Palladium-catalyzed coupling of ammonia with aryl chlorides, bromides, iodides, and sulfonates: A general method for the preparation of primary arylamines

Article abstract of DOI:10.1021/ja903049z

We report that the complex generated from Pd[P(o-tol)₃] ₂ and the alkylbisphosphine CyPF-t-Bu is a highly active and selective catalyst for the coupling of ammonia with aryl chlorides, bromides, iodides, and sulfonates. The couplings of ammonia with this catalyst conducted with a solution of ammonia in dioxane form primary arylamines from a variety of aryl electrophiles in high yields. Catalyst loadings as low as 0.1 mol % were sufficient for reactions of many aryl chlorides and bromides. In the presence of this catalyst, aryl sulfonates also coupled with ammonia for the first time in high yields. A comparison of reactions in the presence of this catalyst versus those in the presence of existing copper and palladium systems revealed a complementary, if not broader, substrate scope. The utility of this method to generate amides, imides, and carbamates is illustrated by a one-pot synthesis of a small library of these carbonyl compounds from aryl bromides and chlorides, ammonia, and acid chlorides or anhydrides. Mechanistic studies show that reactions conducted with the combination of Pd[P(o-tol)₃]₂ and CyPF-t-Bu as catalyst occur with faster rates and higher yields than those conducted with CyPF-t-Bu and palladiun(II) as catalyst precursors because of the low concentration of active catalyst that is generated from the combination of palladium(II), ammonia, and base.

Full text of DOI:10.1021/ja903049z

Published on Web 07/10/2009
Palladium-Catalyzed Coupling of Ammonia with Aryl
Chlorides, Bromides, Iodides, and Sulfonates: A General
Method for the Preparation of Primary Arylamines
Giang D. Vo and John F. Hartwig*
Department of Chemistry, UniVersity of Illinois, 600 South Mathews AVenue,
Urbana, Illinois 61801
Received April 16, 2009; E-mail: jhartwig@illinois.edu
Abstract: We report that the complex generated from Pd[P(o-tol)3]2 and the alkylbisphosphine CyPF-
t-Bu is a highly active and selective catalyst for the coupling of ammonia with aryl chlorides, bromides,
iodides, and sulfonates. The couplings of ammonia with this catalyst conducted with a solution of
ammonia in dioxane form primary arylamines from a variety of aryl electrophiles in high yields. Catalyst
loadings as low as 0.1 mol % were sufficient for reactions of many aryl chlorides and bromides. In the
presence of this catalyst, aryl sulfonates also coupled with ammonia for the first time in high yields. A
comparison of reactions in the presence of this catalyst versus those in the presence of existing copper
and palladium systems revealed a complementary, if not broader, substrate scope. The utility of this
method to generate amides, imides, and carbamates is illustrated by a one-pot synthesis of a small
library of these carbonyl compounds from aryl bromides and chlorides, ammonia, and acid chlorides
or anhydrides. Mechanistic studies show that reactions conducted with the combination of Pd[P(o-
tol)3]2 and CyPF-t-Bu as catalyst occur with faster rates and higher yields than those conducted with
CyPF-t-Bu and palladiun(II) as catalyst precursors because of the low concentration of active catalyst
that is generated from the combination of palladium(II), ammonia, and base.
and iridium-catalyzed allylic amination,8,9 and copper-10-12 and
palladium-catalyzed13-15 coupling of ammonia with aryl halides.
1. Introduction
Although ammonia is among the least expensive bulk
chemicals, its application in transition-metal catalysis is rare.
Because of ammonia’s high basicity, small size, and strong N-H
bond (107 kcal/mol),1 most of its reactions with transition-metal
complexes yield Lewis acid-base adducts that are often highly
stable.2 Thus, catalyst turnover in the presence of ammonia has
been difficult to achieve. There are only a few transition-metal-
catalyzed processes that incorporate ammonia into more com-
plex molecules, and most of these reactions were published
recently. These reactions include rhodium-catalyzed reductive
amination of aldehydes,3 iridium-catalyzed reductive amination
of R-keto acids,4 rhodium- and iridium-catalyzed hydroami-
nomethylation of olefins,5 ruthenium-catalyzed synthesis of
primary amines from primary alcohols and ammonia,6 gold-
catalyzed hydroamination of alkynes and allenes,7 palladium-
The copper- and palladium-catalyzed coupling of ammonia
with aryl halides has attracted attention recently because of the
value of primary arylamines in the preparation of agrochemicals,
dyes, and pharmaceuticals.16,17 The copper-catalyzed method
has been known since the 1960s,18 but significant progress has
only been made recently.10-12 In spite of the recent advances,
copper-catalyzed coupling with ammonia is limited in scope
and requires high loadings of copper and ligand. The copper-
catalyzed coupling does not occur in high yield with electron-
rich aryl bromides or ortho-substituted aryl bromides or iodides.
(8) Nagano, T.; Kobayashi, S. J. Am. Chem. Soc. 2009, 131, 4200–4201.
