Synthesis and X-ray structure determination of highly active Pd(II), Pd(I), and Pd(0) complexes of Di(tert -butyl)neopentylphosphine (DTBNpP) in the arylation of amines and ketones

Article abstract of DOI:10.1021/jo101187q

The air-stable complex Pd(eta;³-allyl)(DTBNpP)Cl (DTBNpP = di(tert-butyl)neopentylphosphine) serves as a highly efficient precatalyst for the arylation of amines and enolates using aryl bromides and chlorides under mild conditions with yields ranging from 74% to 98%. Amination reactions of aryl bromides were carried out using 1-2 mol % Pd(η³-allyl)(DTBNpP)Cl at 23-50 °C without the need to exclude oxygen or moisture. The C-N coupling of the aryl chlorides occurred at relatively lower temperature (80-100 °C) and catalyst loading (1 mol %) using the Pd(eta;³-allyl) (DTBNpP)Cl precatalyst than the catalyst generated in situ from DTBNpP and Pd₂(dba)₃ (100-140 °C, 2-5 mol % Pd). Other Pd(DTBNpP)₂-based complexes, (Pd(DTBNpP)₂ and Pd(DTBNpP)₂Cl₂) were ineffective precatalysts under identical conditions for the amination reactions. Both Pd(DTBNpP)₂ and Pd(DTBNpP)₂Cl₂ precatalysts gave nearly quantitative conversions to the product in the α-arylation of propiophenone with p-chlorotoluene and p-bromoanisole at a substrate/catalyst loading of 100/1. At lower substrate/ca'alyst loading (1000/1), the conversions were lower but comparable to that of Pd(t-Bu₃P)₂. In many cases, the tri-tert-butylphosphine (TTBP) based Pd(I) dimer, [Pd(μ-Br)(TTBP)] ₂, stood out to be the most reactive catalyst under identical conditions for the enolate arylation. Interestingly, the air-stable Pd(I) dimer, Pd₂(DTBNpP)₂(μ-Cl)(μ-allyl), was less active in comparison to [Pd(μ-Br)(TTBP)]₂ and Pd(eta;³-allyl) (DTBNpP)Cl. The X-ray crystal structures of Pd(eta;³-allyl)(DTBNpP) Cl, Pd(DTBNpP)₂Cl₂, Pd(DTBNpP)₂, and Pd ₂(DTBNpP)₂(μ-Cl)(μ-allyl) are reported in this paper along with initial studies on the catalyst activation of the Pd(eta;³-allyl)(DTBNpP)Cl precatalyst.

Full text of DOI:10.1021/jo101187q

pubs.acs.org/joc
Synthesis and X-ray Structure Determination of Highly Active Pd(II),
Pd(I), and Pd(0) Complexes of Di(tert-butyl)neopentylphosphine
(DTBNpP) in the Arylation of Amines and Ketones
Lensey L. Hill, Jason L. Crowell, Strudwick L. Tutwiler, Nicholas L. Massie,
C. Corey Hines, Scott T. Griffin, Robin D. Rogers, and Kevin H. Shaughnessy*
Department of Chemistry, The University of Alabama, Box 870336, Tuscaloosa, Alabama 35487-0336
†
Gabriela A. Grasa, Carin C. C. Johansson Seechurn, Hongbo Li, and
‡
†
,†
Thomas J. Colacot*
†
Johnson Matthey Catalysis & Chiral Technologies, 2001 Nolte Drive, West Deptford, New Jersey 08066,
and Johnson Matthey, Orchard Road, Royston SG8 5HE, U.K.
‡
Joe Chou and Christopher J. Woltermann
FMC Corporation, Lithium Division, Hwy 161, Box 795, Bessemer City, North Carolina 28016-0795
kshaughn@bama.ua.edu; colactj@jmusa.com
Received June 21, 2010
3
The air-stable complex Pd(η -allyl)(DTBNpP)Cl (DTBNpP = di(tert-butyl)neopentylphosphine)
serves as a highly efficient precatalyst for the arylation of amines and enolates using aryl bromides
and chlorides under mild conditions with yields ranging from 74% to 98%. Amination reactions of
3
aryl bromides were carried out using 1-2 mol % Pd(η -allyl)(DTBNpP)Cl at 23-50 °C without the
need to exclude oxygen or moisture. The C-N coupling of the aryl chlorides occurred at relatively
3
lower temperature (80-100 °C) and catalyst loading (1 mol %) using the Pd(η -allyl)(DTBNpP)Cl
precatalyst than the catalyst generated in situ from DTBNpP and Pd (dba) (100-140 °C, 2-5 mol
2
3
%
Pd). Other Pd(DTBNpP) -based complexes, (Pd(DTBNpP) and Pd(DTBNpP) Cl ) were
2 2 2 2
ineffective precatalysts under identical conditions for the amination reactions. Both Pd(DTBNpP)2
and Pd(DTBNpP) Cl precatalysts gave nearly quantitative conversions to the product in the
2
2
R-arylation of propiophenone with p-chlorotoluene and p-bromoanisole at a substrate/catalyst
loading of 100/1. At lower substrate/catalyst loading (1000/1), the conversions were lower but
comparable to that of Pd(t-Bu P) . In many cases, the tri-tert-butylphosphine (TTBP) based Pd(I)
3
2
dimer, [Pd(μ-Br)(TTBP)] , stood out to be the most reactive catalyst under identical conditions
2
for the enolate arylation. Interestingly, the air-stable Pd(I) dimer, Pd (DTBNpP) (μ-Cl)(μ-allyl), was
2
2
3
less active in comparison to [Pd(μ-Br)(TTBP)] and Pd(η -allyl)(DTBNpP)Cl. The X-ray crystal
2
3
structures of Pd(η -allyl)(DTBNpP)Cl, Pd(DTBNpP) Cl , Pd(DTBNpP) , and Pd (DTBNpP) -
2
2
2
2
2
(
μ-Cl)(μ-allyl) are reported in this paper along with initial studies on the catalyst activation of the
3
Pd(η -allyl)(DTBNpP)Cl precatalyst.
DOI: 10.1021/jo101187q
r 2010 American Chemical Society
Published on Web 09/01/2010
J. Org. Chem. 2010, 75, 6477–6488 6477

Hill et al.
JOCArticle
Introduction
The use of Pd-mediated cross-coupling reactions has been
increasing steadily, especially over the past two decades, in
academia and industry due in part to the emergence of new
ligand classes that promote cross-couplings of electrophiles
with a range of leaving groups (Br, Cl, OSO R) and a variety
2
1
of nucleophiles (Figure 1). A common feature among these
new ligand classes is significant steric demand and strong
σ-donating ability necessary to promote the oxidative addi-
tion and reductive elimination steps. Typically such trans-
formations are carried out using a catalyst generated in situ
2
by combining a Pd source, such as Pd(dba) or Pd(dba-Z)
n
n
3
(
ligand or its protonated form to generate the PdL active
n =1.5-2), Pd(OAc) , or [Pd(η -allyl)Cl] , with the free
FIGURE 1. Examples of sterically demanding, electron-rich ligands
used in Pd-catalyzed coupling reactions.
2
2
3
species. Although these practices are quite useful in both
small-scale and process chemistry operations, they suffer
from many drawbacks. The free trialkylphosphine ligands
are typically air-sensitive or even pyrophoric, while the air-
stable phosphonium or imidazolium preligands can be
hygroscopic. Generation of the catalyst in situ can also lead
to reproducibility problems due to difficulty in controlling
the ligand/Pd ratio and the air-sensitivity of the ligands
in solution phase. Catalysts derived from these ligands in
general give optimal results with 1:1 or 2:1 L/Pd ratios, while
excess ligand often inhibits the activity of the catalytic system
and is not cost efficient. Generation of the active species from
the ligand and Pd source may also result in induction periods
or undesired side products due to the formation of metal
complexes with different reactivity.
Therefore, there is an increasing interest in using pre-
formed palladium complexes of these ligands as precatalysts.
Whereas some of the ligands in Figure 1 tend to be relatively
air-sensitive or even pyrophoric, their preformed Pd com-
plexes, particularly Pd(II) complexes, are often air-stable
and easily handled. In addition, it is possible to precisely
control the L/Pd molar ratio of the catalyst on the basis of the
stoichiometry of the precatalyst species. In this way, the
chemistry to form the active species may also be carefully
controlled through the choice of the appropriate precatalyst.
Recent studies by Grasa and Colacot showed that the
FIGURE 2. Examples of precatalysts with sterically demanding,
electron-rich ligands.
selectivity and activity, in comparison to the corresponding
4
in situ systems. Preformed Pd(0)L2 complexes, such as
Pd(TTBP) (2), are kinetically less active and therefore show
2
modest activity at room temperature presumably because of
5
the undesired 2:1 L/Pd ratio, although 2 has been effectively
used at elevated temperatures where ligand dissociation is
6
more facile. The Pd(TTBP) complex has also been studied
by Hartwig to understand the oxidative addition product
2
7
in the catalytic cycle. Prashad of Novartis found that the
TTBP complex of a Pd(I) dimer, [Pd(μ-Br)(TTBP)] (3), was
2
an effective and superior precatalyst in the Buchwald-
Hartwig (B-H) coupling reaction in comparison to the in
situ system. Hartwig also observed similar effects in both
8
preformed catalyst, (DtBPF)PdCl (Pd-118, 1, Figure 2) was
2
C-N coupling and R-arylation reactions using 3 as a
precatalyst. Palladacycle adducts of S-Phos (4) and related
ligands were shown to be highly effective precatalysts for
significantly superior in the R-arylation reactions in terms of
9
(
1) (a) Johansson, C. C. C.; Colacot, T. J. Angew. Chem., Int. Ed. 2010, 49,
1
amination of aryl chlorides. The PEPPSI catalyst system
0
6
7
76–707. (b) Fleckenstein, C. A.; Plenio, H. Chem. Soc. Rev. 2010, 39, 694–
11. (c) Torborg, C.; Beller, M. Adv. Synth. Catal. 2009, 351, 3027–3043.
(5) developed by Organ is a stable precursor to NHC-Pd
(
d) Molander, G. A.; Canturk, B. Angew. Chem., Int. Ed. 2009, 48, 9240–
9
6
261. (e) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338–
361. (f) Marion, N.; Nolan, S. P. Acc. Chem. Res. 2008, 41, 1440–1449.
