlorides, even at elevated
temperatures. Low yields of coupled products were obtained
with 2-chlorotoluene and phenylboronic acid and o-tolylbor-
onic acid (6m and 6n). 2-Chloro-m-xylene and phenylboronic
acid were coupled to give 17% conversion to 6o. Attempts to
couple this chloride with more hindered aryl boronic acids were
unsuccessfull, however. Given the success of TNpP in the
amination of aryl chlorides, the lack of reactivity in the Suzuki−
Miyaura coupling is somewhat suprising.
Table 7. Ligand Effect on the Coupling of Bromomesitylene
and o-Tolylboronic Acid
yield (%)
a
b
entry
PR3
conditions A
conditions B
1
2
3
4
5
TTBP
98
14
53
68
12
98 (96)27
DTBNpP
TBDNpP
TNpP
7
33
42
1
PCy3
a
Conditions A: bromomesitylene (1.0 mmol), 2-tolylboronic acid (1.1
mmol), Pd(OAc)2 (1 mol %), TNpP (1 mol %), Na2CO3 (1.1 mmol)
b
in water/THF (1:1, 2 mL) at 50 °C, 18 h. Conditions B:
bromomesitylene (1.0 mmol), 2-tolylboronic acid (1.2 mmol,
recrystallized from H2O), Pd2(dba)3 (0.5 mol %), TNpP (1 mol %),
KF (3.3 mmol), THF (2 mL), rt, 18 h.
product (68%). The catalyst derived from TBDNpP gave a
lower conversion than the TNpP-derived catalysts, whereas
DTBNpP and PCy3 gave nearly inactive catalysts. The trend
among the neopentylphosphines was the same as that seen in
the amination reactions above. In contrast to the aminations,
TTBP retained high conversion even with the hindered
substrates, whereas PCy3 gave an ineffective catalyst. The
effectiveness of the ligands was also tested under anhydrous
conditions reported by Fu and co-workers.27 The trend was
identical to that seen under the aqueous-biphasic conditions,
but the yields obtained for the neopentylphosphines were lower
under the anhydrous conditions. The TTBP-derived catalyst
again gave a nearly quantitative yield of the biaryl product.
Mechanistic Considerations. To better understand the
nature of the Pd/TNpP catalyst system, we focused our
attention on the unusual rate trend seen with sterically
congested aryl halides compared to unhindered aryl halides in
the Buchwald−Hartwig amination. As previously mentioned,
there is a noticeable time increase with less hindered aryl
bromides. For example, 2-bromo-m-xylene is coupled with 2,6-
diisopropylaniline approximately three times faster than is 4-
bromotoluene (20 min compared to 1 h). To better understand
a,b
Table 8. TNpP/Pd(OAc)2-Catalyzed Suzuki Coupling of Aryl Bromides and Chlorides
a
Aryl bromide substrate unless noted. Reaction conditions: aryl bromide (1.0 mmol), arylboronic acid (1.1 mmol), Pd(OAc)2 (1 mol %), TNpP (1
b
c
d
mol %), Na2CO3 (1.1 mmol) in water/THF (1:1) at 50 °C, 6−24 h. Isolated yields (average of two runs). Room temperature. Estimated GC
yield. 2.0 mol % of Pd(OAc)2 and 2.0 mol % of TNpP. 100 °C. 80 °C. Aryl chloride.
e
f
g
h
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this unexpected reactivity trend, a more detailed rate
comparison was performed.
As shown in Figure 2, the reaction between 2-bromo-m-
xylene and 2,6-diisopropylaniline proceeded at a higher initial
considered that the steric effect on reaction rate might be
due a difference in the equilibrium ratio of the possible
oxidative addition products. To explore this hypothesis, the
oxidative addition of hindered and unhindered aryl bromides to
Pd(TNpP)2 was studied.
Bis(trineopentylphosphine)palladium(0) (7) was prepared
by reacting Pd(η5-Cp)(η3-allyl) with 2 equiv of TNpP (eq 2).32
Recrystallization of 7 from toluene gave crystals suitable for
structural characterization (Figure 3). Complex 7 crystallized in
Figure 2. Conversion profiles for the TNpP/Pd2(dba)3-catalyzed (0.5
mol % of Pd, 1:1 L/Pd) coupling of aryl bromides with 2,6-
diisopropylaniline at 80 °C: 2-bromo-m-xylene (square), 2-bromoto-
luene (diamond), and 1-bromo-4-tert-butylbenzene (triangle).
rate than that of 1-bromo-4-tert-butylbenzene. After 5 min, 85%
of the 2-bromo-m-xylene had converted to the desired diaryl
amine. In contrast, 1-bromo-4-tert-butylbenzene formed the
desired product in only 12% conversion after 5 min. This
reaction appears to show a slight induction period over the first
10 min, after which the reaction follows a normal reaction
profile. The rate of formation of product from 2-bromotoluene
was between that of 2-bromo-m-xylene and 1-bromo-4-tert-
butylbenzene. These results are consistent with our previous
observations in which sterically hindered substrates react at
higher rate than sterically unhindered substrates.
Previous studies of oxidative addition of aryl halides to Pd/
trialkylphosphine complexes have shown that the oxidative
addition product formed depends on the steric properties of the
ligand and aryl halide as well as the identity of the halide.28 The
possible oxidative addition products include 3-coordinated
LPd(Ar)X complexes (A, Scheme 1), dimeric [LPd(Ar)X]2
Figure 3. Thermal ellipsoid plot (50% probability) of the molecular
structure of 7. Hydrogen atoms and disorder are omitted for clarity.
Unlabeled atoms are symmetry equivalents of labeled atoms. Selected
bond lengths (Å) and angles (deg): Pd−P1, 2.282(2); Pd−P2,
2.294(1); P1−Pd−P2, 180.00; Pd−P1−C1, 119.1(1); Pd−P2−C6,
118.5(1); P1−C1−C2, 119.5(2); P2−C6−C7, 121.2(2); C1−P1−
C1′, 98.3(1); C6−P2−C6′, 99.1(1); Pd−P1−C1−C2, 34.2(3); Pd−
P2−C6−C7, −34.9(3). Symmetry code for C1′ and C6′ = (1 + x − y,
1 − x, z).
space group P31c with 3-fold symmetry about the P−Pd−P
axis, although the two TNpP moieties are not symmetrical with
each other. The palladium and phosphorus atoms were found
to be positionally disordered at a ratio of approximately 95 to 5.
The minor P1−Pd−P2 fragment also resides on a crystallo-
graphic 3-fold axis, with the phosphorus atoms apparently
bound to C4 and C10. However, the orientation of the
neopentyl groups relative to the P1−Pd−P2 core is essentially
the same, with the neopentyl groups oriented toward the Pd
center.
Scheme 1. Potential Oxidative Addition Products with
Sterically Hindered Phosphine Ligands
The TNpP ligands adopt a staggered conformation looking
down the P1−Pd−P2 axis. The Pd−P1 and Pd−P2 bond
distances are 2.282(2) and 2.294(1) Å, respectively. The
average Pd−P bond in 7 is shorter than the Pd−P distance in
Pd(DTBNpP)2 (2.2961(4) Å),16c whereas the average Pd−P
distance of 7 is similar to that reported for Pd(TTBP)2
(2.285(3) Å).33 The Pd−P1−C1−C2 dihedral angle is
34.2(3),° and the Pd−P2−C6−C7 dihedral angle is
−34.9(3)°. This conformation with a small Pd−P−C−C
dihedral angle orients the steric bulk of the neopentyl group
toward the metal center. The dihedral angle for complex 7 is
larger than is seen in Pd(DTBNpP)2 (0.3(1)°) due to the steric
complexes (B), and monomeric L2Pd(Ar)X complexes (C).
Type A complexes have been observed with very sterically
demanding ligands, such as TTBP.29 Dimeric complexes (B)
are more commonly observed with hindered phosphine
ligands.30 Sterically undemanding ligands, such as triphenyl-
phosphine or tricyclohexylphosphine, favor the bisphosphine
products (C) when excess phosphine is present.31 We
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strain between the neopentyl substituents on the two
phosphine ligands. The neopentyl substituents have a moderate
P1−C1−C2 angle of 119.5(2)° (P2−C6−C7 = 121.2(2)°),
which is comparable to that seen in Pd(DTBNpP)2
(119.62(9)°). The solid state structure is consistent with the
previously calculated structure of 7, which predicts that the
neopentyl substituents project toward the Pd center exerting
maximal steric influence.6a
The oxidative addition of hindered and unhindered aryl
bromides to bis(trineopentylphosphine)palladium(0) (7) was
performed by reacting 7 with an excess of aryl bromide in
toluene at 70 °C (eq 3).34 The reaction mixture formed from 7
previously reported.30 The Pd−C1 distance of 2.003(5) Å is
similar to those of previously reported complexes, all of which
have values near 2.00 0.02 Å. The Pd−P distance for complex
8 (2.245(1) Å) falls between those of the PEt3 (2.2187(16)
Å)35 and P(t-Bu)2Bu (2.2891(8) Å)30a complexes reported in
the literature.