(9) Pouy, M. J.; Leitner, A.; Weix, D. J.; Ueno, S.; Hartwig, J. F. Org.
Lett. 2007, 9, 3949–3952.
(10) Kim, J.; Chang, S. Chem. Commun. 2008, 3052–3054.
(11) Xia, N.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 337–339.
(12) Ntaganda, R.; Dhudshia, B.; Macdonald, C. L. B.; Thadani, A. N.
Chem. Commun. 2008, 6200–6202. After the submission of our paper,
this paper on the coupling of aryl bromides with ammonia catalyzed
by copper complexes of carbene ligands was retracted and deleted
from the journal website.
(1) Roundhill, D. M. Chem. ReV. 1992, 92, 1–27.
(2) Zhao, J.; Goldman, A. S.; Hartwig, J. F. Science 2005, 307, 1080–
1082.
(13) Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 10028–10029.
(14) Surry, D. S.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 10354–
10355.
(3) Gross, T.; Seayad, A. M.; Ahmad, M.; Beller, M. Org. Lett. 2002, 4,
2055–2058.
(4) Ogo, S.; Uehara, K.; Abura, T.; Fukuzumi, S. J. Am. Chem. Soc. 2004,
126, 3020–3021.
(15) Schulz, T.; Torborg, C.; Enthaler, S.; Scha¨ffner, B.; Dumrath, A.;
Spannenberg, A.; Neumann, H.; Bo¨rner, A.; Beller, M. Chem.sEur.
J. 2009, 15, 4528–4533.
(5) Zimmermann, B.; Herwig, J.; Beller, M. Angew. Chem., Int. Ed. 1999,
38, 2372–2375.
(16) Weissermel, K.; Arpe, H. Industrial Organic Chemistry; Wiley-VCH:
Weinheim, Germany, 1997.
(6) Gunanathan, C.; Milstein, D. Angew. Chem., Int. Ed. 2008, 47, 8661–
8664.
(17) Lawrence, S. A. Amines: Synthesis, Properties, and Application;
Cambridge University Press: Cambridge, UK, 2004.
(18) Lindley, J. Tetrahedron 1984, 40, 1433–1456.
(7) Lavallo, V.; Frey, G. D.; Donnadieu, B.; Soleilhavoup, M.; Bertrand,
G. Angew. Chem., Int. Ed. 2008, 47, 5224–5228.
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A R T I C L E S
Vo and Hartwig
The copper-catalyzed reactions also do not occur in substantial
yields with aryl chlorides or sulfonates, which are less expensive
and more accessible than aryl iodides and bromides or aryl
triflates, respectively.11 Finally, catalyst loadings of greater than
10 mol % are usually required. This high loading can complicate
isolation of basic products from the copper catalyst.
from the typical Pd(0) source Pd2(dba)3 or the typical Pd(II)
source Pd(OAc)2.22 With the strongly electron-donating Josiphos
ligand, back-donation into the remaining dba ligand of the
(CyPF-t-Bu)Pd(dba) leads to slow dissociation of dba to generate
the catalytically active (CyPF-t-Bu)Pd(0).23 With a reagent
lacking ꢀ-hydrogens, a clear pathway to generate the Pd(0)
species from Pd(OAc)2 and the Josiphos ligand does not exist.
A catalyst precursor, in combination with CyPF-t-Bu, that
generates a higher concentration of active catalyst could allow
the coupling of ammonia to occur with less reactive aryl
chlorides and tosylates. Identification of such a catalyst could
also allow the reactions to be conducted under conditions that
are mild enough to be compatible with base-sensitive functional
groups and under conditions involving a lower pressure of
ammonia.
Herein, we report a general method for the coupling of
ammonia with aryl chlorides, bromides, iodides, and tosylates
catalyzed by a combination of Pd[P(o-tol)3]2 and CyPF-t-Bu.
The coupling occurs in high yield and with high selectivity for
formation of the primary arylamines in the presence of catalyst
loadings as low as 0.1 mol %. The substrate scope now includes
a wide range of aryl bromides and chlorides, including those
containing base-sensitive functional groups. For the first time,
the coupling of aryl tosylates and ammonia is also shown to
occur. The utility of this catalyst for sequential, one-pot
arylations of ammonia to prepare unsymmetrical diarylamines
and for the arylation of ammonia to form N-aryl imides, amides,
and carbamates by a one-pot, two-step sequence is demonstrated.
Preliminary mechanistic studies reveal the origins of the greater
reactivity of this catalyst system than that of the CyPF-t-Bu
systems reported previously.