(5) (a) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.;
Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575–5580. (b) Hooper,
M. W.; Utsunomiya, M.; Hartwig, J. F. J. Org. Chem. 2003, 68, 2861–2873.
(c) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020–4028.
(6) (a) Shimizu, M.; Tanaka, K.; Kurahashi, T.; Shimono, K.; Hiyama, T.
Chem. Lett. 2004, 33, 1066–1067. (b) Littke, A. F.; Schwarz, L.; Fu, G. C.
J. Am. Chem. Soc. 2002, 124, 6343–6348. (c) Stauffer, S. R.; Steinbeiser,
M. A. Tetrahedron Lett. 2005, 46, 2571–2575. (d) Dai, C.; Fu, G. C. J. Am.
Chem. Soc. 2001, 123, 2719–2724. (e) Kuwano, R.; Utsunomiya, M.;
Hartwig, J. F. J. Org. Chem. 2002, 67, 6479–6486.
(
g) Fu, G. C. Acc. Chem. Res. 2008, 41, 1555–1565. (h) Hartwig, J. F. Acc.
Chem. Res. 2008, 41, 1534–1544. (i) Corbet, J.-P.; Mignani, G. Chem. Rev.
006, 106, 2651–2710. (j) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew.
Chem., Int. Ed. 2005, 44, 4442–4489. (k) Zapf, A.; Beller, M. Chem. Commun.
005, 431–440. (l) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de
2
2
Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004. (m) Negishi,
E.-i. Handbook of Organopalladium Chemistry for Organic Synthesis; Wiley
Interscience: New York, 2002. (n) Cross-Coupling Reactions: A Practical
Guide; Topics in Current Chemistry Series 219; Miyaura, N., Ed.; Springer-
Verlag: New York, 2002.
(7) Barrios-Landeros, F.; Carrow, B. P.; Hartwig, J. F. J. Am. Chem. Soc.
2008, 130, 5842–5843.
(8) Prashad, M.; Mak, X. Y.; Liu, Y.; Repic, O. J. Org. Chem. 2003, 68,
1163–1164.
(
2) (a) Fairlamb, I. J. S. Org. Biomol. Chem. 2008, 6, 3645–3656.
b) Fairlamb, I. J. S.; Kapdi, A. R.; Lee, A. F. Org. Lett. 2004, 6, 4435–
438. (c) Mac ꢀe , Y.; Kapdi, A. R.; Fairlamb, I. J. S.; Jutand, A. Organome-
(
4
tallics 2006, 25, 1795–1800. (d) Sehnal, P.; Taghzouti, H.; Fairlamb, I. J. S.;
Jutand, A.; Lee, A. F.; Whitwood, A. C. Organometallics 2009, 28, 824–829.
(9) (a) Stambuli, J. P.; Kuwano, R.; Hartwig, J. F. Angew. Chem., Int. Ed.
2002, 41, 4746–4748. (b) Hama, T.; Hartwig, J. F. Org. Lett. 2008, 10, 1545–
1548. (c) Hama, T.; Hartwig, J. F. Org. Lett. 2008, 10, 1549–1552.
(10) Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2008,
130, 6886–6887.
(
3) Christmann, U.; Vilar, R. Angew. Chem., Int. Ed. 2005, 44, 366–374.
4) (a) Grasa, G. A.; Colacot, T. J. Org. Lett. 2007, 9, 5489–5492.
(
b) Grasa, G. A.; Colacot, T. J. Org. Process Res. Dev. 2008, 12, 522–529.
(
6
478 J. Org. Chem. Vol. 75, No. 19, 2010

Hill et al.
JOCArticle
Results and Discussion
Buchwald-Hartwig Amination with Precatalysts. The
Shaughnessy group has previously shown that DTBNpP in
combination with Pd (dba) provides a catalyst capable of
2
3
coupling various amines with aryl bromides at room tem-
perature and aryl chlorides at elevated temperatures (100-
1
5a
1
40 °C).
The ability of 8, 9, and 10 to provide active
FIGURE 3. Preformed DTBNpP complexes from this study.
catalytic species for the coupling of 4-bromoanisole and
aniline in toluene at room temperature (eq 1) was compared
1
1
catalyst systems (NHC = N-heterocyclic carbene, i.e., sIPr).
3
to that of the in situ system derived from Pd (dba) /
2 3
DTBNpP (1:1 Pd/DTBNpP). As has previously been shown,
the in situ system gave complete conversion to N-phenyl-p-
Nolan has shown that Pd(η -allyl)(NHC)Cl complex (6a)
provide effective catalysts for a range of Pd-catalyzed cross-
coupling reactions. There are only a few examples of the
use of Pd-allyl complexes of electron-rich, sterically demand-
ing ligands (6b) as precatalysts, however. Pd(I)-μ-allyl
dimers, such as 7, can also be used as precatalysts.
1
2
anisidine within 30 min (Table 1). Pd(DTBNpP) (8) showed
2
1
3
little activity at room temperature, however. Presumably the
dissociation of DTBNpP from 8 to form the Pd(DTBNpP)
active species is slow at room temperature as has previously
14
Shaughnessy et al. have reported recently that di(tert-
butyl)neopentylphosphine (DTBNpP) in conjunction with
Pd (dba) acts as an effective catalyst system for B-H,
5b,c
been seen with Pd(TTBP)2. In contrast, we had previously
observed that the catalyst derived in situ from DTBNpP
and Pd (dba) gave complete conversion after 1 h at room
temperature with DTBNpP/Pd ratios ranging from 1 to
2
3
2
3
Sonogashira, Suzuki, and Heck coupling reactions of aryl
1
5
bromides and chlorides. In the case of B-H amination,
the DTBNpP-derived catalyst proved to be more active
than that derived from TTBP. The increased activity of the
DTBNpP catalyst system in C-N coupling was attributed to
the larger calculated cone angle of this ligand in comparison
to TTBP.
15a
2
:1. This result may indicate that dba plays a non-innocent
2a
role in this reaction as has been observed by others. The
dichloride complex (9) showed essentially no activity, pre-
sumably as a result of the inability to reduce the Pd(II) cata-
lyst precursor under the conditions employed in the study.
The allyl catalyst (10) gave a higher initial rate of conversion
Because DTBNpP is a pyrophoric material, an air-stable
precatalyst would be highly attractive for large-scale appli-
cations. We also sought to structurally characterize the
palladium complexes of these ligands in order to further
understand their role in creating high activity catalyst sys-
(82%) after 15 min compared with that of the catalyst gene-
rated in situ (40%).
tems. Four new Pd complexes of DTBNpP, Pd(DTBNpP)
2
3
(
(
8), trans-Pd(DTBNpP) Cl (9), Pd(η -allyl)(DTBNpP)Cl
2
2
10), and Pd (DTBNpP) (μ-allyl)(μ-Cl) (11) (Figure 3), were
2
2
structurally characterized during this study. Complex 10
provided a superior catalyst for the arylation of amines
and ketones compared to the active catalysts derived from
On the basis of the promising results with Pd-allyl pre-
catalyst 10, its ability to promote amination of aryl bromides
and chlorides was further explored. Because complex 10 is
air-stable, the coupling of 4-bromoanisole (12a) and aniline
8
or 9 or generated in situ (Pd (dba) /DTBNpP). This study
2 3
also provides our preliminary mechanistic investigations
supporting the formation of the active catalytic species
from 10.
(
13a) was attempted in air (eq 2). The reaction was assembled
in air using reagents stored in air, including complex 10.
The vial was then sealed under air and stirred at ambient
temperature. Complete conversion to product occurred
within 30 min as determined by GC analysis. The product,
N-phenyl-p-anisidine, was isolated in 89% yield (Table 2).
The air-stability of complex 10 is in stark contrast to free
(
11) (a) O’Brien, C. J.; Kantchev, E. A. B.; Valente, C.; Hadei, N.; Chass,
G. A.; Lough, A.; Hopkinson, A. C.; Organ, M. G. Chem.;Eur. J. 2006, 12,
743–4748. (b) Organ, M. G.; Abdel-Hadi, M.; Avola, S.; Dubovyk, I.;
4
Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Sayah, M.; Valente, C.
Chem.;Eur. J. 2008, 14, 2443–2452. (c) Organ, M. G.; Avola, S.; Dubovyk,
I.; Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Valente, C. Chem.;Eur. J.
15b
2
006, 12, 4749–4755.
12) (a) Navarro, O.; Kaur, N.; Mahjoor, P.; Nolan, S. P. J. Org. Chem.
004, 69, 3173–3180. (b) Viciu, M. S.; Germaneau, R. F.; Navarro-Fernandez,
DTBNpP, which is classified as a pyrophoric liquid.
(
2
O.; Stevens, E. D.; Nolan, S. P. Organometallics 2002, 21, 5470–5472. (c) Viciu,
M. S.; Germaneau, R. F.; Nolan, S. P. Org. Lett. 2002, 4, 4053–4056.
(
13) (a) Reddy, C. V.; Kingston, J. V.; Verkade, J. G. J. Org. Chem. 2008,
3, 3047–3062. (b) Tinkl, M.; Hafner, A. WO 2001016057, March 8, 2001;
Chem. Abs. 2001, 134, 222517.
14) (a) Denmark, S. E.; Baird, J. D. Org. Lett. 2006, 8, 793–795.
b) Denmark, S. E.; Baird, J. D.; Regens, C. S. J. Org. Chem. 2008, 73,
440–1455. (c) Elliott, E. L.; Ray, C. R.; Kraft, S.; Atkins, J. R.; Moore, J. S.
7
(
(
1
J. Org. Chem. 2006, 71, 5282–5290. (d) Weissman, H.; Shimon, L. J. W.;
Milstein, D. Organometallics 2004, 23, 3931–3940. (e) Finke, A. D.; Elleby,
E. C.; Boyd, M. J.; Weissman, H.; Moore, J. S. J. Org. Chem. 2009, 74, 8897–
8
900.
15) (a) Hill, L. L.; Moore, L. R.; Huang, R.; Craciun, R.; Vincent, A. J.;
(
Dixon, D. A.; Chou, J.; Woltermann, C. J.; Shaughnessy, K. H. J. Org.
Chem. 2006, 71, 5117–5125. (b) Hill, L. L.; Smith, J. M.; Brown, W. S.;
Moore, L. R.; Guevara, P.; Pair, E. S.; Porter, J.; Chou, J.; Woltermann,
C. J.; Craciun, R.; Dixon, D. A.; Shaughnessy, K. H. Tetrahedron 2008, 64,
The catalyst derived from complex 10 proved to be a gene-
ral catalyst for the arylation of aniline derivatives (Table 2).
