Neopentylphosphines as effective ligands in palladium-catalyzed cross-couplings of aryl bromides and chlorides

Article abstract of DOI:10.1016/j.tet.2008.02.037

The use of neopentylphosphine ligands in the palladium-catalyzed Suzuki, Sonogashira, Heck, and Hartwig-Buchwald couplings of aryl bromides and chlorides are reported. Di-tert-butylneopentylphosphine (DTBNpP) provided highly active catalysts for the coupling of aryl bromides at mild temperatures. Trineopentylphosphine, an air-stable trialkylphosphine, gave inactive catalysts at room temperature, but showed good activity in the H-B amination of aryl chlorides at elevated temperatures.

Full text of DOI:10.1016/j.tet.2008.02.037

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 6920e6934
www.elsevier.com/locate/tet
Neopentylphosphines as effective ligands in palladium-catalyzed
cross-couplings of aryl bromides and chlorides
Lensey L. Hill a, Joanna M. Smith a, William S. Brown a, Lucas R. Moore a, Paul Guevera a,
Emily S. Pair a, Jake Porter a, Joe Chou b, Christopher J. Wolterman b, Raluca Craciun a,
David A. Dixon a, Kevin H. Shaughnessy a,
*
a Department of Chemistry, The University of Alabama, Box 870336, Tuscaloosa, AL 35487-0336, United States
b FMC Corporation, Lithium Division, Hwy 161, Box 795, Bessemer City, NC 28016-0795, United States
Received 25 January 2008; received in revised form 11 February 2008; accepted 12 February 2008
Available online 16 February 2008
Abstract
The use of neopentylphosphine ligands in the palladium-catalyzed Suzuki, Sonogashira, Heck, and HartwigeBuchwald couplings of aryl
bromides and chlorides are reported. Di-tert-butylneopentylphosphine (DTBNpP) provided highly active catalysts for the coupling of aryl bro-
mides at mild temperatures. Trineopentylphosphine, an air-stable trialkylphosphine, gave inactive catalysts at room temperature, but showed
good activity in the HeB amination of aryl chlorides at elevated temperatures.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
While the design of ligands for Pd-catalyzed coupling reac-
tions remains somewhat a trial-and-error enterprise, certain
general concepts have become clear over the past decade. Li-
gands that promote reactions of aryl bromides (<50 ꢀC) and
aryl chlorides (<110 ꢀC) under mild conditions are typically
sterically demanding and strong s donors. Examples of
these types of ligands include sterically demanding trialkyl-
phosphines,10e18 dialkylarylphosphines,19e26 bicyclic triami-
nophosphines,27,28 and N-heterocyclic carbenes.29e37 The
effectiveness of these ligands can be rationalized by consider-
ing the key steps in the generic catalytic cycle (Scheme 1).
The large steric bulk of these ligands promotes ligand dissoci-
ation from the coordinatively saturated PdL2 resting state to
form the highly reactive PdL active species. Sterically de-
manding ligands can also promote reductive elimination and
migratory insertion in cases where these are rate limiting steps.
Electron rich ligands are thought to promote the oxidative ad-
dition step with less reactive substrates, such as aryl chlorides.
On the basis of these trends, we have become interested in
applying neopentylphosphines as ligands in cross-coupling re-
actions. The neopentyl substituent is more sterically demand-
ing than the tert-butyl group, yet it is less electron donating.
Given the importance of ligand size in coupling reactions,
Palladium-catalyzed cross-coupling reactions are one of the
cornerstones of modern synthetic methodology. Despite their
widespread use in academic1 and industrial syntheses,2 there
remains active interest in identifying new catalyst systems
that offer improved activity and stability. Significant advances
have been made in the development of ‘ligand-free’ catalyst
systems, but these catalysts typically require high reaction
temperatures and more reactive aryl bromide or iodide sub-
strates.3,4 In addition, although many of these systems are suc-
cessful for the Suzuki coupling, only a few examples of the
use of ligand free catalyst systems in the more challenging
Heck,5e7 Sonogashira,8,9 and HartwigeBuchwald (HeB) cou-
plings of aryl bromides have been reported. These examples
generally require high temperatures (>120 ꢀC). Ligand sup-
ported catalyst systems are typically required for these more
challenging reactions, particularly when using less reactive
substrates under mild conditions.
* Corresponding author. Tel.: þ1 205 348 4435; fax: þ1 205 348 9104.
E-mail address: kshaughn@bama.ua.edu (K.H. Shaughnessy).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.037

L.L. Hill et al. / Tetrahedron 64 (2008) 6920e6934
6921
L
Pd
L
a suitable substitute for DTBNpP for the Sonogashira, Heck,
and HeB couplings, but not in the Suzuki coupling.
-L
2. Results and discussion
Ar
X
Ar Nu
LPd
2.1. Ligand properties
Ligand steric and electronic properties have been shown to
play important roles in the ability to correlate and predict cat-
alyst activity in a variety of systems. We have previously re-
ported experimentally and computationally derived steric
and electronic properties for a variety of phosphines and cor-
related this data with catalyst activity in cross-coupling reac-
tions.18,41,42 Solid cone angle values were calculated for
DTBMONpP to allow it to be compared with the other neo-
pentylphosphines (Table 1). The cone angle of DTBMONpP
(194ꢀ) was calculated to be smaller than the value calculated
for DTBNpP by 4ꢀ and is identical to the value calculated
for TTBP. The smaller cone angle for DTBMONpP compared
to DTBNpP is consistent with the slightly larger B3LYP BDE
for Pd(DTBMONpP) as compared to the DTBNpP complex.
The relative electronic parameters of DTBMONpP and the
other neopentylphosphines were also compared (Table 1). Ex-
perimentally determined electronic parameters were obtained
from the CO stretching frequency of trans-RhL2(CO)Cl com-
plexes.43 The CO stretching frequencies of the DTBNpP and
DTBMONpP complexes were identical, which suggest that
these two ligands have the same electron donating ability. In
contrast, the calculated electronic parameters for the ligands
and their palladium complexes showed some electronic differ-
ences. The HOMO energy level of DTBMONpP is predicted
to be at lower energy than that of DTBNpP, which would sug-
gest that DTBNpP is a stronger electron donor. The same trend
is observed for the palladium complexes of DTBMONpP and
DTBNpP, although the difference is smaller. We note that the
HOMO on the free phosphine is the P lone pair, whereas the
HOMO on the PdL complex is on the Pd. The HOMO of
a Pd atom is predicted to be ꢁ5.52 eV and complexation
with the ligand increases the HOMO energy in most cases
by about 1 eV. Thus, complexation with the ligand makes
the palladium center a stronger electron donor. We have previ-
ously noted a good correlation between the increasing HOMO
energy levels for the PdL complex and increased catalyst ac-
tivity.18,41,42 Interaction of the ligand with the Pd makes the
highest occupied orbital in the ligand less accessible by about
1 eV. The GAP defined as HOMOeLUMO energy difference
is large in the ligand, w7 eV except for PPh3, where it is just
greater than 5 eV. The gap for the palladium atom is predicted
to be 2.51 eV. The GAP values for the PdL complexes are in-
termediate between those of the free ligand and the free Pd
atom.
L
Ar
X
Pd
Pd
L
Ar Pd
X
L
Ar Pd
Nu
X
Ar
L
MNu
MX
Scheme 1.
introduction of neopentyl substituents may lead to more effec-
tive ligands. Despite the large number of ligands that have
been studied in palladium-catalyzed cross-coupling reactions,
neopentylphosphines have received limited attention.38,39 We
have previously reported the use of di-tert-butylneopentyl-
phosphine (DTBNpP, Fig. 1) and other analogous neopentyl-
phosphines in the HeB coupling of aryl bromides and
chlorides.18 DTBNpP was found to give catalysts with better
activity than those derived from tri-tert-butylphosphine
(TTBP) for the amination of aryl bromides, but the
DTBNpP-derived catalysts were less effective in couplings
of aryl chlorides. DTBNpP and TNpP gave less active cata-
lysts for the amination of aryl bromides.
We now report the use of neopentylphosphines in Suzuki,
Heck, Sonogashira, and HeB coupling of aryl bromides and
chlorides. DTBNpP has been found to be an effective ligand
for the coupling of aryl bromides in each of these reactions.
Surprisingly, the more sterically demanding and less electron
donating TNpP ligand gave catalysts with good activity in
the HeB amination of aryl chlorides. We also report the use
of a new ligand, di-tert-butyl-(3-methoxy-2,2-dimethylpro-
pyl)phosphine (DTBMONpP), which is a methoxy-substituted
analog of DTBNpP. This ligand offers some potential advan-
tages over DTBNpP. The oxygen of DTBMONpP provides
a point of attachment for the addition of solubility control el-
ements, such as hydrophilic groups. In addition, DTBMONpP
is expected to be less expensive to produce than DTBNpP,
since the 3-chloro-2,2-dimethylpropanol precursor is approxi-
mately an order of magnitude less expensive than 3-chloro-
2,2-dimethylpropane.40 DTBMONpP has been found to be
t-Bu
t-Bu
t-Bu
t-Bu
P
OMe
P
t-Bu
t-Bu
P
t-Bu
t-Bu
TTBP
DTBNpP
DTBMONpP
Many trialkylphosphines, such as tri-tert-butylphosphine,
are classified as pyrophoric in pure form and rapidly oxidize
in solution. This air-sensitivity makes them inconvenient to
handle. Conversion to the air-stable phosphonium salts can
overcome this problem, however,45 DTBNpP, like TTBP, is
highly air-sensitive. After exposure of DTBNpP to air for
t-Bu
t-Bu
P
P
t-Bu
t-Bu
t-Bu
t-Bu
TNpP
TBDNpP
Figure 1.