The palladium-catalyzed coupling of ammonia with aryl
halides was first achieved in 2006 in our laboratory (eq 1).13
This process occurred with complexes generated from a Pd(II)
precursor ligated by the electron-rich and sterically bulky
Josiphos ligand (CyPF-t-Bu). We attributed the reactivity of the
catalyst containing this ligand for the arylation of ammonia to
two factors.19 First, the rigid backbone that arises from the
orientation of the methyl and ferrocenyl group directs the
phosphorus atoms and their electron pairs toward the metal
center, creating tight chelation and resulting stability toward
displacement by strong Lewis bases, such as ammonia. Second,
the strong electron donation and steric bulk of the ligand make
palladium(0) complexes of it highly reactive toward oxidative
addition of aryl chlorides and tosylates.20 This work and
subsequent reports by Buchwald14 in 2007 and Beller21 in 2009
constitute the only published palladium-catalyzed couplings of
ammonia with aryl halides.
Although palladium catalysts have the potential to create a
process that occurs with broader scope than the copper-catalyzed
reactions, a detailed evaluation of the reaction scope was not
included in the first reports of palladium-catalyzed coupling of
ammonia. Only one example of the reaction of an aryl chloride
was reported in our preliminary communication.13 No reactions
to form isolated primary arylamines from aryl chlorides were
included in Buchwald’s report although sequences to form four
mixed di- and triarylamines were initiated with aryl chlorides.15
The reactions of aryl bromides and aryl chlorides reported by
Beller required temperatures of 120 °C and were conducted
under 10 bar of N2 to obtain good yields of primary arylmines.15
Finally, the reactions of our studies in 2006 were conducted
with 200 psi ammonia to achieve good selectivity for formation
of the monoarylamine over the corresponding diarylamine.
Moreover, the coupling of aryl sulfonates with ammonia has
not been reported. Cleavage of the S-O bond of the sulfonyl
group was reported to occur faster than C-N coupling in the
presence of ammonia and the strong base NaO-t-Bu.13 For
similar reasons, aryl halides containing base-sensitive functional
groups such as esters, nitriles, and ketones containing enolizable
protons underwent reactions at the functional group faster than
they underwent C-N coupling.
2. Results and Discussion
2.1. Identification of Conditions for the Amination of 1-Bromo-
4-tert-butylbenzene in a 0.5 M Solution of Ammonia. To identify
the conditions for coupling of aryl halides with ammonia at
ambient pressure, we examined reactions of the electronically
neutral and sterically unhindered 1-bromo-4-tert-butylbenzene
in 0.5 M solutions of ammonia in either 1,2-dimethoxyethane
(DME) or 1,4-dioxane. These two solvents were chosen
because previous studies of the coupling of aryl halides with
ammonia in our laboratory showed that reactions in ethereal
solvents occurred to better conversions than those in hydro-
carbon solvents, such as toluene. Catalysts generated from
either one-component precatalysts or combinations of a
precatalyst and the CyPF-t-Bu ligand were tested. NaO-t-
Bu was used as the base. The conversion of the aryl halide
and the selectivity for formation of monoarylamines versus
1
diarylamines were measured by GC and H NMR spectros-
copy, respectively.
We compared reactions initiated with CyPF-t-Bu as ligand
and the commercially available Pd(OAc)2 or Pd2(dba)3 as
palladium source with reactions initiated with the one-
component catalyst (CyPF-t-Bu)PdCl2 that we used in our initial
work on the coupling of ammonia.13 Catalysts generated from
Pd(OAc)2 exhibited much lower reactivity than those generated
from Pd(dba)2 or (CyPF-t-Bu)PdCl2. The test reaction catalyzed
by the complex generated from equimolar amounts of Pd(OAc)2
and CyPF-t-Bu occurred to only 50% conversion after 12 h
(Table 1, entry 1), whereas reactions catalyzed by complexes
To address these limitations, we studied reactions in the
presence of a catalyst that would react under milder conditions
than the one we used for our initial studies. We recently reported
a combination of Pd(0) precursor and the Josiphos ligand that
circumvents the difficulties with generation of the active catalyst
(19) Shen, Q.; Ogata, T.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 6586–
6596.
(20) Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 8704–8705.
(21) Schulz, T.; Torborg, C.; Enthaler, S.; Scha¨ffner, B.; Dumrath, A.;
Spannenberg, A.; Neumann, H.; Bo¨rner, A.; Beller, M. Chem.sEur.
J. 2009, 15, 4528–4533.
(22) Ogata, T.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 13848–13849.
(23) Alvaro, E.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, 7858–7868.
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A R T I C L E S
Table 1. Effects of Precatalysts and Solvents on the Coupling of 4-Bromo-tert-butylbenzene with Ammonia in 0.5 M Solutionsa
entry
catalyst
loading (%)
solvent
concn [M]b
conversion (%)c
A/Bd
1
2
3
4
5
6
Pd(OAc)2/CyPF-t-Bu
Pd2(dba)3/CyPF-t-Bu
(CyPF-t-Bu)PdCl2
(CyPF-t-Bu)PdCl2
Pd[P(o-tol)3]2/CyPF-t-Bu
Pd[P(o-tol)3]2/CyPF-t-Bu
0.5
1,4-dioxane
1,4-dioxane
1,4-dioxane
DME
1,4-dioxane
DME
0.038
0.038
0.038
0.038
0.038
0.038
50
0.25e
0.5
100
100
100
100
100
17:1
7:1
0.7:1.0
>30:1
0.7:1.0
2.0
0.5
0.5
a Reactions conducted with 0.5 mmol 4-bromo-tert-butylbenzene, 5 mL of 0.5 M ammonia solutions, and 1.4 equiv of NaO-t-Bu. b Concentration of
4-bromo-tert-butylbenzene. c Determined by GC with dodecane as an internal standard. d Determined by 1H NMR spectroscopy. e Reaction conducted
with 0.25 mol % of Pd2(dba)3 and 0.5 mol % of CyPF-t-Bu.