Excellent yields were obtained with para-substituted aryl
6
920–6934.
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TABLE 1. Precatalyst Comparison in the Coupling of 4-Bromoanisole
and Aniline
TABLE 3. Coupling of Aryl Bromides and Secondary Amines Using
Precatalyst 10
% yield
(15 min)
% yield
a
(30 min)
a
entry
precatalyst
(dba) /DTBNpP (1:1)
1
2
3
4
a
Pd
8
9
10
2
3
40
3
2
82
100
4
3
90
Yields determined by GCrelative toan internal standard (mesitylene).
TABLE 2. Coupling of Aryl Bromides and Anilines Using
Precatalyst 10
a
Average isolated yield of product (2 trials) obtained from ArBr (0.8
mmol), amine (1.0 mmol), NaOt-Bu (1.2 mmol), and 10 (1 mol %) in
toluene under air (eq 2). Values in parentheses are yields obtained
previously using the Pd (dba) /DTBNpP catalyst system under identical
conditions, but under an N atmosphere.
2
3
1
5a
2
failed to react using either 10 or the in situ catalyst system,
possibly due to competitive binding to the Pd center. The
catalyst derived from 10 also gave good results in the coupl-
ing of sterically demanding substrates. Coupling of mono-
and di-ortho-substituted aryl bromides (entries 5-7) with
aniline gave excellent yields but required a higher catalyst
loading (2 mol %). The yields using 10 were approximately
2
0% higher than those with the in situ system in these cases.
When hindered anilines 13b and 13c were used (entries 8-13),
higher catalyst loadings (2 mol %) and higher temperatures
(
50 °C) were necessary for complete conversion. Even in the
case of 2-substiuted aryl bromides, yields greater than 95%
were obtained. In contrast, the in situ system gave only a
4
15a
7% yield for the coupling of 4-bromotoluene and 13c.
The catalyst derived from 10 also was effective for the
arylation of the secondary amines such as morpholine (13d)
and N-methylaniline (13e) in air. The arylation of morpho-
line required 2 mol % 10 to achieve complete conversion
within a few hours at 50 °C. Excellent yields were obtained
with 4-bromoanisole (12a) and 2-substituted aryl bromides
1
2e and 12f (Table 3). The yields obtained with 10 are
comparable to those previously reported with the in situ
catalyst system. Arylation of N-methylaniline also could be
achieved in high yield. With the unhindered substrate 12a,
the reaction could be carried out at room temperature with
1 mol % 10 to give a nearly quantitative yield of product
a
Average isolated yield of product (2 trials) obtained from ArBr (0.8
mmol), amine (1.0 mmol), NaOt-Bu (1.2 mmol), and 10 (1 mol %) in
toluene under air (eq 2). Values in parentheses are yields obtained
previously using the Pd (dba) /DTBNpP catalyst system under identical
conditions, but under a N
2
3
15a
atmosphere.
2
(entry 4). The 2-substituted substrates 12e and 12f required
bromides and aniline (entries 1-3). Yields of these reactions
were comparable to those obtained under inert conditions
with the in situ catalyst derived from Pd (dba) /DTBNpP
except in the case of substrate 12b. With this electron-rich
aryl bromide, the catalyst derived from 10 gave a higher yield
than obtained with the in situ catalyst. 4-Bromobenzonitrile
that the reaction to be run at 50 °C. For the deactivated
substrate 12f, 2 mol % 10 was required. The yields were
comparable to those obtained with the in situ system with the
exception of the coupling of 12e and 13e. In this case, the
yield with 10 was 74% in comparison to 90% for the in situ
system.
2
3
6
480 J. Org. Chem. Vol. 75, No. 19, 2010

Hill et al.
Aryl chlorides are more challenging substrates than aryl bro-
JOCArticle
TABLE 4. Coupling of Aryl Chlorides and Amines Using Precatalyst 10
16
mides because of their larger bond dissociation energies. The
Pd (dba) /DTBNpP in situ catalyst system was previously
shown to be moderately active toward the coupling of aryl
2
3
15a
chlorides and amines. Good yields could be obtained, but
the reactions typically required higher temperatures (80-
140 °C) and/or higher catalyst loadings (1-5 mol %). Initial
attempts to carry out the amination of aryl chlorides in air with
catalyst 10 gave low conversions presumably as a result of the
faster rate of catalyst decomposition at higher temperature.
Therefore, all reactions with aryl chlorides were carried out
under nitrogen. A direct comparison of the catalyst derived
from 10 and the in situ system was carried out in the coupling
of 4-chloroanisole (15a) and aniline (13a) at 80 °C using 1 mol
%
Pd (eq 3). Precatalyst 10 gave 43% conversion (GC) after
4
h, while the in situ system had only reached 28% conversion.
After 9 h, the catalyst derived from 10 had completely con-
verted the aryl chloride to the product. In contrast, only 38%
conversion was obtained with the in situ catalyst after 9 h.
Thus, it appears that the catalytic species derived from 10 is
more suitable for the coupling of aryl chlorides than the
catalyst generated in situ from Pd (dba) and DTBNpP.
2
3
Since complex 10 showed good activity for the coupling of
aryl chlorides, it was applied to the coupling of 4-chloroani-
sole (15a), 2-chlorotoluene (15b), and 2-chloroanisole (15c)
with a range of amines (eq 4, Table 4). All reactions were
carried out using 1 mol % 10 under nitrogen at 80 to 100 °C.
Coupling of 15a with aniline gave an excellent yield (97%) at
a
Average isolated yields obtained from the reaction of ArCl (0.8
mmol), amine (1.0 mmol), NaOt-Bu (1.2 mmol), 10 (1 mol %) in toluene
under nitrogen (eq 4).
8
0 °C. The more hindered substrates 15b and 15c required
higher temperature (100 °C) but also gave excellent yields for
the arylation of aniline (entries 2-3). Sterically hindered
mesityl amine (13b) was coupled with 4-chloroanisole in 95%
yield at 100 °C. With the more hindered aryl chloride 15b,
only a 54% yield was obtained with 13b. In contrast, the in
situ system required temperatures of 120-140 °C to couple
reaction could be carried out efficiently at 80 °C using 1 mol
% catalyst. With more hindered substrates (15b and 15c), the
reaction had to be performed at 100 °C to achieve complete
conversion when the catalyst loading is 1 mol % 10. Using
the in situ catalyst system, 15a could be coupled with
morpholine at 80 °C but required 5 mol % Pd. N-Methylani-
line was arylated in excellent yield at 100 °C using all three
aryl chlorides with the precatalyst, 10. Under similar condi-
tions, the in situ catalyst system required 5 mol % Pd to
achieve similar conversion at 100 °C.
1
5a
aryl chlorides with aniline at 1 mol % loading.
Preliminary Studies of Pd-DTBNpP-Based Catalysts in the
r-Arylation of Aryl Halides. We were also interested in the
structure-activity relationship of the Pd/DTBNpP-based
catalysts in the R-arylation of ketones. As a model reaction,
R-arylation of propiophenone with an electron-neutral sub-
strate, 4-chlorotoluene, was performed in the presence of
NaOt-Bu base under 1 M substrate concentration, at two
different temperatures (60 and 100 °C) and catalyst loadings
(1 and 0.1 mol %) (eq 5). Table 5 summarizes the relative
activities of both isolated as well as in situ catalysts. When
With morpholine, a trend similar to that observed for
aniline was seen. With the unhindered 15a substrate, the
(
16) Oxidative addition rate has been correlated to the C-X (X = I, Br,
Cl, F) bond dissociation energy (kcal/mol: Ph-I = 67; Ph-Br = 84;
Ph-Cl = 97.1; Ph-F =126), a deciding factor in the oxidative addition
step of the Pd-catalyzed coupling: (a) Blanksby, S. J.; Ellison, G. B. Acc.
Chem. Res. 2003, 36, 255–263. (b) Grushin, V. V.; Alper, H. Chem. Rev. 1994,
3
the reactions were run at 60 °C, Pd(η -allyl)(DTBNpP)Cl
(
high conversions (Table 5, entries 11 and 14), whereas cata-
10) and Pd (DTBNpP) (μ-Cl)(μ-allyl) (11) led to moderate-
2 2
9
1
4, 1047–1062. (c) McMillen, I. F.; Golden, D. M. Annu. Rev. Phys. Chem.
982, 33, 493. (d) Cox, J. D.; Pilcher, G. Thermochemistry of Organic and
Orgonometallic Compounds; Academic Press: London, 1970.
lysts 8 and 9 showed no conversion (Table 5, entries 5 and 8).
J. Org. Chem. Vol. 75, No. 19, 2010 6481

Hill et al.
JOCArticle
TABLE 5. Catalyst Effect in the R-Arylation of Propiophenone with
TABLE 6. Catalyst Effect in the R-Arylation of Propiophenone with
4-Bromoanisole
a
a
4-Chlorotoluene
b
catalyst
loading conv
(mol %) (%)
entry
precatalyst
T (°C)
conv (%)
solvent/T
(°C)
b
1
2
3
4
5
6
7
8
Pd
Pd
2
(dba)
(dba)
3
/DTBNpP (1/1)
/DTBNpP (1/2)
60
60
rt
60
rt
60
rt
60
rt
39
49
NR
95
73
85
61
97
entry
precatalyst
2
3
1
2
3
4
5
6
7
8
9
Pd
2
2
(dba)
3
/DTBNpP (1/1)
/DTBNpP (1/2)
THF/60
Dioxane/100
THF/60
Dioxane/100
THF/60
Dioxane/100
Dioxane/100
THF/60
Dioxane/100
Dioxane/100
1
1
52
42
Pd(DTBNpP)
2
(8)
Pd
(dba)
3
1
1
8
83
Pd(DTBNpP) Cl
2
2
(9)
3
Pd(DTBNpP)
2
(8)
1
1
0.1
1
1
0.1
1
1
0.1
1
1
0.1
NR
>99
55
Pd(DTBNpP)(η -allyl)Cl (10)
Pd (DTBNpP) (μ-Cl)(μ-allyl) (11)
[Pd(μ-Br)(TTBP)] (3)
d
9
2
2
44
76
Pd(DTBNpP)
2
Cl
2
(9)
NR
>99
66
10
11
12
a
60
rt
60
c
c
95
2
d
10
11
12
13
14
15
16
a
99
3
Pd(DTBNpP)(η -allyl)Cl (10) THF/60
Dioxane/100
78
79
20
78
68
18
Reaction conditions: 2 mmol of 4-bromoanisole, 2.2 mmol of
propiophenone, 2.2 mmol of NaOt-Bu, 0.02 mmol of catalyst, 2 mL
THF, 20 h unoptimized reaction time. GC conversion. 89% isolated
yield.
