BippyPhos: A single ligand with unprecedented scope in the Buchwald-Hartwig amination of (hetero)aryl chlorides

Article abstract of DOI:10.1002/chem.201302453

Over the past two decades, considerable attention has been given to the development of new ligands for the palladium-catalyzed arylation of amines and related NH-containing substrates (i.e., Buchwald-Hartwig amination). The generation of structurally diverse ligands, by research groups in both academia and industry, has facilitated the accommodation of sterically and electronically divergent substrates including ammonia, hydrazine, amines, amides, and NH heterocycles. Despite these achievements, problems with catalyst generality persist and access to multiple ligands is necessary to accommodate all of these NH-containing substrates. In our quest to address this significant limitation we identified the BippyPhos/[Pd(cinnamyl)Cl]₂ catalyst system as being capable of catalyzing the amination of a variety of functionalized (hetero)aryl chlorides, as well as bromides and tosylates, at moderate to low catalyst loadings. The successful transformations described herein include primary and secondary amines, NH heterocycles, amides, ammonia and hydrazine, thus demonstrating the largest scope in the NH-containing coupling partner reported for a single Pd/ligand catalyst system. We also established BippyPhos/ [Pd(cinnamyl)Cl]₂ as exhibiting the broadest demonstrated substrate scope for metal-catalyzed cross-coupling of (hetero)aryl chlorides with NH indoles. Furthermore, the remarkable ability of BippyPhos/[Pd(cinnamyl)Cl] ₂ to catalyze both the selective monoarylation of ammonia and the N-arylation of indoles was exploited in the development of a new one-pot, two-step synthesis of N-aryl heterocycles from ammonia, ortho- alkynylhalo(hetero)arenes and (hetero) aryl halides through tandem N-arylation/hydroamination reactions. Although the scope in the NH-containing coupling partner is broad, BippyPhos/[Pd(cinnamyl)Cl]₂ also displays a marked selectivity profile that was exploited in the chemoselective monoarylation of substrates featuring two chemically distinct NH-containing moieties.

Full text of DOI:10.1002/chem.201302453

DOI: 10.1002/chem.201302453
BippyPhos: A Single Ligand With Unprecedented Scope in the Buchwald–
Hartwig Amination of (Hetero)aryl Chlorides
Sarah M. Crawford, Christopher B. Lavery, and Mark Stradiotto*[a]
Abstract: Over the past two decades,
considerable attention has been given
to the development of new ligands for
the palladium-catalyzed arylation of
amines and related NH-containing sub-
strates (i.e., Buchwald–Hartwig amina-
tion). The generation of structurally di-
verse ligands, by research groups in
both academia and industry, has facili-
tated the accommodation of sterically
and electronically divergent substrates
including ammonia, hydrazine, amines,
amides, and NH heterocycles. Despite
these achievements, problems with cat-
alyst generality persist and access to
multiple ligands is necessary to accom-
modate all of these NH-containing sub-
strates. In our quest to address this sig-
nificant limitation we identified the
system as being capable of catalyzing
the amination of a variety of function-
alized (hetero)aryl chlorides, as well as
bromides and tosylates, at moderate to
low catalyst loadings. The successful
transformations described herein in-
clude primary and secondary amines,
NH heterocycles, amides, ammonia and
hydrazine, thus demonstrating the larg-
est scope in the NH-containing cou-
pling partner reported for a single Pd/
ligand catalyst system. We also estab-
cross-coupling of (hetero)aryl chlorides
with NH indoles. Furthermore, the re-
markable ability of BippyPhos/[Pd-
AHCTUNGTREN(GNUN cinnamyl)Cl]2 to catalyze both the se-
lective monoarylation of ammonia and
the N-arylation of indoles was exploit-
ed in the development of a new one-
pot, two-step synthesis of N-aryl het-
erocycles from ammonia, ortho-
alkynylhaloACHTNUGTRNEUNG(hetero)arenes and (hetero)
aryl halides through tandem N-aryla-
tion/hydroamination reactions. Al-
though the scope in the NH-containing
coupling partner is broad, BippyPhos/
lished BippyPhos/[PdACHTNUGTRENUNG(cinnamyl)Cl]2 as
exhibiting the broadest demonstrated
substrate scope for metal-catalyzed
[Pd
(cinnamyl)Cl]2
also
displays
a marked selectivity profile that was
exploited in the chemoselective mono-
arylation of substrates featuring two
chemically distinct NH-containing moi-
eties.
Keywords: amination · catalysis ·
chemoselectivity · cross-coupling ·
palladium
BippyPhos/[PdACHTUNGTRENNUNG(cinnamyl)Cl]2 catalyst
Introduction
plex; activate the palladium center towards (hetero)aryl
(pseudo)halide oxidative addition; provide steric protection
to the palladium coordination sphere as a means of promot-
The palladium-catalyzed amination of aryl and heteroaryl
halides and pseudohalides with NH-containing substrates
(i.e., Buchwald–Hartwig amination, BHA) is an indispens-
À
ing selectivity; and encourage C N bond reductive elimina-
tion en route to arylamine products. These requirements
typically necessitate that the ligand be both electron-rich
and sterically demanding.[3] Adhering to these basic design
principles, many classes of ligands have been developed in
efforts to enable cross-coupling reactions of challenging
NH-containing compounds (Figure 1). Representative exam-
ACHTUNGTRENNUNGable component of the synthetic chemistꢀs toolkit and has
been widely employed in the synthesis of pharmaceuticals,
natural products and materials.[1] Given the ubiquitous
nature of arylamines and arylazoles in compounds of syn-
thetic interest, and the lack of alternative methodologies for
their synthesis that are both mild and generally applicable,
BHA remains a commonly employed methodology both
academically and industrially.[2]
The course of BHA reactions is largely ligand controlled;
as such, ligand design has played a crucial role in the expan-
sion of the field.[3] In most reaction settings, ligands must be
designed to: promote the formation a monoligated Pd0 com-
ples from some of the major ligand classes include bulky,
[4]
electron-rich trialkylphosphines (PACTHNUTRGENUG(N tBu)3 and cataCXiu-
m A[5]), bisphosphines with large bite angles (XantPhos[6]
and JosiPhos[7]), sterically demanding carbenes (IPr[8]) and
mixed P,N donor ligands (MorDalPhos[9] and MeDal-
Phos[10]), as well as (hetero)biaryl monophosphine ligands
featuring large dialkylphosphino groups (RuPhos and Brett-
Phos,[1d,11] BippyPhos,[12] Ad-BippyPhos[13]). Although many
highly active catalyst systems for BHA have been reported
beyond the representative ligands shown in Figure 1, from
a practical perspective only those ligands (ligand precursors,
or their respective palladium precatalysts) that offer robust
tolerance of air and moisture, easily implemented catalytic
protocols, wide substrate scope and commercial availability
[a] Dr. S. M. Crawford, C. B. Lavery, Prof. Dr. M. Stradiotto
Department of Chemistry, Dalhousie University
6274 Coburg Rd., P.O. Box 15000
Halifax, NS, B3H 4R2 (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.201302453.