Table 2. Determination of the Catalyst Loading Required for the
generated from Pd(dba)2, (CyPF-t-Bu)PdCl2, or Pd[P(o-tol)3]2
Coupling of Ammonia with ortho-Substituted Aryl Halidesa
as palladium sources occurred to full conversion after 12 h
(Table 1, entries 2-6). This difference in reactivity contrasts
results recently reported by our group on the coupling of
heteroaryl chloride with primary alkylamines in which com-
plexes generated from Pd(OAc)2 were much more reactive than
those generated from Pd(dba)2.19
Of the reactions that occurred to full conversion, those
conducted in 1,4-dioxane occurred with much greater selectivity
for formation of monoarylamines versus diarylamines than did
reactions conducted in DME (Table 1, entries 3 and 5 vs 4 and
6). In 1,4-dioxane, high selectivity for formation of the primary
arylamine was observed from reactions catalyzed by complexes
generated from Pd2(dba)3 or Pd[P(o-tol)3]2 (Table 1, entries 2
and 5). To determine the method that generates the most active
catalyst, we studied reactions conducted with Pd2(dba)3 or
Pd[P(o-tol)3]2 as precatalyst under the conditions of entries 2
and 5 of Table 1 for the coupling of 4-chlorotoluene with
ammonia. Although both systems led to reactions of aryl
bromides to high conversions, the system comprising Pd[P(o-
tol)3]2 and CyPF-t-Bu was substantially more active than that
comprising Pd2(dba)3 and CyPF-t-Bu for the coupling of
ammonia with aryl chlorides.23 More specifically, the reaction
of 4-bromo-tert-butylbenzene with ammonia catalyzed by
complexes generated from Pd[P(o-tol)3]2 and CyPF-t-Bu oc-
curred with conversion and selectivity that was similar to that
of the reaction catalyzed by complexes generated from Pd2(dba)3
and CyPF-t-Bu. However, the reaction of 4-chlorotoluene with
ammonia in the presence of 0.5 mol % of Pd[P(o-tol)3]2 and
CyPF-t-Bu occurred to full conversion after 12 h, whereas the
reaction catalyzed by 0.5 mol % of the combination of Pd2(dba)3
and CyPF-t-Bu occurred to less than 10% conversion of
4-chlorotoluene after 24 h.
Having established that the combination of Pd[P(o-tol)3]2 and
CyPF-t-Bu provides the more active catalyst system and that a
0.5 M solution of ammonia in dioxane is a suitable reaction
medium for the coupling of ammonia with aryl chlorides and
bromides, we sought reaction conditions for a general coupling
of aryl halides with ammonia at low catalyst loadings. We
identified two general sets of conditions. The first set of
conditions was identified for reactions of meta- and para-
substituted aryl halides. A substrate concentration of 0.038-0.05
M was used to ensure an excess of ammonia is present, and a
catalyst loading of 0.5 mol % was used to ensure suitable rates.
At this concentration and catalyst loading, the reaction of
4-bromo-tert-butylbenzene occurred to full conversion and high
selectivity (Table 2, entry 1). Reactions of these classes of aryl
a Reactions conducted with 1:1 ratio of metal to ligand, 0.5 mmol
aryl bromide, 5 mL of 0.5 M ammonia solution, and 1.4 equiv of
NaO-t-Bu in 1,4-dioxane. b Temperature of bath. c Determined by GC
d
1
analysis. Determined by H NMR spectroscopy.
bromides conducted with catalyst loadings below 0.5 mol %
occurred to low conversion (Table 2, entry 2). Reactions
conducted with higher concentrations of the bromoarene (0.1
M) occurred to completion with only 0.25 mol % of catalyst,
but the selectivity for the monoarylation product was lower
(Table 2, entry 3). Thus, we found the optimal concentration
and catalyst loading for reactions of meta- and para-substituted
aryl halides to be 0.038-0.05 M and 0.5 mol %, respectively.
For reactions of ortho-substituted aryl halides, a second set
of conditions was identified. Reactions of 2-bromotoluene and
2-chlorotoluene with ammonia at 0.1 M of the haloarene
occurred with selectivities that are similar to those of reactions
at 0.05 M concentration (Table 2, entries 4 and 5). At the 0.1
M concentration, these reactions occurred to full conversion of
the aryl halides in the presence of only 0.1 mol % catalyst.