Dioxane/100
THF/60
Dioxane/100
Dioxane/100
b
c
Pd
2 2
(DTBNpP) (μ-Cl)-
(μ-allyl) (11)
gave much better activity in comparison to the in situ system:
Pd (dba) /DTBNpP (Pd/DTBNpP = 1/2) (Table 5, entries 6
and 9 vs entry 4). The Pd(I) dimer 11 behaved somewhat
similar to 10, with slightly lower conversions (Table 5, entry
4-16).
A similar study was carried out for a challenging aryl
Reaction conditions: 2 mmol of 4-chlorotoluene, 2.2 mmol of
2
3
propiophenone, 2.2 mmol of NaOt-Bu, 0.02 mmol of catalyst, 2 mL of
b
solvent, 60 °C, 20 h unoptimized reaction time (eq 5). GC conversion.
c
8
d
5% isolated yield. Reaction conditions: 5 mmol of 4-chlorotoluene,
.5 mmol of propiophenone, 5.5 mmol of NaOt-Bu, 0.005 mmol of
1
5
catalyst (S/C 1000), 5 mL dioxane, 100 °C, 20 h.
bromide substrate (4-bromoanisole), but under milder con-
ditions (room temperature and 60 °C, Table 6). At room
temperature, the isolated catalyst Pd(DTBNpP) Cl was the
Notably, at this lower temperature, the catalytic systems
with a Pd/ligand molar ratio of 1:1 performed better than the
systems with a 1:2 Pd/L molar ratio (Table 5, entries 1 and
2
2
most reactive catalytic system in the DTBNpP series (73%
conversion, entry 5), while [Pd(μ-Br)(TTBP)] led to 95%
1
1 vs entries 3, 5, and 8). However, at higher temperatures
100 °C), the reactivity trend was reversed. The catalysts with
a Pd/DTBNpP ratio of 1:2 gave quantitative conversions
Table 5, entries 6 and 9 vs entry 12). A more pronounced
2
(
conversion at room temperature. Interestingly both the PdL
based neopentyl catalysts (10 and 11) were slightly inferior
under identical conditions. When the temperature was in-
(
difference in reactivity was observed between PdL (8 and 9)
2
and PdL (10) DTBNpP-based catalysts at lower catalyst
loadings (entries 7 and 10 vs entry 13).
creased to 60 °C, Pd(DTBNpP) (8) gave nearly quantitative
2
conversion to the desired product (entry 4). Similarly to the
amination reactions and to the R-arylation of 4-chloroto-
luene, the isolated catalysts were found to perform better
compared to their in situ systems (entries 4 and 6 vs entries
1
and 2). The substrate scope of these catalysts in the
R-arylation of various carbonyl compounds is currently
under investigation and will be addressed in a separate paper.
These results could be explained on the basis that generally
the 12-electron Pd(0)L species is kinetically more active than
the coordinatively saturated 14-electron Pd(0)L counter-
2
5
a,c
Structural Characterization of Palladium Complexes.
Complexes 8-11 gave X-ray quality crystals upon recrys-
tallization from cold hexane (Figures 4-7). The complexes
had structural characteristics similar to those of previously
part at lower temperatures.
Grasa and Colacot have
0
reported that the bulky electron-rich bidentate 1,1 -bis(di-
tert-butylphosphino)ferrocene ligand (DtBPF) remains co-
ordinated during catalysis based on the NMR spectroscopic
evidence. These results indicate the presence of Pd(0)-
1
7
18
3
reported structures of PdL , trans-PdL Cl , Pd(η -allyl)-
2
2
2
1
9
14d
(
L)Cl, and Pd (DTBNpP) (μ-allyl)(μ-Cl)
(L = steri-
2
2
(DtBPF) species at the ground state, which suggests that
the 14-electron Pd(DTBNpP) complex could directly under-
cally demanding alkylphosphine). One feature of note is
the response of the neopentyl substituent to changes in the
coordination environment at the metal center. In the case
4
a
go oxidative addition at elevated temperature. Alterna-
tively, if the PdL species were required, as is generally hypo-
3
thesized for sterically demanding monodentate ligands,
(17) Tanaka, M. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1992,
higher temperature would promote ligand dissociation from
PdL2 species to form the active PdL species. At higher
temperature, the PdL species would presumably be more
C48, 739–740.
(18) DiMeglio, C. M.; Ahmed, K. J.; Luck, L. A.; Weltin, E. E.; Rheingold,
A. L.; Bushweller, C. H. J. Phys. Chem. 1992, 96, 8765–8777.
2
(19) (a) Viciu, M. S.; Navarro, O.; Germaneau, R. F.; Kelly, R. A., III;
stable than low-coordination PdL species, however. Thus
at higher temperature, a higher L/Pd ratio could lead to
catalysts with longer lifetimes than those derived from the
optimal 1:1 ratio. Notably, at 100 °C, precatalysts 8 and 9
Sommer, W.; Marion, N.; Stevens, E. D.; Cavallo, L.; Nolan, S. P. Organo-
metallics 2004, 23, 1629–1635. (b) Albert, J.; Bosque, R.; Cadena, J. M.;
Delgado, S.; Granell, J.; Muller, G.; Ordinas, J. I.; Bardia, M. F.; Solans, X.
Chem.;Eur. J. 2002, 8, 2279–2287. (c) Alberti, D.; Goddard, R.; P o€ rschke,
K.-R. Organometallics 2005, 24, 3907–3915.
6
482 J. Org. Chem. Vol. 75, No. 19, 2010

Hill et al.
JOCArticle
FIGURE 4. Thermal ellipsoid plot (50% level) of the molecular
structure of Pd(DTBNpP) (8). Ellipsoids are drawn at the 50%
2
level. Hydrogen atoms on the DTBNpP ligand have been removed
˚
for clarity. Selected bond lengths (A) and angles (deg): Pd1-P1,
FIGURE 6. Thermal ellipsoid plot (50% level) of the molecular
structure of Pd(η -allyl)(DTBNpP)Cl (10). Hydrogen atoms on the
DTBNpP ligand have been removed for clarity. Selected bond
3
2.2961(4); P1-C1, 1.869(1); P1-C6, 1.893(2); P1-C10, 1.894(2);
P1-Pd1-P1, 180.0; C1-P1-C6, 101.55(7); C1-P1-C10, 102.17(7);
C1-P1-Pd1, 118.14(5); C6-P1-C10, 110.58(7); C6-P1-Pd1
˚
lengths (A
2.3781(7); Pd1-C14, 2.198(3); Pd1-C15, 2.145(3); Pd1-C16,
.121(4); P1-C1, 1.862(3); P1-C10, 1.900(2); P1-C6, 1.893(3);
P1-Pd1-Cl1, 103.98(2); C16-Pd1-P1, 97.9(1); C14-Pd1-Cl1,
) and angles (deg): Pd1-P1, 2.3439(6); Pd1-Cl1,
1
12.12(5); C10-P1-Pd1, 111.48(5); C2-C1-P1, 119.62(9).
2
9
0.5(1); C6-P1-Pd1, 114.93(8); C10-P1-Pd1, 107.90(9); C1-
P1-Pd1, 114.76(9); C2-C1-P1, 126.3(2).
the P-C-C(Me) angle. For less-hindered complexes 8 and
3
1
1, which are able to adopt Pd-P-C-C(Me) dihedral
3
angles near zero, the P-C-C(Me) angles are 119.62(9)°
3
and 122.1(3)°, respectively. Complexes 9 and 10, with more
hindered Pd centers, have larger P-C-C(Me) angles of
3
1
26.52(9)° and 126.3(2)°, respectively, which reflects the
additional steric strain of these systems. These results suggest
that the neopentyl substituent has a certain degree of con-
formational flexibility to allow coordination of additional
ligands at Pd.
Initial Studies of the Generation of the Active Species from
0. The improved performance of precatalyst 10 for the
1
arylation of amines compared to the in situ catalyst system
raises the question of how the active species generated from
FIGURE 5. Thermal ellipsoid plot (50% level) of one of the two
molecules of trans-Pd(DTBNpP) Cl (9) in the asymmetric unit.
Hydrogen atoms have been removed for clarity. Selected bond
1
0 differs from that obtained from Pd (dba) and DTBNpP.
2 3
2
2
Combinations of Pd (dba) and DTBNpP give exclusively
2 3
˚
lengths (A) and angles (deg) for both unique molecules: Pd-P,
Pd(DTBNpP) (8) as the P/Pd ratio is varied from 1 to 3 as
2
3
1
2
1
.4148(4), 2.4082(4); Pd-Cl, 2.3036(4), 2.3096(4); P-C1, 1.8522(14),
.8518(13); P-C6/10, 1.9031(14), 1.9079(14), 1.9017(13), 1.9027(14);
determined by P NMR spectroscopy. This result is similar
to what has previously been reported for the TTBP/Pd (dba)
2
3
Cl-Pd-P, 90.78(1), 89.22(1), 91.79(1), 88.21(1); C1-P-C6/10,
5c
system. Complex 8 acts as a precursor to the 12-electron
100.92(6), 106.85(6), 106.65(6), 101.70(6); C6-P-C10, 109.04(6),
108.85(6); C1-P-Pd, 112.60(5), 113.45(5); C10-P-Pd 120.16(4),
119.66(4); C6-P-Pd 105.53(4), 104.99(4); C2-C1-P, 126.24(9),
126.52(9).
3
Pd(DTBNpP) active species (18), which cannot be observed
31
by P NMR spectroscopy. In the case of 10, we presumed that
a nucleophilic species (i.e., tert-butoxide) would displace the
allyl ligand to generate the Pd(DTBNpP) active species in
solution. The Pd(DTBNpP) complex would be expected to
0
of 8, the neopentyl arms are essentially syn coplanar with the
Pd-P bond (Pd1-P1-C1-C2 = 0.3(1)°) resulting in the
neopentyl group exerting maximal steric demand. This con-
formation is similar to the calculated structure of Pd-
disproportionate into Pd(DTBNpP) and uncoordinated Pd
2
in the absence of other trapping ligands. Nolan has proposed a
similar activation mechanism for Pd(allyl)NHC precatalysts
and has trapped the transient Pd(NHC) complex with phos-
1
5a
(DTBNpP). In contrast, complexes 9 and 10 have large
19a,20
phine ligands.