The conformation of the trineopentylphosphine moiety is
markedly different in complex 8 than in the Pd0 precursor 7. In
complex 7, the ligands maintain a 3-fold symmetry with the
neopentyl substituents directed in toward the palladium center
resulting in small Pd−P−C−C dihedral angles. In complex 8,
the TNpP ligand adopts a C1 conformation with each
neopentyl substituent having a different Pd−P−C−C dihedral
angle. Two of the neopentyl groups are located above and
below the P2Br2 plane and have Pd−P−C−C dihedral angles of
55.8(4)° and −81.8(4)°, respectively. The third neopentyl
group is in the P2Br2 plane approximately eclipsing the Pd−aryl
bond (C1−Pd−P1−C11= 6.9(2)°). In this case, the Pd−P−
C−C dihedral angle is 179.9(4)°. The P−C−C angle in this
neopentyl substituent is significantly larger (127.5(4)°) than for
the other two neopentyl groups (111.1(2)° and 121.9(4)°),
which suggests significant strain for the anti-oriented neopentyl
group. The neopentyl substituents of complex 8 adopt a similar
conformation to the ethyl substituents of [Pd(PEt3)(p-
tol)Cl]2.35 Because of the smaller steric demand of the ethyl
groups compared to the neopentyl substituents, the P−C−C
angles are much smaller (112.0(5)°, 112.9(5)°, and 116.2(5)°),
however.
The reaction of 7 with the aryl halide produces 0.5 equiv of 8
and 1 equiv of free TNpP. The31P{1H} NMR spectrum of the
crude reaction mixture showed only complex 7 (7.74 ppm), a
small peak at 6.3 ppm (<10% of 7), and free TNpP (−57 ppm).
Although the peak at 6.3 ppm has not been identified, it is likely
a stereoisomer of 8 in which the aryl rings are cis-oriented.
Similar trans/cis equilibria have been proposed to occur in
solution for other [Pd(PR3)(Ar)X]2 complexes.30 Notably,
Pd(TNpP)2(4-C6H4-t-Bu)Cl2 (11) was not present in any
significant amount. Thus, dimer 8 is strongly favored in the
equilibrium with 11 even in the presence of a significant TNpP
concentration (eq 4).
and 1-bromo-4-tert-butylbenzene showed complete loss of 7
and new resonances for free TNpP (−57 ppm) and a new
species at 7.7 ppm in a 1:1 ratio (Figure S1, Supporting
Information). The pentane-insoluble material showed only the
1
resonance at 7.7 ppm in its 31P NMR spectrum. The H NMR
spectrum of this material showed a 1:1 ratio of TNpP to the
aryl group, suggesting the structure was of either type A or B.
Recrystallization of complex 8 from pentane gave X-ray
quality crystals that upon crystallographic analysis showed the
structure to be a dimeric type B structure (Figure 4). Complex
8 crystallized in the P21/c space group. The structure is
consistent with dimeric structures of this type that have been
Analysis of the reaction mixture formed by heating 2-
Figure 4. Thermal ellipsoid plot (50% probability) of the molecular
structure 8. Hydrogen atoms are omitted for clarity. Unlabeled atoms
are symmetry equivalents of labeled atoms. Selected bond lengths (Å)
and angles (deg): Pd−Br, 2.4992(7); Pd−Br′, 2.5978(7), Pd−P,
2.245(1); Pd−C1, 2.003(5); Br−Pd−P, 177.27(4); Br′−Pd−P,
92.50(4); Br−Pd−C1, 89.8(1); Br′−Pd−C1, 174.5(1); Pd−Br−Pd′,
93.44(2); Br−Pd−Br′, 86.56(2); Pd−P1−C11, 118.4(2); Pd−P1−
C16, 108.4(2); Pd−P1−C21, 111.1(2); P1−C11−C12, 127.5(4); P1−
C16−C17, 121.9(4); P1−C21−C23, 113.3(5); Br−Pd−C1−C2,
−83.9(4); Pd−P1−C11−C12, −179.9(4); Pd−P1−C16−C17,
55.8(4); Pd−P1−C21−C22, −81.8(4); C1−Pd−P1−C11, 6.9(2).
Symmetry code for Br′ and Pd′ = (1 − x, 1 − y, 1 − z).
bromotoluene and complex 7 in C6D6 at 70 °C for 12 h by 31
P
NMR spectroscopy showed complete consumption of 7 and
the formation of free TNpP and four new 31P NMR resonances
at 7.45, 7.51, 8.57, and 8.66 ppm (1.1:1.0:4.0:5.1, Figure S2,
Supporting Information). After separation from residual aryl
halide and TNpP, the recovered material showed only the four
resonances between 7 and 9 ppm in the same ratio as the
reaction mixture. The 1H NMR spectrum of this mixture gave a
resolved set of 2-tolyl resonances and a very broad set of
resonances for the neopentyl substituents. At 10 °C, neopentyl
resonances were resolved to a single tert-butyl resonance and
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two resonances for the methylene proton. The tolyl methyl
group resolved into two peaks. The 31P NMR spectrum of the
sample in CD2Cl2 showed only two peaks at 8.45 and 8.54
ppm. Removing the solvent and redissolving this material in
C6D6 gave the same pattern of four resonances to that originally
observed in the crude mixture (Figure S2, Supporting
Information). The 1H NMR spectrum of 9 in CD2Cl2 at
room temperature was similar to that seen with C6D6 with
resolved tolyl resonances and a very broad set of neopentyl
resonances. At −20 °C, the neopentyl resonances resolved into
multiple resonances with diastereotopic methylene units.
An X-ray quality crystal of complex 9 was obtained by
recrystallization from diethyl ether. Structural analysis of this
crystal showed a molecular structure (9, Figure 5) that is
Figure 6. Stereoisomeric structures of complex 9.
in which the aryl groups are pseudo-cis and the methyl groups
can be either syn or anti. The cis/trans equilibrium was reported
to be dependent on solvent polarity for the diadamantyl-n-
butylphosphine analog of 9.30a The major/minor ratio
increased from 3:1 to 9:1 upon changing the solvent from
THF-d8 to toluene-d8, which was rationalized as an increased
preference for the trans-isomer in the less polar solvent.
Complex 9 displays a similar solvent dependent equilibria, but
in this case the major/minor ratio increases from approximately
5:1 in C6D6 to >20:1 for the major isomer in CDCl3. Assuming
that the major isomer observed in solution is the trans-isomer
obtained in the solid state (9), the solvent effect would appear
to be opposite to that proposed by Beller.30a
Figure 5. Thermal ellipsoid plot (50% probability) of the molecular
structure of 9. Hydrogen atoms are omitted for clarity. Unlabeled
atoms are symmetry equivalents of labeled atoms. Selected bond
lengths (Å) and angles (deg): Pd−Br, 2.504(2); Pd−Br′, 2.573(2),
Pd−P1, 2.266(3); Pd−C1, 2.00(2); Br−Pd−P1, 172.8(1); Br′−Pd−
P1, 97.58(2); Br−Pd−C1, 87.1(4); Br′−Pd−C1, 173.8(5); Pd−Br−
Pd′, 93.13(6); Br−Pd−Br′, 86.87(6); Pd−P1−C8, 110.7(4); Pd−P1−
C13, 114.3(5); Pd−P1−C18, 114.4(5); P1−C8−C9, 124(1); P1−
C13−C14, 128.7(9); P1−C18−C19, 122(1); Br−Pd−C1−C2,
−84(1); Pd−P1−C8−C9, 174(1); Pd−P1−C13−C14, 153(1); Pd−
P−C18−C19, −71(1); C1−Pd−P1−C13, 30.0(6). Symmetry code for
Br′ and Pd′ = (1 − x, 2 − y, −z).
Reaction of 2-bromo-m-xylene with complex 7 did not result
in the isolation of an oxidative addition complex (10) in
analogy to complexes 8 and 9. Instead, two peaks at 38 and 39
ppm in a 3.3:1 ratio along with free TNpP (38/39 ppm:TNpP
= 1:1) were observed in the 31P NMR spectrum of the reaction
mixture. After the crude product was washed with pentane to
remove excess 2-bromo-m-xylene and TNpP, a colorless
1
powder (15) was obtained. The H NMR spectrum of 15
shows no protons in the aromatic region. Thus, complex 15 is
not an oxidative addition product. Repeating the reaction with
bromomesitylene gave an identical 31P NMR spectrum. Gas
chromatographic analysis of the reaction mixture showed the
formation of mesitylene. This result suggests the formation of
an oxidative addition product that decomposes to give complex
15 and mesitylene.
During the course of the reaction of 7 with 2-bromo-m-
xylene, an intermediate is observed at 8.5 ppm, which decays
away as the starting material is consumed (Figure S3,
Supporting Information). The intermediate observed at 8.5
ppm suggests that a dimeric complex similar to 8 and 9 is
formed (10), but that this complex decomposes to give 15.
Because the species observed at 8.5 ppm decomposes as it is
being formed, it could not be isolated and characterized.
Complex 15 was observed in very small amounts in the
oxidative addition of 1-bromo-4-tert-butylbenzene and 2-
bromotoluene to complex 7. The process to form 15 is
apparently favored with the more sterically hindered m-xylyl
and mesityl substituents, however. Attempts to obtain X-ray
quality crystals of 15 have so far been unsuccessful.
analogous to complex 8. Both crystallized in the P21/c space
group and have similar structural parameters. Because of the
perturbation of the o-methyl group, the TNpP ligand is rotated
relative to the Pd2Br2 plane, and as a result, the large Pd−P−
C−C dihedral angle is 153(1)° rather than the 179.9(4)° value
seen in 8. The other two dihedral angle values are qualitatively
the same as found in 8. The additional steric strain in this
system is apparent in the increased P−C−C angles of the
neopentyl groups (122(1)°, 124(1)°, and 128.7(9)°) compared
to complex 8 (113.3(5)°, 121.9(4)°, 127.5(4)°).
