A highly versatile catalyst system for the cross-coupling of aryl chlorides and Amines

Article abstract of DOI:10.1002/chem.200902316

The syntheses of 2-(di-tertbutylphosphino)-N,N-dimethylaniline (L1, 71%) and 2-(di-1-adamantylphosphino)-N,N-dimethylaniline (L2, 74%), and their application in BuchwaldHartwig amination, are reported. In combination with [Pd(allyl)Cl]₂ or [Pd(cinnamyl)Cl]₂, these structurally simple and air-stable P,N ligands enable the cross-coupling of aryl and heteroaryl chlorides, including those bearing as substituents enolizable ketones, ethers, esters, carboxylic acids, phenols, alcohols, olefins, amides, and halogens, to a diverse range of amine and related substrates that includes primary alkyl- and arylamines, cyclic and acyclic secondary amines, N-H imines, hydrazones, lithium amide, and ammonia. In many cases, the reactions can be performed at low catalyst loadings (0.5-0.02 mol % Pd) with excellent functional group tolerance and chemoselectivity. Examples of cross-coupling reactions involving 1,4-bromochlorobenzene and iodobenzene are also reported. Under similar conditions, inferior catalytic performance was achieved when using Pd(OAc)2, PdCl2, [PdCl₂(cod)] (cod = 1,5-cyclooctadiene), [PdCl ₂(MeCN)₂], or [Pd₂(dba)₃] (dba = dibenzylideneacetone) in combination with L1 or L2, or by use of [Pd(allyl)Cl]₂ or [Pd(cinnamyl)Cl]₂ with variants of L1 and L2 bearing less basic or less sterically demanding substituents on phosphorus or lacking an ortto-dimethylamino fragment. Given current limitations associated with established ligand classes with regard to maintaining high activity across the diverse possible range of C-N coupling applications, L1 and L2 represent unusually versatile ligand systems for the cross-coupling of aryl chlorides and amines

Full text of DOI:10.1002/chem.200902316

FULL PAPER
DOI: 10.1002/chem.200902316
A Highly Versatile Catalyst System for the Cross-Coupling of Aryl Chlorides
and Amines
Rylan J. Lundgren, Antonia Sappong-Kumankumah, and Mark Stradiotto*[a]
À
Abstract: The syntheses of 2-(di-tert-
butylphosphino)-N,N-dimethylaniline
(L1, 71%) and 2-(di-1-adamantylphos-
phino)-N,N-dimethylaniline (L2, 74%),
and their application in Buchwald–
Hartwig amination, are reported. In
acyclic secondary amines, N H imines,
hydrazones, lithium amide, and ammo-
nia. In many cases, the reactions can be
performed at low catalyst loadings
(0.5–0.02 mol% Pd) with excellent
functional group tolerance and chemo-
selectivity. Examples of cross-coupling
reactions involving 1,4-bromochloro-
benzene and iodobenzene are also re-
ported. Under similar conditions, infe-
rior catalytic performance was ach-
[PdCl
diene), [PdCl
(dba=dibenzylideneacetone) in combi-
nation with L1 or L2, or by use of [Pd-
ACHUTNGRENN(UG allyl)Cl]2 or [PdCAHTUNGTREN(NUNG cinnamyl)Cl]2 with
variants of L1 and L2 bearing less
basic or less sterically demanding sub-
stituents on phosphorus or lacking an
ortho-dimethylamino fragment. Given
current limitations associated with es-
tablished ligand classes with regard to
maintaining high activity across the di-
(cod)]
(cod=1,5-cycloocta-
(MeCN)2], or [Pd2A(dba)3]
G
CHTUNGTRENNUNG
combination with [Pd
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG(cinnamyl)Cl]2, these
simple and air-stable P,N ligands
enable the cross-coupling of aryl and
heteroaryl chlorides, including those
bearing as substituents enolizable ke-
tones, ethers, esters, carboxylic acids,
phenols, alcohols, olefins, amides, and
halogens, to a diverse range of amine
and related substrates that includes pri-
mary alkyl- and arylamines, cyclic and
ieved when using Pd
ACHTUNGTRENNUNG
À
verse possible range of C N coupling
applications, L1 and L2 represent un-
usually versatile ligand systems for the
cross-coupling of aryl chlorides and
amines.
Keywords: amination
·
·
homogeneous catalysis · palladium ·
phosphanes
Introduction
coupling have enabled the development of several highly
active classes of catalysts for the cross-coupling of less ex-
pensive and more abundant (compared to bromo and iodo
compounds), but less reactive, aryl chloride substrates to
amines at low catalyst loadings, with excellent yields and
reasonable scope.[8] There now exist several ligand classes
À
The Pd-catalyzed cross-coupling of aryl halides and N H-
containing compounds (Buchwald–Hartwig coupling) has
rapidly emerged as an indispensable method for the con-
À
struction of C N bonds in contemporary organic synthe-
sis.[1–4] The high levels of selectivity, broad substrate scope,
and excellent functional group tolerance displayed by state-
of-the-art Pd-based catalysts have resulted in the widespread
application of this reaction in the synthesis of pharmaceuti-
cal intermediates, natural products, and organic materials,
both in industrial and academic settings.[5–7] Insights gained
that promote such difficult C N coupling reactions of aryl
À
chlorides, including (Figure 1) bulky trialkylphosphanes,[9–12]
N-heterocyclic carbenes,[13–15] biaryldialkylphosphanes[7] and
chelating bisphosphanes,[16,17] as well as N- or O-heteroa-
tom-functionalized phosphanes.[18–26] More recently, difficul-
ties associated with particularly challenging classes of amine
substrates have been addressed by the use of specialized
ꢀtask-specificꢁ ligands in combination with a judiciously se-
lected Pd precursor. These reactivity challenges include the
selective monoarylation of small primary alkylamines (in-
cluding methylamine),[19,27] the arylation of poorly nucleo-
philic[27–29] or heteroatom-functionalized anilines,[30–32] the
coupling of base-sensitive substrates,[33] the arylation of lithi-
um amide,[34,35] and the synthesis of anilines from ammo-
nia.[35–38] However, the structural complexity that is intro-
duced in order to address these specific reactivity challenges
À
regarding the key mechanistic steps in Pd-catalyzed C N
[a] R. J. Lundgren, A. Sappong-Kumankumah, Prof. Dr. M. Stradiotto
Department of Chemistry
Dalhousie University
Nova Scotia B3H 4J3 (Canada)
E-mail: mark.stradiotto@dal.ca
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902316.