6922
L.L. Hill et al. / Tetrahedron 64 (2008) 6920e6934
Table 1
Steric and electronic parameters of phosphine ligands
b
c
d
Ligand
Cone
anglea (ꢀ)
nCO (cmꢁ1
)
BDEPdeP
(kcal/mol)
RPdeH
˚
(A)
Free ligand
Pd0L complex
q(P)e
HOMOf (eV)
GAPg (eV)
q(P)e
HOMOf
Pd (eV)
HOMOh
PLP (eV)
GAPg (eV)
TTBP
194
198
194
210
227
182
177
173
1921i
1939
1939
1946
1950
1946j
1953j
1978j
37.3
35.8
36.2
35.2
33.7
38.7
39.2
37.1
2.69
2.41
2.47
2.32
2.38
2.93
3.06
3.07
0.34
0.36
0.34
0.36
0.36
0.36
0.40
0.35
ꢁ5.66
ꢁ5.74
ꢁ5.84
ꢁ5.85
ꢁ5.86
ꢁ5.87
ꢁ5.99
ꢁ5.98
7.20
7.03
7.18
7.01
7.04
7.04
7.31
5.13
0.47
0.53
0.51
0.55
0.57
0.54
0.60
0.47
ꢁ4.51
ꢁ4.50
ꢁ4.63
ꢁ4.52
ꢁ4.46
ꢁ4.64
ꢁ4.66
ꢁ4.91
ꢁ8.07
ꢁ8.08
ꢁ8.10
ꢁ8.20
ꢁ8.20
ꢁ8.22
ꢁ8.39
ꢁ6.96
3.33
3.27
3.32
3.24
3.16
3.47
3.48
3.42
DTBNpP
DTBMONpP
TBDNpP
TNpP
(i-Pr)3P
(n-Bu3)P
Ph3P
a
Cone angle values determined from LDFT-optimized LPd(0) structures using the STERIC program.
Carbonyl stretching frequency measured in solution of in situ prepared trans-(L)2Rh(CO)Cl complex.
Calculated at the DFT level with the B3LYP exchange-correlation functional at the LDA optimized geometries.
Closest non-bonded PdeH distances.
Calculated charge on the phosphorus atom.
b
c
d
e
f
HOMO energy at the B3LYP level.
GAP¼HOMOꢁLUMO energy difference.
g
h
i
Energy of P lone pair orbital.
Estimated using the reported value for Ni(TTBP)(CO)3 and the correlation reported by Vastag et al.43
44
j
Literature values.43
3 h, 75% of the DTBNpP had been oxidized as determined by
1H NMR spectroscopy (Fig. 2). After 6 h, nearly 90% of the
DTBNpP had been oxidized, while no DTBNpP was present
after exposure to air for 30 h. TBDNpP showed a similar, al-
though slower, rate of decomposition upon exposure to air. Af-
ter 3 h, only 56% of the phosphine remained, while 28%
remained after 30 h. In contrast, TNpP is quite stable in air,
both as a solid and in solution. A pure sample of TNpP was
exposed to air for 9 days, after which the percentage of
TNpP in the sample had remained essentially unchanged (97
to 96.7%). A solution of TNpP in toluene (10 wt %) also
showed no evidence of oxidation after exposure to air for
24 h. This degree of air stability is unusual for a simple trial-
kylphosphine. The air stability of TNpP compared with
DTBNpP may be explained in part by the lower electron do-
nating ability of TNpP as determined both by the measured
nCO values and the calculated HOMO energies for these two
ligands. TBDNpP has similar calculated electronic parameters
to TNpP, yet is also much less air-stable. Thus electronic
properties do not appear to be the sole explanation. Steric
shielding of the lone pair in TNpP, which has a much larger
cone angle than TBDNpP, may also contribute to the stability
of TNpP.
2.2. Application in palladium-catalyzed coupling reactions
We have previously reported that DTBNpP in combination
with Pd2(dba)3 gave a highly efficient catalyst for the amina-
tion of aryl bromides under mild conditions.18 In direct com-
parisons, DTBNpP gave a more active catalyst than TTBP.
DTBNpP gave active catalysts for the coupling of aryl chlo-
rides at elevated temperatures, although higher temperatures
and/or catalysts loadings were required than had been reported
with TTBP. TBDNpP gave a lower activity catalyst for the
amination of aryl bromides than DTBNpP, whereas catalysts
derived from TNpP were ineffective.
2.2.1. Suzuki coupling of aryl halides
Catalysts derived from DTBNpP, TBDNpP, and TNpP all
gave effective catalysts for the Suzuki coupling of aryl bro-
mides in the presence of sodium carbonate in a 1:1 mixture
of THF/water (Table 2). DTNpP- and TBDNpP-derived cata-
lysts gave high yields for Suzuki coupling reactions at room
temperature, even with an electron rich aryl bromide (1c). 2-
Bromotoluene (1d) gave good yields at room temperature as
well, but 2-bromo-m-xylene (1e) gave no product, even at el-
evated temperatures. The catalyst derived from TNpP gave
a good yield at room temperature with an activated aryl bro-
mide (1a), but gave no reaction with non-activated or unacti-
vated aryl bromides at room temperature. At 80 ꢀC, TNpP/
Pd2(dba)3 did give good yields for the coupling of 1c and
1d. The catalyst derived from DTBMONpP was not active
for the Suzuki coupling of aryl bromides, despite having sim-
ilar structural and electronic properties to those of DTBNpP.
Figure 2. Decomposition of trialkylphosphines in air as determined by 1H
NMR spectroscopy; DTBNpP (diamond), TBDNpP (square), TNpP (triangle).

L.L. Hill et al. / Tetrahedron 64 (2008) 6920e6934
6923
Table 2
Suzuki coupling of aryl halides using neopentylphosphines
X
Ar
Pd2(dba)3(0.5 mol%)
L (1 mol%)
+ Ar(B(OH)2
Entry 1/2
3
4
Ligand
T (ꢀC) Yielda
(%)
Na2CO3
1:1 THF/H2O, T °C
Rn
Rn
3a-c
4
1a-d
2a-b
DTBNpP
TBDNpP
TNpP
23
23
23
94
94
84
1
2
1a
3a
NC
O
1: X = Br
3a: Ar = Ph
1a: R = 4-CN
1b: R = 4-Ac
1c: 4-OMe
1d: 2-Me
3b: Ar = 4-FC6H4
3c: Ar = 2,4-F2C6H3
DTBNpP
TBDNpP
23
23
91
98
1b 3a
Me
2: X = Cl
1e: 2,6-Me2
1f: 2-Cl
2a: R = CN
2b: R = OMe
DTBNpP
TBDNpP
TNpP
23
23
80
99
99
85
3
4
1c
3a
MeO
2.2.2. Sonogashira coupling of aryl bromides
Me
DTBNpP
TBDNpP
TNpP
23
23
80
95
93
99
The neopentylphosphines were screened for their ability to
promote the Sonogashira coupling of 4-bromotoluene (1g) and
phenylacetylene (5a) using Pd2(dba)3 (2 mol % Pd, 2:1 L/Pd),
CuI (2 mol %), and triethylamine in toluene. The catalyst de-
rived from DTBNpP gave complete conversion to product in
4 h (Fig. 3). The TBDNpP-derived catalyst showed compara-
ble activity to the DTBNpP system after 1 h, but gave little
conversion after that time. No conversion was observed with
the TNpP-derived catalyst.
Based on the success of the DTBNpP/Pd2(dba)3 system,
couplings of aryl bromides with phenylacetylene were carried
out (Table 3). Similar yields were obtained with activated (1b)
and deactivated aryl bromides (1c). The DTBMONpP/
Pd2(dba)3 catalyst system also gave good yields in these reac-
tions. In most cases, the yields were nearly identical for
DTBNpP and DTBMONpP. Good yields were also obtained
with a moderately sterically hindered aryl bromide (1d). No
conversion to product occurred in attempts to couple 2-
bromo-m-xylene (1e) and phenylacetylene at 80 ꢀC using the
catalysts derived from DTBNpP or DTBMONpP, however.
1d 3a
Me
Me
DTBNpP 23
DTBNpP 100
0
0
5
6
1e
1c
3a
3b
DTBNpP
23
80
MeO
F
F
MeO
7
8
1c
1f
3c
3a
DTBNpP
TNpP
23
23
95
97
F
Cl
TBDNpP
TBDNpP
TNpP
23
23
23
73
99
99
9
2a
3a
NC
DTBNpP 100
TBDNpP 100
40
78
80
10
2b 3a
MeO
TNpP
100
a
Average isolated yield of two trials agreeing within 5%.
Pd2(dba)3 (1.5%)
L (4.75%)
Br
R'
Rn
Based on the performance in other coupling reactions (vide in-
fra), this result is surprising. We do note that the HOMO of the
PdL complex is calculated to be at lower energy for
DTBMONpP as compared to DTBNpP, but it is unclear if
this difference is responsible for the failure of this ligand in
the Suzuki coupling.
CuI (2%)
+
HC
C Ph
Et3N (1.25 equiv)
toluene, rt
Rn
5a
6
1b-e,g
1b: R = 4-Ac
1c: R = 4-OMe
1d: R = 2-Me
1e: R = 2,6-Me2
1g: R = 4-Me
Catalysts derived from the neopentylphosphine ligands
showed modest activity toward aryl chlorides. Good yields
of coupled products were obtained in the coupling of an acti-
vated aryl chloride (2a) with phenylboronic acid using all
three ligands, although the catalyst derived from DTBNpP
gave a lower isolated yield than the catalysts employing
TBDNpP or TNpP. Higher temperatures were required with
a deactivated aryl chloride (2b). Again, the catalyst derived
from DTBNpP gave a lower yield than those derived from
TBDNpP or TNpP. These results are surprising, since
TBDNpP and TNpP are less electron donating than DTBNpP,
which would suggest that they should give less effective
catalysts for the coupling of aryl chlorides. Coupling of aryl
chlorides would be expected to be promoted by a more
electron rich ligand if oxidative addition is the rate limiting
step.
Attempts to extend the scope of the reaction to alkyl-
substituted alkynes gave slow conversion rates and modest
yields. Further optimization showed that the catalyst derived
from Pd(PhCN)2Cl2 was more effective than that derived
from Pd2(dba)3 and that diisopropylamine was the optimal
base.46 The DTBNpP- and DTBMONpP-derived catalysts
gave similar yields for most combinations of substrates (Table
4). The catalyst derived from DTBMONpP gave measurably
lower yields in the coupling of 4-bromoanisole with 1-hexyne
and TMS/acetylene than did the DTBNpP system, however.
The catalysts derived from DTBNpP and DTBMONpP were
inactive for the Sonogashira coupling of aryl chlorides even
at high temperature (100 ꢀC, 3 mol % Pd).