In this structure, the methyl groups of the o-tolyl substituent
are in an anti conformation and the two aromatic substituents
are in a pseudo-trans orientation. We hypothesize that the other
species observed by 31P NMR spectroscopy represent stereo-
isomers of the structure seen in the solid state. The peaks at
8.57 and 8.66 ppm are due to structures 9 and 12 in which the
aryl groups are pseudo-trans and the methyl substituents are
either syn or anti (Figure 6). In solution, these isomers are
observed in nearly equal amounts, whereas only the anti-isomer
9 was observed in the solid state structure. The minor peaks
seen at 7.45 and 7.51 ppm may be due to structures 13 and 14
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DISCUSSION
Scheme 2. Mechanistic Pathway for Palladium-Catalyzed
Coupling Reactions
■
Trineopentylphosphine provides a catalyst that is highly
effective for the Buchwald−Hartwig amination of sterically
hindered substrates. The Pd/TNpP catalyst system is one of
the few systems reported to successfully couple a 2,6-
diisopropyl-substituted aryl halide with a 2,6-diisopropylaniline
derivative7d,8,22 and the first example of arylation of 2-tert-
butylaniline with a 2,6-disubstituted aryl halide. Although
TNpP is calculated to have a very large cone angle based on the
structure of Pd(TNpP), the catalyst derived from TNpP
outperforms a range of other phosphine ligands, including
those with smaller calculated cone angles.
Based on solid-state structures obtained for complexes 7, 8,
and 9, the conformational flexibility of TNpP likely accounts
for its ability to provide effective catalysts for these challenging
coupling reactions. In the two-coordinate complex 7, the
neopentyl substituents adopt a conformation in which they are
directed toward the palladium center. This conformation is
similar to that obtained for the calculated gas-phase structure
and predicts a large cone angle for TNpP coordinated to a low-
coordination number metal. Complexes 8 and 9 show that the
TNpP is able to adopt a less sterically demanding conformation
in order to accommodate additional ligands at the metal center.
This conformational flexibility may account for the particular
effectiveness of the Pd/TNpP catalyst system with sterically
hindered substrates. It is possible that the TNpP-derived
catalyst has an effectively smaller steric demand that allows it to
effectively react with sterically demanding substrates. Ligands
with more rigid substituents, such as tert-butyl or cyclohexyl,
are less able to accommodate these hindered substrates.
Interestingly, the Pd/TNpP catalyst system gives higher
cross-coupling rates for sterically hindered aryl halides and
amines than for less hindered substrates. Plenio has observed a
slight increase in rate for 2-substituted aryl bromides in
Sonogashira couplings catalyzed by Pd/P(t-Bu)nCy3−n systems,
but the more hindered 2,6-disubstituted aryl bromides were
significantly less reactive.15f In our case, we observe that the 2-
bromo-m-xylene gives a higher rate than the 2-bromotoluene
(Figure 2), which reacts faster than the 4-bromotoluene. Even if
the flexibility of the TNpP ligand allows it to better
accommodate sterically demanding substrates, we initially
would have predicted that less hindered substrates would
provide higher reaction rates. We hypothesize that this
unusually reactivity trend has to do with the speciation of the
oxidative addition intermediates as a function of ligand and
substrate steric demand. The identity of the oxidative addition
product could be expected to affect the rate of the overall
catalytic cycle.
to cleavage by TNpP to form Pd(TNpP)2(Ar)Br (C).
Therefore, C-type species likely do not play a role in the
catalytic cycle with TNpP. Both 1-bromo-4-tert-butylbenzene
and 2-bromotoluene gave the same oxidative addition products
with qualitatively similar rates. Although we do not see a
difference in the oxidative addition product formed, it is
possible that the presence of the ortho-substituent would affect
the equilibrium between A and B. Thus, with more hindered
aryl halides, a higher equilibrium concentration of A would be
present. In contrast, a sterically demanding, rigid ligand like
TTBP gives stable 3-coordinate complexes independent of the
steric demand of the aryl substituent.29
Unfortunately, the oxidative addition product formed from
Pd(TNpP)2 and 2-bromo-m-xylene was unstable, so it was not
possible to determine the structure of this product. Based on
the chemical shift of the initially formed product, it is likely a
dimeric structure similar to 8 and 9. The low stability of this
oxidative addition product does not appear to be relevant to the
catalytic cycle given the high yields obtained with this and other
2,6-disubstituted aryl halides. Thus, in the presence of substrate,
the oxidative addition product is sufficiently stable to continue
on to product formation.
The identity of the decomposition products (15) is
unknown, but there is prior precedent for similar decom-
positions of palladium aryl complexes with hindered ligands.
The analogous [Pd(TTBP)(Ph)(μ-I)]2 readily undergoes
decomposition to biphenyl and [Pd(TTBP)(μ-I)]2 upon
heating.28a Hartwig reported the formation of [Pd(TTBP)(μ-
Br)]2 and bithiophene when Pd(dba)2, TTBP, and 2-
bromothiophene were reacted together.36 The [Pd(TTBP)(μ-
Br)]2 complex has also been seen as a byproduct in the
oxidative addition of bromobenzene to Pd(TTBP)2.37
The observation of hydrodehalogenation products by GC in
the oxidative addition of bromomesitylene to 7 is consistent
with a similar decomposition pathway. The TNpP-derived
materials (15) recovered from this reaction are not consistent
with [Pd(TNpP)(μ-Br)]2, however. Other known [Pd(PR3)(μ-
Br)]2 complexes are intensely colored,38 whereas the isolated
material is a colorless solid. In addition, [Pd(PR3)(μ-Br)]2
complexes give 31P NMR shifts that are similar to those of the
Pd(PR3)2 complexes, whereas the shifts we observe are
significantly downfield of Pd(TNpP)2, which is observed at
−32 ppm. Finally, formation of [Pd(TNpP)(μ-Br)]2 would not
account for the appearance of two 31P NMR resonances that
With sterically demanding ligands, the monophosphine
complex (A) is believed to be the oxidative addition product
that lies on the catalytic cycle (Scheme 2). Therefore,
conditions that favor this structure would be expected to
produce higher rates. Complexes B and C would represent
catalyst resting states whose presence would slow down the
overall catalytic process. We hypothesized that the unusual rate
trends that we observed as a function of the substrate steric
demand may be related to a difference in the oxidative addition
product distribution formed with each aryl halide.
Initial study of the oxidative addition of aryl halides to
Pd(TNpP)2 shows that unhindered and 2-substituted aryl
halides both form halide bridge dimer oxidative addition
products (B). In solution, the dimeric complexes are resistant
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H3PO4. HRMS were obtained on a magnetic sector mass spectrometer
using EI ionization and operating in the positive ion mode.
appear to involve equilibrating species. The observed chemical
shifts are inconsistent with other trineopentylphosphine
derivatives that we have characterized, including trineopentyl-
phosphine oxide (40 ppm), Pd(TNpP)2Br2 (25 ppm),
[Pd(TNpP)(μ-Br)Br]2 (0 ppm), Pd(TNpP)2 (−32 ppm).
In the Suzuki coupling, TNpP provided a less effective
catalyst than TTBP for the coupling of sterically demanding
substrates, in contrast to the Buchwald−Hartwig amination.
The increased steric demand of TTBP appears to be critical to
the success of the Suzuki coupling based on our results (Table
7). This observation may reflect the need to maintain a higher
equilibrium concentration of the 3-coordinate oxidative
addition intermediate (A) relative to the halide bridged dimer
(B). The TTBP ligand promotes formation of stable 3-
coordinate oxidative addition products.29 It is possible that the
organoboron nucleophile is less effective in splitting the dimeric
intermediate than more strongly coordinating amine substrates.
Thus, the preference for the dimeric structure B may hinder the
coupling reaction when TNpP is used as the ligand. It is
noteworthy that TTBP is able to catalyze the Suzuki coupling
of 2,6-disubstituted aryl bromides in contrast to DTBNpP,
which provides an inactive catalyst. This result may suggest that
DTBNpP has a larger effective steric demand that TTBP.
General Procedure for Buchwald−Hartwig Amination. A 10
mL screw-capped vial was placed in a glovebox where Pd2(dba)3 (0.5−
2.0 mol %), TNpP (1.0−4.0 mol %), and NaO-t-Bu (1.5 equiv) were
added. The vial was sealed with a rubber/Teflon septum and taken out
of the glovebox. The aryl halide (1 mmol), arylamine (1.2 equiv), and
2 mL of toluene were added, and the reaction was placed in an oil bath
preheated to 80 °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.
Bis(2,6-dimethylphenyl)amine (2a, 3e).6a Using the general
procedure, 2-bromo-m-xylene (133 μL, 1.00 mmol) and 2,6-
dimethylaniline (147 μL, 1.20 mmol) were coupled using 0.5 mol %
of Pd2(dba)3 and 1.0 mol % of TNpP at 80 °C to give the product as a
white solid (211 mg, 94%). 1H NMR (500 MHz, CDCl3): δ 7.11 (d, J
= 7.5 Hz, 4H), 6.97 (t, J = 7.5 Hz, 2H), 4.92 (s, 1H), 2.15 (s, 12H).
13C NMR (125 MHz, CDCl3): δ 141.9, 129.7, 128.9, 121.9, 19.3.