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FULL PAPER
offers such a diverse reactivity profile. We disclose the appli-
cation of this catalyst system toward the arylation of ammo-
nia, hydrazine, primary and secondary amines, diamines,
amides, and indoles with a variety of functionalized aryl and
heteroaryl halides at moderate to low catalyst loadings. The
unprecedented scope of this catalyst system toward NH-con-
taining substrates also facilitated the development of a new
one-pot, two-step tandem synthesis of N-aryl heterocycles
from ammonia, ortho-alkynylhaloarenes and (hetero)aryl
halides. Moreover, the marked NH-substrate selectivity
preference of the catalyst system was exploited in the che-
moselective monoarylation of substrates featuring two
chemically distinct and potentially reactive NH-containing
moieties.
Results and Discussion
Ligand selection: In our search to find a practical catalyst
system with improved generality in the BHA of aryl chlor-
ides with a wide range of NH-containing substrates, we
started by screening representative commercially available
ligands (Figure 1) in judiciously selected BHA reactions
using adapted literature protocols.[9b–d,10,14] In this context,
we investigated the N-arylation of primary amines, secon-
dary amines, indole, and ammonia with chlorobenzene using
Figure 1. A representative selection of commercially available ligands for
use in Buchwald–Hartwig amination.
are most likely to experience significant uptake by end-
users.
Despite significant advances in BHA catalysis, a number
of challenges persist, including that of catalyst generality.
Although palladium catalysts featuring the ligands in
Figure 1 have each proven useful for multiple NH substrate
classes, absent from the literature are reports of a single Pd/
ligand catalyst system with the demonstrated ability to pro-
mote the cross-coupling of aryl halides with structurally di-
verse NH-containing substrates ranging from relatively
acidic azoles and amides, to amines, to more nucleophilic
NH-containing substrates including hydrazine and ammonia.
Although limited progress towards addressing deficiencies
in the scope of the NH-containing coupling partner has
been achieved through the use of multiple ligand catalytic
systems,[11a] in general the practicing synthetic chemist is typ-
ically required to assemble and/or screen an inventory of lig-
1 mol% [Pd
ACHTUNGTERNUN(NG cinnamyl)Cl]2 and 4 mol% ligand. [Pd-
AHCTUNGTRENG(NUN cinnamyl)Cl]2 was selected as a palladium source as it is
commercially available, easily prepared and handled on the
benchtop,[15] has proven useful in combination with most of
the ligands featured in Figure 1,[9b,c,10,16] and readily forms
the desired ligated palladium(0) catalyst initiated by nucleo-
philic attack on the h3-bound cinnamyl group of the generat-
ed precatalyst complex.[3a,17] We chose to focus primarily on
rather challenging aryl chloride substrates because they are
typically less expensive and more readily available from
commercial sources in comparison to aryl bromides and io-
dides. It should be noted that there is literature precedent
for the use of several of the commercial ligands featured in
our preliminary BHA screen in some of the BHA transfor-
mations explored. However, direct reactivity comparisons
between ligand classes based on literature data are difficult
to make because additives, bases, solvents, palladium sour-
ces and concentration are not consistent. Full details of the
screening reaction conditions and graphical representation
of the results can be found in the Supporting Information.
The ligand classes behaved as expected in the cross-cou-
pling reactions screened, on the basis of literature reports of
their N-arylation abilities,[1d,4–6,7c–e,8a,c,9b,d,10–12,18] thereby con-
firming that the results disclosed herein can serve as a valid
platform for comparison between ligand classes. The majori-
ty of the catalyst systems were effective in the arylation of
primary and secondary amines, with some exceptions: both
cataCXium A and XantPhos gave low yields of N-phenyloc-
tylamine whereas JosiPhos and BrettPhos gave low yields of
N-phenylmorpholine. JosiPhos, BrettPhos, RuPhos, Bippy-
Phos and Ad-BippyPhos were effective in the N-arylation of
ACHTUNGTRENNUNGands for which only task-specific synthetic utility has been
established; this is especially true when faced with a particu-
lar BHA application for which optimal conditions are not
clearly specified in the literature.[3a,11b] While the acquisition
and use of a toolkit of commercially available ligands can
accomplish some synthetic objectives, selecting a ligand and
optimizing conditions for each NH-containing substrate is
both cost and time ineffective, especially for the nonspecial-
ist. In this regard, the identification of a single Pd/ligand cat-
alyst system, derived from commercially available air-stable
components, which could serve as a reliable “first-choice”
for use in a diversity of BHA applications, would represent
an important achievement in the quest to expand the scope,
utility and usage of BHA chemistry in both academic and
industrial settings.
Herein we report on the development and application of
the BippyPhos/[PdACHTUNGTRENNUNG(cinnamyl)Cl]2 catalyst system, which
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M. Stradiotto et al.
indole affording high yields of N-phenylindole, but only Jo-
siPhos, MorDalPhos and BippyPhos were effective in the se-
lective monoarylation of ammonia to generate aniline. Nota-
bly, of all the ligands screened, only BippyPhos gave appre-
Having established for the first time the unusual ability of
BippyPhos/[PdACHTNUGRTENUNG(cinnamyl)Cl]2 mixtures to catalyze the mon-
oarylation of the rather divergent coupling partners, such as
ammonia and indole, we set about investigating BHA reac-
tions involving challenging NH-containing cross-coupling
partners, for which the utility of Pd/BippyPhos catalysts had
yet to be demonstrated prior to our report herein.