6924
L.L. Hill et al. / Tetrahedron 64 (2008) 6920e6934
Table 4
Sonogashira coupling of aryl bromides with aliphatic alkynes
Pd(PhCN)2Cl2 (3%)
L (6%)
Br
R'
Rn
CuI (2%)
Yielda (%)
95
+
HC
C R'
Entry
1
5
6
Ligand
Rn
(i-Pr)2NH (1.2 equiv)
dioxane, rt
5b-d
Me
1b-e,g
6
C4H9
TMS
1
1a 5b
1a 5c
1a 5d
1c 5b
DTBNpP
O
Me
1b: R = 4-Ac
1c: R = 4-OMe
1d: R = 2-Me
1e: R = 2,6-Me2
1g: R = 4-Me
5b: R = C4H9
5c: R = TMS
5d: R = -CH2CH2OH
2
3
4
DTBNpP
97
O
Me
OH
DTBNpP
DTBNpP
93
92
O
C4H9
TMS
MeO
DTBMONpP 79
DTBNpP 97
DTBMONpP 66
5
6
1c 5c
1c 5d
MeO
OH
DTBNpP 90
DTBMONpP 99
MeO
Me
Me
DTBNpP 87
DTBMONpP 85
7
8
1d 5b
1d 5c
C4H9
DTBNpP 81
DTBMONpP 91
TMS
Me
DTBNpP 86
DTBMONpP 77
OH
9
1d 5d
Figure 3. Coupling of 4-bromotoluene with phenylacetylene Pd2(dba)3
(1 mol %), ligand (4 mol %), CuI (2 mol %), and trimethylamine; DTBNpP
(square), TBDNpP (triangle), TNpP (circle).
a
Average isolated yield of two trials agreeing within 5%.
the more electron rich 4-bromo-N,N-dimethylaniline (1h)
gave complete conversion to product at 80 ꢀC. Aryl halides
with ortho-substituents were unreactive toward styrene using
these catalyst systems. TBDNpP and TNpP gave modestly ac-
tive catalysts for the coupling of 1c with styrene at 100 ꢀC.
The isolated yields decreased with increasing numbers of neo-
pentyl substituents.
2.2.3. Heck coupling of aryl bromides
The Heck coupling of aryl bromides using the DTBNpP
and DTBMONpP catalyst systems required higher reaction
temperatures than the Suzuki or Sonogashira coupling. Elec-
tron-deficient and non-activated aryl bromides gave good
yields when coupled with styrene at 80 ꢀC (Table 5). 4-Bro-
moanisole (1c) required a higher reaction temperature
(100 ꢀC) to give complete conversion to product, although
Ph
Br
Pd2(dba)3 (1.5%)
DTBNpP (3%)
Table 3
Sonogashira coupling of aryl bromides with phenylacetylene
+
Ph
Cy2NMe
Rn
Rn
dioxane, 80-100 °C
Entry
1
6
Ligand
Yielda (%)
1a-d,g,h
7
1a: R = 4-CN
1b: R = 4-Ac
1c: R = 4-OMe
1d: R = 2-Me
1g: R = 4-Me
1h: R = 4-NMe2
Me
O
DTBNpP
DTBMONpP
85
97
1
1a
2
3
1g
1c
DTBMONpP
99
Me
DTBNpP
DTBMONpP
95
98
MeO
2.2.4. HeB coupling of aryl bromides
In our previous report, we found that DTBNpP in combina-
tion with palladium sources gave a catalyst for the coupling of
aryl bromides with amines that gave similar or higher activity
to the catalyst derived from TTBP.18 These reactions could be
carried out at room temperature, with the exception of the cou-
pling of secondary alkyl amines, which required a reaction
temperature of 50 ꢀC in order to go to completion within
a few hours. Catalysts derived from TBDNpP and TNpP
were ineffective in these reactions.
Me
DTBNpP
DTBMONpP
93
97
4
1d
1e
Me
Me
DTBNpP
DTBMONpP
0b
0b
5
a
Average isolated yield of two trials agreeing within 5%.
Reaction carried out at 80 ꢀC.
b

L.L. Hill et al. / Tetrahedron 64 (2008) 6920e6934
6925
Table 5
Heck coupling of aryl bromides using neopentylphosphines
Table 6
HeB amination of aryl bromides catalyzed by DTBMONpP/Pd
Entry
1
7
Ligand
Yielda (%)
Entry
1
1
8
9
T (ꢀC)
Yielda (%)
90 (84)b
H
N
DTBNpP
DTBMONpP
64
79
NC
O
1
1a
1i
8a
50
Ph
F
DTBNpP
DTBMONpP
86
84
H
2
3
1b
1g
N
95 (86)b
89 (92)b
92 (78)b
Me
Ph
2
3
4
1g
1c
1h
8a
8a
8a
50
50
50
DTBNpP
DTBMONpP
75
75
Me
Me
H
Ph
N
DTBNpP
DTBMONpP
TBDNpP
TNpP
76b
83b
67b
36b
MeO
H
N
MeO
Me2N
4
5
1c
Ph
Me2N
DTBNpP
DTBMONpP
89
67
1h
1d
Me
H
N
Ph
5
6
1d
1g
8a
8b
50
23
84 (79)b
97 (60)
Me
DTBNpP
DTBMONpP
0
0
6
Me
H
N
Ph
a
Average isolated yield of two trials agreeing within 5%.
Reaction carried out at 100 ꢀC.
b
Me
Me
Me
Me
N
7
8
1c
8c
8c
23
23
73 (89)
73 (90)
In order to determine what effect, if any, the methoxy sub-
MeO
stituent would have on catalyst activity in the HeB amination,
we have repeated a number of the amination reactions previ-
ously reported with DTBNpP (Table 6). The catalyst derived
from DTBMONpP and Pd2(dba)3 gave similar yields to that
derived from DTBNpP, although there were some noticeable
differences in the optimal conditions required by these cata-
lysts. In the DTBNpP system, coupling of aryl bromides and
aniline could be accomplished at room temperature. In con-
trast, the DTBMONpP-derived catalyst gave very slow conver-
sion at room temperature, although the reactions could be
completed within a few hours at 50 ꢀC. The opposite situation
was found with morpholine. In the case of DTBNpP, the
reactions were carried out at 50 ꢀC in order to give complete
conversion within a few hours. In contrast, the DTBMONpP-
derived catalyst gave good activity for these coupling reactions
at room temperature. Similar yields (within 10%) were
obtained in reactions using DTBMONpP and DTBNpP for a
variety of aryl bromide and amine substrates. The one excep-
tion to this trend was in the coupling of a sterically hindered
aniline derivative (2b). The yield obtained with this substrate
was 30% higher when using the DTBMONpP-derived catalyst
system compared to the catalyst derived from DTBNpP. It is
possible that the slightly smaller size of DTBMONpP com-
pared to DTBNpP allowed the arylations of 8b to proceed
more efficiently. In contrast, the catalyst derived from
DTBNpP gave higher yields than the DTBMONpP catalyst
system in the arylations of N-methylaniline (8c).
Me
Me
N
1d
9
1i
8d
8d
8d
23
23
23
85
F
N
N
O
10
11
1g
1c
83 (89)c
90 (97)c
Me
O
MeO
N
O
12
1h
1d
8d
8d
23
23
95 (89)c
96 (93)c
Me2N
N
O
Me
13
N
O
a
Average isolated yield of two trials agreeing within 5%. Values in paren-
theses are yields obtained using DTBNpP.18
b
DTBNpP reaction carried out at room temperature.
DTBNpP reaction carried out at 50 ꢀC using Pd(OAc)2.
c
after 30 min, but showed only slow conversion after this time.
The TNpP catalyst showed no activity over the first 30 min, af-
ter which it gave a small amount of product. When the com-
parison was repeated at 100 ꢀC (Fig. 5), both the DTBNpP
and DTBMONpP systems gave complete conversion after
1 h, although the DTBNpP system reached completion slightly
sooner. The TNpP system again showed an induction period
and a slower overall rate of conversion than the other two li-
gands. After 75 min, the TNpP reaction had reached about
75% conversion with the catalyst continuing to show good
activity.
We had previously shown that the DTBNpP/Pd catalyst sys-
tem gave modest yields for the amination of aryl chlorides at
elevated temperatures. Based on the unexpected effectiveness
of TNpP in the Suzuki coupling of aryl chlorides, we com-
pared the activity of the TNpP catalyst system with those of
DTBNpP and DTBMONpP. At 75 ꢀC (Fig. 4), the DTBNpP
and DTBMONpP catalyst systems gave about 50% conversion
It is interesting to note that the TNpP/Pd2(dba)3 catalyst
shows little to no activity in the coupling of aryl bromides at
room temperature. At 100 ꢀC, this catalyst shows good activity

6926
L.L. Hill et al. / Tetrahedron 64 (2008) 6920e6934
Pd2(dba)3 (0.5 mol%)
DTBMONpP (1 mol%)
NaOt-Bu
NR'R"
Br
+ HNR'R"
Toluene
23 - 50 °C
Rn
Rn
1c,d,g-i
8a-d
9
8a: aniline
1c: R = 4-OMe
1d: R = 2-Me
1g: R = 4-Me
1h: R = 4-NMe2
1i: R = 4-F
8b: mesityl amine
8c: N-methylaniline
8d: morpholine
for the coupling of aryl chlorides, however. The observation of
an induction period with the TNpP/Pd2(dba)3 catalyst systems
suggests that formation of the catalytically active species in-
volves a step that is slow even at 80 ꢀC. The complete absence
of activity at room temperature using TNpP may indicate that
the active catalyst cannot be formed with TNpP as the ligand
at this temperature. In the DTBNpP/Pd2(dba)3 systems, forma-
tion of the active species occurs rapidly at room temperature,
as an induction period has not been seen with this catalyst sys-
tem.18 Given the very large cone angle for TNpP, it is tempting
to suggest that the induction period is due to the slow forma-
tion of Pd(TNpP)2 from Pd2(dba)3. Initial studies of the com-
plexation of DTBNpP, TBDNpP, and TNpP with Pd2(dba)3
have shown that the ligand substitution occurs at approxi-
mately the same rate with all three ligands. Another possible
explanation would be that Pd(TNpP)2 does not readily un-
dergo ligand dissociation to form the active Pd(TNpP) species
(Scheme 1). This hypothesis is inconsistent with the fact that
TNpP has a lower calculated BDE than DTBNpP, however;
if the BDEs for the PdL2 complex track those for the PdL
complex. It is also possible that the induction period represents
the conversion of the Pd(TNpP)2 species into an as yet uniden-
tified active species, rather than the Pd(TNpP) expected based
on the mechanism in Scheme 1.
Figure 5. Reaction profile in the coupling of 4-chloroanisole with aniline at
100 ꢀC using Pd2(dba)3 (0.5 mol %), ligand (1 mol %); DTBNpP (square),
DTBMONpP (diamond), TNpP (triangle).
TNpP (Table 7). The catalyst derived from DTBMONpP
was found to be effective for the coupling of aryl chlorides
and amines. In the amination of 4-chloroanisole, the
DTBMONpP catalyst gave similar or better efficiency than
Table 7
HeB amination of aryl chlorides using neopentylphosphines
Entry
2
8
9
% Pd T (ꢀC) Ligand
Yielda (%)
89b
Ph
HN
1
1
1
140
110
110
DTBNpP
DTBMONpP 94
1
2b 2a
TNpP
70
OMe
Ph
MeN
5
4
4
100
120
120
DTBNpP
DTBMONpP 78
99b
Based on the promising results at 100 ꢀC, we carried out
preparative scale couplings of two challenging aryl chloride
substrates, 4-chloroanisole and 2-chloroanisole, with aniline,
N-methylaniline, and morpholine using DTBMONpP and
2
3
2b 2d
TNpP
92
OMe
O
N
5
2
2
80
120
120
DTBNpP
DTBMONpP 97
79b
2b 2e
TNpP
90
OMe
HN
Ph
Ph
1
1
1
120
110
110
DTBNpP
DTBMONpP 94
95b
Me
Me
4
5
2c 2a
TNpP
87
MeN
1
2
2
120
120
120
DTBNpP 89
DTBMONpP 89
2c 2d
TNpP
63
O
N
1
2
2
120
120
120
DTBNpP
90
6
2c 2e
DTBMONpP 98
TNpP 90
Me
Figure 4. Reaction profile in the coupling of 4-chloroanisole with aniline at
75 ꢀC using Pd2(dba)3 (0.5 mol %), ligand (1 mol %); DTBNpP (square),
DTBMONpP (diamond), TNpP (triangle).
a
Average isolated yield of two trials agreeing within 5%.
Previously published results.18
b