2.2. Coupling of Ammonia with Aryl Bromides. Using the
reaction conditions identified in section 2.1, we evaluated the
scope of the coupling of aryl bromides with ammonia as a 0.5
M solution in dioxane. The results of this study are summarized
in Tables 3 and 4. The scope of these reactions encompasses
those of aryl bromides that are electron-rich, electron-neutral,
and electron-poor and those of aryl bromides that have a range
of substitution patterns.
2.2.1. Reactions of ortho-Substituted Aryl Bromides. The
reactions of ortho-substituted aryl bromides with ammonia
encompass substrates containing a wide range of electronic and
steric properties. For example, ammonia coupled with electron-
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A R T I C L E S
Vo and Hartwig
Table 3. Coupling of ortho-Substituted Aryl Bromides with Ammoniaa
a Reactions conducted with 1:1 ratio of metal to ligand, 0.5 mmol aryl bromide, 5 mL of 0.5 M ammonia solution, and 1.4 equiv of NaO-t-Bu in
d
1,4-dioxane. b Temperature of bath. c Isolated yield after purification by flash column chromatography. Determined by H NMR spectroscopy.
1
2.2.2. Reactions of meta- and para-Substituted Aryl Bro-
mides. In our prior work, the reactions of sterically unhindered
aryl bromides occurred with lower selectivity for formation of
monoarylamine versus diarylamines, especially when a low pres-
sure of ammonia was used.13 Under our new conditions, however,
high selectivities were observed for the formation of primary
arylamines from reactions of para-substituted, as well as meta-
substituted, aryl bromides, with ammonia as a 0.5 M solution in
dioxane. These results are summarized in Table 4. Electron-neutral
1-bromo-4-tert-butylbenzene and 1-bromo-3,5-di-tert-butylbenzene
coupled with ammonia to afford primary arylamine products in
88 and 78% yields, respectively (Table 4, entries 1 and 2).
4-Bromobiphenyl also coupled with ammonia in excellent yield
(Table 4, entry 3).
neutral and sterically hindered aryl bromides (Table 3, entries
1 and 3), as well as ortho-substituted aryl bromides containing
aromatic and vinylic substituents (Table 3, entries 9 and 13) to
form the primary arylamine products in excellent yields in the
presence of 0.5 mol % of the catalyst. It is notable that the
reaction of 2-bromostyrene occurred without substantial po-
lymerization. Electron-rich, ortho-substituted aryl halides also
coupled with ammonia in high yields to form the primary
arylamines. For example, the reactions of ammonia with
2-bromo-N,N-dimethylaniline and 2-bromoanisole occurred with
0.5 mol % of the catalyst at 80 °C in only 4 h to afford excellent
yields of the coupled products (Table 3, entries 5 and 7).
2-Bromo-m-xylene is a challenging substrate for both palladium-
and copper-catalyzed amination chemistry because of its steric
bulk.12 Nevertheless, the reaction of this substrate with ammonia
occurred with 0.5 mol % of the catalyst at 100 °C in 15 h to
afford excellent yield of the primary arylamine product (Table
3, entry 12).
The scope of this process also encompasses aryl bromides
possessing a wide range of electronic properties. For example,
reactions of electron-deficient 3-bromoanisole and 3,5-bis(trifluo-
romethyl)bromobenzene with ammonia occurred with 0.5 mol %
catalyst loading at substrate concentration of 0.038 M to give the
primary arylamine products in excellent yields and selectivities
(Table 4, entries 4 and 5). An aryl bromide containing keto
functionality also coupled with ammonia in high yield (Table 4,
entry 6). Reactions of electron-rich aryl bromides with ammonia
occurred to give good yields of primary arylamine products but
required somewhat higher temperatures and catalyst loadings.
However, 4-bromoanisole and 4-bromothioanisole still coupled with
ammonia in the presence of 1 mol % of the catalyst at 90-100 °C
to give 53% and 91% yields, respectively (Table 4, entries 7 and 8).
Reactions of ammonia with a 0.1 M concentration of ortho-
substituted aryl halides even occurred with catalyst loadings down
to 0.1 mol %. Reactions conducted with 0.1 mol % catalyst required
a longer reaction time (12 h) and a higher temperature (100 °C)
for complete conversion than those conducted with 0.5 mol % of
catalyst. However, yields and selectivities of the primary arylamines
remained high for substrates containing alkyl, aryl, amino, and
methoxy substituents (Table 3, entries 2, 4, 6, 8, 10, and 11). These
reactions were conducted with the lowest loadings of any copper
or palladium catalyst for the coupling of aryl halides with ammonia.
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Preparation of Primary Arylamines
A R T I C L E S
Table 4. Coupling of meta- and para-Substituted Aryl Bromides with Ammoniaa
a Reactions conducted with 1:1 ratio of metal to ligand, 0.5 mmol aryl bromide, 5 mL of 0.5 M ammonia solution, and 1.4 equiv of NaO-t-Bu in
d
1,4-dioxane. b Temperature of bath. c Isolated yield after purification by flash column chromatography. Determined by H NMR spectroscopy.