À
ciable yields of each desired C N cross-coupling product.
Repeating the reaction screen with BippyPhos/[Pd-
ACHTUNGTRENNUNG(cinnamyl)Cl]2 at 0.5 mol% [PdACHTUGNTREN(NUNG cinnamyl)Cl]2 loading re-
sulted in a decrease in GC yield for the products of the
N-arylation reactions of morpholine and indole of greater
than 10%, but no decrease in GC yield for the products
generated with the other NH-containing cross-coupling part-
ners. These encouraging results led us to focus on the fur-
Cross-coupling of ammonia and hydrazine: The selective
monoarylation of ammonia with aryl chlorides by use of
BHA protocols has proven to be a considerable challenge.
Difficulties in achieving appropriate levels of catalytic activi-
ty and selectivity in such transformations can be attributed
in part to preferential uptake of the product aniline leading
to di- and triarylation, and the decreased propensity of
requisite [LPd(Ar)NH2] intermediates to undergo reductive
elimination.[24] These challenges were largely overcome
ther application of the BippyPhos/[PdACTHUNGRTNE(NUG cinnamyl)Cl]2 catalyst
system in the cross-coupling of functionalized (hetero)aryl
halides with a wide range of NH-containing substrates, in an
effort to establish a broadly useful catalyst system for BHA.
The nonproprietary, air-stable ligand BippyPhos was first
disclosed in 2006 by Singer and co-workers,[12a] along with
a demonstration of its utility in the BHA of primary and
secondary alkyl and aryl amines. An additional report in
2008 outlined a kilogram-scale synthesis of BippyPhos along
with its further application in a limited selection of palladi-
through the development of the JosiPhos/[Pd(PACTHUNTRGNEUNG(o-tol)3)2]
catalyst system, which proved capable of selectively monoar-
ylating ammonia with aryl halides and sulfonates,[7e] as well
as the MorDalPhos/[PdACHTNUTRGNE(NUG cinnamyl)Cl]2 catalyst system, which
is able to selectively monoarylate ammonia with a variety of
functionalized (hetero)aryl halides under mild conditions
with low catalyst loadings.[9b] The recent development of the
BHA of ammonia with aryl halides has been reviewed in
detail.[25] Although the reaction now has precedent, there
are still relatively few reported catalyst systems capable of
achieving this selective transformation.
À
À
À
um-catalyzed C N, C O and C C cross-coupling reactions
with aryl and heteroaryl chlorides.[12b] Following these initial
reports, BippyPhos has been applied in a small number of
À
À
other palladium-catalyzed C N and C O cross-coupling re-
actions, and is now commercially available from multiple
sources (Figure 2).
In addition to sharing the aforementioned challenges as-
sociated with employing ammonia as a reaction partner in
BHA, hydrazine presents additional difficulties owing to its
strong reducing abilities and the potential for side reactions
À
involving N N bond cleavage. In 2010, we disclosed the first
examples of the selective monoarylation of hydrazine, by
use of the MorDalPhos/[PdACTHNUTRGNE(NUG cinnamyl)Cl]2 catalyst system at
loadings of 5-10 mol% Pd.[9c] Following our study, only one
other report of palladium-catalyzed hydrazine cross-cou-
pling has appeared, which employed as catalysts palladacy-
cles derived from Buchwaldꢀs biaryl monophosphine lig-
À
Figure 2. Previous applications of Pd/BippyPhos catalyst systems in C N
cross-coupling reactions.
AHCTUNGTRENNUNG
ands.[26] Encouraged by the observation in our screening ex-
ercise that BippyPhos/[PdACTHNUTRGNE(NUG cinnamyl)Cl]2 mixtures catalyze
the selective monoarylation of ammonia using chloroben-
zene, we turned our attention to exploring further this
chemistry. As a starting point, we employed published con-
ditions developed for the BHA of ammonia[9b] and hydrazi-
ne[9c] in combination with selected representative (hetero)-
Pd/BippyPhos catalyst systems have been used to facili-
À
tate the C N cross-coupling of primary and secondary
amines,[12] substituted hydroxylamines,[19] ureas[20] and, in
two examples, imidazoles[21] (Figure 2). In addition to C N
À
bond formation, there are several examples in which a Pd/
ACHTUNGTRENNUNG
À
BippyPhos catalyst system is used to facilitate C O bond
formation, with primary alcohols[12b,13b] and hydroxide,[22]
ACHTUNGTRENNUNG
[12b,23]
À
and C C bond formation.
The first crystal structure of
products (Figure 3a) in high isolated yields (62–83%, 1-1–1-
3). Representative electron-rich (1-1), electron poor (1-2),
and heterocyclic (1-3) aryl chlorides were each successfully
cross-coupled with ammonia; a more detailed examination
of ammonia monoarylation in the context of indole synthesis
a BippyPhos palladium(II) complex was reported by our
group recently,[22] which revealed the ability of BippyPhos to
bind in a k2-P,C-bidentate fashion through phosphorus and
the ipso carbon of the lower pyrazole ring, in a manner very
similar to the binding mode observed in palladium(II) com-
plexes of the ubiquitous biarylphosphine ligand family de-
veloped by Buchwald.[1d]
employing BippyPhos/[Pd
Extension of the catalyst system to the challenging mono-
AHCTUNGTREGaNNUN rylation of hydrazine required a secondary derivatization
ACHTUNGTERNUN(NG cinnamyl)Cl]2 is provided later.
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Buchwald–Hartwig Amination of (Hetero)aryl Chlorides
FULL PAPER
give 1-4 in 62% yield. Although the catalyst loadings used
herein are higher than those reported recently by Buchwald
in a continuous flow system,[26] they are within the same
range used for the MorDalPhos/[Pd
system.[9c] The BippyPhos/[Pd
(cinnamyl)Cl]2 catalyst system
also has an advantage over MorDalPhos/[Pd(cinnamyl)Cl]2
ACHTUNGTRENUN(NG cinnamyl)Cl]2 catalyst
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
in that it can accommodate electron-rich aryl chloride sub-
strates (1-8, 1-9, 1-10) in synthetically useful isolated yields
(69–74%).