L.L. Hill et al. / Tetrahedron 64 (2008) 6920e6934
6927
the DTBNpP catalyst. In the coupling of 4-chloroanisole with
aniline, the DTBNpP catalyst system showed little activity be-
low 140 ꢀC, while excellent yields were obtained at 110 ꢀC
with the DTBMONpP catalyst. In the case of morpholine,
the DTBMONpP catalyst gave the best yield using 2 mol %
Pd at 120 ꢀC, while the DTBNpP system required 5 mol %
Pd, although at lower temperature (80 ꢀC). In the case of
DTBNpP, lower catalyst loadings were ineffective even if
the reaction temperature was raised to 120 ꢀC. DTBMONpP
also gave effective catalysts for the coupling 2-chlorotoluene
with 8aec under similar conditions to those used for 4-
chloroanisole.
As suggested by the comparative rate studies, TNpP gave
an effective catalyst for the amination of aryl chlorides at ele-
vated temperatures. Although Figure 5 shows that the TNpP-
derived catalyst is less active than the DTBNpP-derived cata-
lyst, comparable yields were obtained in most cases when the
reactions were allowed to proceed for several hours. The
TNpP-derived catalyst gave significantly lower yields than
the DTBNpP and DTBMONpP systems in two cases: the cou-
pling of 4-chloroanisole and aniline, and the coupling of 2-
chlorotoluene and N-methylaniline. In the coupling of 4-chloro-
anisole and N-methylaniline, the TNpP-derived catalyst gave
a measurably higher yield than the DTBMONpP-derived
catalyst.
In summary, DTBNpP provides effective catalysts for the
Suzuki, Sonogashira, HartwigeBuchwald, and Heck cou-
plings of aryl bromides. With the exception of the Heck cou-
pling, the reactions can be carried out at room temperature.
The TBDNpP and TNpP ligands give less active catalysts
for couplings of aryl bromides at room temperature than
DTBNpP, with the exception of the Suzuki coupling. The
lower activity of catalysts derived from these ligands is likely
due to a combination of the larger size and the decreased elec-
tron donating ability of TBDNpP and TNpP. While we have
previously seen a good correlation between larger cone angle
and increased catalyst activity,41,42 catalyst activity appears to
drop off at cone angles larger than 205ꢀ.18 The decrease in
catalyst effectiveness with very large ligands may be due to a
decrease in catalyst activity due to steric congestion, or may
reflect decreased catalyst stability resulting in shorter catalyst
lifetimes. Further studies of the role of ligand sterics on cata-
lyst activity and lifetime are ongoing. The disparity in activity
between DTBNp and TNpP disappears at elevated tempera-
tures. Thus at 100 ꢀC, TNpP provides a catalyst with compa-
rable activity the DTBNpP-derived catalyst for the HeB
amination of aryl chlorides. Although the TNpP-derived
catalyst is less general than the DTBNpP system, the air stabil-
ity of TNpP may make it an attractive ligand in some
applications.
provided by FMC Lithium in pure form. DTBMONpP and
the ligand solutions were stored in a dry box under nitrogen.
Toluene was distilled from molten sodium and then degassed
under vacuum prior to use. THF was distilled from a sodium/
benzophenone ketyl and degassed under vacuum prior to use.
Deionized water used as a reaction solvent was deoxygenated
by sparging with nitrogen gas for at least 15 min prior to use.
All other reagents were obtained from commercial sources and
were used as received.
3.2. Computational determination of ligand properties
Geometries of Pd0L complexes were optimized at the
LDFT level with the polarized double-z DZVP2 basis set on
all atoms except Pd.47 We used the Stuttgart relativistic pseu-
dopotential and the associated basis set for Pd48 with 28 elec-
trons in the core of the ECP. The basis set for Pd was
contracted to [6s5p3d]. The LDFT calculations were done
with the potential fit of Vosko, Wilk and Nusair for the corre-
lation functional49 and the exchange functional of Slater.50
The calculations were done with the program Gaussian 0351
on Cray XD-1 and Silicon Graphics Altix computers at the
Alabama Supercomputing Center. The bond dissociation ener-
gies (BDE¼EPdþELꢁEPdL) were calculated at the LDA geom-
etries with the B3LYP exchange-correlation functional52,53
and above basis set. Cone angle values for TPPTS, TXPTS,
and TMAPTS were calculated from the LDA optimized geom-
etries for the Pd0(phosphine) complexes by using the STERIC
program and the volumetric parameters for the atoms therein
with the Pd atom set at the origin.54,55
3.3. General procedure for the Suzuki coupling of aryl
bromides
In a dry box, a 1 dram vial was charged with Pd2(dba)3
(0.005 mmol, 4.58 mg), ligand (0.01 mmol), arylboronic acid
(1.1 mmol), Na2CO3 (1.1 mmol, 116.0 mg), aryl halide
(1 mmol), and THF (1 mL). The vial was then removed from
the dry box and charged with deoxygenated water (1 mL). The
reaction mixture was stirred at room temperature until judged
complete by GC. Reactions carried out at elevated temperatures
were stirred in an oil bath preheated to the desired temperature.
Ethyl acetate (25 mL) was added to the reaction mixture, which
was then washed with 2ꢂ25 mL portions of brine. The organic
layer was dried over MgSO4 and the solvent removed under re-
duced pressure. The crude products were purified using flash
chromatography through a short plug of silica gel using a gradi-
ent mixture of hexanes and ethyl acetate (100:0e85:15 hexane/
EtOAc) as the eluent. All products were spectroscopically pure
and consistent with previously reported spectra.
3. Experimental
3.3.1. 4-Cyanobiphenyl (Table 2, entries 1 and 9)20
4-Bromobenzonitrile (1.00 mmol, 181 mg) and phenylboro-
nic acid (1.30 mmol, 161 mg) were coupled under the general
procedure. The product was isolated as a cream-colored solid
(DTBNpP: 94%, 174 mg; TBDNpP: 94%, 174 mg; TNpP:
84%, 155 mg). 1H NMR (500 MHz, CDCl3): d 7.72 (d,
3.1. General experimental details
DTBNpP, TBDNpP, and TNpP were obtained from FMC
Lithium as 10 wt % solutions in toluene. DTBMONpP was

6928
L.L. Hill et al. / Tetrahedron 64 (2008) 6920e6934
J¼8.2 Hz, 2H), 7.68 (d, J¼8.2 Hz, 2H), 7.58 (t, J¼6.5 Hz,
2H), 7.47 (t, J¼6.5 Hz, 2H), 7.41 (t, J¼7.2 Hz, 1H). 13C
NMR (126 MHz, CDCl3): d 145.7, 139.2, 132.6, 129.1, 128.7,
127.7, 127.2, 118.9, 110.9. Mp: 83e84 ꢀC (lit. Mp: 86e
87 ꢀC).
Alternatively, 4-chlorobenzonitrile (1.00 mmol, 138 mg)
was coupled with phenylboronic acid (1.30 mmol, 161 mg)
to give the product in 73% yield (190 mg) using DTBNpP,
99% yield (192 mg) using TBDNpP, and 99% yield (203 mg)
using TNpP.
128.2 (d, J¼7.3 Hz), 128.0, 115.5 (d, J¼21.0 Hz), 114.3,
55.4. Mp: 86e87 ꢀC (lit. Mp 84e86 ꢀC).
3.3.6. 2,4-Difluoro-40-methoxybiphenyl (Table 2, entry 7)60
2,4-Difluorophenylboronic acid (1.10 mmol, 174 mg) and
4-bromoanisole (1 mmol, 125 mL) were coupled under the
general procedure using DTBNpP. The product was isolated
in a 95% yield as a white solid (220.0 mg). 1H NMR
(500 MHz, CDCl3): d 7.44 (dd, J¼1.87, 7.04 Hz, 2H), 7.38
(m, 1H), 6.98 (d, J¼8.9 Hz, 2H), 6.92 (m, 1H), 6.89 (m,
1H), 3.85 (s, 3H). 13C NMR (126 MHz, CDCl3): d 161.8
(dd, J¼11.9, 247.4 Hz), 160.8 (dd, J¼11.9, 237.4 Hz), 159.2,
131.1 (dd, J¼5.49 Hz), 129.9 (d, J¼2.7), 127.3 (d, J¼1.8,),
125.0 (dd, J¼3.7, 13.7 Hz), 114.0, 111.4 (dd, J¼3.67,
21.1 Hz), 104.3 (dd, J¼25.7 Hz), 55.2.
3.3.2. 40-Phenylacetophenone (Table 2, entry 2)56
4-Bromoacetophenone (1.00 mmol 199 mg) and phenylboro-
nic acid (1.30 mmol, 161 mg) were coupled under the general
procedure. The product was isolated as a white solid
(DTBNpP: 91%, 186 mg; TBDNpP: 98%, 192 mg). 1H
NMR (500 MHz, CDCl3): d 8.02 (d, J¼8.4 Hz, 2H), 7.67 (d,
J¼8.5 Hz, 2H), 7.61 (d, J¼7.2 Hz, 2H), 7.46 (t, J¼6.9 Hz,
2H), 7.39 (t, J¼7.2 Hz, 1H), 2.62 (s, 3H). 13C NMR
(126 MHz, CDCl3): d 197.6, 145.7, 139.8, 135.8, 128.8,
128.7, 128.1, 127.2, 127.1, 26.7. Mp: 116e118 ꢀC (lit. Mp:
120e121 ꢀC).
3.3.7. 2-Chlorobiphenyl (Table 2, entry 8)61
Phenylboronic acid (1.30 mmol, 160 mg) and 2-bromo-
chlorobenzene (1 mmol, 122 mL) were coupled under the gen-
eral procedure using TNpP. The product was isolated in 97%
yield as a low-melting, tan solid. GC/MS: 188 (100%), 190
(33%). 1H NMR (360 MHz, CDCl3): d 7.46 (m, 9H). 13C
NMR (126 MHz, CDCl3): d 140.6, 139.5, 132.6, 131.5, 130.0,
129.5, 128.6, 128.1, 1277, 126.9.
3.3.3. 4-Methoxybiphenyl (Table 2, entries 3 and 10)57
4-Bromoanisole (1 mmol, 125 mL) and phenylboronic acid
(1.30 mmol, 161 mg) were coupled under the general proce-
dure. The product was isolated as a white solid (DTBNpP:
99%, 183 mg; TBDNpP: 94%, 174 mg; TNpP: 85%, 156 mg
3.4. General procedure for the Sonogashira coupling of aryl
halides with phenylacetylene
1
at 80 ꢀC). H NMR (500 MHz, CDCl3): d 7.56 (d, J¼7.2 Hz,
In a dry box, Pd2(dba)3 (0.012 mmol, 11.0 mg), CuI
(0.016 mmol, 3.1 mg), DTBNpP (0.038 mmol, 84.8 mL of
a 10 wt % solution) or DTBMONpP (0.03 mmol, 8.7 mL),
and toluene (1 mL) were combined in a septa topped vial.
The reaction mixture was removed from the dry box and the
aryl halide (0.8 mmol), alkyne (1.0 mmol), and triethylamine
(1.00 mmol, 135 mL) were added via syringe. The mixture
was stirred at room temperature for several hours and moni-
tored by TLC or GC. Upon completion, the product was puri-
fied by flash chromatography using a mixture of ethyl acetate
and hexanes as the eluent. All products were spectroscopically
pure and consistent with previous reported spectra.
2H), 7.52 (d, J¼8.8 Hz, 2H), 7.40 (t, J¼10.9 Hz, 1H), 7.29
(t, J¼7.5 Hz, 2H), 6.97 (d, J¼8.8 Hz, 2H), 3.83 (s, 3H). 13C
NMR (126 MHz, CDCl3): d 159.1, 140.9, 133.8, 128.8,
128.2, 126.8, 126.7, 114.2, 55.4.
Alternative, 4-chloroanisole (1.0 mmol 122 mL) and phe-
nylboronic acid (1.30 mmol, 161 mg) were coupled under
the general procedure, but at 100 ꢀC using dioxane in place
of toluene (DTBNpP: 40% (GC); TBDNpP: 78%, 154 mg;
TNpP: 80%, 156 mg).
3.3.4. 2-Methylbiphenyl (Table 2, entry 4).58
2-Bromotoluene (1.0 mmol, 120 mL) and phenylboronic
acid (1.30 mmol, 161 mg) were coupled under the general pro-
cedure. The product was isolated as a translucent liquid
(DTBNpP: 95%, 161 mg; TBDNpP: 93%, 158 mg; TNpP:
3.4.1. 40-(Phenylethynyl)acetophenone (Table 3, entry 1)62
The above procedure was carried out using 4-bromoaceto-
phenone (0.80 mmol, 159 mL) and phenylacetylene
(0.96 mmol, 105 mL). The crude product mixture was purified
by column chromatography (2:98 EtOAc/hexanes) to afford the
product as a gray solid (DTBNpP: 149 mg, 83%; DTBMONpP:
170 mg, 97%). 1H NMR (500 MHz, CDCl3): d 7.95 (d,
J¼8.5 Hz, 2H), 7.63 (d, J¼8.5 Hz, 2H), 7.57 (m, 2H), 7.39
(m, 3H), 2.63 (s, 3H). 13C NMR (90.6 MHz, CDCl3):
d 197.3, 136.2, 121.8, 121.7, 128.8, 128.5, 128.3, 128.2,
122.7, 92.7, 88.6, 26.6. Mp: 94e96 ꢀC (lit. Mp: 95e97 ꢀC).
1
99%, 166 mg at 80 ꢀC). H NMR (500 MHz, CDCl3): d 7.52
(m, 2H), 7.44 (m, 3H), 7.37 (m, 4H), 2.39 (s, 3H). 13C NMR
(126 MHz, CDCl3): d 142.1, 135.4, 130.5, 130.0, 128.8,
128.2, 127.4, 127.3, 126.8, 125.9, 20.6.
3.3.5. 40-Fluoro-4-methoxybiphenyl (Table 2, entry 6)59
4-Fluorophenylboronic acid (1.10 mmol, 154 mg) and 4-
bromoanisole (1 mmol, 125 mL) were coupled under the gen-
eral procedure using DTBNpP. The product was isolated in
80% yield as a tan solid. 1H NMR (500 MHz, CDCl3):
d 7.49 (m, 2H), 7.43 (d, J¼8.8 Hz, 2H), 7.09 (t, J¼8.5 Hz,
2H), 6.96 (d, J¼8.8 Hz, 2H), 3.84 (s, 3H). 13C NMR
(126 MHz, CDCl3): d 162.1 (d, 246 Hz), 159.1, 137.0, 132.7,
3.4.2. 4-(Phenylethynl)toluene (Table 3, entry 2)63
The above procedure was carried out using 4-bromotoluene
(0.90 mmol, 115 mL) and phenylacetylene (0.96 mmol,
105 mL). The mixture was purified by column chromatography