1
2.2.3. Comparison to the Reactions Catalyzed by Copper
Catalysts. Chang,10 Taillefer,11 and Thadani12 recently reported
copper-catalyzed coupling of aryl halides with ammonia.25
Chang showed that complexes generated from 20 mol % of CuI
and 40 mol % of L-proline catalyze the coupling of aryl iodides
and electron-poor aryl bromides with NH4Cl or NH4OH.
Taillefer reported the coupling of aryl iodides and aryl bromides
with NH4OH in the presence of 10 mol % of Cu(acac)2 and 40
mol % of 2,4-pentanedione. Although the reactions conducted
with 2,4-pentanedione as the ligand precursor occur with broader
scope than those with proline, both papers reported that aryl
iodides and bromides containing ortho-substituents coupled with
ammonia in low yields. In contrast to these two reports, Thadani
and co-workers recently reported that the copper-carbene
complex 3 catalyzes the coupling of ortho-substituted as well
as electron-rich aryl bromides.
Heteroaryl bromides also reacted with ammonia in the
presence of Pd[P(o-tol)3]2 and CyPF-t-Bu to give valuable
heteroaryl amines in good yields. For example, reactions of
3-bromopyridine and 3-bromoquinoline with ammonia in the
presence of 0.5 mol % of the catalyst occurred to full
conversion after 12 h at 80 °C to give the primary arylamine
products in good yields (Table 4, entries 9 and 10). 4,4′-
Benzidine is the core motif of N,N′-bis(3-methylphenyl)-N,N′-
diphenylbenzidine (TPD), which is used in hole-transport
layer in electroluminescent devices.24 The coupling of 4,4′-
dibromobiphenyl with ammonia to afford 4,4′-benzidine by
formation of two C-N bonds occurred with 2.0 mol % of
the catalyst at 100 °C in good yield. Overall, the results
presented in Table 4 demonstrate the broadest substrate scope
under the mildest conditions for the coupling of ammonia
with aryl bromides with any current catalyst.
Table 5 provides a comparison of the activity of the palladium
catalyst generated from Pd[P(o-tol)3]2 and CyPF-t-Bu (condition
D) to the copper catalysts generated in situ from CuI and
L-proline 1 (condition A) or 2,4-pentanedione 2 (condition B)
(24) Shen, Y.; Klein, M. W.; Jacobs, D. B.; Scott, J. C.; Malliaras, G. G.
Phys. ReV. Lett. 2001, 86, 3867.
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A R T I C L E S
Vo and Hartwig
Table 5. Comparison of the Activity of Copper Catalysts versus Pd[P(o-tol)3]2 and CyPF-t-Bu in the Coupling of Ammonia with Aryl Halides
a Reaction conditions A: 0.5 mmol aryl halide, 0.65 mmol NH4OH, 0.1 mmol CuI, 0.2 mmol L-proline, 1.5 mmol K2CO3, 1 mL of DMSO, 0.05 mL
of H2O, 80 °C, 24 h. b Reaction conditions B: 1 mmol aryl halide, 300 mL of NH4OH, 0.1 mmol Cu(acac)2, 0.4 mmol 2,4-pentadione, 2 mmol Cs2CO3,
2 mL of DMF, 90 °C, 24 h. c Reaction conditions C: 1 mmol aryl halide, 0.05 mmol 3, 2 mmol K2CO3, 5 mL (1:1, MeOH/NMP), 90 °C, 24 h.
d Reaction conditions D: 0.5 mmol aryl halide, 5 mL of 0.5 M ammonia in dioxane, 0.7 mmol NaOtBu; entry 1: 0.0025 mmol Pd[P(o-tol)3]2/CyPF-t-Bu,
5 mL of 0.5 M ammonia in dioxane, 80 °C; entry 2: 0.0005 mmol Pd[P(o-tol)3]2/CyPF-t-Bu, 5 mL of 0.5 M ammonia in dioxane, 100 °C; entry 3:
0.0025 mmol Pd[P(o-tol)3]2/CyPF-t-Bu, 5 mL of 0.5 M ammonia in dioxane, 5 mL dioxane, 80 °C. e No product observed by GC/MS.
or the discrete complex 3 containing an N-heterocyclic carbene
ligand (condition C) for the reactions of ammonia with ortho-
substituted 2-iodotoluene and 2-bromoanisole and electron-
neutral 4-bromo-tert-butylbenzene. The data in this table were
obtained from reactions conducted under the reported optimal
conditions for each of the catalyst systems.10-12 The reaction
of 2-iodotoluene with ammonia in dioxane in the presence of
0.5 mol % of an equimolar amount of Pd[P(o-tol)3]2 and CyPF-
t-Bu gave 73% of ortho-toluidine. The reaction of 2-iodotoluene
with ammonia in water catalyzed by copper complexes contain-
ing L-proline 1 and 2,4-pentanedione 2 gave substantially lower
yields. The reaction conducted with complex 3 did not occur
to form any coupled product that could be observed by GC/
MS. Likewise, the coupling of the ortho-substituted 2-bro-
moanisole with ammonia in the presence of the copper catalysts
occurred with yields that are substantially lower than those of
the reaction catalyzed by 0.1 mol % of an equimolar amount
of Pd[P(o-tol)3]2 and CyPF-t-Bu (Table 5, entry 2).26
4-tert-butylaniline, respectively. Again, the reaction catalyzed
by complex 3 afforded no coupled product that could be
observed by GC/MS. In contrast, the reaction catalyzed by 0.5
mol % of Pd[P(o-tol)3]2 and CyPF-t-Bu formed the primary
arylamine in 88% yield.