Chem. Eur. J. 2010, 16, 1983 – 1991
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1983

À
Figure 1. Selected examples within the evolution of ligands for Pd-catalyzed C N cross-coupling reactions.
often limits the efficacy of the respective ligands with a
wider range of amine substrate classes.
Results and Discussion
Despite significant research effort, a singular catalyst
system that can couple the broad spectrum of potential
amine partners with aryl chlorides at modest Pd loadings is
not known. While certain ligand systems display high activi-
We recently initiated a research program aimed at exploring
the utility of simple P,N-substituted phenylene ligands in
transition metal catalysis[39] and postulated that variants of
such ligands possessing a basic and sterically demanding
phosphane donor in addition to a weakly coordinating sec-
ondary donor might promote highly effective catalysis in
À
ty for selected substrates in Pd-mediated C N coupling re-
actions, these ligands often fail when alternative amine
classes are employed, or require substantially higher Pd/
ligand loadings to achieve reasonable yields. For instance,
Hartwig and co-workers have demonstrated that specific
ligand variants within the Josiphos family display high activi-
ty and scope in the cross-coupling of aryl bromides and
chlorides to primary amines; however, secondary amines
proved to be rather poor partners.[16,17,35] Sterically demand-
ing N-heterocyclic carbenes represent another well-explored
À
Pd-mediated C N coupling reactions. Indeed, while simple
alkylphosphane ligands have found success in amine aryla-
tion chemistry, catalyzed reactions conducted using low Pd
loadings or transformations involving difficult substrates
often require ligand systems that feature additional donor
groups to promote catalyst stability or activity.[7,16] Ligand
L1 was prepared in 71% yield (after recrystallization) by a
À
catalytic P C coupling reaction of 2-Br-N,N-dimethylaniline
À
ligand class for C N coupling reactions, led primarily by the
and tBu2PH employing Pd
A
groups of Nolan and Organ.[13–15] While secondary amines
are readily cross-coupled to aryl chlorides under mild condi-
tions with low Pd loadings, adequate reactivity with smaller,
nucleophilic primary amines has not been accom-
plished.[13–15] Finally, examples of Buchwaldꢁs family of biar-
ylphosphane ligands[7] have shown broad activity for a
number of challenging amination reactions, and these are
propylphosphino)ferrocene); the related 1-adamantyl (1-
Ad)-substituted ligand L2 was prepared in an analogous
fashion in 74% yield (Scheme 1). The use of the robust and
À
perhaps the most versatile class of ancillary ligands for C N
coupling chemistry. However, these achievements have typi-
cally been accomplished through the use of specially de-
signed, task-specific variants within the rather large biaryl-
phosphane ligand family.[7] This has led to serious limitations
with regard to the generality of Pd-catalyzed amine aryla-
tion, for which ideally a single catalyst system would be
active towards all amine classes in addition to maintaining
activity with a broad range of aryl halide partners.
Herein, we report a structurally simple and air-stable P,N
ligand system that allows the Pd-catalyzed cross-coupling of
aryl and heteroaryl chlorides to a diverse range of amine
and related substrates, including primary alkyl- and aryla-
À
Scheme 1. Synthesis of ligands L1 and L2 by P C cross-coupling.
air-stable secondary phosphane (1-Ad)2PH in the prepara-
tion of L2 circumvents the use of highly oxygen- and mois-
ture-sensitive and/or pyrophoric reagents, which are com-
monly required for the synthesis of bulky alkylphosphane li-
À
gands for use in Pd-catalyzed C N coupling reactions. Both
L1 and L2 were found to be stable (by H and 31P NMR) in
1
the solid state for at least two months when stored under
air. The ease with which L1 and L2 can be synthesized is in
contrast to the situation for some of the most widely used li-
À
mines, cyclic and acyclic secondary amines, N H imines, hy-
drazones, lithium amide, and ammonia. In many cases, the
loading of Pd required is low (0.5–0.02 mol%), establishing
these easily prepared, air-stable P,N ligands as a versatile so-
À
gands for challenging Pd-catalyzed C N coupling reactions,
which commonly require multistep syntheses from less read-
ily available and/or costly reagents.
À
lution for many challenging C N cross-coupling applica-
tions.