Complementary routes for accessing substituted indoles:
The indole core structure is arguably one of the most stud-
ied organic frameworks in synthetic medicinal chemistry,
and is featured in a diverse array of pharmaceutical com-
pounds.[27] Limitations associated with more traditional
preparative routes to indoles have inspired the development
of efficient, selective and modular metal-catalyzed protocols
that in turn have transformed modern indole synthesis.[28]
One conceptually attractive route to substituted indoles in-
volves the metal-catalyzed N-arylation of NH-indoles with
aryl halides; however, such reactions have proven challeng-
ing owing to the relatively poor nucleophilicity and high NH
acidity of NH-indoles, as well as the potential for competing
N- and C-arylation.[3a] In 2000 and 2002, Buchwald and co-
workers disclosed breakthrough catalyst systems based on
Pd2dba3/biarylphosphine[14b] or CuI/diamine[29] mixtures, re-
spectively, which are capable of promoting such transforma-
tions. However, practical drawbacks still exist with these
and other reported catalysts systems, including in the case of
copper systems the need for high metal/ligand loadings as
well as the poor reactivity observed with (hetero)aryl chlo-
ride reagents. Furthermore, no single Pd/ligand catalyst
system that exhibits broad reactivity scope in the N-aryla-
tion of NH-indoles with aryl halides has been reported to
date, and among those reports that have appeared in the lit-
erature, successful transformations involving the use of (het-
ero)aryl chlorides are very few.
Figure 3. The BippyPhos/[Pd
ammonia or hydrazine with (hetero)aryl chlorides (mol% [Pd-
(cinnamyl)Cl]2 (x) given in parentheses; isolated yields).
ACHTUNGTRENN(UNG cinnamyl)Cl]2 catalyzed cross-coupling of
ACHTUNGTRENNUNG
Inspired by the success of the BippyPhos/[Pd-
step, as the arylhydrazine products resulting from the initial
cross-coupling reaction were found to be of varying stability.
Reaction in neat acetylacetone (1108C) of the arylhydrazine
ACHTUNGTRENN(NUG cinnamyl)Cl]2 catalyst system for the N-arylation of indole
as observed in our preliminary ligand screening, we identi-
fied conditions that address some of the important short-
comings associated with the cross-coupling of NH indoles
with (hetero)aryl (pseudo)halides. Under the conditions out-
lined in Figure 4, a selection of (hetero)aryl chlorides and
bromides featuring electron-donating and withdrawing sub-
stituents were found to be well-accommodated, forming the
corresponding N-arylated indoles in synthetically useful iso-
lated yields (71–93%, 2-1–2-14). Specifically, when employ-
ing the parent indole as the coupling partner, both chloro-
benzene and phenyl tosylate (as proof-of-principle), were
shown to be well-tolerated with no appreciable difference in
reactivity observed (2-1).
À
intermediates generated following the successful C N cross-
coupling of hydrazine and the aryl chloride afforded the cor-
responding N-arylpyrazole derivatives, which in turn were
isolated and characterized. Application of BippyPhos/[Pd-
ACHTUNGTRENNUNG(cinnamyl)Cl]2 to hydrazine monoarylation (Figure 3b) af-
forded the corresponding N-arylpyrazoles in good isolated
yields (46–93%, 1-4–1-12).
A variety of electron-neutral (1-4, 1-5), electron-rich (1-8,
1-9) and ortho-substituted (1-6, 1-7, 1-9, 1-12) aryl chlorides
were accommodated at a 5–10 mol% Pd loading. A hetero-
aryl chloride was accommodated (1-11), albeit in lower iso-
lated yield. The reaction also displays functional group toler-
ance and chemoselectivity with a silyl-protected alcohol (1-
7) and a secondary amine (1-12) each being accommodated
under the reaction conditions. Attempts to employ 1-chloro-
4-fluorobenzene in the reaction resulted in defluorination to
Aryl chlorides featuring 4-methoxy or 4-trifluoromethyl
groups proved to be successful coupling partners (2-2, 2-3),
as did 2-chloropyridine (2-4). Although ortho-substitution
on the aryl halide was in general not well tolerated (2-chlor-
otoluene and 2,6-dimethylchlorobenzene were not effective
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M. Stradiotto et al.
a primary amine with an ortho-alkynylhaloarene, proceeded
by a base-promoted[30] intramolecular cyclohydroamination
of the intermediate 2-aminophenylacetylene, as developed
by Ackermann and co-workers.[31] The modular nature of
this transformation provides an appealing avenue to func-
tionalized indoles, as structural variation can easily be incor-
porated into the alkynyl group by use of Sonogashira tech-
niques and various substitution at nitrogen can be integrated
through the selection of the amine coupling partner.[28a]
A
number of catalysts have been identified that are capable of
promoting such cross-couplings,[28a] collectively enabling the
incorporation of NH-containing substrates ranging from
very small nucleophilic amines, such as ammonia[7a] and
methylamine,[32] to more sterically demanding alkyl-[31b] and
(hetero)aryl amines.[32] Nonetheless, there are some impor-
tant limitations in this chemistry. For example, in the only
report of such transformations involving ammonia,[7a] which
makes use of JosiPhos/[PdACHTUNGRTEN(NUNG cinnamyl)Cl]2, scope in the
ortho-alkynylhalo(hetero)arene reagent was limited to bro-
AHCTUNGTRENNUNG
mide variants; furthermore, heteroaryl halides as well as
ortho-alkynylbromoarenes featuring sp3-substituents at the
alkyne terminus proved incompatible with this JosiPhos-
based catalyst system.