To test this hypothesis, a solution of 10 was treated with
Pd-P-C-C(Me) dihedral angles (9, 64.5(1)° and 64.3(1)°;
3
1
0, -59.8(3)°) to allow space for the other substituents at the
3
1
1
1
.3 equiv of NaOt-Bu in C D . A P{ H} NMR spectrum
6 6
Pd center. The Pd(I) μ-allyl complex (11) has small Pd-P-
C-C(Me) dihedral angles of 0.5(3)° and 3.2(3)° similar to
3
that of 8. The steric strain in these systems can also be seen in
(20) Fantasia, S.; Nolan, S. P. Chem.;Eur. J. 2008, 14, 6987–6993.
J. Org. Chem. Vol. 75, No. 19, 2010 6483

Hill et al.
JOCArticle
3
FIGURE 7. Thermal ellipsoid plot (50% level) of the molecular structure of [Pd(μ-η -allyl)(DTBNpP)(μ-Cl)]
2
(11). Hydrogen atoms on the
˚
DTBNpP ligand have been removed for clarity. Selected bond lengths (A) and angles (deg): Pd1-Pd2, 2.6561(5); Pd1-P1, 2.336(1); Pd1-Cl1,
2
1
1
.430(1); Pd1-C1, 2.063(4); Pd1-C2, 2.388(4); Pd2-P2, 2.3219(9); Pd2-Cl1, 2.426(1); Pd2-C3, 2.044(4); Pd2-C2, 2.389(4); P1-C9,
.899(4); P1-C4, 1.870(4); P1-C13, 1.909(4); P1-Pd1-Cl1, 111.13(4); P1-Pd1-C1, 104.45(11). Pd1-P1-C9, 111.18(13); Pd1-P1-C4,
20.3(1); P1-C4-C5, 120.8(3), P2-Pd2-Cl1, 111.63(3); P2-Pd2-C3, 104.7(1); Pd2-P2-C22, 108.6(1); Pd2-P2-C17, 117.5(1);
P2-C17-C18, 122.1(3).
taken after 10 min (see Supporting Information) showed com-
plete loss of 10 and formation of 11 (79%) along with small
amounts of 8 (6%), and free DTBNpP (15%). These results
SCHEME 1. Proposed Mechanism for the Generation of the
Active Species from 10 in the Presence of NaOt-Bu
are consistent with previous reports of the synthesis of [Pd(μ-
3
allyl)(L)Cl] complexes by treatment of Pd(η -allyl)(L)Cl with
2
14d,21
hydroxide or alkoxide bases.
The Pd(DTBNpP) complex
appears to form, but rapidly reacts with 10 to form 11. Under
the catalytic conditions, the aryl halide would presumably
compete with 10 for the Pd(DTBNpP) intermediate. To deter-
mine whether 11 is formed under the catalytic reaction condi-
tions, the coupling of 4-bromotoluene and aniline was carried
out under our normal conditions, but with a higher loading
of 10 (7.5 mol %). The reaction mixture was then analyzed by
31
1
P{ H} NMR spectroscopy (see Supporting Information).
A complex spectrum was obtained with major peaks at 59
(
(
10, 4%), 53 (26%), 51.5 (8%), 49.8 (11, 34%), 46.7 (6%), 44.2
8, 10%), and 18.5 (DTBNpP, 12%) ppm. The species res-
ponsible for the peaks at 53, 51.5, and 46.7 ppm have not
been identified, although these may be oxidative addi-
tion products as they were observed only in the presence of
aryl bromide.
These results show that in the presence of an alkoxide
nucleophile, 10 is rapidly converted to the Pd(I) dimer 11.
Presumably, the reaction of tert-butoxide with 10 results in
the generation of Pd(DTBNpP) (18), which is then trapped
by unreacted 10 to give 11 (Scheme 1). Complex 11 is also
observed as a major phosphorus-containing species under
the catalytic reaction conditions. We hypothesize that the
Pd(DTBNpP) species generated from 10 can be competi-
tively trapped by the aryl halide (catalytic cycle) or by
remaining 10 to produce 11. The role of complex 11 in the
catalytic reaction is not yet known. Complex 11 could serve
as a source of 18 if its formation is reversible, alternatively
it could be a catalyst deactivation pathway if its formation
is not reversible. Initial studies show that complex 11 is a
competent precatalyst in the enolate arylation reactions,
although it was somewhat less active for the coupling of
identical results. In contrast, complex 11 was a significantly
less effective precatalyst in the coupling of 4-bromoanisole
and N-methylaniline. In this reaction, complex 10 gave 93%
conversion after 1 h, while the catalyst derived from complex
11 gave only 9% conversion. The reaction with complex 11
did reach 91% conversion after 24 h, however. Further
studies on the role of 11 in these catalyst systems are ongoing.
Conclusions
In conclusion, complex 10 serves as an air-stable precata-
lyst that is highly effective for the coupling of aryl halides and
amines. The catalyst derived from 10 is sufficiently air-stable
to allow amination of aryl bromides in air under mild
conditions. Significantly, this catalyst system is highly effec-
tive with electronically and sterically challenging aryl bro-
mide and aniline substrates. Higher yields are obtained in
these cases (Table 2) than with the catalyst generated in situ
from Pd (dba) and DTBNpP. Complex 10 also provides a
4-bromoanisole and propiophenone than 10. In the coupling
of 4-chlorotoluene with propiophenone, 10 and 11 gave
(21) Sieler, J.; Helms, M.; Gaube, W.; Svensson, A.; Lindqvist, O.
J. Organomet. Chem. 1987, 320, 129–136.
2
3
6
484 J. Org. Chem. Vol. 75, No. 19, 2010

Hill et al.
JOCArticle
by column chromatography through SiO using a mixture of
hexanes and ethyl acetate as the eluent.
N-Phenyl-p-anisidine (Table 2, entry 1). Using the general
procedure, 4-bromoanisole (100 μL, 0.799 mmol) and aniline
more active catalyst for the amination of aryl chlorides than
the catalyst generated in situ, allowing the reactions to
be carried out at moderate temperatures with low catalyst
loadings. Complex 10 gave a more active catalyst for the
coupling of 4-bromoanisole with propiophenone than the in
situ catalyst system. Precatalysts 8 and 9 gave results com-
parable to those using 10, in contrast to the amination
reaction where these precatalysts were completely ineffec-
tive. The catalyst derived from 10 also gave good yields in the
coupling of 4-chlorotoluene with propiophenone, but the
catalysts derived from 8, 9, and DTBNpP/Pd (dba) (2:1 L/
2
2
2
(
91 μL, 1.0 mmol) were coupled using 1 mol % 10 at room
temperature. Purification by flash chromatography yielded a
1
tan solid (141 mg, 89%). H NMR (500 MHz, CDCl ): δ 7.22 (t,
3
J = 7.57 Hz, 2H), 7.08 (d, J = 7.25 Hz, 2H), 6.91 (d, J = 7.57,
2
MHz, CDCl
13
H), 6.86 (m, 3H), 5.49 (bs, 1H), 3.81 (s, 3H). C NMR (90.6
3
): δ 155.0, 144.9, 135.5, 129.0, 121.9, 119.3, 115.4,
1
14.4, 55.3. Mp: 102-103 °C, lit. mp 104-105.
N,N-Dimethyl-N -phenylbenzene-1,4-diamine (Table 2, entry 2).
0
23
2
3
Pd) gave higher yields. Complexes 8, 9, 10, and 11 were
structurally characterized. Complex 10 reacts with NaOt-Bu
to generate the μ-allyl Pd(I)-dimer 11 even in the presence of
aryl halides. Complex 11 is an air-stable Pd(I) species that is
catalytically competent in the coupling of aryl halides with
propiophenone, which suggests that it may serve as a stable
resting state under the catalytic conditions. Although we are
reporting the C-N coupling of aryl bromides using 10 at
room temperature in air to prove the concept, we recommend
large-scale operations be carried under inert conditions as
organic solvents need to be handled under nitrogen for safety
reasons.
Using the general procedure, aniline (91 μL, 1.0 mmol), and
4-bromo-N,N-dimethylaniline (156.9 mg, 0.7845 mmol) were
coupled using 1 mol % 10 at room temperature to give the product
1
as a gray solid (161.0 mg, 99%). H NMR (500 MHz, CDCl
3
):
δ 7.19 (t, J = 7.25 Hz, 2H), 7.07 (d, J = 8.83 Hz, 2H), 6.86 (d,
J = 7.57 Hz, 2H), 6.80-6.74 (m, 3H), 5.42 (bs, 1H), 2.93 (s, 6H).
13
C NMR (90.6 MHz, CDCl ): δ 147.3, 146.1, 132.4, 129.2,
3
24
1
23.3, 118.8, 115.0, 114.0, 41.2. Mp: 123-125 °C, lit. mp
26-128 °C.
1
25
N-Phenyl-p-toluidine (Table 2, entry 3). Using the general
procedure, 4-bromotoluene (102 μL, 0.829 mmol) and aniline
(91 μL, 1.0 mmol) were coupled using 1 mol % 10 at room
temperature to give the product as a tan solid (146 mg, 88%). H
1
NMR (500 MHz, CDCl ): δ 7.28-7.22 (m, 2H), 7.10 (d, J=
3
8
.17 Hz, 2H), 7.04-6.99 (m, 4H), 6.89 (t, J = 7.50 Hz, 1H), 5.63
Experimental Section
13
(
bs, 1H), 2.32 (s, 3H). C NMR (90.6 MHz, CDCl ): δ 144.2,
3
General Experimental Details. Complexes 8-11 are available
in gram to multikilograms through JMCCT. DTBNpP was
obtained from FMC, Lithium Division as a 10 weight% solu-
tion in toluene. Toluene was distilled from sodium under nitro-
gen. All other reagents were obtained from commercial sources
and used as received. Reactions carried out in air were as-
sembled on the benchtop using reagents that had not been
degassed in glass vials that were sealed under air with rubber
septa. Reactions carried out under inert conditions were as-
sembled in a nitrogen-filled glovebox using deoxygenated re-
agents and solvents and carried out in septum-sealed vials under
140.6, 131.2, 130.1, 129.5, 120.5, 119.2, 117.1, 20.9. Mp: 86-
26
87 °C, lit. mp 87-88
6
e
N-Phenyl-o-toluidine (Table 2, entry 5). Using the general
procedure, aniline (91 μL, 1.0 mmol) and 2-bromotoluene
(94 μL, 0.78 mmol) were coupled using 2 mol % 10 at room
temperature to give the product as a brown oil (146.0 mg, 99%).