Alternatively, 2-chloro-m-xylene (132 μL, 1.00 mmol) and 2,6-
dimethylaniline (147 μL, 1.20 mmol) were coupled using 1.0 mol % of
Pd2(dba)3 and 2.0 mol % of TNpP at 100 °C to obtain bis(2,6-
dimethylphenyl)amine (214 mg, 95%).
N-(2,6-Dimethylphenyl)-2,4,6-trimethylaniline (2b).6a Using
the general procedure, bromomesitylene (153 μL, 1.00 mmol) and
2,6-dimethylaniline (147 μL, 1.20 mmol) were coupled using 0.5 mol
% of Pd2(dba)3 and 1.0 mol % of TNpP at 80 °C to give the product
as a white solid (222 mg, 93%). 1H NMR (500 MHz, CDCl3): δ 7.14
(d, J = 7.4 Hz, 2H), 6.96−6.99 (m, 3H), 4.88 (s, 1H), 2.44 (s, 3H),
2.19 (s, 12H). 13C NMR (125 MHz, CDCl3): δ 142.4, 139.2, 131.7,
130.7, 129.4, 128.9, 128.6, 121.2, 20.8, 19.3, 19.2.
CONCLUSIONS
■
TNpP is a sterically demanding, electron-rich phosphine that
effectively catalyzes the Hartwig−Buchwald amination of
sterically hindered aryl bromides and chlorides with sterically
demanding anilines. The TNpP-derived catalyst provides a
significantly more effective catalyst with hindered substrates
than TTBP. The TNpP-derived catalyst promoted amination of
aryl chlorides occurs at lower temperature than was required by
the DTBNpP-derived catalyst, even with unhindered aryl
chlorides. The TNpP/Pd catalyst system catalyzes the Suzuki
coupling of moderately hindered biaryl products, but is less
effective with hindered substrates than TTBP. Structural
analysis of TNpP complexes shows that TNpP adopts a large
cone angle conformation when coordinated to a two-coordinate
palladium but adopts a less hindered conformation when
coordinated to a four-coordinate palladium center. This
flexibility may account for trineopentylphospine’s unique ability
to promote cross-coupling of high steric demand substrates.
Notably, the TNpP-derived catalyst produces higher rates in
the amination of sterically hindered aryl bromides than with
unhindered aryl bromides. This unusual trend is hypothesized
to be the result of a different equilibrium distribution of the
oxidative addition products as a function of aryl halide steric
demand. Further mechanistic studies to address this question
are ongoing.
N-(2,6-Dimethylphenyl)-2,6-diisopropylaniline (2c, 3d).39
Using the general procedure, 2-bromo-m-xylene (133 μL, 1.00
mmol) and 2,6-diisopropylaniline (226 μL, 1.20 mmol) were coupled
using 0.5 mol % of Pd2(dba)3 and 1.0 mol % of TNpP at 80 °C to give
1
the product as a clear, colorless oil (259 mg, 92%). H NMR (500
MHz, CDCl3): δ 7.19−7.23 (m, 3H), 7.03 (d, J = 7.4 Hz, 2H), 6.81 (t,
J = 7.4 Hz, 1H), 4.89 (s, 1H), 3.25 (sept, J = 6.9 Hz, 2H), 2.08 (s, 6H),
1.22 (d, J = 6.9 Hz, 12H). 13C NMR (125 MHz, CDCl3): δ 144.3,
143.3, 139.0, 129.7, 125.9, 125.0, 123.5, 119.8, 28.3, 23.7, 19.5.
Alternatively, 2-chloro-m-xylene (132 μL, 1.00 mmol) and 2,6-
diisopropylaniline (226 μL, 1.20 mmol) were coupled using 1.0 mol %
of Pd2(dba)3 and 2.0 mol % of TNpP at 100 °C to obtain N-(2,6-
dimethylphenyl)-2,6-diisopropylaniline (267 mg, 95%).
N-(2,4,6-Trimethylphenyl)-2,6-diisopropylaniline (2d).40
Using the general procedure, bromomesitylene (153 μL, 1.00 mmol)
and 2,6-diisopropylaniline (226 μL, 1.20 mmol) were coupled using
0.5 mol % of Pd2(dba)3 and 1.0 mol % of TNpP at 80 °C to give the
product as a white solid (286 mg, 97%). 1H NMR (500 MHz, CDCl3):
δ 7.21 (s, 3H), 6.86 (s, 2H), 4.81 (s, 1H), 3.24 (sept, J = 6.9 Hz, 2H),
2.33 (s, 3H), 2.07 (s, 6H), 1.23 (d, J = 6.9 Hz, 12H). 13C NMR (125
MHz, CDCl3): δ 143.5, 140.7, 139.4, 130.3, 129.3, 126.5, 124.4, 123.4,
123.4, 28.2, 23.7, 20.6, 19.5.
N-(4-Methylphenyl)-2,6-diisopropylaniline (2e).16a Using the
general procedure, 4-bromotoluene (123 μL, 1.00 mmol) and 2,6-
diisopropylaniline (226 μL, 1.20 mmol) were coupled using 0.5 mol %
of Pd2(dba)3 and 1.0 mol % of TNpP at 80 °C to give the product as a
EXPERIMENTAL SECTION
■
General Experimental Details. All chemicals were obtained from
commercial sources and used as received, except where noted. TNpP
was obtained from FMC, Lithium Division. TNpP is stable in air for
several days as a solid16b but was stored in a nitrogen-filled glovebox.
Pd(OAc)2 and Pd2(dba)3 were provided by Johnson-Matthey.
Toluene was distilled from sodium under nitrogen prior to use in
coupling reactions. THF was distilled from sodium/benzophenone
under nitrogen. Water was deoxygenated by sparging with nitrogen
prior to use in Suzuki coupling reactions. All cross-coupling reactions
were assembled in a nitrogen-filled glovebox. Reaction temperatures
refer to previously equilibrated oil bath temperatures. 1H and 13C
NMR spectra are referenced to the NMR solvent peaks or internal
TMS. 31P{1H} NMR spectra were externally referenced to 85%
1
clear, colorless oil (257 mg, 96%). H NMR (500 MHz, CDCl3): δ
7.37−7.40 (m, 1H), 7.30−7.33 (m, 2H), 7.06 (d, J = 8.2 Hz, 2H), 6.52
(d, J = 8.3 Hz), 5.13 (s, 1H), 3.30 (sept, J = 6.9 Hz, 2H), 2.34 (s, 3H),
1.26 (d, J = 6.9 Hz, 12H). 13C NMR (125 MHz, CDCl3): δ 147.6,
146.0, 135.8, 129.9, 127.2, 127.0, 124.0, 113.3, 28.4, 24.1, 20.6.
N-(4-Methoxyphenyl)-2,6-diisopropylaniline (2f, 3a).16c
Using the general procedure, 4-bromoanisole (125 μL, 1.0 mmol)
and 2,6-diisopropylaniline (226 μL, 1.20 mmol) were coupled using
0.5 mol % of Pd2(dba)3 and 1.0 mol % of TNpP at 80 °C to give the
1
product as a clear, colorless oil (263 mg, 93%). H NMR (500 MHz,
CDCl3): δ 7.37−7.40 (m, 1H), 7.33−7.34 (m, 2H), 6.86 (d, J = 9.0
Hz, 2H), 6.57 (d, J = 8.9 Hz, 2H), 5.11 (s, 1H), 3.83 (s, 3H), 3.34
K
dx.doi.org/10.1021/jo400435z | J. Org. Chem. XXXX, XXX, XXX−XXX

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Featured Article
(sept, J = 6.8 Hz, 2H), 1.27 (d, J = 6.9 Hz, 12H). 13C NMR (125
MHz, CDCl3): δ 152.4, 147.2, 142.4, 136.3, 126.9, 124.0, 114.9, 114.4,
55.8, 28.3, 24.0.
Alternatively, 4-chloroanisole (122 μL, 1.00 mmol) and 2,6-
diisopropylaniline (226 μL, 1.20 mmol) were coupled using 0.5 mol
% of Pd2(dba)3 and 1.0 mol % of TNpP at 100 °C to obtain N-(4-
methoxyphenyl)-2,6-diisopropylaniline (235 mg, 83%).
N-(2,6-Diisopropylphenyl)-2,4,6-trisopropylaniline (2l).8
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 % of Pd2(dba)3 and 1.0 mol % of
TNpP at 80 °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 = 0.8 Hz, J = 6.9 Hz, 6H), 1.92 (t, J = 7.1 Hz, 24H).
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.
N-(4-Methoxy-2-methylphenyl)-2,6-diisopropylaniline (2g).
Using the general procedure, 4-bromo-3-methylanisole (141 μL, 1.00
mmol) and 2,6-diisopropylaniline (226 μL, 1.20 mmol) were coupled
using 0.5 mol % of Pd2(dba)3 and 1.0 mol % of TNpP at 80 °C to give
N-(2-tert-Butylphenyl)-2,4,6-triisopropylaniline (2m). Using
the general procedure, 1-bromo-2,4,6-triisopropylbenzene (253 μL,
1.00 mmol) and 2-tert-butylaniline (187 μL, 1.20 mmol) were coupled
using 2.0 mol % of Pd2(dba)3 and 4.0 mol % of TNpP at 80 °C to give
1
the product as a red crystal (247 mg, 83%). H NMR (500 MHz,
CDCl3): δ 7.31−7.34 (m, 1H), 7.27−7.29 (m, 2H), 6.82 (d, J = 2.8
Hz, 1H), 6.59 (dd, J = 2.8, J = 8.7 Hz, 1H), 6.13 (d, J = 8.7 Hz, 1H),
4.74 (s, 1H), 3.79 (s, 3H), 3.16 (sept, J = 6.9 Hz, 2H), 2.40 (s, 3H),
1.21 (br, 12H). 13C NMR (125 MHz, CDCl3): δ 152.2, 146.9, 140.4,
136.8, 126.2, 124.0, 123.5, 116.8, 113.0, 111.8, 55.8, 28.4, 24.9, 23.2,
18.1. HRMS m/z calcd for C20H27NO (M+) 297.2097, found
297.2090.