The reaction of chlorobenzene and aniline using
0.5 mol% Pd at 1008C in toluene was selected to assess the
catalytic utility of L1 and related P,N ligands in Pd-catalyzed
À
C N coupling. Under these screening conditions, most of
the commonly employed Pd starting materials, including Pd-
1984
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Catalysts for Coupling Aryl Chlorides with Amines
FULL PAPER
A
N
(MeCN)2], and [Pd2-
(GC) data. The importance of the nitrogen donor group was
A
evidenced by the failure of mixtures of [PdACTHNGUTERNN(UG cinnamyl)Cl]2
A
and ligands L5 or L6 to provide the desired cross-coupling
product in appreciable yield after 2.5 h. The failure of the
structurally similar ligands L7 and L8 to provide significant
yields of diphenylamine under our standard conditions was
surprising; L7 has been demonstrated to be an excellent
ligand for Suzuki–Miyaura reactions of heteroaryl chlor-
ides.[40] Collectively, these results provide compelling evi-
dence in support of the concept that both the basic and ster-
ically demanding phosphane donor and the ortho-situated
dimethylamino group in L1 and L2 are necessary for achiev-
catalyst system, providing 91% isolated yield of diphenyla-
mine in 4 h, with no significant amount of diarylation prod-
uct (triphenylamine) being formed. The use of [Pd-
ACHTUNGTRENNUNG(cinnamyl)Cl]2 provided even better catalytic activity (92%
yield in 2.5 h; Table 1, entry 1), while the use of L2 with [Pd-
Table 1. Ligand screening in the cross-coupling of aniline or ammonia to
chlorobenzene.[a]
À
ing high activity in this particular Pd-catalyzed C N cou-
pling application.
Having established L1 and L2 as superior ligands for a
À
relatively facile C N coupling process, we sought to explore
Entry
[L]
L1
Conditions
Yield [%]
their utility in a considerably more difficult transformation.
Although the high abundance and low cost of ammonia
make it an ideal nitrogen source in amine synthesis, the
small and highly nucleophilic, deactivating nature of this
substrate present considerable challenges with respect to its
1
2
A
B
92
77 (1:1.3)
3
4
A
B
87
L2
L3
L4
>99 (2.9:1)
À
efficient utilization in metal-catalyzed C N coupling reac-
5
6
A
B
<10
13 (1:6)
tions. While cross-couplings of ammonia with aryl bromides
and iodides have been reported using catalysts based on
Pd[35–38] and Cu,[41–44] the selective monoarylation of ammo-
nia with aryl chlorides represents a challenging reaction,
one that has only started to be addressed very recently by
the use of specially designed ancillary ligands. Furthermore,
selective monoarylation of ammonia employing deactivated
aryl chlorides lacking ortho-substituents represents a partic-
ular challenge; transformations of this type are limited to
examples by Buchwald and co-workers[36] and a very recent
report by Hartwig.[35b] After a brief optimization campaign,
7
8
A
B
<10
n.d.
9
10
A
B
<10
n.d.
L5
L6
L7
11
12
A
B
<10
56 (1:16)
13
14
A
B
17
67 (<1:20)
15
16
A
B
<10
49 (<1:20)
it was discovered that employing L2 with [PdACTHNURTGNENG(U allyl)Cl]2
L8
(2 mol% Pd; Pd/L 1:4) at 1108C in 1,4-dioxane resulted in
the complete conversion of chlorobenzene to a mixture of
aniline and diphenylamine after 20 h (Table 1, entry 4); se-
lectivity in favor of the monoarylation product was achieved
(PhNH2:Ph2NH=2.9:1) and the reaction was conveniently
conducted by employing ammonia as a commercially avail-
able 0.5m stock solution in 1,4-dioxane. We found the struc-
tural features of L2 to be prerequisites for obtaining high
activity and selectivity, as other related ligands afforded
lower conversions and favored the formation of diphenyla-
mine, the undesired diarylation product (Table 1). The range
of anilines that could be prepared by monoarylation of am-
monia employing aryl or heteroaryl chlorides with [Pd-
[a] Conditions A: ArCl/aniline/NaOtBu 1:1.2:1.4, 1.0 mmol scale in 2 mL
toluene at 1008C, 2.5 h, 0.25 mol% [Pd(cinnamyl)Cl]2, and Pd/L 1:2.
Yields of isolated product. Conditions B: ArCl/NH3/NaOtBu 1:10:1.4–1.6,
[ArCl]=0.025m, 1 mol% [Pd(allyl)Cl]2, Pd/L 1:4, 20 h at 1108C in 1,4-di-
oxane. Conversions determined by consumption of chlorobenzene, with
PhNH2:Ph2NH indicated in parentheses as determined on the basis of
calibrated GC data. Data represents an average of two runs. n.d.=not
determined.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG(cinnamyl)Cl]2 gave high yields (87%) under similar condi-
tions (Table 1, entry 3). The use of two equivalents of L1 or
L2 was found to be ideal under these conditions and toluene
was identified as the solvent of choice, although 1,4-dioxane
or dimethoxyethane could also be employed. The influence
of the position and nature of the substituents on both the P-
and N-donor fragments was explored by testing a series of
related ligands under the conditions that proved favorable
for L1 and L2. Ligands possessing less basic or less sterically
demanding substituents on phosphorus (L3 and L4, Table 1,
entries 5 and 7) were found to be largely ineffective for the
cross-coupling of chlorobenzene and aniline, each giving less
than 10% conversion on the basis of gas chromatographic
AHCTUNGTRENNUNG
(allyl)Cl]2 and L2 was found to be good (Table 2).[35,36,38] The
use of ortho-substituted aryl or heteroaryl chlorides resulted
in very high selectivities in favor of monoarylation (gener-
ally >20:1), while maintaining high levels of conversion. Al-
though the use of the deactivated aryl chloride substrates 3-
and 4-chlorotoluene still gave complete conversion at
4 mol% Pd, the selectivity in favor of the monoarylation
product was substantially reduced (ca. 1:1); in this instance,
it appears that the use of a chelating bisphosphine ligand
can provide better selectivity with electron-rich aryl chlori-
Chem. Eur. J. 2010, 16, 1983 – 1991
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1985