H NMR (500 MHz, CDCl
1
3
): δ 7.19 (d, J = 7.25 Hz, 1H),
.13 (t, J = 7.25 Hz, 1H), 6.94 (t, J = 5.99 Hz, 3H), 6.89 (t, J=
7
6
1
3
.31 Hz, 1H), 5.36 (s, 1H), 2.25 (s, 3H). C NMR (90.6 MHz,
): δ 143.7, 140.9, 130.7, 129.0, 128.1, 126.5, 121.7, 120.2,
18.6, 117.2, 17.6.
N-Phenyl-o-anisidine (Table 2, entry 6). Using the general
procedure, 2-bromoanisole (99 μL, 0.79 mmol) and aniline
CDCl
1
3
1
13
2
7
nitrogen. H and C NMR spectra are referenced to the NMR
3
1
1
solvent peaks or internal TMS. P{ H} NMR spectra were
externally referenced to 85% H PO . HRMS were obtained on a
magnetic sector mass spectrometer operating in the EI mode.
3
4
(
The product (145 mg, 91%) was obtained as a brown oil after
91 μL, 1.0 mmol) were coupled using 2 mol % 10 at 50 °C.
3
1
purification by flash chromatography. H NMR (500 MHz,
Procedure for the Preparation of Pd(η -allyl)(DTBNpP)Cl
10). In a glovebox, a vial was charged with [Pd(allyl)Cl] (200
2
(
CDCl
.57, 1H), 6.88 (m, 3H), 6.14 (s, 1H), 3.88 (s, 3H). C NMR
90.6 MHz, CDCl ): δ 148.5, 143.0, 133.3, 129.5, 121.4, 121.0,
20.1, 118.8, 114.9, 110.8, 55.8.
,6-Dimethyl-N-phenylaniline (Table 2, entry 7). Using the
3
): δ 7.27,(m, 3H), 7.14 (d, J = 8.51 Hz, 2H), 6.93 (t, J =
13
mg, 0.546 mmol), 2 equiv of DTBNpP (2.43 mL, 1.10 mmol),
and toluene (10 mL). The reaction mixture was stirred for 3 h
and then gravity filtered to remove any residual palladium
black. The remaining phosphine and solvent were removed
under vacuum (0.1 Torr), leaving behind the desired palladium
7
(
3
1
2
8
2
general procedure, 2-bromo-m-xylene (147.9 mg, 0.7990 mmol)
and aniline (91 μL, 1.0 mmol) were coupled using 2 mol % 10 at
50 °C. The product (147 mg, 95%) was obtained as an off-white
1
solid after purification by flash chromatography. H NMR
1
complex as a yellow solid (350 mg, 80%). H NMR (500 MHz,
C
D
6 6
): δ 4.80-4.72 (m, 1H), 4.56 (t, J = 6.84 Hz, 1H), 3.44 (dd,
J = 8.97, 13.27 Hz, 1H), 3.47 (bs, 1H), 2.21 (d, J = 11.55 Hz,
1
9
H), 2.14 (d, J = 11.71 Hz, 1H), 2.01 (t, J = 11.64, 1H), 1.29 (s,
(
6
500 MHz, CDCl ): δ 7.12 (m, 5H), 6.76 (t, J = 7.25 Hz, 1H),
3
1
3
1
.51 (d, J = 7.88 Hz, 2H), 5.18 (s, 1H), 2.22 (s, 6H). C NMR
3
H), 1.22 (d, J = 12.91 Hz, 9H), 1.14 (d, J = 12.66 Hz, 9H).
): δ 113.8 (d, JC-P = 4.42 Hz), 80.3 (d,
C-P = 19.88 Hz), 54.0, 34.7 (d, JC-P = 7.24 Hz), 33.2 (d,
C
6 6
NMR (90.6 MHz, C D
(
1
90.6 MHz, DMSO): δ 146.3, 138.3, 135.9, 129.2, 128.5, 125.7,
18.2, 113.5, 18.3. Mp: 50-52 °C, lit. mp 52-53 °C.
J
J
3
1
1
= 6.20 Hz), 31.3, 30.6. P{ H} NMR (C D ): δ 59.0 (s).
C-P
6
6
Calculated for C16
7.99; H, 8.63.
H34ClPPd: C, 48.13; H, 8.58. Found: C,
(
22) McNulty, J.; Cheekoori, S.; Bender, T. P.; Coggan, J. A. Eur. J. Org.
Chem. 2007, 1423–1428.
23) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 3694–
703.
4
(
General Procedure for Hartwig-Buchwald Amination of Aryl
3
Bromides with Primary and Secondary Amines. A vial was
charged with 10 (1-2 mol %), sodium tert-butoxide (96.1 mg,
(
24) Geller, B. A.; Samosvat, L. S. Zh. Obsh. Khim. 1961, 31, 1681–1684.
25) Li, G. Y.; Zeng, G.; Noonan, A. F. J. Org. Chem. 2001, 66, 8677–
(
8681.
1
.20 mmol), aryl bromide (0.8 mmol), amine (1.0 mmol), and
(
(
26) McNab, H. J. Chem. Soc., Perkin Trans. 1 1980, 2200–2204.
27) Gajare, A. S.; Toyota, K.; Yioshifuji, M.; Ozawa, F. J. Org. Chem.
toluene (2 mL) in the presence of air and sealed under air.
Reactions were allowed to stir at room temperature unless
otherwise noted. All reactions were monitored by GC to ensure
completion, which typically took 3-6 h. Products were purified
2
004, 69, 6504–6506.
28) Li, J.; Cui, M.; Yu, A.; Wu, Y. J. Organomet. Chem. 2007, 692, 3732–
3742.
(
J. Org. Chem. Vol. 75, No. 19, 2010 6485

Hill et al.
JOCArticle
N-(4-Methoxyphenyl)-2,4,6-trimethylaniline (Table 2, entry 8).
2
9
6.71 (m, 2H), 6.14 (d, J = 7.57 Hz, 1H), 5.66 (s, 1H), 3.99 (s, 3H),
1
3
Using the general procedure, 2,4,6-trimethylaniline (140 μL, 0.994
mmol) and 4-bromoanisole (100 μL, 0.799 mmol) were coupled
using 2 mol % 10 at 50 °C. The product (175.0 mg, 91%) was
3.19 (sept, J = 6.94 Hz, 2H), 1.17 (d, J = 6.62, 12H). C NMR
(90.6 MHz, CDCl ):δ 147.7, 146.3, 137.9, 135.5, 127.1, 123.7,
121.2, 116.7, 111.0, 109.8, 55.7, 28.1, 23.9.
3
3
4
obtainedas atansolidafter purificationbyflashchromatography.
N-(4-Methoxyphenyl)morpholine (Table 3, entry 1). Using
the general procedure, morpholine (70 μL, 0.80 mmol) and
4-bromoanisole (100 μL, 0.799 mmol) were coupled using 2
1
3
H NMR (500 MHz, CDCl ): δ 6.95 (s, 2H), 6.76 (d, J = 9.14 Hz,
2
3
1
9
H), 6.49 (d, J = 8.83 Hz, 2H), 4.96 (bs, 1H), 3.77 (s, 3H), 2.33 (s,
13
H), 2.19 (s, 6H). C NMR (90.6 MHz, CDCl ): δ 152.5, 140.6,
mol % 10 at 50 °C to yield the product (147.0 mg, 95%) as a light
3
1
36.6, 135.1, 134.7, 129.2, 114.8, 107.7, 55.7, 20.9, 18.2. Mp:
8-99 °C, lit. mp 100.5-101.5 °C.
N-(2-Methylphenyl)-2,4,6-trimethylaniline (Table 2, entry 9).
brown solid after purification by flash chromatography.
H
NMR (500 MHz, CDCl
J = 4.73 Hz, 4H), 3.77 (s, 3H), 3.06 (t, J = 4.88 Hz, 4H).
3
): δ 6.88 (q, J = 9.62 Hz, 4H), 3.86 (t,
3
0
13
C
Using the general procedure, 2,4,6-trimethylaniline (140 μL, 0.994
mmol) and 2-bromotoluene (96 μL, 0.80 mmol) were coupled
using 1 mol % 10 at 50 °C. The product (153.6 mg, 85%) was
NMR (90.6 MHz, CDCl ): δ 154.0, 146.6, 117.8, 114.5, 67.0,
3
55.5, 50.8. Mp: 69-70 °C, lit. mp 71 °C.
3
2
N-(2-Methylphenyl)morpholine (Table 3, entry 2). Using the
general procedure, morpholine (70 μL, 0.80 mmol) and 2-bro-
motoluene (96 μL, 0.80 mmol) were coupled using 2 mol % 10 at
room temperature to give the product (128.0 mg, 90%) as an
obtained as a peach solid after purification by flash chromato-
1
graphy. H NMR (500 MHz, CDCl
3
): δ 7.14 (d, J = 7.25 Hz, 1H),
6
.98 (m, 3H), 6.71 (t, J = 7.25 Hz, 1H), 6.15 (d, J = 7.88 Hz, 1H),
13
1
4.89 (bs, 1H), 2.34 (d, J = 5.26 Hz, 6H), 2.17 (s, 6H). C NMR
orange oil after purification by flash chromatography. H NMR
(500 MHz, CDCl ): δ 7.18 (q, J = 7.57 Hz, 2H), 7.00 (q, J =
(
90.6 MHz, CDCl ): δ 144.5, 136.0, 135.6, 135.2, 130.2, 129.2,
3
3
1
3
7.25 Hz, 2H), 3.85 (m, 4H), 2.91 (m, 4H), 2.31 (s, 3H). C NMR
1
26.9, 122.1, 117.8, 111.5, 20.9, 18.1, 17.6. Mp: 75-77 °C, lit. mp
78.5-79.5
(90.6 MHz, CDCl
67.1, 52.0, 17.5.