2.3. Coupling of Ammonia with Aryl Chlorides and Aryl
Iodides. Because aryl chlorides are less expensive than aryl
bromides and iodides and more derivatives are commercially
available, the synthesis of primary arylamines from aryl
chlorides would be particularly valuable. However, the
carbon-chlorine bonds in these reagents are less reactive than
their bromide and iodide counterparts.27,28 Prior to our current
work, only one example of the coupling of ammonia with an
aryl chloride had been reported to give high isolated yield of
the primary arylamine product, and this example was conducted
with a catalyst generated from CyPF-t-Bu.13 We show here that
the reactions of a series of aryl chlorides with ammonia
catalyzed by the combination of Pd[P(o-tol)3]2 and CyPF-t-Bu
lead to high yields of primary arylamines with relatively low
catalyst loadings.
The scope of the coupling of ammonia with aryl chlorides
and iodides is summarized in Table 6. The catalyst generated
from Pd[P(o-tol)3]2 and CyPF-t-Bu catalyzed the coupling of
ammonia with aryl chlorides in high yields under the same
reaction conditions described for the coupling of aryl bromides.
The reactions of ortho-substituted aryl chlorides occurred in
particularly high yields and selectivities for the primary ary-
lamines. For example, reactions of 2-chlorotoluene and 2,5-
dimethylchlorobenzene with ammonia occurred with 0.5 mol
% of the catalyst at 80 °C for 24 h to afford the primary
arylamines in 64% and 85% yields, respectively (Table 6, entries
1 and 3). Like the couplings of ortho-substituted aryl bromides,
the coupling of ortho-substituted aryl chlorides with ammonia
occurred in the presence of only 0.1 mol % of catalyst at
substrate concentration of 0.1 M without significant reduction
in yield (Table 6, entries 2 and 4). The electron-rich 2-chloro-
anisole also reacted under this low catalyst loading to give high
The differences in yields from the reactions of sterically
unhindered substrates with the different catalysts were less
dramatic, but the reaction catalyzed by 0.5 mol % of Pd[P(o-
tol)3]2 and CyPF-t-Bu still formed the primary arylamine in the
highest yield. The coupling of 4-bromo-tert-butylbenzene with
ammonia in the presence of copper complexes containing 40
mol % of 1 and 40 mol % of 2 gave 84% and 55% yield of
(25) Soon after the submission of this article, a report on ligandless copper-
catalyzed coupling of aryl bromides and chlorides with ammonia in
water was published Xu, H. Wolf, C. Chem. Commun. 2009, 3035–
3037. In our hands, the reaction of 2-bromotoluene with aqueous
ammonia by the published protocols using various sources of copper
iodide, open or closed vessels, and reaction vessels with varying
headspaces afforded less than 10% of ortho-toluidine. Thus, we
abandonded studies to compare our system to this one.
(26) While this work was under review, Ma and co-workers reported the
coupling of 2-bromoanisole and 2-bromotoluene with ammonia in
water in the presence of 20% CuI and 40 mol % of 4-hydroxy-L-
proline to give 81 and 55% yields of the primary arylamines,
respectively: Jiang, L.; Lu, X.; Zhang, H.; Jiang, Y.; Ma, D. J. Org.
Chem. 2009, 74, 4542–4546. In contrast to the work with ligandless
catalysts in ref 25, we have obtained yields (69 and 60%, respectively)
that are close to those published, but these yields are still lower than
those in the current work with palladium catalysts.
(27) Grushin, V. V.; Alper, H. Chem. ReV. 1994, 94, 1047–1062.
(28) Littke, A.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176–4211.
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Preparation of Primary Arylamines
A R T I C L E S
Table 6. Coupling of Aryl Chlorides and Iodides with Ammoniaa
a Reactions conducted with 1:1 ratio of metal to ligand, 0.5 mmol aryl chloride, 5 mL of 0.5 M ammonia solution, and 1.4 equiv of NaO-t-Bu in
d
1,4-dioxane. b Temperature of bath. c Isolated yield after purification by flash column chromatography. Determined by H NMR spectroscopy.