L.L. Hill et al. / Tetrahedron 64 (2008) 6920e6934
6929
(1:99 EtOAc/hexanes) to afford the product as a yellow solid
(DTBNpP: 153 mg, 99%). 1H NMR (500 MHz, CDCl3):
d 7.52 (d, J¼8.2 Hz, 2H), 7.43 (d, J¼8.2 Hz, 2H), 7.33 (m,
3H), 7.16 (d, J¼8.2 Hz, 2H), 2.37 (s, 3H). 13C NMR
(90.6 MHz, CDCl3): d 138.4, 131.6, 131.5, 129.1, 128.3,
128.0, 123.5, 120.2, 88.7, 89.6, 21.5. Mp: 69e70 ꢀC (lit. Mp:
72e73 ꢀC).
CDCl3): d 197.0, 135.5, 131.4, 129.0, 128.0, 94.1, 79.9,
30.5, 26.3, 21.8, 19.0, 13.4.
3.5.2. 40-(Trimethylsilylethynyl)acetophenone (Table 4,
entry 2)65
The above procedure was carried out using 4-bromoaceto-
phenone (1.00 mmol, 199 mg) and TMS/acetylene
(1.20 mmol, 170 mL). The mixture was purified by column
chromatography (1:99 EtOAc/hexanes) to afford the product
as an oil (185 mg, 92%). 1H NMR (500 MHz, CDCl3):
d 7.87, (d, J¼8.5 Hz, 2H), 7.52 (d, J¼8.2 Hz, 2H), 2.58 (s,
3H), 0.26 (s, 9H). 13C NMR (90.6 MHz, CDCl3): d 197.3,
136.4, 132.1, 128.1, 128.0, 104.0, 98.1, 26.6, ꢁ0.18 (3C).
3.5.3. 4-(4-Acetylphenyl)-3-butyn-1-ol (Table 4, entry 3)66
The above procedure was carried out using 4-bromoaceto-
phenone (1.0 mmol, 199 mg) and 3-butyn-1-ol (1.2 mmol,
91 mL). The mixture was purified by column chromatography
(1:99 EtOAc/hexanes) to afford the product as a yellow solid
(174 mg, 93%). 1H NMR (500 MHz, CDCl3): d 7.87 (d,
J¼8.5 Hz, 2H), 7.47 (d, J¼8.5 Hz, 2H), 3.84 (t, J¼6.3 Hz,
2H), 2.72 (t, J¼6.3 Hz, 2H), 2.58 (s, 3H), 1.95 (br s, 1H).
13C NMR (90.6 MHz, CDCl3): d 197.4, 136.0, 131.8, 128.4,
128.2, 90.2, 81.8, 61.0, 26.6, 23.9. Mp: 68e70 ꢀC (lit. Mp:
65e66 ꢀC).
3.4.3. 4-(Phenylethynl)anisole (Table 3, entry 3)63
The above procedure was carried out using 4-bromoanisole
(0.80 mmol, 100 mL) and phenylacetylene (0.96 mmol,
105 mL). The crude product mixture was purified by column
chromatography (2:98 EtOAc/hexanes) to afford the product
as a yellow solid (DTBNpP: 159 mg, 95%; DTBMONpP:
164 mg, 98%). 1H NMR (500 MHz, CDCl3): d 7.52 (d,
J¼7.9 Hz, 2H), 7.47 (d, J¼9.1 Hz, 2H), 7.3 (m, 3H), 6.88
(d, J¼8.8 Hz, 2H), 3.83 (s, 3H). 13C NMR (90.6 MHz,
CDCl3): d 159.7, 133.1, 131.5, 128.3, 127.9, 123.6, 115.4,
114.0, 89.4, 88.1, 55.3. Mp: 54e56 ꢀC (lit. Mp: 56e58 ꢀC).
3.4.4. 2-(Phenylethynyl)toluene (Table 3, entry 4)63
The above procedure was carried out using 2-bromotoluene
(0.80 mmol, 96.1 mL) and phenylacetylene (0.96 mmol,
105 mL). The crude product mixture was purified by column
chromatography (1:99 EtOAc/hexanes) to afford the product
as a clear oil (DTBNpP: 142 mg, 93%; DTBMONpP: 97%,
3.5.4. 1-(4-Methoxyphenyl)hex-1-yne (Table 4, entry 4)64
The above procedure was carried out using 4-bromoanisole
(1.00 mmol, 125 mL) and 1-hexyne (1.20 mmol, 135 mL). The
crude product mixture was purified by column chromatogra-
phy (1:99 EtOAc/hexanes) to afford the product as an oil
1
147 mg). H NMR (500 MHz, CDCl3): d 7.53 (d, J¼6.6 Hz,
2H), 7.49 (d, J¼7.6 Hz, 1H), 7.32 (m, 3H), 7.22 (d, J¼
4.4 Hz, 2H), 7.16 (m, 1H), 2.51 (s, 3H). 13C NMR (90.6 MHz,
CDCl3): d 140.3, 131.9, 131.6, 129.6, 128.44, 128.40, 128.3,
125.7, 123.7, 123.1, 93.5, 88.5, 20.8.
1
(DTBNpP: 185 mg, 92%; DTBMONpP: 158 mg, 79%). H
NMR (500 MHz, CDCl3): d 7.33 (d, J¼8.8 Hz, 2H), 6.81 (d,
J¼9.1 Hz, 2H), 3.79 (s, 3H), 2.39 (t, J¼6.9 Hz, 2H), 1.58
(qn, J¼6.9 Hz, 2H), 1.47 (sx, J¼7.2 Hz, 2H), 0.94 (t, J¼7.6,
3H). 13C NMR (90.6 MHz, CDCl3): d 159.0, 132.8, 116.3,
113.8, 88.7, 80.2, 55.2, 31.0, 22.0, 19.2, 13.7.
3.5. General procedure for the Sonogashira coupling of aryl
bromides and aliphatic alkynes
In a dry box, Pd(PhCN)2Cl2 (0.03 mmol, 11.5 mg), CuI
(0.02 mmol, 3.81 mg), DTBNpP (0.06 mmol, 132 mL of
a 10 wt % solution) or DTBMONpP (0.06 mmol, 16.2 mL),
and dioxane (1.0 mL) were combined in a septa topped vial.
The reaction mixture was removed from the dry box and the
aryl halide (1.0 mmol), alkyne (1.2 mmol), and diisopropyl-
amine (1.20 mmol, 170 mL) were added via syringe. The mix-
ture was stirred at room temperature for several hours and
monitored by TLC or GC. Upon completion, the product
was purified by flash chromatography using a mixture of ethyl
acetate and hexanes as the eluent.
3.5.5. 2-(4-Methoxyphenyl)ethynyltrimethylsilane (Table 4,
entry 5)67
The above procedure was carried out using 4-bromoanisole
(1.00 mmol, 125 mL) and TMS/acetylene (1.2 mmol, 170 mL).
The crude product mixture was purified by column chromatog-
raphy (1:3:96 EtOAc/NEt3/hexanes) to afford the product as
an oil (DTBNpP: 197 mg, 97%; DTBMONpP: 134 mg,
66%). 1H NMR (500 MHz, CDCl3): d 7.40 (d, J¼8.8 Hz,
2H), 6.81 (d, J¼8.8 Hz, 2H), 3.80 (s, 3H), 0.24 (s, 9H). 13C
NMR (90.6 MHz, CDCl3): d 159.7, 133.4, 115.3, 113.8,
105.2, 92.4, 55.2, 0.04 (3C).
3.5.1. 40-(1-Hexyn-1-yl)acetophenone (Table 4, entry 1)64
The above procedure was carried out using 4-bromoaceto-
phenone (1.00 mmol, 199 mg) and 1-hexyne (1.20 mmol,
135 mL). The crude product mixture was purified by column
chromatography (1:99 EtOAc/hexanes) to afford the product
as an oil (204 mg, 95%). 1H NMR (500 MHz, CDCl3):
d 7.86 (d, J¼8.9 Hz, 2H), 7.45 (d, J¼8.6 Hz, 2H), 2.58 (s,
3H), 2.43 (t, J¼7.0 Hz, 2H), 1.61 (qn, J¼7.0 Hz, 2H), 1.47
(sx, J¼8.2, 2H), 0.95 (t, J¼7.3, 3H). 13C NMR (90.6 MHz,
3.5.6. 4-(4-Methoxyphenyl)-3-butyn-1-ol (Table 4,
entry 6)68
The above procedure was carried out using 4-bromoanisole
(1.00 mmol, 125.2 mL) and 3-butyn-1-ol (1.20 mmol, 91 mL).
The crude product mixture was purified by column chromatog-
raphy (5:95 EtOAc/hexanes) to afford the product as a yellow
solid (DTBNpP: 159 mg, 90%; DTBMONpP: 175 mg, 99%).