3
): δ 151.0, 132.3, 130.9, 126.3, 123.1, 118.7,
31
N-(2-Methoxyphenyl)-2,4,6-trimethylaniline (Table 2, entry 10).
Using the general procedure, 2,4,6-trimethylaniline (140 μL, 0.994
mmol) and 2-bromoanisole (99 μL, 0.79 mmol) were coupled
3
2
N-(2-Methoxyphenyl)morpholine (Table 3, entry 3). Using
the general procedure, morpholine (70 μL, 0.80 mmol), 2-bro-
moanisole (99 μL, 0.79 mmol) were coupled using 2 mol % 10 at
50 °C. The product (136.3 mg, 88%) was obtained as an orange
using 2 mol % 10 at 50 °C. The product (188.0 mg, 98%) was
1
obtained as a peach solid. H NMR (500 MHz, CDCl ): δ 7.11 (d,
3
1
J = 7.25 Hz, 1H), 6.94 (s, 3H), 6.68 (t, J = 7.25 Hz, 1H), 6.14 (d,
oil after purification by flash chromatography. H NMR (500
13
J = 7.88, 1H), 4.85 (s, 1H), 2.30 (9s, 6H), 2.14 (s, 6H). C NMR
90.6 MHz, CDCl ): δ 144.7, 136.2, 135.8, 135.4, 130.4, 129.4,
MHz, CDCl
J = 7.88 Hz, 1H), 3.89 (t, J = 4.73 Hz, 4H), 3.87 (s, 3H), 3.08 (t,
3
): δ 7.01 (m, 1H), 6.93 (d, J = 4.10 Hz, 2H), 6.87 (d,
(
3
1
3
1
27.1,, 122.3, 118.0, 111.7, 21.1, 18.3, 17.8. Mp: 96-98 °C, lit. mp
J = 4.41 Hz, 4H). C NMR (90.6 MHz, CDCl ): δ 151.3, 132.7,
3
100-100.5 °C.
131.2, 126.7, 123.4, 119.0, 67.5, 52.3, 17.9.
6
e
N-(2,6-Diisopropylphenyl)-p-anisidine (Table 2, entry 11).
Using the general procedure, 2,6-diisopropylaniline (188 μL,
.997 mmol) and 4-bromanisole (100 μL, 0.799 mmol) were
N-Methyl-N-phenyl-p-anisidine (Table 3, entry 4). Using the
general procedure, 4-bromoanisole (100 μL, 0.799 mmol) and
N-methylaniline (108 μL, 1.00 mmol) were coupled using 1 mol
0
coupled using 2 mol % 10 at 50 °C. The product (218.0 mg, 97%)
was obtained as a brown oil after purification by flash chroma-
% 10 at room temperature to yield the product (166.0 mg, 98%)
1
as an orange oil. H NMR (500 MHz, CDCl
7.15 (d, J = 8.83 Hz, 2H), 6.95 (d, J = 8.83 Hz, 2H), 6.84 (m,
3
): δ 7.25 (m, 2H),
1
tography. H NMR (500 MHz, CDCl ): δ 7.24-7.17 (m, 3H),
3
1
3
6
3
.78 (d, J = 9.14, 2H), 6.49 (bd, 2H), 5.00 (bs, 1H), 3.78 (s, 3H),
.24 (t, J =6.94 Hz, 2H), 1.19 (d, J= 6.94, 12H). C NMR
3H), 3.86 (s, 3H), 3.31 (s, 3H). C NMR (90.6 MHz, CDCl ): δ
3
1
3
156.3, 149.8, 142.3, 128.9, 126.2, 118.4, 115.9, 114.8, 55.5, 40.5.
35
(
1
90.6 MHz, CDCl
14.8, 114.3, 55.7, 28.2, 23.9. HRMS-EI (m/z): [M] calcd for
3
): δ 152.3, 147.1, 142.3, 136.1, 126.7, 123.8,
N-Methyl-N-phenyl-o-toluidine (Table 3, entry 5). Using the
general procedure, 2-bromotoluene (96 μL, 0.80 mmol) and
N-methylaniline (108 μL, 1.00 mmol) were coupled using 1 mol %
at 50 °C. The product (140.0 mg, 74%) was obtained as an
þ
C
19
H
25NO 283.1936, found 283.1931.
N-(2,6-Diisopropylphenyl)-o-toluidine (Table 2, entry 12).
Using the general procedure, 2,6-diisopropylaniline (188 μL,
.997 mmol) and 2-bromtoluene (96 μL, 0.80 mmol) were
coupled using 2 mol % 10 at 50 °C. The product (182 mg,
6%) was obtained as an oil after purification by flash chroma-
3
2
1
orange oil after purification by flash chromatography. H NMR
0
(500 MHz, CDCl ):δ 7.17 (m, 6H), 6.70 (t, J = 8.20 Hz, 1H), 6.53
3
1
3
(d, J = 8.83 Hz, 2H), 3.22 (s, 3H), 2.14 (s, 3H). C NMR (90.6
MHz, CDCl ):δ148.9, 146.5, 136.6, 131.1, 128.7, 128.1, 127.2, 126.1,
116.5, 112.6, 38.7, 17.6.
8
3
1
tography. H NMR (500 MHz, CDCl ): δ 7.34-7.30 (m, 1H),
3
28
7
.24 (d, J = 2.27, 1H), 7.14 (d, J = 7.04, 1H), 6.97 (t, J = 6.81
Hz, 1H), 6.69 (t, J = 6.56 Hz, 1H), 6.13 (d, J = 7.04 Hz, 1H) 4.93
bs, 1H), 3.13 (sept, J = 7.04, 2H), 2.36 (s, 3H), 1.16 (dd, J = 19.3
N-Methyl-N-phenyl-o-anisidine (Table 3, entry 6). Using the
general procedure, 2-bromoanisole (99 μL, 0.79 mmol) and
N-methylaniline (108 μL, 1.00 mmol) were coupled using
2 mol % 10 at 50 °C. The product (166.0 mg, 97%) was obtained
(
13
Hz, 12H). C NMR (90.6 MHz, CDCl ): δ 147.3, 146.0, 135.8,
3
1
130.2, 127.1, 123.8, 121.3, 117.5, 111.5, 28.3, 24.8, 23.0, 17.7.
N-(2,6-Diisopropylphenyl)-o-anisidine (Table 2, entry 13).
as a brown oil after purification by flash chromatography. H
3
3
NMR (500 MHz, CDCl
2H) 6.78 (t, J = 7.25 Hz, 1H), 3.83 (s, 3H), 3.28 (s, 3H).
3
): δ 7.30-7.21 (m, 4H), 7.05-7.01 (m,
13
Using the general procedure, 2,6-diisopropylaniline (188 μL,
.997 mmol) and 2-bromanisole (0.8 mmol, 98.0 μL) were
coupled using 2 mol % 10 at 50 °C. The product (217.0 mg,
7%) was obtained as a tan oil after purification by flash
C
0
NMR (90.6 MHz, CDCl ): δ 156.1, 149.6, 136.9, 129.2, 128.8,
3
127.0, 121.4, 117.2, 113.5, 112.8, 55.7, 39.0.
9
General Procedure for Amination of Aryl Chlorides with
Primary and Secondary Amines. Under an inert atmosphere of
nitrogen gas in a glovebox, a vial was charged with 10 (1-2 mol
1
chromatography. H NMR (500 MHz, CDCl ): δ 7.32 (t, J=
3
8
.51 Hz, 2H), 7.26 (t, J = 8.51 Hz, 1H), 6.89 (d, J = 9.14, 1H),
%
), sodium tert-butoxide (96.1 mg, 1.2 mmol), and dry toluene
(2 mL). The vial was then removed from the glovebox, and the
amine (1.0 mmol) and aryl bromide substrates (0.8 mmol) were
(
29) Sapountzis, I.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 897–900.
30) Freeman, H. S.; Butler, J. R.; Freedman, L. D. J. Org. Chem. 1978,
(
3, 4975–4978.
4
(
(
31) Sundberg, R. J.; Sloan, K. B. J. Org. Chem. 1973, 38, 2052–2057.
32) Marion, N.; Ecarnot, E. C.; Navarro, O.; Amoroso, D.; Bell, A.;
(34) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1996, 61, 1133–1135.
(35) Rataboul, F.; Zapf, A.; Jackstell, R.; Harkal, S.; Reiermeier, T.;
Monsees, A.; Dingerdissen, U.; Beller, M. Chem.;Eur. J. 2004, 10, 2983–
2990.
Nolan, S. P. J. Org. Chem. 2006, 71, 3816–3821.
33) Ehrentraut, A.; Zapf, A.; Beller, M. J. Mol. Catal. A: Chem. 2002,
82-183, 515–523.
(
1
6
486 J. Org. Chem. Vol. 75, No. 19, 2010

Hill et al.
JOCArticle
1
13
added via glass microsyringe. Reactions were allowed to stir
under nitrogen at 80-100 °C for 3-6 h. All reactions were
monitored by GC to ensure completion, which typically re-
quired 4-6 h. Products were purified by column chromatogra-
phy through SiO
the eluent.
N-Phenyl-p-anisidine (Table 4, entry 1). Using the general
procedure, 4-chloroanisole (98 μL, 0.80 mmol) and aniline
(91 μL, 1.0 mmol) were coupled using 1 mol % 10 at 80 °C.
The crude product was purified by flash chromatography to
H and C NMR data were identical to the product produced
from 4-bromoanisole (Table 3, entry 4).
3
5
N-Methyl-N-phenyl-o-toluidine (Table 4, entry 10). Using
the general procedure, N-methylaniline (108 μL, 1.00 mmol) and
2-chlorotoluene (96 μL, 0.82 mmol) were coupled using 1 mol %
10 at 100 °C. N-Methyl-N-phenyl-o-toluidine(153 mg, 98%) was
obtained as a brown oil after purification by flash chromato-
2
using a mixture of hexanes and ethyl acetate as
2
2
1
13
graphy. H and C NMR data were identical to the product
produced from 2-bromotoluene (Table 3, entry 5).
2
8
N-Methyl-N-phenyl-o-anisidine (Table 4, entry 11). Using
the general procedure, N-methylaniline (108 μL, 1.00 mmol)
and 4-chloroanisole (98 μL, 0.80 mmol) were coupled using
1 mol % 10 at 100 °C. N-Methyl-N-phenyl-o-anisidine (166.0
mg, 97%) was obtained as an orange oil after purification
1
13
yield an off-white solid (154 mg, 97%). H and C NMR data
were identical to the product produced from 4-bromoanisole
(
Table 2, entry 1). Mp: 100-102 °C, lit. mp 104-105.