1
the product as a clear, colorless oil (278 mg, 79%). H NMR (500
MHz, CDCl3): δ 7.53 (d, J = 7.8 Hz), 7.31 (s, 2H), 7.15 (t, J = 7.6 Hz,
1H), 6.90 (t, J = 7.6 Hz,1H), 6.43 (d, J = 8.1 Hz, 1H), 5.42 (s, 1H),
3.32 (sept, J = 6.8 Hz, 2H), 3.16 (sept, J = 6.8 Hz, 1H), 1.77 (s, 9H),
1.52 (d, J = 6.9 Hz, 6H), 1.40 (d, J = 6.9 Hz, 6H), 1.34 (d, J = 6.9 Hz,
6H). 13C NMR (125 MHz, CDCl3): δ 147.3, 146.9, 146.4, 133.7,
132.7, 127.2, 126.4, 122.0, 117.7, 113.6, 34.5, 34.4, 30.1, 28.6, 25.1,
24.4, 23.2. HRMS: m/z calcd for C25H37N (M+) 351.2926, found
351.2917.
N-(2-Methoxyphenyl)-2,6-diisopropylaniline (2h, 3b).16c
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 % of Pd2(dba)3 and 1.0 mol % of TNpP at 80 °C to give the
1
product as a clear, colorless oil (244 mg, 86%). H NMR (500 MHz,
N-(1-Naphthyl)-2,4,6-triisopropylaniline (2n). Using the gen-
eral procedure, 1-bromo-2,4,6-triisopropylbenzene (253 μL, 1.00
mmol) and 1-naphthylamine (172 mg, 1.20 mmol) were coupled
using 2.0 mol % of Pd2(dba)3 and 4.0 mol % of TNpP at 80 °C to give
CDCl3): δ 7.42−7.45 (m, 1H), 7.37−7.38 (m, 2H), 6.99 (dd, J = 1.1
Hz, J = 7.6 Hz, 1H), 6.80−6.89 (m, 2H), 6.29 (dd, J = 1.6 Hz, J = 7.6
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.
Alternatively, 2-chloroanisole (127 μL, 1.00 mmol) and 2,6-
diisopropylaniline (226 μL, 1.20 mmol) were coupled using 0.5 mol
% of Pd2(dba)3 and 1.0 mol % of TNpP at 100 °C to obtain N-(2-
methoxyphenyl)-2,6-diisopropylaniline (274 mg, 97%).
N-(2-Biphenyl)-2,6-diisopropylaniline (2i). 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
% of Pd2(dba)3 and 1.0 mol % of TNpP at 80 °C to give the product
as a white solid (273 mg, 83%). 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 = 1.0 Hz, J = 7.8
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, 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)-1-naphthalenamine (2j). 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 % of Pd2(dba)3 and 1.0 mol % of TNpP at 80 °C to give the
product as a white solid (282 mg, 93%). 1H 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.
1
the product as a white solid (183 mg, 53%). H NMR (500 MHz,
CDCl3): δ 8.13−8.15 (m, 1H), 7.93−7.95 (m, 1H), 7.58−7.63 (m,
2H), 7.33−7.35 (m, 1H), 7.27−7.30 (m, 1H), 7.21 (s, 2H), 6.30 (dd, J
= 0.9 Hz, J = 7.4 Hz, 1H), 5.76 (s, 1H), 3.24 (sept, J = 6.8 Hz, 2H),
3.06 (sept, J = 6.6 Hz, 1H), 1.41 (d, J = 6.9 Hz, 6H), 1.28 (d, J = 6.9
Hz, 6H), 1.20 (d, J = 6.9 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ
147.7, 146.9, 143.8, 134.7, 133.3, 129.1, 126.8, 126.0, 125.0, 123.3,
122.1, 120.2, 117.9, 106.9, 34.5, 28.5, 25.0, 24.4, 23.5. HRMS m/z
calcd for C25H31N (M+) 345.2457, found 345.2469.
N-(2,6-Dimethylphenyl)-1-naphthalenamine (2o, 3g).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 % of Pd2(dba)3 and 1.0 mol % of TNpP at 80 °C to give
1
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.
Alternatively, 2-chloro-m-xylene (132 μL, 1.00 mmol) and 1-
naphthylamine (172 mg, 1.20 mmol) were coupled using 1.0 mol % of
Pd2(dba)3 and 2.0 mol % of TNpP at 100 °C to obtain N-(2,6-
dimethylphenyl)-1-naphthalenamine (222 mg, 90%).
N-(2-Biphenyl)-1-naphthalenamine (2p). Using the general
procedure, 2-bromobiphenyl (172 μL, 1.00 mmol) and 1-naphthyl-
amine (172 mg, 1.20 mmol) were coupled using 0.5 mol % of
Pd2(dba)3 and 1.0 mol % of TNpP at 80 °C to give the product as a
white solid (274 mg, 93%). 1H NMR (500 MHz, CDCl3): δ 7.94 (t, J
= 10.8 Hz, 2H), 7.67−7.68 (m, 3H), 7.44−7.56 (m, 7H), 7.40 (d, J =
7.5 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.06−
7.09 (m, 1H), 6.08 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 142.1,
139.3, 139.2, 134.9, 130.9, 130.8, 129.5, 129.2, 128.7, 128.5, 128.4,
127.8, 126.3, 126.2, 125.9, 123.3, 122.1, 120.6, 117.1, 116.7. HRMS:
m/z calcd for C22H17N (M+) 295.1361, found 295.1359.
N-(2,6-Diisopropylphenyl)-2-methoxy-1-naphthalenamine
(2k). Using the general procedure, 1-bromo-2-methoxynaphthalene
(237 mg, 1.00 mmol) and 2,6-diisopropylaniline (226 μL, 1.20 mmol)
were coupled using 0.5 mol % of Pd2(dba)3 and 1.0 mol % of TNpP at
N-(2-Tolyl)diphenylamine (2q).6b Using the general procedure,
2-bromotoluene (120 μL, 1.00 mmol) and diphenylamine (203 mg,
1.20 mmol) were coupled using 0.5 mol % of Pd2(dba)3 and 1.0 mol %
of TNpP at 80 °C to give the product as a white solid (251 mg, 97%).
1H NMR (500 MHz, CDCl3): δ 7.35−7.36 (m, 1H), 7.24−7.32 (m,
7H), 7.10 (dd, J = 1.1 Hz, J = 8.7 Hz, 4H), 7.03 (t, J = 7.3 Hz, 2H),
2.17 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 147.7, 145.6, 136.7,
131.9, 129.8, 129.2, 127.5, 126.2, 121.7, 121.6, 18.8.
1
80 °C to give the product as a colorless oil (290 mg, 83%). H NMR
(500 MHz, CDCl3): δ 7.84 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 8.8 Hz,
1H), 7.48 (d, J = 8.8 Hz, 1H), 7.40−7.43 (m, 2H), 7.32−7.36 (m,
3H), 7.15−7.18 (m, 1H), 6.12 (s, 1H), 4.07 (s, 3H), 3.51 (sept, J = 6.8
Hz, 2H), 1.33 (d, J = 6.9 Hz, 6H), 1.12 (d, J = 6.9 Hz, 6H). 13C NMR
(125 MHz, CDCl3): δ 146.1, 143.7, 139.2, 131.5, 130.5, 128.4, 126.2,
125.0, 124.2, 123.8, 123.5, 123.1, 118.8, 113.7, 57.1, 28.3, 24.4, 22.9.
HRMS: m/z calcd for C23H27NO (M+) 333.2093, found 333.2091.
L
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The Journal of Organic Chemistry
Featured Article
N-(2-tert-Butylphenyl)-2,6-dimethylaniline (2r, 3f). 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 % of
Pd2(dba)3 and 1.0 mol % of TNpP at 80 °C to give the product as a
white solid (215 mg, 85%). 1H NMR (500 MHz, CDCl3): δ 7.49 (dd,
J = 1.4 Hz, J = 7.8 Hz, 1H), 7.27−7.29 (m, 2H), 7.20−7.23 (m, 1H),
7.09−7.12 (m, 1H), 6.91 (dt, J = 1.1 Hz, J = 8.2 Hz, 1H), 6.39 (dd, J =
1.1 Hz, J = 8.0 Hz), 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.
133.5, 133.2, 132.9, 131.2, 127.7, 127.5, 124.1, 123.9, 123.8, 29.1, 23.0.
HRMS: m/z calcd for C26H25NO (M+) 367.1936, found 367.1947.
10-(2,6-Dimethylphenylimino)-9(10H)-anthracenone (5b).