6930
L.L. Hill et al. / Tetrahedron 64 (2008) 6920e6934
1H NMR (500 MHz, CDCl3): d 7.90 (d, J¼7.6 Hz, 2H), 7.50
(d, J¼8.2 Hz, 2H), 3.86, (t, J¼5.4 Hz, 2H), 2.75 (t,
J¼6.3 Hz, 2H), 2.61 (s, 3H), 1.90 (s, 1H). 13C NMR
(90.6 MHz, CDCl3): d 159.3, 133.0, 115.5, 113.9, 84.7, 82.3,
61.2, 55.3, 23.8. Mp: 59e61 ꢀC (lit. Mp: 61 ꢀC).
(5:95 EtOAc/hexanes). All products were spectroscopically
pure and consistent with previous reported spectra.
3.6.1. E-4-Cyanostilbene (Table 5. entry 1)70
The above procedure was carried out using 4-bromobenzo-
nitrile (0.80 mmol, 146 mg) to afford the product as a white
solid (DTBNpP: 106 mg, 64%; DTBMONpP: 129 mg, 79%).
1H NMR (500 MHz, CDCl3): d 7.63 (d, J¼8.2 Hz, 2H), 7.58
(d, J¼8.3 Hz, 2H), 7.53 (d, J¼7.4 Hz, 2H), 7.39 (t,
J¼7.6 Hz, 2H), 7.32 (t, J¼7.2 Hz, 1H), 7.22 (d, J¼16.4 Hz,
1H), 7.09 (d, J¼16.3, 1H). 13C NMR (90.6 MHz, CDCl3):
d 141.9, 136.3, 132.5, 132.4, 128.9, 128.7, 126.9, 126.8,
126.7, 119.0, 110.6. Mp: 112e114 ꢀC (lit. Mp: 114e116 ꢀC).
3.5.7. 1-(2-Methylphenyl)hex-1-yne (Table 4, entry 7)69
The above procedure was carried out using 2-bromotoluene
(1.0 mmol, 120 mL) and 1-hexyne (1.2 mmol, 135 mL). The
mixture was purified by column chromatography (hexanes)
to afford the product as a yellow oil (DTBNpP: 149 mg,
87%; DTBMONpP: 146 mg, 85%). 1H NMR (500 MHz,
CDCl3): d 7.45 (d, J¼7.2 Hz, 1H), 7.25 (m, 2H), 7.19 (m,
1H), 2.55 (t, J¼6.9 Hz, 2H), 2.51 (s, 3H), 1.71 (qn, J¼8.2,
2H), 1.49 (sx, J¼7.2, 2H), 1.06 (t, J¼7.2 Hz, 3H). 13C NMR
(90.6 MHz, CDCl3): d 139.9, 131.8, 129.3, 127.4, 125.4,
123.9, 94.4, 79.5, 31.0, 22.0, 20.7, 19.3, 13.7.
3.6.2. E-4-Acetylstilbene (Table 5, entry 2)70
The above procedure was carried out using 4-bromoaceto-
phenone (0.8 mmol, 159 mg) to afford the product as a yellow
solid (DTBNpP: 153 mg, 86%; DTBMONpP: 149 mg, 84%).
1H NMR (500 MHz, CDCl3): d 7.95 (d, J¼8.1 Hz, 2H), 7.58
(d, J¼8.2 Hz, 2H), 7.54 (d, J¼6.8 Hz, 2H), 7.39 (t, J¼7.6,
2H), 7.30 (t, J¼7.5 Hz, 1H), 7.23 (d, J¼16.4 Hz, 1H), 7.13
(d, J¼16.4 Hz, 1H), 2.61 (s, 3H). 13C NMR (90.6 MHz,
CDCl3): d 197.5, 142.0, 136.7, 136.0, 131.5, 128.9, 128.8,
128.3, 127.5, 126.8, 126.5, 26.6. Mp: 137e138 ꢀC (lit. Mp:
139e141 ꢀC).
3.5.8. Trimethyl-(2-methylphenyl)ethynylsilane (Table 4,
entry 8)
The above procedure was carried out using 2-bromotoluene
(1.00 mmol, 120 mL) and TMS/acetylene (1.20 mmol,
170 mL). The crude product mixture was purified by column
chromatography (3:97 NEt3/hexanes) and dried using a vac-
uum line to afford the product as an oil (DTBNpP: 152 mg,
81%; DTBMONpP: 171 mg, 91%). 1H NMR (500 MHz,
CDCl3): d 7.50 (d, J¼7.6 Hz, 1H), 7.26 (m, 2H), 7.18 (t,
J¼6.94 Hz, 1H), 2.52 (s, 3H), 0.34 (s, 9H). 13C NMR
(90.6 MHz, CDCl3): d 140.6, 132.1, 129.4, 128.5, 125.4,
122.9, 104.0, 98.2, 20.6, 0.09 (3C). HRMS (EI): Calculated
for C10H16Si 188.1021; found 188.1017.
3.6.3. E-4-Methylstilbene (Table 5, entry 3)70
The above procedure was carried out using 4-bromotoluene
(0.8 mmol, 138 mg) to afford the product as a yellowish solid
(DTBNpP: 131.4 mg, 75%; DTBMONpP: 131.0 mg, 75%). 1H
NMR (500 MHz, CDCl3): d 7.54 (d, J¼6.8 Hz, 2H), 7.45 (d,
J¼8.1 Hz, 2H), 7.39 (t, J¼7.6 Hz, 2H), 7.28 (t, J¼7.4, 1H),
7.20 (d, J¼7.6 Hz, 2H), 7.13 (d, J¼16.4 Hz, 1H), 7.09 (d,
J¼16.4 Hz, 1H), 2.40 (s, 3H). 13C NMR (90.6 MHz,
CDCl3): d 137.5, 137.4, 134.5, 129.3, 128.6, 128.6, 127.7,
127.4, 126.4, 126.3, 21.2. Mp: 112e114 ꢀC (lit. Mp: 117e
119 ꢀC).
3.5.9. 4-(2-Methylphenyl)-3-butyn-1-ol (Table 4, entry 9)5
The above procedure was carried out using 2-bromotoluene
(1.00 mmol, 120 mL) and 3-butyn-1-ol (1.20 mmol, 91 mL).
The mixture was purified by column chromatography (hex-
anes) to afford the product as a yellow oil (DTBNpP:
138 mg, 86%; DTBMONpP: 123 mg, 77%). 1H NMR
(500 MHz, CDCl3): d 7.38 (d, J¼7.6 Hz, 1H), 7.18 (m, 2H),
7.12 (m, 1H), 3.83, (br s, 2H), 2.73 (t, J¼6.3 Hz, 2H), 2.42
(s, 3H), 2.02 (br s, 1H). 13C NMR (90.6 MHz, CDCl3):
d 140.0, 131.9, 129.4, 127.9, 125.5, 123.1, 90.2, 81.4, 61.3,
24.0, 20.7.
3.6.4. E-4-Methoxystilbene (Table 5, entry 3)70
The above procedure was carried out using 4-bromoanisole
(0.8 mmol, 150 mg) and a reaction temperature of 100 ꢀC to
afford the product as a whittish solid (DTBNpP: 139 mg,
76%; DTBMONpP: 152 mg, 83%; TBDNpP: 122 mg, 67%;
1
TNpP: 65 mg, 36%). H NMR (500 MHz, CDCl3): d 7.50e
3.6. General procedure for the Heck coupling of aryl
bromides with styrene
7.45 (m, 4H), 7.35 (t, J¼7.8 Hz, 2H), 7.24 (t, J¼7.4 Hz,
1H), 7.07 (d, J¼16.3 Hz, 1H), 6.97 (d, J¼16.3 Hz, 1H), 6.90
(d, J¼8.9 Hz, 2H), 3.84 (s, 3H). 13C NMR (90.6 MHz,
CDCl3): d 159.3, 137.7, 130.2, 128.6, 128.2, 127.7, 127.2,
126.6, 126.3, 114.1, 55.3. Mp: 125e126 ꢀC (lit. Mp: 131e
132 ꢀC).
In a dry box, Pd2(dba)3 (0.03 mmol, 13.8 mg), DTBNpP
(0.03 mmol, 70.0 mL of a 10 wt % solution) or DTBMONpP
(0.03 mmol, 7.41 mg), and dioxane (0.8 mL) were combined
in a septa top vial. The reaction mixture was removed from
the dry box and the aryl halide (0.8 mmol), styrene
(1.10 mmol, 108.6 mg), and dicyclohexylmethylamine
(1.03 mmol, 200.6 mg) were added via syringe. The mixture
was placed in a preheated oil bath at 80 ꢀC and stirred for sev-
eral hours until judged complete by TLC or GC. Upon com-
pletion, the product was purified by column chromatography
3.6.5. E-4-(N,N-Dimethylamino)stilbene (Table 3, entry 5)70
The above procedure was carried out using 4-bromo-N,N-
dimethylaniline (0.80 mmol, 160 mg) to afford the product
as
DTBMONpP: 119 mg, 67%). H NMR (500 MHz, CDCl3):
a
peach-colored solid (DTBNpP: 152 mg, 89%;
1
d 7.48 (d, J¼6.9 Hz, 2H), 7.42 (d, J¼8.6 Hz, 2H), 7.33 (t,