M. Stradiotto et al.
Table 2. Cross-coupling of aryl and heteroaryl chlorides with ammonia.[a]
have disclosed the use of PR2-substituted phenylene ligands
À
conceptually related to L1 and L2 in Pd-catalyzed C N cou-
pling reactions, their optimal ligand configuration required
2 mol% Pd and 6 mol% ligand to achieve a 92% yield of
N-(2,5-dimethylphenyl)octylamine; in comparison, an 87%
isolated yield was achieved using our catalyst system with
one-twentieth of this Pd loading (0.1 mol%). Aryl chlorides
substituted at the ortho, meta, or para position each proved
to be compatible substrates under our standard conditions,
with negligible diarylation being observed. Couplings of 2-
or 3-pyridyl and related N-heteroaryl chlorides to primary
amines proceeded with high efficiency, allowing catalyst
loadings as low as 0.02 mol% Pd to be employed. The
broad scope of this reactivity is exemplified by the fact that
both the sterically demanding substrate tert-butylamine, as
well as the unhindered methylamine, could each be cross-
coupled in high yield with no significant diarylation. Fur-
2–1 >99 (2.9:1)
2–5 88[b]
2–2 >99 (>20:1) 2–3 98 (>20:1) 2–4 98 (>20:1)
2–6 91 (>20:1)[c] 2–7 98
2–8 96
(>20:1)[c]
(>20:1)[c]
2–9 >99 (1.1:1)[d] 2–10 >99
2–11 84[c,e]
2–12 90[c,e]
(1:1.1)[d]
À
thermore, other classes of N H-containing substrates, in-
cluding imines and benzophenone hydrazone, could also be
cross-coupled in good yields. The cross-coupling of aryl and
pyridyl chlorides with amines bearing pendant olefin groups
also proved to be feasible. In these cases, good to excellent
yields of the N-aryl aminoalkene could be achieved without
competing isomerization or Heck chemistry at the olefin po-
sition.[46]
Having established L1 and L2 as excellent ligands for
cross-couplings of aryl chlorides with ammonia as well as a
wide range of primary alkyl- and arylamines, we sought to
explore the reactivity profile of this system with secondary
amine substrates. Given that most catalyst systems tend to
drastically favor either primary or secondary amine sub-
strates with respect to their productivity, we were pleased to
2–13 >99
(>20:1)
2–14 99 (>20:1)[c]
[a] ArCl/NH3/NaOtBu 1:10:1.4–1.6, [ArCl]=0.025–0.04m, conversions
determined by consumption of ArCl, with ArNH2/Ar2NH indicated in
parentheses as determined on the basis of calibrated GC data, 16–20 h,
110–1208C in 1,4-dioxane. [b] From ca. 90% pure 1-chloronaphthalene.
[c] Using Pd/L 1:2. [d] Using 4 mol% Pd. [e] Isolated yield.
des.[35b] The activated substrate 4-chlorostyrene provided
high conversions (>99%) and excellent selectivities in favor
of monoarylation (>20:1), suggesting that both the steric
profile and nucleophilicity of the product aniline are factors
in determining mono- versus diarylation ratios when em-
ploying ammonia as a nitrogen source.
discover that L1 or L2 in combination with [Pd
ACHTUNGTRENN(UNG allyl)Cl]2 or
[Pd(cinnamyl)Cl]2 could also couple secondary amines, such
AHCTUNGTRENNUNG
Encouraged by the successful demonstration that L1 and
L2 represent highly effective ligands for Pd-catalyzed cou-
plings of chlorobenzene with aniline and ammonia, we
sought to explore further the scope of this catalyst system
with primary and secondary amines (Tables 3 and 4, respec-
tively). Throughout these catalytic studies, we observed that
in combination with either L1 or L2, the complexes [Pd-
as morpholine, piperidine, and N-methylpiperazine, to a di-
verse set of electronically activated, deactivated, and neutral
aryl chlorides, as well as to N-heteroaryl chlorides, at low
catalyst loadings (0.5–0.05 mol% Pd; Table 4). N,N-Dime-
thylanilines were also successfully prepared by employing
dimethylamine as the substrate. The use of dimethylamine
as a 2.0m solution in THF required the reactions to be per-
formed at 658C (instead of 100–1108C); nonetheless, high
isolated yields were obtained by using 0.2–2 mol% Pd. The
use of dimethylamine as a coupling partner is very uncom-
mon,[7,47,48] and the results presented herein represent rare
examples in which ubiquitous N,N-dimethylanilines have
been prepared by cross-coupling of aryl chlorides.[48] While
secondary N-methylanilines represented more challenging
substrates for our catalyst system, good yields of the corre-
sponding diarylalkylamines were obtained by modifying our
standard conditions (Pd/L 1:0.9 in 1,4-dioxane; Table 4).[49]
In this manner, a series of unsymmetrical diarylmethyla-
mines could be prepared, a process that corresponds to a se-
lective two-step diarylation starting from H2NMe (Table 3).