Using the general procedure, 9-bromoanthracene (257 mg, 1.00
mmol) and 2,6-dimethylaniline (147 μL, 1.20 mmol) were coupled
using 0.5 mol % of Pd2(dba)3 and 1.0 mol % of TNpP at 80 °C to give
the product as a red solid (264 mg, 85%). 1H NMR (500 MHz,
CDCl3): δ 8.37 (d, J = 7.8 Hz, 2H), 8.00 (br, 2H), 7.62 (t, J = 7.4 Hz,
2H), 7.53 (br, 2H), 7.12 (d, J = 7.5 Hz, 2H), 7.00 (t, J = 7.5 Hz, 1H),
2.02 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 183.7, 153.1, 149.4,
133.3, 132.6, 131.2, 128.7, 127.4, 127.0, 123.4, 123.3, 18.1. HRMS: m/
z calcd for C22H17NO (M+) 311.1315, found 311.1310.
Alternatively, 2-chloro-m-xylene (132 μL, 1.00 mmol) and 2-tert-
butylaniline (187 μL, 1.20 mmol) were coupled using 1.0 mol % of
Pd2(dba)3 and 2.0 mol % of TNpP at 100 °C to obtain N-(2-tert-
butylphenyl)-2,6-dimethylaniline (241 mg, 95%).
N-Phenyl-9-anthramine (4c).42 Using the general procedure, 9-
bromoanthracene (257 mg, 1.00 mmol) and aniline (109 μL, 1.20
mmol) were coupled using 1.0 mol % of Pd2(dba)3 and 2.0 mol % of
TNpP at 80 °C to give the product as a yellow solid (234 mg, 87%).
1H NMR (500 MHz, CDCl3): δ 8.24 (s, 1H), 8.21 (d, J = 7.7 Hz, 2H),
8.06 (d, J = 8.3 Hz, 2H), 7.44−7.51 (m, 4H), 7.16 (t, J = 7.5 Hz, 2H),
6.79 (t, J = 7.3 Hz, 1H), 6.60 (d, J = 7.7 Hz, 2H), 6.01 (br, 1H). 13C
NMR (125 MHz, CDCl3): δ 148.2, 132.7, 132.5, 129.5, 129.3, 129.0,
126.1, 125.7, 125.5, 124.1, 118.7, 114.1.
N-(2-Methoxyphenyl)-2,6-dimethylaniline (2s, 3h).6b 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 % of
Pd2(dba)3 and 1.0 mol % of TNpP at 80 °C to give the product as a
white solid (186 mg, 82%). 1H NMR (500 MHz, CDCl3): δ 7.22−7.23
(m, 2H), 7.16−7.19 (m, 1H), 6.96 (dd, J = 1.8 Hz, J = 7.4 Hz, 1H),
6.82 (dp, J = 1.7 Hz, J = 7.4 Hz, 2H), 6.25 (dd, J = 2.1 Hz, J = 7.5 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.
N-(2-tert-Butylphenyl)-9-anthramine (4d). Using the general
procedure, 9-bromoanthracene (257 mg, 1.00 mmol) and 2-tert-
butylaniline (187 μL, 1.20 mmol) were coupled using 1.0 mol % of
Pd2(dba)3 and 2.0 mol % of TNpP at 80 °C to give the product as a
1
Alternatively, 2-chloro-m-xylene (132 μL, 1.00 mmol) and o-
anisidine (135 μL, 1.20 mmol) were coupled using 1.0 mol % of
Pd2(dba)3 and 2.0 mol % of TNpP at 100 °C to obtain N-(2-
methoxyphenyl)-2,6-dimethylaniline (207 mg, 91%).
yellow solid (260 mg, 80%). H NMR (500 MHz, CDCl3): δ 8.41 (s,
1H), 8.13 (d, J = 8.7 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 7.42−7.51 (m,
5H), 6.78−6.85 (m, 2H), 6.21 (s, 1H), 6.11 (dd, J = 1.6 Hz, J = 7.7
Hz, 1H), 1.79 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 146.2, 134.0,
133.6, 132.6, 129.0, 128.9, 127.3, 126.7, 126.1, 125.7, 124.9, 124.1,
118.9, 115.8, 34.9, 30.4. HRMS: m/z calcd for C24H23N (M+)
325.1830, found 325.1829.
N-(2-Methoxyphenyl)-9-anthramine (4e). Using the general
procedure, 9-bromoanthracene (257 mg, 1.00 mmol) and o-anisidine
(135 μL, 1.20 mmol) were coupled using 1.0 mol % of Pd2(dba)3 and
2.0 mol % of TNpP at 80 °C to give the product as an orange solid
(254 mg, 85%). 1H NMR (500 MHz, CDCl3): δ 8.46 (s, 1H), 8.27 (d,
J = 8.6 Hz, 2H), 8.11 (d, J = 8.2 Hz, 2H), 7.50−7.56 (m, 4H), 7.05 (d,
J = 8.0 Hz, 1H), 6.83 (dt, J = 1.2 Hz, J = 7.6 Hz, 1H), 6.67−6.71 (m,
2H), 6.17 (dd, J = 1.2 Hz, J = 7.9 Hz, 1H), 4.16 (s, 3H). 13C NMR
(125 MHz, CDCl3): δ 146.7, 137.9, 113.2, 132.4, 129.3, 128.9, 126.0,
125.6, 125.3, 124.2, 121.3, 118.0, 112.3, 110.1, 55.9. HRMS: m/z calcd
for C21H17NO (M+) 299.1310, found 299.1321.
General Procedure for the Suzuki−Miyaura Cross-Coupling.
In a drybox, a 10 mL vial was charged with Pd(OAc)2 (1−2 mol %),
TNpP (1−2 mol %), arylboronic acid (1.10 mmol), Na2CO3 (1.10
mmol, 116 mg), and aryl halide (1.00 mmol). The vial was sealed with
a septum cap, removed from the drybox, and charged with
deoxygenated, dry THF (1 mL) and deoxygenated water (1 mL).
The reaction mixture was allowed to stir in a 50 °C (or other
temperature where noted) oil bath for 24 h or until determined to be
complete by GC. Ethyl acetate (25 mL) was added to the reaction
mixture, which was then washed with three 25 mL portions of brine.
The organic layer was dried over MgSO4, and the solvent was removed
under reduced pressure. The crude products were purified by column
chromatography through a short plug of silica gel using a gradient
solution of hexane and ethyl acetate (0−10% EtOAc/hexanes) as the
eluent.
N-(2-Tolyl)-3-amino-N,N-diethyl-4-methoxybenzenesulfona-
mide (2t). Using the general procedure, 2-bromotoluene (120 μL,
1.00 mmol) and fast red ITR (310 mg, 1.20 mmol) were coupled using
1.0 mol % of Pd2(dba)3 and 2.0 mol % of TNpP at 80 °C to give the
product as a yellow solid (293 mg, 85%). 1H NMR (500 MHz,
CDCl3): δ 7.25−7.30 (m, 4H), 7.19 (t, J = 7.5 Hz, 1H), 7.04 (t, J = 7.4
Hz, 1H), 6.91 (d, J = 9.0 Hz, 1H), 6.01 (s, 1H), 3.97 (s, 3H), 3.19 (q, J
= 7.2 Hz, 4H), 2.27 (s, 3H), 1.11 (t, J = 7.2 Hz, 6H). 13C NMR (125
MHz, CDCl3): δ 150.3, 139.3, 135.0, 132.4, 131.2, 130.8, 126.9, 123.8,
121.3, 118.3, 110.8, 109.5, 56.0, 42.0, 17.8, 14.2. HRMS: m/z calcd for
C18H24N2O3S (M+) 348.1508, found 348.1517.
N-(2-Tolyl)-2-methoxy-4-nitroaniline (2u). Using the general
procedure, 2-bromotoluene (120 μL, 1.00 mmol) and 2-methoxy-4-
nitroaniline (202 mg, 1.20 mmol) were coupled using 2.0 mol % of
Pd2(dba)3 and 4.0 mol % of TNpP at 80 °C to give the product as a
white solid (150 mg, 58%). 1H NMR (500 MHz, CDCl3): δ 7.82 (dd,
J = 2.3 Hz, J = 8.9 Hz, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.32 (d, J = 8.5
Hz, 2H), 7.27 (t, J = 6.3 Hz, 1H), 7.19 (t, J = 7.4 Hz, 1H), 6.69 (d, J =
8.9 Hz, 1H), 6.53 (s, 1H), 4.04 (s, 3H), 2.28 (s, 3H). 13C NMR (125
MHz, CDCl3): δ 145.8, 141.9, 138.6, 137.6, 133.2, 131.5, 127.2, 126.0,
124.7, 119.3, 109.2, 105.6, 56.3, 17.9. HRMS: m/z calcd for
C14H14N2O3 (M+) 258.1004, found 258.1010.
N-(2-Tolyl)-2,6-diisopropylaniline (3c).16c Using the general
procedure, 2-chlorotoluene (120 μL, 1.00 mmol) and 2,6-diisopropy-
laniline (226 μL, 1.20 mmol) were coupled using 0.5 mol % of
Pd2(dba)3 and 1.0 mol % of TNpP at 100 °C to give the product as a
1
clear, colorless oil (262 mg, 98%). H NMR (500 MHz, CDCl3): δ
7.47−7.50 (m, 1H), 7.41−7.43 (m, 2H), 7.31 (d, J = 7.3 Hz, 1H), 7.14
(t, J = 7.5 Hz, 1H), 6.86 (t, J = 7.3 Hz, 1H), 6.33, (d, J = 8.1 Hz, 1H),
5.10 (s, 1H), 3.33 (sept, J = 6.8 Hz, 2H), 2.53 (s, 3H), 1.38 (d, J = 6.7
Hz, 6H), 1.32 (d, J = 6.7 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ
147.4, 146.2, 135.9, 130.3, 127.3, 127.2, 124.0, 121.4, 117.7, 111.6,
28.4, 24.9, 23.2, 17.8.