L.L. Hill et al. / Tetrahedron 64 (2008) 6920e6934
6931
J¼7.7 Hz, 2H), 7.21 (t, J¼7.3, 1H), 7.06 (d, J¼16.4 Hz, 1H),
general procedure, but at 50 ꢀC, to afford yellow crystals
(152 mg, 92%). 1H NMR (500 MHz, CDCl3): d 7.18 (t,
J¼7.8 Hz, 2H), 7.06 (d, J¼8.8 Hz, 2H), 6.85 (d, J¼7.8 Hz,
2H), 6.78 (t, J¼7.3 Hz, 1H), 6.74 (d, J¼8.8 Hz, 2H), 5.41 (s,
1H), 2.92 (s, 6H). 13C NMR (90.6 MHz, CDCl3): d 147.3,
132.4, 129.2, 123.3, 118.8, 115.0, 114.9, 114.0, 41.2. Mp:
123e125 ꢀC (lit. Mp: 115 ꢀC).
6.92 (d, J¼16.5 Hz, 1H), 6.72 (d, J¼8.8, 2H), 2.99 (s, 6H). 13
C
NMR (90.6 MHz, CDCl3): d 150.1, 138.2, 128.8, 128.6, 127.6,
126.7, 126.0, 125.8, 124.4, 112.5, 40.5 (2C). Mp: 130 ꢀC (lit.
Mp: 144e146 ꢀC).
3.7. General procedure for HartwigeBuchwald amination of
aryl bromides
3.7.5. N-Phenyl-o-toluidine (Table 6, entry 5)75
Under an inert atmosphere of nitrogen gas in a glove box,
a 1 dram vial with a flea stir bar and a septa screw top was
charged with Pd2(dba)3 (0.005 mmol, 4.6 mg), sodium tert-
butoxide (1.00 mmol, 96.1 mg), DTBMONpP (0.01 mmol,
2.7 mL), and dry toluene (2 mL). The vial was then removed
from the glove box and the amine (1.0 mmol) and aryl bro-
mide (0.8 mmol) were added via a glass micro-syringe. The
reaction was allowed to stir at room temperature unless other-
wise noted. All reactions were monitored by GC until judged
complete. Upon completion, the crude product was purified by
column chromatography eluting with a 95:5 mixture of hex-
anes and ethyl acetate.
Aniline (91 mL, 1.0 mmol) and 2-bromotoluene (94 mL,
0.8 mmol) were coupled under the standard conditions to yield
the product as a yellow oil (121 mg, 84%). 1H NMR
(500 MHz, CDCl3): d 7.24 (m, 3H), 7.19 (d, J¼7.6 Hz, 1H),
7.13 (t, J¼7.7 Hz, 1H), 6.94 (m, 3H), 6.89 (t, J¼7.4 Hz,
1H), 5.34 (br s, 1H), 2.24 (s, 3H). 13C NMR (90.6 MHz,
CDCl3): d 144.0, 141.3, 131.0, 129.4, 128.4, 126.8, 122.1,
120.5, 118.9, 117.5, 17.9.
3.7.6. N-(4-Methylphenyl)-2,4,6-trimethylaniline (Table 6,
entry 6)76
2,4,6-Trimethylaniline (140 mL, 1.00 mmol) and 4-bromo-
toluene (100 mL, 0.80 mmol) were coupled under the standard
conditions to give a yellow oil (171 mg, 97%). 1H NMR
(500 MHz, CDCl3): d 6.95 (d, J¼7.88 Hz, 2H), 6.93 (3, 2H),
6.41 (d, J¼8.51 Hz, 2H), 5.00 (br s, 1H), 2.30 (s, 3H), 2.24
(s, 3H), 2.17 (s, 6H). 13C NMR (90.6 MHz, CDCl3):
d 144.3, 136.0, 135.6, 135.1, 129.7, 129.2, 127.1, 113.5,
20.9, 20.4, 18.2.
3.7.1. N-(4-Fluorophenyl)aniline (Table 6, entry 1)71
Aniline (91 mL, 1.0 mmol) and 1-bromo-4-fluoro-benzene
(86.1 mL, 0.8 mmol) were coupled using the procedure above
at 50 ꢀC to give a yellow oil (132 mg, 90%). 1H NMR
(500 MHz, CDCl3): d 7.23 (t, J¼7.3 Hz, 2H), 7.02 (m, 2H),
6.96 (m, 4H), 6.89 (t, J¼7.3 Hz, 1H), 5.54 (s, 1H). 13C
NMR (90.6 MHz, CDCl3): d 158.0 (d, JCeF¼240.1 Hz),
144.0, 139.0, 129.4, 120.6, 120.58, 116.8, 115.9 (d, JCe
3.7.7. N-Methyl-N-phenyl-p-anisidine (Table 6, entry 7)75
N-Methylaniline (109 mL, 1.00 mmol) and 4-bromoanisole
(98 mL, 0.80 mmol) were coupled under the standard condi-
¼23.0 Hz).
F
3.7.2. N-Phenyl-p-toluidine (Table 6, entry 2)72
1
tions to give the product as a yellow oil (155 mg, 73%). H
Aniline (91 mL, 1.0 mmol) and 4-bromotoluene (100 mL,
0.78 mmol), were coupled using the general procedure above,
but at 50 ꢀC to afford the product as pale yellow crystals
(120.5 mg, 95%). 1H NMR (500 MHz, CDCl3): d 7.23 (t,
J¼7.3 Hz, 2H), 7.08 (d, J¼8.8 Hz, 2H), 7.01 (m, 4H), 6.87
(t, J¼7.3 Hz, 1H), 5.59 (s, 1H), 1.53 (s, 3H). 13C NMR
(90.6 MHz, CDCl3): d 144.0, 140.3, 130.9, 129.9, 129.3,
120.3, 118.9, 116.9, 20.7. Mp: 85e87 ꢀC (lit. Mp: 87e88 ꢀC).
NMR (500 MHz, CDCl3): d 7.18 (t, J¼7.8 Hz, 2H), 7.08 (d,
J¼8.9 Hz, 2H), 6.88 (d, J¼8.8 Hz, 2H), 6.77 (t, J¼7.9 Hz,
3H), 3.79 (s, 3H), 3.24 (s, 3H). 13C NMR (90.6 MHz,
CDCl3): d 156.3, 149.8, 142.3, 129.0, 126.2, 118.4, 115.8,
114.8, 55.5, 40.5.
3.7.8. N-Methyl-N-phenyl-o-toluidine (Table 6, entry 8)26
N-Methylaniline (109 mL, 1.00 mmol) was reacted with 2-
bromotoluene (98 mL, 0.8 mmol) according to the general pro-
cedure to give the product as a yellow oil (143.1 mg, 73%). 1H
NMR (500 MHz, CDCl3): d 7.28 (d, J¼7.2 Hz, 1H), 7.22 (d,
J¼7.6 Hz, 1H), 7.16 (m, 4H), 6.70 (t, J¼7.2 Hz, 1H), 6.53
(d, J¼8.0 Hz, 2H), 3.21 (s, 3H), 2.14 (s, 3H). 13C NMR
(90.6 MHz, CDCl3): d 149.2, 136.9, 146.9, 131.5, 129.1,
128.4, 127.6, 126.5, 116.9, 112.9, 39.1, 17.9.
3.7.3. N-Phenyl-p-anisidine (Table 6, entry 3)73
Aniline (91 mL, 1.00 mmol) and 4-bromoanisole (98 mL,
0.80 mmol) were coupled using the general procedure, but at
50 ꢀC, to give a pale yellow crystalline product (140 mg,
89%). 1H NMR (500 MHz, CDCl3): d 7.20 (t, J¼7.5 Hz,
2H), 7.06 (d, J¼8.8 Hz, 2H), 6.90 (d, J¼8.5 Hz, 2H), 6.85
(d, J¼8.8 Hz, 2H), 6.82 (t, J¼7.3 Hz, 1H), 5.47 (s, 1H), 3.79
(s, 3H). 13C NMR (90.6 MHz, CDCl3): d 155.3, 145.2,
135.7, 129.3, 122.2, 119.6, 115.7, 114.7, 55.6. Mp: 99e
101 ꢀC (lit. Mp: 102e103 ꢀC).
3.7.9. 4-(4-Fluorophenyl)morpholine (Table 6, entry 9)77
Morpholine (87 mL, 1.0 mmol) with 1-bromo-4-fluorobenz-
ene (86 mL, 0.8 mmol) were coupled using the coupled using
the general procedure above to give the product as pale yellow
3.7.4. N,N-Dimethyl-N0-phenylbenzene-1,4-diamine (Table
6, entry 4).74
Aniline (91 mL, 1.00 mmol) and (4-bromo-phenyl)-di-
methyl-amine (157 mg, 0.8 mmol) were coupled under the
1
crystals (121 mg, 85%). H NMR (500 MHz, CDCl3): d 6.98
(t, J¼8.4 Hz, 2H), 6.88 (m, 2H), 3.86 (t, J¼4.8 Hz, 4H),
3.08 (t, J¼4.8 Hz, 4H). 13C NMR (90.6 MHz, CDCl3):