In the quest to overcome these notable limitations, and in
an effort to harness the unusual capabilities of the Bippy-
Phos/[PdACHTUNTRGEN(UNG cinnamyl)Cl]2 catalyst system in the monoarylation
of both ammonia and NH indoles (vide supra), we sought to
develop unprecedented one-pot, two-step syntheses of func-
tionalized N-arylated indoles directly from ammonia in
À
which three distinct C N bonds are formed in a highly se-
lective manner. We envisioned two possible routes for ac-
cessing N-arylated indoles from ammonia in this manner:
1) monoarylation of ammonia with an ortho-alkynylhaloar-
ene in the presence of excess base to form an NH indole
that can then be cross-coupled with an aryl halide to form
the corresponding N-arylated indole (method A, Figure 5);
or 2) monoarylation of ammonia with an aryl halide to form
an aniline that can then be cross-coupled with an ortho-alky-
nylhaloarene in the presence of excess base to form the cor-
responding substituted N-arylated indole (method B,
Figure 5).
Figure 4. The BippyPhos/[PdACTHNUTRGNE(NUG cinnamyl)Cl]2 catalyzed N-arylation of in-
doles and related heterocycles (isolated yields); [a] 4mol% Pd, 8 mol%
ligand; [b] K3PO4 used as the base.
coupling partners), bromonapthalene was shown to be an ef-
fective coupling partner, leading to 2-5. Substrates featuring
synthetically relevant keto, phenol and benzyl ether moieties
were each well-accommodated (2-6–2-8). Carbazole and pyr-
role were also shown to be effective coupling partners with
chlorobenzene (2-9, 2-10). Finally, the more sterically de-
manding 2-phenylindole was selectively cross-coupled with
a representative collection of (hetero)aryl chlorides (2-11–2-
14), thereby demonstrating that C2-substituted indoles can
be accommodated. Although more varied substitution has
previously been demonstrated in this transformation by em-
ploying (hetero)aryl iodides and bromides, to the best of our
BippyPhos/[PdACHTNUGRTENUNG(cinnamyl)Cl]2 mixtures proved capable of
catalyzing the formation of substituted N-arylated indoles
through each of these reaction pathways, providing access to
a variety of functionalized indoles and related heterocyclic
derivatives in synthetically useful isolated yields (54–85%
total over both steps, 2-11–2-14 and 3-1–3-12). Under the
conditions outlined in Figure 5, 2-phenylindole 2-11 could
be readily accessed via method A or B by employing either
1-bromo- or 1-chloro-2-(phenylethynyl)benzene and chloro-
benzene in the appropriate steps. The successful combina-
tion of ammonia with an ortho-alkynylchloroarene in step 1
of method A represents an important practical advancement
in this transformation, in that previously only ortho-alkynyl-
bromoarenes could be employed (vide supra).[7a]
knowledge the BippyPhos/[PdACHTNUTRGENNUG(cinnamyl)Cl]2 catalyst system
featured herein exhibits the broadest known substrate scope
for the metal-catalyzed cross-coupling of (hetero)aryl chlor-
ides with NH indoles.
A number of complementary palladium-catalyzed synthet-
ic strategies exist for accessing functionalized N-aryl indoles
beyond the aforementioned arylation of preformed NH in-
doles.[28] One attractive route involves the cross-coupling of
In exploring this chemistry further, N-aryl indoles featur-
ing methoxy, trifluoromethyl, 2-pyridyl, and naphthyl N-aryl
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Buchwald–Hartwig Amination of (Hetero)aryl Chlorides
FULL PAPER
Figure 5. Scope of BippyPhos/[Pd
lated yields). Method A conditions: step 1: ArX (1 equiv), ammonia (3 equiv), if X=Br, BippyPhos/[Pd
pyPhos/[Pd(cinnamyl)Cl]2 (8 mol%/2 mol%), KOtBu (3 equiv), 1,4-dioxane, 1108C, 8 h; step 2: ArX (1 equiv), BippyPhos/[Pd
1 mol%), NaOtBu (1.4 equiv), toluene, 1108C, 12 h. Method B conditions: ArX (1 equiv), ammonia (3 equiv), BippyPhos/[Pd(cinnamyl)Cl]2 (4 mol%/
1 mol%), NaOtBu (1.4 equiv), 1,4-dioxane, 1108C, 3–6 h; step 2: Ar-X (1 equiv), BippyPhos/[Pd(cinnamyl)Cl]2 (4 mol%/1 mol%), KOtBu (1.4 equiv),
toluene, 1108C, 8 h. [a] Method A, step 2, BippyPhos/[Pd(cinnamyl)Cl]2 (8 mol%/2 mol%). [b] Reaction conducted under air.
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
groups were also efficiently prepared via method A employ-
ing 1-chloro-2-(phenylethynyl)benzene in step 1 along with
the appropriate (hetero)aryl chlorides in step 2 (2-12–2-14
and 3-1). Notably, indoles 2-12–2-14 could also be straight-
forwardly prepared via method B by use of appropriate
(hetero)aryl chloride reagents. In exploring the scope of
method B further, 2,6-chloro-meta-xylene was employed suc-
cessfully, affording the corresponding doubly ortho-substitut-
ed N-aryl indole (3-2) in 82% isolated yield. When repeat-
ing the synthesis of 3-2 by employing method B under air,
no significant difference in reactivity was observed (78%
isolated yield). We next turned our attention to investigating
substitution on the ortho-alkynylhaloarene, using chloroben-
zene as the standard reaction partner in step 2 of method A
and 2,6-chloro-meta-xylene in step 1 of method B. We were
pleased to observe that both methylated and fluorinated de-
rivatives of 1-bromo-2-(phenylethynyl)benzene were well
tolerated in methods A and B, affording the corresponding
indoles (3-3–3-6) in high isolated yield (79–85%). The use
of ortho-alkynylhaloarenes featuring heteroaromatic substi-
tution at the alkynyl terminus as well as within the alkyny-
larene backbone was also successful. Specifically, a thio-
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M. Stradiotto et al.