10-(2,6-Diisopropylphenylimino)-9(10H)-anthracenone (5a).
Using the general procedure, 9-bromoanthracene (257 mg, 1.00
mmol) and 2,6-diisopropylaniline (226 μL, 1.20 mmol) were coupled
using 0.5 mol % of Pd2(dba)3 and 1.0 mol % of TNpP at 80 °C to give
the product as a red oil (334 mg, 91%). 1H NMR (500 MHz, CDCl3):
δ 8.40 (d, J = 7.8 Hz, 2H), 8.01 (br, 2H), 7.63 (t, J = 7.4 Hz, 2H), 7.54
(br, 2H), 7.13−7.25 (m, 3H), 2.81 (sept, J = 6.8 Hz, 2H), 1.10 (d, J =
6.8 Hz, 12H). 13C NMR (125 MHz, CDCl3): δ 183.8, 152.9, 147.5,
2,4,6-Trimethylbiphenyl (6a).43 Using the general procedure,
bromomesitylene (153 μL, 1.00 mmol) and phenylboronic acid (161
mg, 1.10 mmol) were coupled using 1 mol % of Pd(OAc)2 and 1 mol
% of TNpP at room temperature. The product was isolated as a
yellow/clear oil (176 mg, 90%). 1H NMR (500 MHz, CDCl3): δ
7.32−7.20 (m, 3H), 7.04 (d, J = 7.5 Hz, 2H), 6.84 (s, 2H), 2.23 (s,
3H), 1.91 (s, 6H); 13C NMR (126 MHz, CDCl3): δ 140.1, 138.0,
135.5, 134.5, 128.3, 127.3, 127.0, 125.5, 19.9, 19.7.
2,2′,4,6-Tetramethylbiphenyl (6b, 6i).44 Using the general
procedure, bromomesitylene (153 μL, 1.00 mmol) and 2-tolylboronic
acid (149 mg, 1.10 mmol) were coupled using 1 mol % of Pd(OAc)2
and 1 mol % of TNpP. The product was isolated as an orange oil (132
M
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mg, 63%). 1H NMR (500 MHz, CDCl3): δ 7.39−7.32 (m, 3H), 7.13−
7.11 (m, 1H), 7.05 (s, 2H), 2.45 (s, 3H), 2.03 (s, 6H); 13C NMR (126
MHz, CDCl3): δ 140.7, 138.3, 136.4, 135.8, 129.9, 129.3, 128.1, 127.0,
126.1, 21.2, 20.3, 19.5.
2.18 (s, 6H); 13C NMR (126 MHz, CDCl3): δ 162.4 (dd, J = 11.8,
246.9 Hz), 159.7 (dd, J = 11.8, 246.9 Hz), 137.7, 131.6, 128.4, 124.2
(dd, J = 3.9, 19.5 Hz), 111.4 (dd, J = 3.8, 21.0 Hz), 104.1 (q, J = 1.0,
25.4 Hz), 21.1, 20.4. HRMS-EI (m/z): [M+] calcd for C15H14F2
232.1064, found 232.1061.
Alternatively, using the general procedure, 2-bromotoluene (85 mg,
0.50 mmol) and mesitylboronic acid (90 mg, 0.55 mmol) were
coupled using 1 mol % of Pd(OAc)2,1 mol % of TNpP, and 1.1 equiv
of Na2CO3 (58 mg, 0.55 mmol). Gas chromatography was used to
determine that the reaction had proceeded to 17% completion.
2,4,6-Triisopropylbiphenyl (6c). Using the general procedure, 1-
bromo-2,4,6-triisopropylbenzene (245 μL, 1.00 mmol) and phenyl-
boronic acid (161 mg, 1.10 mmol) were coupled using 2 mol % of
Pd(OAc)2 and 2 mol % of TNpP. Gas chromatography was used to
determine that the reaction had proceeded to 30% completion.
2-Isopropylbiphenyl (6e).45 Using the general procedure, 1-
bromo-2-isopropylbenzene (153 μL, 1.00 mmol) and phenylboronic
acid (161 mg, 1.10 mmol) were coupled using 1 mol % of Pd(OAc)2
and 1 mol % of TNpP. The product was isolated as a colorless oil (184
2-Methylbiphenyl (6n).48 Using the general procedure, 2-
chlorotoluene (117 μL, 1.00 mmol) and phenylboronic acid (161
mg, 1.10 mmol) were coupled at 80 °C using 1 mol % of Pd(OAc)2
and 1 mol % of TNpP. The product was isolated as a colorless oil (59
mg, 35%). 1H NMR (500 MHz, CDCl3): δ 7.50−7.47 (m, 2H), 7.42−
7.39 (m, 3H), 7.35−7.28 (m, 4H), 2.35 (s, 3H); 13C NMR (126 MHz,
CDCl3): δ 142.0, 141.9, 135.4, 130.3, 129.8, 129.2, 128.1, 127.3, 126.8,
125.8, 20.5.
2,2′-Dimethylbiphenyl (6o). Using the general procedure, 2-
chlorotoluene (117 μL, 1.00 mmol) and 2-tolylboronic acid (149 mg,
1.10 mmol) were coupled using 1 mol % of Pd(OAc)2 and 1 mol % of
TNpP. Gas chromatography was used to determine that the reaction
had proceeded to 14% completion.
1
mg, 94%). H NMR (500 MHz, CDCl3): δ 7.59−7.28 (m, 9H), 3.23
2,6-Dimethylbiphenyl (6p). Using the general procedure, 2-
chloro-m-xylene (133 μL, 1.00 mmol) and phenylboronic acid (161
mg, 1.10 mmol) were coupled at 80 °C. Gas chromatography was used
to determine that the reaction had proceeded to 17% completion.
Synthesis of bis(trineopentylphosphine)palladium(0) (7). In
a glovebox, allyl(cyclopentadiene)palladium(II)25 (200 mg, 0.94
mmol) and trineopentylphosphine (505 mg, 2.07 mmol) were
added to a 25 mL round-bottom flask, which was capped with a 14/
20 septum and placed on a Schlenk line. Toluene (10 mL) was added
to the solids, and the solution was stirred at room temperature for 12 h
and then heated to 50 °C and stirred overnight. After stirring, a gray
precipitate formed and the solid was filtered under an inert
atmosphere. The resulting solid was washed with pentane to remove
(sept, J = 7.0 Hz, 1H), 1.33 (d, J = 6.7 Hz, 6H); 13C NMR (126 MHz,
CDCl3): δ 146.5, 142.3, 141.2, 130.1, 129.4, 128.1, 127.8, 126.8, 125.6,
125.4, 29.5, 24.4.
2-Isopropyl-2′-methylbiphenyl (6f).46 Using the general
procedure, 1-bromo-2-isopropylbenzene (153 μL, 1.00 mmol) and
2-tolylboronic acid (149 mg, 1.10 mmol) were coupled using 1 mol %
of Pd(OAc)2 and 1 mol % of TNpP. The product was isolated as a
1
colorless oil (192 mg, 93%). H NMR (360 MHz, CDCl3): δ 7.33−
6.98 (m, 8H), 2.63 (sept, J = 7.2 Hz, 1H), 2.0 (s, 3H), 1.08 (d, J = 7.2
Hz 3H), 1.01 (d, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ
146.8, 140.6, 136.2, 130, 129.9, 129.7, 127.9, 127.4, 125.6, 125.5, 30.1,
24.9, 23.5, 20.5.
1
2-Methyl-1,1′,2′,1″-terphenyl (6g). Using the general proce-
dure, 2-bromobiphenyl (171 μL, 1.00 mmol) and 2-tolylboronic acid
(149 mg, 1.10 mmol) were coupled using 2 mol % of Pd(OAc)2 and 2
mol % of TNpP. The product was isolated as an orange oil (204 mg,
86%). 1H NMR (360 MHz, CDCl3): δ 7.36−7.16 (m, 4H), 7.04−6.94
(m, 9H), 1.79 (s, 3H); 13C NMR (126 MHz, CDCl3): δ 141.5, 141.4,
141.1, 140.4, 135.9, 130.8, 130.7, 130.0, 129.9, 129.5, 127.9, 127.6,
127.2, 127.1, 126.5, 125.4, 20.2. HRMS m/z calcd for C19H16 (M+)
244.1252, found 244.1246.
any excess phosphine to obtain 7 as a gray solid (477 mg, 85%). H
NMR (500 MHz, C6D6): δ, 1.47 (t, J = 3.0 Hz, 12 H), 1.35 (s, 54 H).
13C NMR (500 MHz, C6D6): δ, 49.4 (t, JC−P = 8.8 Hz), 32.2 (t, JC−P
=
3.9 Hz), 31.8 (t, JC−P = 2.3 Hz). 31P{1H} (202.5 MHz, C6D6): δ, 31.7
(s).
General Procedure for the Synthesis of the Oxidative
Addition Products. In a glovebox, 1 equiv of 7 was added to a 50
mL round-bottom flask, which was placed onto a Schlenk line and
suspended in 10 mL of toluene, 5 equiv of the aryl bromide was added,
and the reaction mixture was heated to 70 °C until 7 was fully
consumed. The reaction mixture was dried, and pentane was added to
precipitate the oxidative addition products.