The sterically demanding, acyclic secondary amine N-meth-
ylisopropylamine could also be employed as a substrate. In
this case, para-, meta-, and even challenging ortho-substitut-
ACHTUNGTRENNUNG(cinnamyl)Cl]2 and [PdACHTUGNTREN(NNGU allyl)Cl]2 could be used interchange-
ably. An initial survey of various aryl or heteroaryl chlorides
and anilines revealed this catalyst system to be generally in-
sensitive to the nature of the coupling partners. Good to ex-
cellent yields were obtained for the coupling of a series of
substituted aryl chlorides to anilines, including 2-aminopyri-
dine and 8-aminoquinoline, as well as some electron-poor
À
anilines that are often difficult substrates in C N coupling
reactions (Table 3). Lithium amide (LiNH2) could be used
as an alternative nitrogen source, providing high yields of
the corresponding symmetrical diarylamine under appropri-
ate conditions. Electronically neutral or deactivated aryl
chlorides could be coupled with simple primary alkylamines
such as octylamine, benzylamine, and cyclohexylamine in
high yields at catalyst loadings of 0.1–0.05 mol% Pd. It is
worthy of mention that while Guram and co-workers[45]
1986
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Catalysts for Coupling Aryl Chlorides with Amines
FULL PAPER
Table 3. Cross-coupling of aryl and heteroaryl chlorides with primary amines.[a]
3–1 91 (0.2); 89 (1)[b]
3–2 99 (0.5)
3–3 93 (0.5)
3–4 92 (0.2)
3–5 99 (0.2)
3–6 88 (0.2)
3–11 94 (1.0)
3–7 98 (0.5)
3–8 99 (0.2)
3–9 97 (0.5); 99 (0.5)[b]
3–14 94 (0.05)
3–10 83 (0.2)
3–15 90 (0.02)
3–12 98 (0.05)
3–13 94 (0.02)
3–16 87 (0.1)
3–21 77 (0.02)
3–17 79 (0.05)
3–22 70 (0.05)
3–18 91 (0.2)
3–23 97 (0.05)
3–19 84 (0.1)
3–24 91 (0.05)
3–20 87 (0.05)
3–25 99 (0.02)
3–26 85 (0.4)
3–31 97 (0.5)
3–27 68 (0.5)
3–32 98 (0.5)
3–28 83 (0.3)
3–33 83 (1.5)
3–29 99 (0.2)
3–34 95 (1)
3–30 80 (1)
3–35 97 (1)[c]
3–36>99 (2)[c,d]
3–42 94 (0.5)[f]
3–37 (2)[e]
3–38 97 (2)[c,d]
3–44 90 (0.2)[f]
3–39 78 (0.5)[f]
3–45 73 (0.5)[f]
3–40 95 (0.5)[f]
3–46 98 (0.5)[f]
3–41 97 (0.5)[f]
3–43 68 (0.5)[f]
[a] ArCl/amine/NaOtBu 1:1.2:1.4, 1.0 mmol scale, 3–48 h (reaction times not optimized; see the Supporting Information). Isolated yields are an average
of two runs, mol% Pd employed (from [Pd(allyl)Cl]2 or [Pd(cinnamyl)Cl]2) indicated in parentheses (Pd/L 1:2). [b] Using 10 equiv of LiNH2, [ArCl]=
A
ACHTUNGTRENNUNG
0.2m. [c] Using 4 equiv H2NMe at 658C. [d] Percent conversion determined on the basis of GC data; where ambiguous, the left portion of the product is
derived from the aryl chloride. [e] Using 4 equiv of H2NMe at 858C. [f] Using 1.05 equiv of amine.
ed, deactivated aryl chloride substrates could be employed,
delivering the product amine in acceptable yields. These cat-
alytic reactions involving secondary amines are particularly
impressive in view of the ability of L1 and L2 to also pro-
mote the arylation of much smaller nitrogen substrates such
as ammonia and methylamine.
While for convenience most of the experiments docu-
mented herein were conducted under inert conditions with
exclusion of oxygen and moisture by employing an inert-at-
mosphere glovebox, the stability of our catalyst system al-
lowed the reactions to be run under less rigorous conditions.
For example, in the coupling of chlorobenzene with octyl-
amine at 0.1 mol% Pd, >99% conversion was achieved
after 20 h by following a protocol in which the catalyst com-
ponents (Pd source and L1 or L2) were weighed out on the
benchtop and combined with NaOtBu in anhydrous toluene,
and only then was the reaction vial placed under an atmos-
phere of dinitrogen. When the coupling of chlorobenzene
and piperidine at 0.2 mol% Pd was conducted in air em-
ploying toluene that had not been purified to remove water
Chem. Eur. J. 2010, 16, 1983 – 1991
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1987

M. Stradiotto et al.
Table 4. Cross-coupling of aryl and heteroaryl chlorides with secondary amines.[a]
4–1 99 (0.2)
4–7 83 (0.2)
4–2 88 (0.2)
4–8 94 (0.2)
4–3 86 (0.2)
4–9 94 (0.2)
4–4 81 (0.2)
4–10 98 (0.2)
4–5 89 (0.2)
4–6 84 (0.2)
4–12 92 (0.2)
4–11 80 (0.05)
4–13 95 (0.5)
4–14 96 (0.1)
4–15 94 (0.2)
4–16 87 (0.2)[b]
4–22 76 (1)[d]
4–17 93 (0.2)[b]
4–23 87 (1)
4–18 89 (0.5)[b]
4–24 83 (2)[b,c]
4–19 91 (0.5)[b,c]
4–25 87 (2.0)
4–20 80 (1)[d]
4–26 72 (2.5)
4–21 81 (1.5)[d]
4–27 65 (4.0)
[a] ArCl/amine/NaOtBu 1:1.2:1.4, 1.0 mmol scale, 3–48 h (reaction times not optimized; see the Supporting Information). Isolated yields are an average
of two runs, mol% Pd employed (from [Pd(allyl)Cl]2 or [Pd(cinnamyl)Cl]2) indicated in parentheses (Pd/L 1:2). [b] ArCl/HNMe2 1:2, at 658C in toluene/
A
ACHTUNGTRENNUNG
THF 1:1. [c] Percent conversion determined on the basis of GC data; where ambiguous, the left portion of the product is derived from the aryl chloride.