phen-3-yl moiety on the alkynyl terminus was well-tolerated
in both methods A and B, yielding the corresponding N-sub-
stituted indoles featuring a thiophen-3-yl fragment in the C2
position (3-7, 3-8). It is worthy of mention that the use of
3-chloro-2-(phenylethynyl)pyridine in method A to form the
corresponding 4-azaindole (3-9, 88%) represents the first
successful reaction of an ortho-alkynylhaloheteroarene with
ammonia in such palladium-catalyzed indole syntheses. Sim-
ilarly, 3-bromo-2-(phenylethynyl)thiophene could easily be
accommodated in method B to form the respective thieno-
pyrrole (3-10, 83%). Finally, ortho-alkynylhaloarenes featur-
ing alkyl substitution at the alkynyl terminus, in the form of
a tert-butyl group in method A and an n-propyl group in
method B, were successfully converted to the corresponding
N-aryl indoles featuring alkyl substitution in the C2 position
(3-11, 3-12). The success of 1-bromo-2-(3,3-dimethylbut-1-
yn-1-yl)benzene in method A leading to 3-11 represents the
first example of an ortho-alkynylhaloarene featuring alkyl
substitution at the alkynyl terminus to be successfully cross-
coupled with ammonia, thereby further demonstrating the
dicated that 1,4-dioxane and tert-butanol were the optimal
solvents and both potassium carbonate and potassium phos-
phate were effective bases for this transformation. The stan-
dard optimized conditions involved heating the amide or
sulfonamide (1.0 equiv) with the aryl chloride (1.0 equiv),
potassium carbonate (2 equiv), BippyPhos (2–5 mol%) and
[PdACTHNUTRGNEG(NU cinnamyl)Cl]2 (0.5–1.25 mol%) at 908C for 18 h in
1,4-dioxane.
Using these standard conditions, functionalized (hetero)-
aryl chlorides were successfully cross-coupled with a variety
of amides and sulfonamides in synthetically useful yields
(44–99%, 4-1–4-23; Figure 6). Chlorobenzene was success-
fully cross-coupled under the standard conditions with
amides (4-1, 4-9, 4-15) and sulfonamides (4-18, 4-19). Substi-
robust scope and utility of the BippyPhos/[Pd
catalyst system.
ACHTUNGTRENUN(NG cinnamyl)Cl]2
Cross-coupling of amides and sulfonamides: Amides are
À
challenging substrates for intermolecular C N cross-cou-
pling reactions due to their low nucleophilicity and ability to
bind in a bidentate fashion to a metal center once deproton-
ated, providing an additional barrier to the reductive elimi-
nation of N-arylamide products.[33] In 2000, Yin and Buch-
wald reported the use of the XantPhos/PdACTHNURTGNENG(U OAc)2 system,
which was capable of promoting the intermolecular cross-
coupling of aryl halides, including activated aryl chlorides
with primary amides and sulfonamides at catalyst loadings
between 1–4 mol% Pd.[34] Subsequent use of a biaryl mono-
phosphine/PdACHTUNGTRENNUNG(OAc)2 catalyst system allowed for the cross-
coupling of a broader scope of aryl chlorides and aryl mesy-
lates at 1 mol% Pd,[35] and moving to JackiePhos/[Pd-
ACHTUNGTRENNUNG(allyl)Cl]2 allowed for the cross-coupling of aryl chlorides
with acyclic secondary amides and carbamates.[36] Notwith-
standing these selected advances, reports of the palladium-
catalyzed amidation of aryl chlorides remain limited. In an
initial publication, Singer and co-workers reported on the
poor catalytic performance of BippyPhos/Pd
tures for the cross-coupling of aryl chlorides and amides.[12b]
Subsequently, BippyPhos/Pd2A(dba)3 has been reported to
couple aryl bromides and chlorides to a variety of aryl,
benzyl and aliphatic ureas,[20a] and BippyPhos/[Pd
(allyl)Cl]2
ACHTUNGRTENN(UNG OAc)2 mix-
CTHUNGTRENNUNG
AHCTUNGTRENNUNG
has been employed successfully in the coupling of an aryl
bromide with methanesulfonamide, although this catalyst
system was not applied to a broader aryl chloride or amide
substrate scope.[37] Despite these few recent reports, a Bippy-
Phos/Pd catalyst system for cross-coupling aryl halides and
amides with broad scope has not been reported to date.
Our initial efforts in amide cross-coupling focused on the
identification of suitable conditions for the cross-coupling of
chlorobenzene and acetamide with the BippyPhos/[Pd-
Figure 6. Scope for the BippyPhos/[Pd
pling of amides and sulfonamides with (hetero)aryl chlorides (mol% [Pd-
(cinnamyl)Cl]2 (x) given in parentheses; isolated yields). [a] K3PO4 used
ACHTUNGTERNUN(NG cinnamyl)Cl]2 catalyzed cross-cou-
AHCTUNGTRENNUNG
A
as base; [b] tBuOH used as solvent.
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Buchwald–Hartwig Amination of (Hetero)aryl Chlorides
FULL PAPER
tution in the ortho-position was also tolerated and 2-chloro-
toluene was successfully cross-coupled with amides (4-4, 4-
14, 4-17). Electron-poor 4-chlorobenzotrifluoride was also
cross-coupled with amides (4-3, 4-11, 4-16), sulfonamides
(4-21, 4-22) and formamide (4-23). Electron-rich 4-chloroa-
nisole proved to be a more challenging coupling partner.
Under the standard cross-coupling conditions at a catalyst
loading of 2.5 mol% Pd, 4-2 was only isolated in 59% and
4-10 in 54%. However, changing the base to K3PO4 and the
solvent to tert-butanol allowed 4-chloroanisole to be accom-
modated in the reaction at a 2.5 mol% Pd loading to give
4-2 in a 92% yield and 4-10 in a 99% yield. 2-Chloropyri-
dine and 3-chloropyridine were each successfully coupled
with representative amides (4-7, 4-8, 4-12, 4-13) when using
Beyond applying the BippyPhos/[PdACHTNGUTERNNU(G cinnamyl)Cl]2 cata-
lyst system to BHA reactions involving the particularly chal-
lenging NH-containing substrates discussed thus far (vide
supra), we were also interested in investigating its efficiency
in cross-coupling 4-chloroanisole (a representative electroni-
cally deactivated aryl chloride) with a series of more com-
monly employed and synthetically relevant primary and sec-
ondary amines over the course of 24 h (unoptimized) at
1108C (Figure 8).