1-(2-Methylphenyl)naphthalene (6h, 6l).47 Using the general
procedure, 1-bromonapthalene (140 μL, 1.00 mmol) and 2-
tolylboronic acid (149 mg, 1.10 mmol) were coupled using 1 mol %
of Pd(OAc)2 and 1 mol % of TNpP. The product was isolated as a
white solid (201 mg, 92%). 1H NMR (500 MHz, CDCl3): δ 7.81 (dd,
J = 8.5,18.9 Hz, 2H), 7.46−7.17 (m, 9H), 1.95 (s, 3H); 13C NMR
(126 MHz, CDCl3): δ 139.2, 138.8, 135.8, 132.51, 130.9, 129.3, 128.8,
127.2, 126.5, 125.4, 125.6, 125.1, 124.9, 124.7, 124.5, 124.3, 18.9. Mp:
66−67 °C (lit.47 mp 65−66 °C).
Alternatively, using the general procedure, 2-bromotoluene (120
μL, 1.00 mmol) and 1-napthaleneboronic acid (189 mg, 1.10 mmol)
were coupled using 2 mol % of Pd(OAc)2 and 2 mol % of TNpP. The
product was isolated as a white solid (190 mg, 87%).
[Pd(TNpP)(4-tert-butylphenyl)(μ-Br)]2 (8). Using the general
procedure, 7 (100 mg, 0.17 mmol) was reacted with 1-bromo-4-tert-
butylbenzene (146 μL, 0.84 mmol) to give a white solid (89 mg, 94%).
Crystals suitable for X-ray analysis were obtained from a concentrated
1
solution of pentane cooled to 0 °C. H NMR (500 MHz, C6D6): δ,
7.63 (brd, J = 5.9 Hz, 2H), 7.10 (brd, J = 7.5 Hz, 2H), (brd, JP−H
=
10.1 Hz, 6H), 1.26 (brs, 27H), 1.23 (s, 9H).13C NMR (500 MHz,
C6D6): δ, 146.1, 135.5, 125.4, 40.1 (m), 34.4, 33.8 (m), 32.9 (d, JC−P
=
3.1 Hz), 32.1. 31P{1H} (202.5 MHz, C6D6): δ, 7.7 (s).
[Pd(P(Np)3)(o-tolyl)(Br)]2 (9). Using the general procedure, 7 (100
mg, 0.17 mmol) was reacted with 2-bromotoluene (101 μL, 0.84
mmol) to give a white solid (78 mg, 89%). Crystals suitable for X-ray
analysis were obtained from a concentrated solution of diethyl ether
cooled to 0 °C. 1H NMR (500 MHz, C6D6, 298 K): δ, 7.70 (brs, 1H),
7.02 (brs, 1H), 6.91 (brm, 2H), 3.00 (s, 3H), 0.6−2.1 (vbm, 33H);
(500 MHz, C6D6, 283 K): δ, 7.63 (brs, 1H), 6.96 (brs, 1H), 6.85 (brm,
2H), 2.96, 2.93 (s, isomers, 3H), 2.96 (brs, 3H), 1.69−1.74 (m, 3H),
1.22 (brs, 27); (500 MHz, CD2Cl2, 298 K): δ, 7.34 (brs, 1H), 6.92
(brs, 1H), 6.81 (brm, 2H), 2.71, 2.68 (s, isomers, 3H), 1.72 (vbrs,
6H), 1.25 (vbrs, 27H); (500 MHz, CD2Cl2, 253 K): δ, 7.2−7.31 (m,
1H), 6.91 (brd, J = 6.6 Hz, 1H), 6.76−6.81 (m, 2H), 2.66, 2.63 (s,
isomers, 3H), 2.33−2.41 (m, 1H), 2.00−2.04 (m, 1H), 1.76−1.85 (m,
2H), 1.47, 1.42, 1.32, 1.28 (s, 18 H), 0.86−0.93 (m, 1H), 0.73 (s, 9H),
one P-CH2 proton overlaps with the peaks at 1.28−1.47. 31P{1H}
(202.5 MHz, C6D6): δ, 7.45, 7.51, 8.57, and 8.66 ppm
(1.1:1.0:4.0:5.1), mixture of stereoisomers; (202.5 MHz, CD2Cl2): δ,
8.55, 8.62 (1:1.5), mixture of stereoisomers.
2,4-Difluoro-2′-methylbiphenyl (6k). Using the general proce-
dure, 2-bromotoluene (120 μL, 1.00 mmol) and 2,4-difluorophenyl-
boronic acid (173 mg, 1.10 mmol) were coupled using 2 mol % of
Pd(OAc)2 and 2 mol % of TNpP. The product was isolated as a
1
colorless oil (188 mg, 91%). H NMR (500 MHz, CDCl3): δ 7.43−
7.29 (m, 5H), 7.05−6.97 (m, 2H), 2.31 (s, 3H); 13C NMR (126 MHz,
CDCl3): δ 162.5 (dd, J = 11.3, 246.6 Hz), 159.8 (dd, J = 11.3, 246.6
Hz), 136.8, 134.9, 132.2 (dd, J = 5.4, 9.3 Hz), 130.3, 130.1, 128.2,
125.8, 125.5 (dd, J = 4.1, 17.1 Hz), 111.2 (dd, J = 5.3, 20.6 Hz), 103.9
(dd, J = 1.0, 26.4 Hz), 19.90 (d, J = 3.5 Hz). HRMS-EI: m/z [M+]
calcd for C13H10F2 204.0751, found 204.0743.
2,4-Difluoro-2′,4′,6′-trimethylbiphenyl (6m). Using the gen-
eral procedure, bromomesitylene (153 μL, 1.00 mmol) and 2,4-
difluorophenylboronic acid (173 mg, 1.10 mmol) were coupled using
1 mol % of Pd(OAc)2 and 1 mol % of TNpP. The product was isolated
1
as a colorless oil (206 mg, 89%). H NMR (500 MHz, CDCl3): δ
7.28−7.21 (m, 1H), 7.12 (s, 2H), 7.10−7.02 (m, 2H), 2.48 (s, 3H),
N
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Reaction of 7 and 2-Bromo-m-xylene (11). Using the general
procedure, 7 (100 mg, 0.17 mmol) was reacted with 2-bromo-m-
xylene (112 μL, 0.84 mmol) to give a white solid (yield not
determined due to inability to characterize the final product). 31P{1H}:
(202.5 MHz, C6D6): δ, 38.8 (s), 37.9 (s) (1:2.3) ppm.
(e) Torborg, C.; Beller, M. Adv. Synth. Catal. 2009, 351, 3027−3043.
(f) Magano, J.; Dunetz, J. Chem. Rev. 2011, 111, 2177−2250.
(2) (a) Blaser, H.-U.; Indolese, A. F.; Naud, F.; Nettekoven, U.;
Schnyder, A. Adv. Synth. Catal. 2004, 346, 1583−1598. (b) Hartwig, J.
F. Acc. Chem. Res. 2008, 41, 1534−1544. (c) Surry, D. S.; Buchwald, S.
L. Angew. Chem., Int. Ed. 2008, 47, 6338−6361. (d) Surry, D. S.;
Buchwald, S. L. Chem. Sci. 2011, 2, 27−50.
X-ray Crystallographic Data. X-ray crystallographic data
collection was performed at 173.0(1) K using a Bruker diffractometer
with a Platform 3-circle goniometer and an Apex 2 CCD area detector.
Crystals were cooled under a cold nitrogen stream using an N-Helix
cryostat. A hemisphere of data was collected for each crystal using a
strategy of omega scans with 0.5° frame widths. Unit cell
determination, data integration, absorption correction, and scaling
were performed using the Apex2 software suite from Bruker.49 Space
group determination, structure solution, refinement, and generation of
ORTEP diagrams were done using the SHELXTL software package.50
The crystal structures of 7−9 were solved by direct methods and
refined by full-matrix least-squares refinement against F2. Non-
hydrogen atoms were located from the difference map and allowed
to refine anisotropically. Hydrogen atoms were placed in calculated
positions and refined using a riding model.
During the refinement of 7, three difference map peaks consistently
appeared on an adjacent crystallographic 3-fold axis parallel to P1, Pd,
and P2 after all expected atoms had been assigned and the refinement
had converged. Certain carbon atoms also showed oblate thermal
ellipsoids. Based on their position, it was realized that the difference
map peaks could indicate positional disorder of the P1−Pd−P2 core
across two separate 3-fold axes. To model this disorder, the
occupancies of corresponding atoms were allowed to refine while
the anisotropic displacement parameters of the atoms in the minor
part were constrained to be equal to those of the corresponding atom
in the major part. With this model, the site occupancies refined to a
ratio of approximately 95:5. The atomic positions of the major part
were not greatly affected, but the thermal ellipsoids improved while the
R-factor decreased from 0.0563 to 0.0395. Because the site occupancy
of the minor part was so small, carbon atoms or hydrogen atoms
belonging to the minor part were not modeled.
(3) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, 5th ed.;
Springer: New York, 2007.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for coupling products in Tables 3−5
1
and 8; H, 13C, and 31P NMR spectra of palladium complexes;
and crystallographic information files for compounds 7−9
(CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kshaughn@as.ua.edu.
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Notes
The authors declare no competing financial interest.
́
M. Z.; Escudero-Adan, E. C.; Benet-Buchholz, J.; Nolan, S. P.
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ACKNOWLEDGMENTS
■
We thank the National Science Foundation (CHE-1058984)
for financial support of this work, FMC, Lithium Division for
donation of TNpP, and Johnson-Matthey for donation of
palladium compounds. T.M.L. thanks the DAAD-RISE
program.
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