[d] Pd/L 1:0.9 in 1,4-dioxane.
or oxygen, quantitative conversion to N-phenylpiperidine
was still achieved after 24 h.
product being favored over that of the morpholine-derived
product by a factor of 18:1 (Scheme 2). Competition experi-
The use of Pd–allyl-type starting materials presents a po-
tential drawback, namely the requirement for a strongly nu-
cleophilic base for the in situ generation of a Pd(0) cata-
lyst.[50] However, we found that base-sensitive compounds
could be employed as substrates by using a catalytic amount
Table 5. Cross-coupling of base-sensitive substrates.[a]
5–1 96 (0.5)[b]
5–4 82 (2.0)[c]
5–2 74 (0.5)[b]
5–5 73 (1.0)[d]
5–3 96 (0.5)[c]
5–6 72 (0.5)[d]
of NaOtBu to activate the Pd
stoichiometric amount of a more appropriate base such as
Cs2CO3 or LiN(SiMe3)2 to facilitate the cross-coupling
ACHTUNGTRNE(NUNG allyl)-type precatalyst, and a
ACHTUNGTRENNUNG
chemistry. This technique allowed the cross-coupling of aryl
chloride substrates containing enolizable ketone, ester, car-
boxylic acid, phenol, alcohol, and amide groups with pri-
mary or secondary amines (Table 5).
À
Chemoselectivity in Pd-catalyzed C N cross-coupling re-
5–7 80 (0.5)[d]
5–8 70 (0.5)[d]
5–10 98 (1.0)[d]
5–9 67 (1.5)[d]
actions remains a relatively unexplored challenge.[51] Despite
the high activity displayed by our catalyst system for a wide
À
range of amine substrates, intermolecular C N couplings
proceeded chemoselectively. For example, when one equiva-
lent of chlorobenzene was reacted with 1.05 equivalent each
of octylamine and morpholine in the presence of
0.125 mol% [PdACHTUNGTRENNUNG(cinnamyl)Cl]2 and L2 at 958C, 88% con-
version of the aryl chloride was observed (on the basis of
GC data), with formation of the octylamine cross-coupling
[a] ArCl/amine/base 1:1.2:2.2, 0.5–1.0 mmol scale, 2–4 mol% NaOtBu, 2–
48 h (reaction times not optimized; see the Supporting Information),
1108C; mol% Pd employed (from [PdACHTNURGTENNUG(allyl)Cl]2 or [PdAHCTUNGTRNE(NUGN cinnamyl)Cl]2) in-
dicated in parentheses (Pd/L 1:2). [b] Using Cs2CO3 in 1,4-dioxane.
[c] Using LiHMDS in THF/dioxane at 658C. [d] Using LiHMDS in tolu-
ene.
1988
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ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 1983 – 1991

Catalysts for Coupling Aryl Chlorides with Amines
FULL PAPER
À
Scheme 2. Chemoselective C N cross-coupling reactions. All reactions employ [Pd
determined on the basis of GC data unless indicated.
N
ments between benzylamine and N-methylaniline also dem-
onstrated high selectivity for arylation of the primary amine,
giving 85% conversion to N-benzylaniline after 2 h (accom-
panied by only a trace amount of Ph2NMe) when employing
0.5 mol% Pd. Anilines can also be chemoselectively coupled
to chlorobenzene in the presence of a secondary amine
(e.g., piperidine), with excellent conversions and good selec-
tivities over the course of 1 h, by employing 1 mol% Pd. Fi-
nally, while our current study has focused on the cross-cou-
pling of more challenging aryl chloride substrates, aryl io-
dides and bromides can also be employed with excellent re-
sults. Iodobenzene and octylamine could be coupled with
>99% conversion by employing 0.05 mol% Pd under stan-
dard conditions.[52] Chemoselective amination (1008C;
0.5 mol% Pd) at the bromide position of 1,4-bromochloro-
benzene with 4-anisidine was obtained by using [Pd-
resent an unusually versatile ligand system for the cross-cou-
pling of aryl chlorides and amines and an important contri-
bution towards the development of more general catalysts
À
for Pd-catalyzed C N coupling reactions. Studies aimed at
examining the utility of L1 and L2 in other challenging Pd-
catalyzed cross-coupling reactions, as well as mechanistic
studies concerning the origin of the broad scope and high
activity in the catalysis featured herein, are ongoing.