BippyPhos/[PdACHTUNGTRENNUNG(cinnamyl)Cl]2 in tert-butanol solvent. 2-
Chloropyridine could also be coupled with p-tolylbenzene-
sulfonamide (4-20), albeit in a low yield. The functional
group tolerance of the catalyst system was further demon-
strated by the successful cross-coupling of two other hetero-
cyclic aryl chlorides (4-5, 4-6) with acetamide.
Under the standard conditions, N-butylacetamide, an acy-
clic secondary amide, could not be cross-coupled with chlor-
obenzene. Attempts were made to optimize the base, sol-
vent and reaction temperature; nonetheless, the product
could not be isolated in a synthetically useful yield. Despite
this particular scope limitation, we have established herein
that the BippyPhos/[PdACTHUNTRGNE(NUG cinnamyl)Cl]2 catalyst system can
accommodate a broad scope of functionalized (hetero)aryl
chlorides in combination with primary amides or sulfona-
mides as cross-coupling partners.
Cross-coupling of amines: Although the BippyPhos/Pd-
ACHTUNGTRENNUNG(OAc)2 catalyst system has proven capable of cross-coupling
Figure 8. BippyPhos/[PdACTHNUTRGNEUNG(cinnamyl)Cl]2 catalyzed cross-coupling of pri-
mary and secondary amines with 4-chloroanisole at low catalyst loadings.
Conversions were determined on the basis of GC analysis of reaction
mixtures. A GC calibration curve was generated with 4-chloroanisole
using the internal standard calibration method with dodecane as an inter-
nal standard. Product identity was determined on the basis of retention
time comparison with authentic product samples.
both primary and secondary amines with aryl halides at 0.5–
1.0 mol% Pd,[12] we were interested in investigating the ap-
plication of BippyPhos/[PdACTHNUTRGNE(UNG cinnamyl)Cl]2 to a few select ex-
amples of challenging secondary amine substrates. Using
this catalyst system, dihexylamine (5-1) and heptaethylenei-
mine (5-2) each were successfully arylated in synthetically
useful yields using 2 mol% Pd (Figure 7). In our hands,
these substrates proved difficult to arylate when using Xant-
Phos, MeDalPhos or IPr under analogous conditions. To our
knowledge, there are very few reports of cross-coupling of
these particular secondary amines with aryl chlorides.[38]
We were pleased to observe quantitative conversion of
4-chloroanisole to form the target cross-coupling product (6)
with a range of primary and secondary alkyl- and arylamines
employing catalyst loadings as low as 0.05–0.3 mol% Pd
(Pd/BippyPhos, 1:2). At the outset, the lowest catalyst load-
ings at which full conversion of 4-chloroanisole could be
achieved were determined for the sterically differing pri-
mary alkylamines methylamine (0.1 mol% Pd), n-octyl-
AHCTUNGTREGaNNUN mine (0.05 mol% Pd) and 1-adamantylamine (0.3 mol%
Pd). Although aniline (0.3 mol% Pd) was also easily accom-
modated at such low catalyst loadings, the more hindered
2,6-dimethylaniline proved somewhat more challenging
under similar conditions, requiring a slightly higher catalyst
loading (0.5 mol% Pd) to achieve full conversion. Finally,
we confirmed that these protocols could be extended to the
hydrazine derivative, 4-methylpiperazin-1-amine (0.3 mol%
Pd), and the secondary alkylamine, morpholine (0.3 mol%
Pd) as coupling partners. Collectively, these results further
Figure 7. Selected application of the BippyPhos/[PdACHTUNTRGNE(UNG cinnamyl)Cl]2 cata-
lyst system for the cross-coupling of challenging secondary amines with
chlorobenzene (isolated yields).
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M. Stradiotto et al.
exemplify the broadly useful nature of the BippyPhos/[Pd-
ACHTUNGTRENNUNG(cinnamyl)Cl]2 catalyst system in BHA chemistry involving
cation of highly effective catalysts for BHA that are capable
of chemoselectively arylating diamine substrates featuring
two different and potentially competitive NH moieties re-
mains a persistent challenge and has recently begun to at-
tract attention in the chemical literature.[7b,9d,40] Given the
commonly encountered primary and secondary amine reac-
tion partners, and bring to light the preference of this cata-
lyst system for smaller, more nucleophilic primary amines
over both primary arylamines and secondary alkylamines.
To further demonstrate the substrate preferences of the
distinct
preference
exhibited
by
BippyPhos/[Pd-
AHCTUNGTRENG(NUN cinnamyl)Cl]2 in our low catalyst loading (Figure 8) and
BippyPhos/[Pd
(cinnamyl)Cl]2 catalyst system, a set of amine
amine competition experiments (Figure 9) for relatively
small, nucleophilic primary amines, we envisioned that this
catalyst system should be capable of chemoselectively ary-
lating appropriate diamine substrates.
arylation competition experiments were carried out using
chlorobenzene. Indeed, under the conditions outlined in
Figure 9, the catalyst system preferentially and selectively
cross-coupled the primary amines 4-methylpiperazin-1-
We were delighted to observe that BippyPhos/[Pd-
AHCTUNGTRENG(UNN cinnamyl)Cl]2 mixtures could indeed be applied successfully
in such chemoselective transformations, affording a number
of structurally varied monoarylated diamine products in
high isolated yields (73–93%, 8-1–8-10) as the only observed
products under the conditions employed (Figure 10). In
keeping with our observed trends (vide supra), the selective
monoarylation of the primary alkylamine moiety in N1-phe-
nylethane-1,2-diamine was achieved with a range of hin-
dered or unhindered (hetero)aryl chlorides featuring elec-
tron-donating or withdrawing groups (8-1–8-5).
Figure 9. Application of BippyPhos/[PdACHTUNRTGNEUNG(cinnamyl)Cl]2 in amine competi-
tion experiments. Conversions were determined on the basis of GC anal-
ysis of reaction mixtures. A GC calibration curve was generated with
chlorobenzene using the internal standard calibration method with do-
decane as an internal standard. Product identity was determined on the
basis of retention time comparison with authentic product samples.
amine or n-octylamine over morpholine to produce a single
product, despite the fact that morpholine had proven to be
a competent substrate in this chemistry (Figure 8). Interest-
ingly, when employing n-octylamine and indole as the com-
peting NH-containing substrates, no conversion of chloro-
benzene was observed. Evidently indole acts as a catalyst in-
hibitor at the low loadings employed, effectively shutting
down the otherwise feasible n-octylamine arylation reaction.