6932
L.L. Hill et al. / Tetrahedron 64 (2008) 6920e6934
d 157.0 (d, J¼239 Hz), 147.9 (d, J¼2.8 Hz), 117.5 (d,
J¼7.3 Hz), 115.7 (d, J¼22.0 Hz), 66.9, 50.3. Mp: 52e54 ꢀC.
purified by column chromatography eluting with a 95:5 mix-
ture of hexanes and ethyl acetate.
3.7.10. 4-(4-Methylphenyl)morpholine (Table 6, entry 10)75
Morpholine (87 mL, 1.0 mmol) and 4-bromotoluene
(100 mL, 0.80 mmol) were coupled under the general proce-
dure to give the product as a pale yellow crystalline solid
(115 mg, 83%). 1H NMR (500 MHz, CDCl3): d 7.12 (d,
J¼8.6 Hz, 2H), 6.86 (d, J¼7.9 Hz, 2H), 3.89 (t, J¼4.6 Hz,
4H), 3.13 (t, J¼4.8 Hz, 4H), 2.30 (s, 3H). 13C NMR
(90.6 MHz, CDCl3): d 149.2, 129.7, 129.6, 116.1, 67.0, 49.9,
20.4. Mp: 45e46 ꢀC (lit. Mp: 49e50 ꢀC).
3.8.1. N-Phenyl-p-anisidine (Table 7, entry 1)73
The above procedure was carried out using Pd2(dba)3
(4.6 mg, 0.005 mmol), DTBMONpP (0.01 mmol, 2.7 mL) or
TNpP (0.01 mmol, 23 mL), 4-chloroanisole (0.80 mmol,
98.0 mL), and aniline (1.0 mmol, 93.1 mg) at 110 ꢀC to afford
the product as a gray solid (DTBMONpP: 94%, 149 mg;
1
TNpP: 112 mg, 70%). H NMR (500 MHz, DMSO): d 7.21
(t, J¼7.4 Hz, 2H), 7.08 (d, J¼8.8 Hz, 2H), 6.91 (d, J¼7.6,
2H), 6.86 (m, 3H), 5.49 (br s, 1H), 3.81 (s, 3H). 13C NMR
(90.6 MHz, DMSO): d 155.3, 145.2, 135.8, 129.3, 122.2,
119.6, 115.7, 114.7, 55.6. Mp: 97e99 ꢀC (lit. Mp: 102e
103 ꢀC).
3.7.11. 4-(4-Methoxyphenyl)morpholine (Table 6,
entry 11)75
Morpholine (87 mL, 1.0 mmol) and 4-bromoanisole (98 mL,
0.8 mmol) were coupled using the general procedure above to
3.8.2. N-Methyl-N-phenyl-p-anisidine (Table 7, entry 2)75
The above procedure was carried out using Pd2(dba)3
(18.3 mg, 0.02 mmol), DTBMONpP (0.02 mmol, 5.43 mL) or
TNpP (0.02 mmol, 45.8 mL), 4-chloroanisole (0.80 mmol,
98.0 mL), and N-methylaniline (0.9 mmol, 98 mL) at 120 ꢀC
to afford the product as an orange oil (DTBMONpP:
133 mg, 78%; TNpP: 157 mg, 92%). 1H NMR (500 MHz,
DMSO): d 7.18 (t, J¼6.9 Hz, 2H), 7.08 (d, J¼9.1 Hz, 2H),
6.88 (d, J¼8.8 Hz, 2H), 6.78 (d, J¼8.5 Hz, 3H), 3.80 (s,
3H), 3.25 (s, 3H). 13C NMR (90.6 MHz, DMSO): d 156.3,
149.8, 142.2, 128.9, 126.2, 118.4, 115.8, 114.8, 55.5, 40.5.
1
give the product as pale yellow crystals (136 mg, 90%). H
NMR (500 MHz, CDCl3): d 6.87 (m, 4H), 3.86 (t, J¼4.8 Hz,
4H), 3.77 (s, 3H), 3.06 (t, J¼4.8 Hz, 4H). 13C NMR
(90.6 MHz, CDCl3): d 154.0, 145.7, 117.8, 114.5, 67.1, 55.6,
50.8. Mp: 70e71 ꢀC (lit. Mp: 71 ꢀC).
3.7.12. 4-(4-N,N-Dimethylaminophenyl)morpholine (Table
6, entry 12)78
Morpholine (87 mL, 1.0 mmol) was reacted with 4-bromo-
N,N-dimethylaniline (157 mg, 0.8 mmol) using the general
procedure above to give the product as yellowish crystals
(153 mg, 95%). 1H NMR (360 MHz, CDCl3): d 6.89 (d,
J¼9.1 Hz, 2H), 6.75 (d, J¼9.1, 2H), 3.86 (t, J¼4.7 Hz, 4H),
3.04 (t, J¼4.8 Hz, 4H), 2.88 (s, 6H). 13C NMR (90.6 MHz,
CDCl3): d 145.9, 143.2, 118.0, 114.5, 67.1, 51.1, 41.5. Mp:
115e117 ꢀC (lit. Mp: 117e120 ꢀC).
3.8.3. 4-(4-Methoxyphenyl)morpholine (Table 7, entry 3)75
The above procedure was carried out using Pd(OAc)2
(4.4 mg, 0.02 mmol), DTBMONpP (0.02 mmol, 5.43 mL of
a 10 wt % solution) or TNpP (0.02 mmol, 45.8 mL of
a 10 wt % solution), 4-chloroanisole (0.80 mmol, 98.0 mL),
and morpholine (1.0 mmol, 87 mL) were coupled under the
standard conditions at 120 ꢀC. The product was isolated as
3.7.13. 4-(2-Methylphenyl)morpholine (Table 6, entry 13)75
Morpholine (87.1 mL, 1.0 mmol) and 2-bromotoluene
(94.3 mL, 0.8 mmol) were coupled using the general procedure
a
lavender solid (DTBMONpP: 149 mg, 97%; TNpP
138 mg, 90%). 1H NMR (500 MHz, DMSO): d 6.89 (m,
4H), 3.88 (m, 4H), 3.80 (s, 3H), 3.08 (m, 4H). 13C NMR
(90.6 MHz, DMSO): d 154.0, 145.6, 117.8, 114.6, 67.0,
55.6, 50.9. Mp: 68e70 ꢀC (lit. Mp: 71 ꢀC).
1
to give the product as a pale yellow oil (133 mg, 96%). H
NMR (500 MHz, CDCl3): d 7.17 (t, J¼7.3 Hz, 2H), 7.01 (m,
2H), 3.84 (t, J¼4.5 Hz, 4H), 2.90 (t, J¼4.5 Hz, 4H), 2.31 (s,
3H). 13C NMR (90.6 MHz, CDCl3): d 150.3, 131.6, 130.1,
125.6, 122.4, 117.9, 66.4, 51.2, 16.8.
3.8.4. N-Phenyl-o-toluidine (Table 7, entry 4)75
The above procedure was carried out using Pd2(dba)3
(4.6 mg, 0.005 mmol), DTBMONpP (0.01 mmol, 2.7 mL) or
TNpP (0.01 mmol, 23 mL), 2-chlorotoluene (0.77 mmol,
94 mL), and aniline (1.00 mmol, 93.1 mg) at 110 ꢀC to give
the product as a yellow oil (DTBMONpP: 138 mg, 94%;
3.8. General procedure for the HeB coupling of amines with
aryl chlorides
In a dry box, Pd2(dba)3 (0.005e0.025 mmol, 4.6e23 mg),
DTBNpP (0.01 mmol 23 mL), DTBMONpP (0.01e
0.04 mmol, 2.7e10.8 mL) or TNpP (0.01e0.04 mmol, 22.9e
91.6 mL of a 10 wt % solution), and sodium tert-butoxide
(1.00 mmol, 96.1 mg) were combined in a round bottom flask
with toluene (1.0 mL) and a stir bar. After placing a rubber
septa on the flask, the reaction mixture was removed from
the dry box. The amine (1.0 mmol) and the aryl halide
(0.8 mmol) were added by syringe. The mixture was placed
in a preheated oil bath at 80e140 ꢀC and stirred until judged
complete by GC. Upon completion, the crude product was
1
TNpP: 129 mg, 87%). H NMR (500 MHz, DMSO): d 7.30
(t, J¼8.04 Hz, 3H), 7.25 (d, J¼7.25 Hz, 1H), 7.19 (t,
J¼7.57 Hz, 1H), 6.98 (m, 4H), 5.42 (br s, 1H), 2.31 (s, 3H).
13C NMR (90.6 MHz, DMSO): d 144.0, 141.2, 131.0, 129.3,
128.4, 126.8, 122.0, 120.5, 118.9, 117.5, 17.9.
3.8.5. N-Methyl-N-phenyl-o-toluidine (Table 7, entry 5)26
2-Chlorotoluene (0.77 mmol, 94.0 mL) and N-methylaniline
(0.9 mmol, 98 mL) were coupled using Pd2(dba)3 (9.2 mg,
0.01 mmol) and DTBMONpP (0.02 mmol, 5.43 mL) or TNpP

L.L. Hill et al. / Tetrahedron 64 (2008) 6920e6934
6933
14. Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 6343e
6348.
(0.02 mmol, 45.8 mL of a 10 wt % solution) under the proce-
dure above to give the product as an orange oil (DTBNpP:
140 mg, 89%; DTBMONpP: 125 mg, 84%; TNpP: 95 mg,
15. Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem., Int. Ed. 2000, 39,
4153e4155.
1
63%). H NMR (500 MHz, DMSO): d 7.31 (m, 6H), 6.82 (t,
16. Ehrentraut, A.; Zapf, A.; Beller, M. J. Mol. Cat. A: Chem. 2002, 182-183,
515e523.
J¼7.7 Hz, 1H), 6.65 (d, J¼8.5 Hz, 2H), 3.33 (s, 3H), 2.26
(s, 3H). 13C NMR (90.6 MHz, DMSO): d 149.2, 146.9,
136.9, 131.5, 129.0, 128.4, 127.6, 126.5, 116.9, 112.9, 39.1,
17.9.
Alternatively, N-methyl-N-phenyl-o-toluidine was prepared
as above, but using Pd2(dba)3 (4.6 mg, 0.005 mmol) and
DTBNpP (0.01 mmol, 23.3 mL) as the catalyst precursor at
120 ꢀC to give the product as an orange oil (140 mg, 89%).
17. Schareina, T.; Zapf, A.; Magerlein, W.; Muller, N.; Beller, M. Tetrahedron
¨
Lett. 2007, 48, 1087e1090.
¨
18. Hill, L. L.; Moore, L. R.; Huang, R.; Craciun, R.; Vincent, A. P.; Dixon,
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3.8.6. 4-(2-Methylphenyl)morpholine (Table 7, entry 6)75
The above procedure was carried out using 2-chlorotoluene
(0.77 mmol, 94.0 mL) and morpholine (1.0 mmol, 87 mL) with
Pd(OAc)2 (4.4 mg, 0.02 mmol), DTBMONpP (0.02 mmol,
5.43 mL) or TNpP (0.02 mmol, 45.8 mL of a 10 wt % solution)
at 120 ꢀC to give the product as a yellow oil (DTBMONpP:
133 mg, 89%; TNpP: 121 mg, 90%). 1H NMR (500 MHz,
DMSO): d 7.23 (m, 2H), 7.06 (m, 2H), 3.89 (m, 4H), 2.95
(m, 4H), 2.37 (s, 3H). 13C NMR (90.6 MHz, DMSO):
d 151.3, 132.7, 131.2, 126.7, 123.5, 119.0, 67.5, 52.3, 17.9.
Alternatively, 4-(2-methylphenyl)morpholine was prepared
as above, but using Pd(OAc)2 (0.01 mmol, 2.2 mg) and
DTBNpP (0.01 mmol, 23.3 mL of a 10 wt % solution) as the
catalyst precursor. The reaction yielded the above product
(129 mg, 91%) as a yellow oil.
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Acknowledgements
32. Campeau, L.-C.; Thansandote, P.; Fagnou, K. Org. Lett. 2005, 7, 1857e
1860.
Financial support for this work by FMC, Lithium Division,
Chemical Sciences, Geosciences and Biosciences Division,
Office of Basic Energy Sciences, U.S. Department of Energy
(DOE) (catalysis center program), the Robert Ramsay Chair
Foundation is gratefully acknowledged. Assistance on the
coupling reactions by F. Maryam Khan, Fatima T. Carmichael,
M. Quentin Sonnier, and Brent R. Graves is also
acknowledged.
33. Viciu, M. S.; Kissling, R. M.; Stevens, E. D.; Nolan, S. P. Org. Lett. 2002,
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