Experimental Section
General considerations: Unless noted otherwise, all reactions were set up
inside a dinitrogen-filled inert atmosphere glovebox. Toluene was deoxy-
genated by sparging with dinitrogen and then passed through a double-
column solvent purification system purchased from mBraun Inc. 1,4-Di-
oxane (Aldrich) was dried over Na/benzophenone and then distilled
under an atmosphere of dinitrogen. 1,2-Dimethoxyethane was deoxygen-
ated by sparging with dinitrogen gas and then stored over activated 4 ꢃ
molecular sieves for 48 h prior to use. Chloroform-d1 (Cambridge Iso-
topes) was used as received. All solvents used within the glovebox were
stored over activated 4 ꢃ molecular sieves. Aniline was distilled under
ACHTUNGTRENNUNG(cinnamyl)Cl]2 and L2 to afford the chloro-functionalized di-
arylamine in 76% isolated yield. The powerful combination
of high catalytic activity, broad substrate scope, and excel-
lent chemoselectivity displayed by Pd catalysts featuring L1
or L2 suggests that these catalyst systems should be of wide-
spread utility in the construction of complex molecular
reduced pressure prior to use. [PdACHTUNGTRNEUNG
(cinnamyl)Cl]2,[53] diphenyl-2-dimethyl-
aminophenylphosphane (L4),[54] di(tert-butyl)-(2-isopropylphenyl)phos-
phane (L5),[55,56] di(tert-butyl)phenylphosphane (L6),[55,56] di-1-adamantyl-
phosphane,[57] and amino alkene substrates[58] were prepared according to
literature procedures. Di(tert-butyl)-(2-methoxyphenyl)phosphane (L8)
was prepared in a similar manner to L2, and the spectroscopic features
of the isolated complex matched those reported previously.[59] Pd starting
materials, as well as NaOtBu and Cs2CO3, were desiccated under reduced
pressure for 24 h prior to use and stored under an inert atmosphere in a
glove box. All other reagents were used as received from commercial
sources. Conversions in the arylation of aniline and ammonia based on
gas chromatography data were determined by calibration with chloroben-
zene, aniline, or diphenylamine as standards; product identity was con-
firmed on the basis of 1H NMR and GC-MS data and/or by comparison
with authentic samples. 1H, 13C, and 31P NMR spectra were acquired at
300 K on a Bruker AV-500 spectrometer operating at 500.1, 125.8, and
202.5 MHz, respectively, with chemical shifts reported in parts per million
downfield of the signals of SiMe4 for 1H and 13C, and of 85% H3PO4 in
D2O for 31P.
À
frameworks by the use of C N coupling techniques.
Conclusion
In summary, the results presented herein reveal the structur-
ally simple and air-stable ligands L1 and L2 to be broadly
useful for the Pd-catalyzed cross-coupling of aryl and heter-
oaryl chlorides with amines and related substrates. Good to
excellent yields can be obtained using a wide range of
amine partners, including primary aryl- and alkylamines,
À
cyclic and acyclic secondary amines, lithium amide, N H
imines, hydrazones, and ammonia. In many cases, the reac-
tions can be performed at low catalyst loadings with excel-
lent functional group tolerance and chemoselectivity. Given
current limitations associated with established ligand classes
with regard to maintaining high activity across the diverse
Improved synthesis of 2-(di-tert-butylphosphino)-N,N-dimethylaniline
(L1): In an analogous manner to the synthesis of L2 (see below), the title
compound was prepared by Pd-catalyzed cross-coupling of tBu2PH and
2-bromo-N,N-dimethylaniline. The product was isolated in 71% yield
À
possible range of C N coupling applications, L1 and L2 rep-
Chem. Eur. J. 2010, 16, 1983 – 1991
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1989

M. Stradiotto et al.
after recrystallization from hexane at À358C. Its spectral properties were
tylamine (200 mL, 1.2 mmol) were added by means of a microlitre sy-
ringe. The reaction mixture was heated at 1108C and periodically moni-
tored by TLC or gas chromatography. Upon completion of the reaction,
the mixture was worked-up by column chromatography on silica
(hexane/EtOAc, 20:1) and the product was isolated as a colorless oil
(0.203 g, 99%). Alternatively, the appropriate amounts of [Pd-
consistent with those reported previously.[39]
Synthesis of 2-(di-1-adamantylphosphino)-N,N-dimethylaniline (L2): Pd-
ACHTUNGTRENNUNG(OAc)2 (6.3 mg, 0.028 mmol) was placed in a glass vial and dissolved in
toluene (2 mL). This solution was then transferred to a vial containing
DiPPF (1,1’-bis(diisopropylphosphino)ferrocene; 14.2 mg, 0.034 mmol)
and the mixture was stirred for 10 min. A separate glass vial was first
charged with NaOtBu (192 mg, 2.0 mmol), and then a solution of (1-ada-
mantyl)2PH (410 mg, 1.36 mmol) in toluene (2 mL) was added. 2-Bromo-
AHCTUNGTRE(GUNNN cinnamyl)Cl]2, ligand, and NaOtBu stored under N2 could be weighed
out on the benchtop into a vial. Following the addition of chlorobenzene,
octylamine, and anhydrous toluene, the vial was sealed with a cap con-
taining a PTFE septum, purged with N2, and heated at 1108C. The results
were similar to those obtained from reactions conducted in a glovebox
(99% conversion on the basis of GC data at 0.1 mol% Pd).