This latter phenomenon is consistent with our observation
that higher loadings of BippyPhos/[PdACTHNUTRGNEG(NU cinnamyl)Cl]2
(4 mol%/1 mol%) are needed in order to promote the effi-
cient cross-coupling of chlorobenzene and indole (2-1,
Figure 5).
Figure 10. Scope of BippyPhos/[Pd
tive monoarylation of diamine substrates (isolated yields). [a] Experiment
was conducted under air. [b] BippyPhos/[Pd(cinnamyl)Cl]2 (10 mol%,
2.5 mol%) [c] K2CO3 (1.5 equiv), 1,4-dioxane, 908C.
ACHTUNGTRNEUN(NG cinnamyl)Cl]2 catalyzed chemoselec-
Chemoselective arylation of diamines: The many difficulties
associated with chemoselective palladium-catalyzed transfor-
mations have been described.[39] Among these, the identifi-
AHCTUNGTRENNUNG
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Buchwald–Hartwig Amination of (Hetero)aryl Chlorides
FULL PAPER
For proof-of-principle, the synthesis of 8-2 was reex-
amined under air, and separately using phenyl tosylate as an
aryl pseudohalide coupling partner; in both cases only
modest decreases in yield were observed. The ability of Bip-
pyPhos/[PdACHTUNGTRENNUNG(cinnamyl)Cl]2 to arylate n-octylamine is inhibit-
ed in the presence of indole (or accompanying substrate im-
purities) at the 1 mol% Pd loading level (Figure 9). Howev-
er, at higher catalyst loadings (5 mol% Pd, 10 mol% Bippy-
Phos) the presence of an indole moiety within a diamine is
accommodated, as evidenced by the selective monoarylation
of the primary amine fragment in tryptamine (8-6).
The preferential arylation of the primary alkylamine
moiety could also be achieved in diamine substrates featur-
ing competing primary arylamine (8-7) and secondary cyclic
dialkylamine (8-9) fragments. Despite the preferential aryla-
tion of primary alkylamines over arylamines that was estab-
lished for this catalyst system (Figure 8), primary arylamine
fragments were selectively monoarylated in diamine sub-
strates featuring contending sulfonamide (8-8) and secon-
dary arylamine (8-10) functionalities. In the case of 8-8, fur-
ther support for the spectroscopic identification of the prod-
uct was obtained by use of single-crystal X-ray diffraction
techniques (see the Supporting Information).
Figure 11. Broad scope of N-arylated products accessible employing Bip-
pyPhos/[PdACHTUNTRGNE(UNG cinnamyl)Cl]2.
Conclusion
While not a “universal” catalyst for BHA, the unprece-
dented breadth and depth of scope established herein for
In summary, the results presented herein establish the Bip-
the BippyPhos/[PdACHTGNUTERN(NUG cinnamyl)Cl]2 catalyst system, in terms
pyPhos/[Pd
G
of the NH-containing coupling partner, offers an important
À
the largest scope of NH-containing substrates in Buchwald–
Hartwig amination (BHA) reported to date for a single Pd/
practical advance to the many users of this ubiquitous C N
bond-forming reaction. In particular, by establishing a single
and reliable “first-choice” for use in addressing the diversity
of challenging BHA applications that are faced by synthetic
chemists, we hope to increase the accessibility and utility of
the methodology for nonspecialists in both academia and in-
dustry.
ligand
catalyst
system.
Utilizing
BippyPhos/[Pd-
ACHTUNGTRENNUNG(cinnamyl)Cl]2 in the cross-coupling of functionalized
(hetero)aryl halides, we have expanded significantly the pre-
viously known reactivity profile for BippyPhos/Pd cata-
lysts[12,13b,19–22] to now include the sterically/electronically
varied and challenging NH-containing substrates ammonia,
hydrazine, indole, amides, and sulfonamides (Figure 11).
During the course of this research, we have established
Acknowledgements
that the BippyPhos/[PdACHTNUGTRNEUNG(cinnamyl)Cl]2 catalyst system exhib-
its the broadest demonstrated substrate scope for metal-cat-
alyzed cross-coupling of (hetero)aryl chlorides with NH in-
doles reported thus far in the literature. Furthermore, we
were able to exploit the broadly useful nature of BippyPhos/
[PdACHTUNGTRENNUNG(cinnamyl)Cl]2 in the development of a new and versatile
one-pot, two-step synthesis of N-aryl indoles and related
We are grateful to NSERC of Canada and Dalhousie University for their
support of this work. Digital Specialty Chemicals is thanked for a gift of
BippyPhos and Dr. Scott Laneman (DSC) is thanked for helpful discus-
sions. Dr. Michael Lumsden (NMR-3, Dalhousie) is thanked for technical
assistance in the acquisition of NMR spectroscopy data and Mr. Xiao
Feng (Maritime Mass Spectrometry Laboratories, Dalhousie) is thanked
for technical assistance in the acquisition of mass spectrometric data.
Dr. Robert MacDonald (X-Ray Crystallography Laboratory, Alberta) is
thanked for the acquisition of X-ray data and Dr. Craig Wheaton (Dal-
housie) is thanked for structural solution and refinement of compound
8-8.
heterocyclic derivatives involving three sequential and selec-
À
tive C N bond-forming steps starting from ammonia.
Through a series of low catalyst loading and amine competi-
tion experiments, a clear catalyst preference for smaller,
more nucleophilic primary amine coupling partners was de-
lineated and subsequently exploited in the chemoselective
monoarylation of a range of substrates featuring two distinct
and potentially competitive NH moieties. Although not ex-
haustively explored, proof-of-principle experiments con-
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Chem. Eur. J. 2013, 19, 16760 – 16771

Buchwald–Hartwig Amination of (Hetero)aryl Chlorides
FULL PAPER
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Received: June 26, 2013
Published online: November 4, 2013
Chem. Eur. J. 2013, 19, 16760 – 16771
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16771