6e
N-Phenyl-o-toluidine (Table 4, entry 2). Using the general
procedure, aniline (91 μL, 1.0 mmol) and 2-chlorotoluene
96 μL, 0.82 mmol) were coupled using 1 mol % 10 at 100 °C
1
13
by flash chromatography. H and C NMR data were identi-
cal to the product produced from 4-bromoanisole (Table 3,
entry 6).
(
1
13
to give the product as a brown oil (138 mg, 95%). H and
C
NMR data were identical to the product produced from 2-bro-
motoluene (Table 2, entry 5).
N-Phenyl-o-anisidine (Table 4, entry 3). Using the general
procedure, 2-chloroanisole (102 μL, 0.801 mmol) and aniline
General Procedure for r-Arylation of Propiophenone. 10 and
NaOt-Bu were loaded in a Radley carousel tube in the air. The
tube was evacuated by performing three vacuum/nitrogen refill
cycles and anhydrous solvent, aryl halide and propiophenone
were injected. The resulting mixture was degassed by performing
three vacuum/nitrogen refill cycles and stirred at the indicated
temperature, and conversion was determined by GC.
NMR Study of Precatalyst 10 Activation by NaOt-Bu. In a
nitrogen-filled drybox, an NMR tube was charged with complex
2
7
(
91 μL, 1.0 mmol) were coupled using 1 mol % 10 at 100 °C. The
product (152 mg, 96%) as obtained as a brown oil after
purification by flash chromatography.
29
N-(4-Methoxyphenyl)-2,4,6-trimethylaniline (Table 4, entry 4).
Using the general procedure, 2,4,6-trimethylaniline (140 μL,
.994 mmol) and 4-chloroanisole (98 μL, 0.80 mmol) were
coupled using 1 mol % 10 at 100 °C. N-(4-Methoxyphenyl)-
,4,6-trimethylaniline (183.0 mg, 95%) was obtained as a brown
0
10 (25 mg, 0.06 mmol), NaOt-Bu (7.0 mg, 0.07 mmol), and C
(0.8 mL). The mixture was allowed to stand at room tempera-
6 6
D
3
1
1
2
ture for 10 min and then was analyzed by P{ H} NMR
spectroscopy (see Supporting Information).
1
13
solid after purification by flash chromatography. H and
NMR data were identical to the product produced from 4-bro-
C
NMR Study of Precatalyst 10 Activation under Catalytic
Conditions. In a nitrogen-filled drybox, a vial was charged with
complex 10 (25 mg, 0.06 mmol), NaOt-Bu (96.1 mg, 1.00 mmol),
aniline (93.1 μL, 1.02 mmol), 4-bromoanisole (100 μL, 0.799
mmol), and toluene (1.5 mL). The mixture was allowed to stir at
room temperature for 1 h. An aliquot (0.5 mL) was removed
moanisole (Table 2, entry 8). Mp: 97-98 °C, lit. mp 100.5-
1
01.5 °C.
N-(2-Methylphenyl)-2,4,6-trimethylaniline (Table 4, entry 5).
30
Using the general procedure, 2,4,6-trimethylaniline (140 μL,
.994 mmol) and 2-chlorotoluene (96 μL, 0.82 mmol) were
coupled using 1 mol % 10 at 100 °C. N-(2-Methylphenyl)-
,4,6-trimethylaniline (96.0 mg, 54%) was obtained as a peach
0
and transferred to an NMR tube sealed under nitrogen. C
(0.3 mL) was added as a lock solvent, and the reaction mixture
D
6 6
2
1
31
1
solid after purification by flash chromatography. H and
was analyzed by P{ H} NMR spectroscopy (see Supporting
Information). Major resonances were observed at 59 (10, 4%),
53 (26%), 51.5 (8%), 49.8 (11, 34%), 46.7 (6%), 44.2 (8, 10%),
and 18.5 ppm (DTBNpP, 12%).
1
3
C NMR data were identical to the product produced from
-bromotoluene (Table 2, entry 9). Mp: 76-78 °C, lit. mp
8.5-79.5 °C.
2
7
3
4
N-(4-Methoxyphenyl)morpholine (Table 4, entry 6). Using
X-ray Crystallographic Data. X-ray crystallographic data
collection was performed at 173(2) K using a Siemens SMART
diffractometer with a CCD area detector and graphite mono-
chromated Mo KR radiation. The SHELXTL software, version
the general procedure, morpholine (70 μL, 0.80 mmol) and
-chloroanisole (98 μL, 0.80 mmol) were coupled using 1 mol
4
%
10 at 80 °C yielded 4-(4-methoxyphenyl)morpholine as a
1 13
36
cream-colored solid (140.0 mg, 91%). H and C NMR data
were identical to the product produced from 4-bromoanisole
5, was used for solution and refinement. Absorption correc-
3
tions were made with SADABS. ORTEP and other structural
7
3
6
(
Table 3, entry 1). Mp: 68-70 °C lit. mp 71 °C.
N-(2-Methylphenyl)morpholine (Table 4, entry 7). Using the
drawings were made with SHELXTL.
Crystal Data for 8. C26 Pd; M = 539.06 g mol ; color-
3
2
-1
58 2
H P
general procedure, morpholine (70 μL, 0.80 mmol) and 2-chlo-
rotoluene (96 μL, 0.82 mmol) were coupled using 1 mol % 10 at
less plates, 0.48 mm ꢀ 0.32 m ꢀ 0.14 mm; orthorhombic Pbca,
˚
a = 8.5967(15), b = 16.076(3), c = 21.506(4) A; R = β = γ =
3
-3
˚
1
00 °C. 4-(o-Tolyl)morpholine (128 mg, 91%) was obtained as a
yellow oil after purification by flash chromatography. H and
90°; V = 2972.2(9) A ; Z = 4, D = 1.205 Mg m ; T = 173(2)
1
-1
K; μ (Mo KR) = 0.742 mm ; 19172 reflections, 3578 unique
reflections (Rint = 0.0172) which were used in all calculations.
1
3
C NMR data were identical to the product produced from
-bromotoluene (Table 3, entry 2).
2
R
1
= 0.0278, wR
0.0480 (I >2σ(I)).
Crystal Data for 9. C26
amber rectangular, 0.64 mm ꢀ 0.34 mm ꢀ 0.12 mm, monoclinic
2 1 2
= 0.0510 (all data), R = 0.0200, wR =
3
2
N-(2-Methoxyphenyl)morpholine (Table 4, Entry 8). Using
the general procedure, morpholine (70 μL, 0.80 mmol) and
-chloroanisole (102 μL, 0.801 mmol) were coupled using 1
-
1
H
2 2
58Cl P Pd; M = 609.96 g mol ,
2
˚
mol % 10 at 100 °C. The product (129.0 mg, 84%) was obtained
as an orange oil after purification by flash chromatography. H
P2
1
/c, a = 9.0627(9), b = 19.012(2), c = 18.002(2) A; R = 90,
1
˚
3
β = 99.276(2), γ = 90°; V = 3062.4(5) A ; Z = 4, D = 1.323 Mg
m
tions, 7561 unique reflections (Rint = 0.0238) which were used
13
-3
-1
and C NMR data were identical to the product produced from
-bromoanisole (Table 3, entry 3).
N-Methyl-N-phenyl-p-anisidine (Table 4, entry 9). Using the
; T = 173(2) K; μ(Mo KR) = 0.898 mm ; 47256 reflec-
2
6
e
general procedure, N-methylaniline (108 μL, 1.00 mmol) and 4-chlo-
roanisole (98 μL, 0.80 mmol) were coupled using 1 mol % 10 at
(
36) Sheldrick, G. M. SHELXTL, Version 5.05; Siemens Analytical
X-Ray Instruments, Inc.: Madison, WI, 1996.
37) Sheldrick, G. M. Program for Semiempirical Absorption Correlation
100 °C. N-Methyl-N-phenyl-p-anisidine (162.0 mg, 95%) as ob-
(
tained as an orange oil after purification by flash chromatography.
of Area Detector Data; University of G o€ ttingen: Germany, 1996.
J. Org. Chem. Vol. 75, No. 19, 2010 6487

Hill et al.
JOCArticle
in all calculations. R =0.0274, wR =0.0475 (all data), R =
which were used in all calculations. R = 0.0621, wR = 0.0987
1
1
2
1
2
0
.0210, wR
Crystal Data for 10. C16
2
= 0.0455 (I > 2σ(I)).
(all data), R
1
= 0.0419, wR
2
= 0.0927 (I>2σ(I )).
-1
H34ClPPd; M = 399.25 g mol
,
orthorhombic P2 2 2 , a = 8.9219(5), b = 13.8729(8), c =
Acknowledgment. Johnson-Matthey acknowledges Fred
Hancock, JMCCT Technical Director and Gerard Compagoni,
JMCCT Business Director for their support on new catalyst
and technology development.
1
1 1
3
˚
˚
1
5.1814(9) A; R = β = γ = 90°; V = 1879.04(19) A ; Z = 4,
-3 -1
D = 1.411 Mg m ; T = 173(2) K; μ(Mo KR) = 1.203 mm
;
3195 reflections, 4441 unique reflections (Rint = 0.0305) which
1
were used in all calculations. R = 0.0307, wR = 0.0449 (all
1
2
data), R
1
= 0.0242, wR
2
= 0.0434 (I>2σ(I)).
Supporting Information Available: Experimental details,
characterization data for compounds in Tables 2-4, X-ray
-1
2 2
Crystal Data for 11. C29H63ClP Pd ; M = 721.98 g mol ,
3
1
yellow plate, monoclinic C2/c, a = 46.091(7), b = 8.9249(14),
˚
crystallographic data for compounds 8-11, P NMR spectra
1 13
c = 16.729(3) A; R = 90, β = 96.884(3), γ = 90°; V = 6831.8(18)
of catalyst activation studies, and H and C NMR spectra of
the products in Tables 2-4. This material is available free of
charge via the Internet at http://pubs.acs.org.
3
-3
˚
A ; Z = 8, D = 1.404Mgm ; T = 173(2) K; μ(MoKR) = 1.240
mm ; 20461 reflections, 6976 unique reflections (Rint = 0.0552)
-
1
6
488 J. Org. Chem. Vol. 75, No. 19, 2010