N,N-dimethylaniline (230 mL, 1.4 mmol) and the above PdACHTNUTRGNEUNG(OAc)2/DiPPF
solution were then added and the vial was sealed with a cap containing a
PTFE septum. The mixture was stirred for 20 h at 1108C, at which point
the reaction was deemed complete on the basis of 31P NMR data ob-
tained from a withdrawn aliquot. The reaction mixture was then allowed
to cool and passed through a plug of silica, and the plug was then washed
with CH2Cl2 (40 mL). The combined eluent was collected and the solvent
was removed in vacuo. The resulting pale-orange solid was washed with
cold hexanes (2ꢄ4 mL). Removal of volatile materials in vacuo yielded
the product as an off-white powder (0.424 g, 1.01 mmol; 74%). 1H NMR
(CDCl3): d=7.71 (m, 1H; Ar-H), 7.32 (m, 1H; Ar-H), 7.20 (m, 1H; Ar-
Representative procedure for the coupling of ammonia with aryl chlor-
ides: In an inert atmosphere glovebox, [PdACTHNUTRGNEN(UG allyl)Cl]2 (2.2 mg,
0.006 mmol) and L2 (10.1 mg, 0.024 mmol) were vigorously mixed in di-
oxane (4 mL) for 10 min. An aliquot (1.000 mL) of this stock solution
was withdrawn and added to a vial containing NaOtBu (20 mg). The vial
was sealed with a cap containing a PTFE septum and removed from the
glovebox. 2-Chloro-3-methylpyridine (16 mL, 0.15 mmol) was added by
means of a microlitre syringe, followed by a 0.5m solution of NH3 in 1,4-
dioxane (3 mL). The mixture was stirred at 1108C and the progress of
the reaction was monitored by gas chromatography.
H), 7.05 (m, 1H; Ar-H), 2.71 (s, 6H; N
Ad), 1.67 ppm (s, 12H; 1-Ad); 13C{1H} NMR (CDCl3): d=161.6 (d, JPC
21.6 Hz; Cquat), 137.4 (d, JPC =3.3 Hz), 131.1 (d, JPC =22.9 Hz; Cquat),
129.6, 122.2, 120.6 (d, JPC =3.9 Hz), 46.1 (d, JPC =4.2 Hz; N(CH3)2), 41.8
ACHTUNGTREN(NNUG CH3)2), 2.01–1.89 (m, 18H; 1-
=
AHCTUNGTRENNUNG
(d, JPC =13.0 Hz; CH2), 37.1 (CH2), 29.0 ppm (d, JPC =8.6 Hz; CH);
31P{1H} NMR (CDCl3): d=20.1 ppm; HRMS (ESI): calcd for C28H40N1P1
([M+H]+): 422.2971; found: 422.2978; elemental analysis calcd (%) for
C28H40P1N1: C 79.77, H 9.56, N 3.32; found: C 79.47, H 9.46, N 3.31.
Acknowledgements
We acknowledge the Natural Sciences and Engineering Research Council
of Canada (including a Discovery Grant for M.S., a Postgraduate Schol-
arship for R.J.L., and an Undergraduate Summer Research Award for
A.S.-K.), the Canada Foundation for Innovation, the Nova Scotia Re-
search and Innovation Trust Fund, the Killam Trusts, the Walter C.
Sumner Foundation, and Dalhousie University for their generous support
of this work. Drs. Michael Lumsden and Katherine Robertson (Nuclear
Magnetic Resonance Research Resource, Dalhousie) are thanked for
their assistance in the acquisition of NMR data.
Synthesis of 2-(dicyclohexylphosphino)-N,N-dimethylaniline (L3): nBuLi
(759 mL, 2.2 mmol) was added to a precooled (À358C) solution of 2-
bromo-N,N-dimethylaniline (288 mL, 2.0 mmol) in Et2O (3 mL) in a glass
vial. After 30 min at À358C and an additional 15 min at room tempera-
ture, the yellow precipitate obtained was isolated by removing the super-
natant by means of a pipette, washing the remaining solid with cold hex-
anes (3ꢄ2 mL), and removing the volatile materials in vacuo. The result-
ing solid was dissolved in Et2O (6 mL) and then ClPCy2 (440 mL,
2.0 mmol) was added dropwise and the mixture was stirred magnetically
at room temperature for 48 h. The solvent and volatile materials were
then removed in vacuo. The residue was redissolved in CH2Cl2 and this
solution was washed with saturated aqueous NaHCO3 solution (10 mL)
and water (10 mL). The organic layer was collected, dried in vacuo, and
passed through a plug of silica eluting with pentane. Removal of the sol-
vents in vacuo yielded the product as a white solid (0.162 g, 0.51 mmol,
25%). 1H NMR (CDCl3): d=7.35 (d of t, J=7.6, 1.9 Hz, 1H), 7.28 (m,
1H), 7.13 (d of d of d, J=8.0, 4.3, 1.2 Hz, 1H), 7.05 (d of t, J=7.4,
1.3 Hz, 1H), 2.72 (s, 6H), 1.90–1.74 (m, 12H), 1.30–0.99 ppm (m, 10H);
13C{1H} NMR (CDCl3): d=160.8, 133.8 (d, J=2.7 Hz), 132.0, 129.8, 123.6,
120.2 (d, J=2.9 Hz), 46.4 (d, J=5.0 Hz), 34.2 (d, J=14.3), 30.8 (d, J=
16.6 Hz), 29.6 (d, J=8.9 Hz), 27.8 (d, J=11.6 Hz), 27.7 (d, J=7.6 Hz),
27.0 ppm; 31P{1H} NMR (CDCl3): d=À12.7 ppm.
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1
closed. H NMR (CDCl3): d=7.54 (m, 2H), 6.68 (d, J=8.7 Hz, 2H), 2.98
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ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 1983 – 1991

Catalysts for Coupling Aryl Chlorides with Amines
FULL PAPER
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