1
yield of ortho-anisidine (Table 6, entry 5). Even the coupling
of the 2,6-disubstituted 2-chloro-m-xylene with ammonia in the
presence of 1 mol % of catalyst occurred to full conversion of
the aryl chloride to afford high yield of the primary arylamine
product (Table 6, entry 6). The reaction of ammonia with the
pseudo-ortho-substituted, fused polyarene 1-chloronaphthalene
also occurred in high yield (Table 6, entry 7).
Sterically unhindered aryl chlorides and heteroaryl chlorides
ranging from electron-deficient to electron-rich also coupled with
ammonia in high yields and selectivities. For example, reactions
of 4-chlorotoluene and 3-chloroanisole with ammonia occurred
at 0.038 M concentration of the substrates to afford good yields
of coupled products (Table 6, entries 8 and 9). The coupling of
electron-rich substrates with ammonia is challenging for reasons
that are discussed later in this paper. Nevertheless, the reaction
of electron-rich 4-chloroanisole with ammonia occurred with 1
mol % of the catalyst at 100 °C for 12 h to give 69% yield of
anisidine. The conditions for reactions of aryl chlorides proved
to be suitable for the reactions of heteroaryl chlorides. The
reaction of 3-chloropyridine with ammonia occurred in 64%
isolated yield (Table 6, entry 11).
The generality of this method is further demonstrated by the
high yields of primary arylamines derived from aryl iodides.
The reactions of aryl iodides with nitrogen nucleophiles are
known to occur in yields and selectivities that are often lower
than those of reactions of aryl bromides.29-42 Nevertheless, the
(29) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 7369–
7370.
(30) Urgaonkar, S.; Xu, J.-H.; Verkade, J. G. J. Org. Chem. 2003, 68, 8416–
8423.
(38) Urgaonkar, S.; Nagarajan, M.; Verkade, J. G. J. Org. Chem. 2003,
68, 452–459.
(31) Grasa, G. A.; Viciu, M. S.; Huang, J.; Nolan, S. P. J. Org. Chem.
2001, 66, 7729–7737.
(39) Enguehard, C.; Allouchi, H.; Gueiffier, A.; Buchwald, S. L. J. Org.
Chem. 2003, 68, 4367–4370.
(32) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1996, 61, 1133–1135.
(33) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 7217–
7218.
(40) Meyers, C.; Maes, B. U. W.; Loones, K. T. J.; Bal, G.; Lemiere,
G. L. F.; Dommisse, R. A. J. Org. Chem. 2004, 69, 6010–6017.
(41) Gerristma, D.; Brenstrum, T.; McNulty, J.; Capretta, A. Tetrahedron
Lett. 2004, 45, 8319–8321.
(34) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1997, 62, 6066–6068.
(35) Huang, J.; Grasa, G.; Nolan, S. P. Org. Lett. 1999, 1, 1307–1309.
(36) Ali, M. H.; Buchwald, S. L. J. Org. Chem. 2001, 66, 2560–2565.
(37) Arterburn, J. B.; Pannala, M.; Gonzalez, A. M. Tetrahedron Lett. 2001,
42, 1475–1477.
(42) For recent reports on efficient couplings of aryl iodides, see ref 19
and the following reference: Fors, B. P.; Davis, N. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2009, 131, 5766–5768.
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A R T I C L E S
Vo and Hartwig
Table 7. Coupling of Ammonia with Aryl Tosylatesa
a Reactions conducted with 1:1 ratio of metal to ligand, 0.5 mmol aryl chloride, 5 mL of 0.5 M ammonia solution, and 1.4 equiv of NaO-t-Bu in
1,4-dioxane. b Temperature of bath. c Isolated yield after purification by flash column chromatography. d Determined by 1H NMR spectroscopy.
e
1
Selectivity was not determined due to overlapping resonances in the aromatic region of the H NMR spectra of the crude reaction mixtures.
reaction of 2-iodotoluene with ammonia in the presence of 0.5
mol % of catalyst occurred to full conversion and formed a good
yield of the coupled product (Table 6, entry 12).
less sterically hindered tosylates. For example, the reactions of
1-naphthyl p-toluenesulfonate and 2-naphthyl p-toluenesulfonate
with ammonia occurred with 2 mol % of the catalyst to afford
the coupled products in 67% yield in both cases (Table 7, entries
3 and 4). Heteroaryl tosylates also coupled with ammonia to
form synthetically useful, albeit lower, yields of the primary
heteroarylamines. For example, the reaction of 6-quinolinyl
p-toluenesulfonate with ammonia afforded 55% yield of the
coupled product (Table 7, entry 5). Improvements in the
reactions of sterically unhindered aryl tosylates will be the focus
of future work, but these results represent the first coupling of
aryl sulfonates with ammonia and demonstrate that the synthesis
of primary arylamines from aryl alcohols by this approach is
feasible.
2.4. Coupling of Aryl Sulfonates with Ammonia. Prior to this
work, the coupling of ammonia with aryl sulfonates formed
the primary arylamines in low yields.13 The yields were low
because the C-N coupling process competes with the uncata-
lyzed cleavage of the S-O bond of the sulfonyl group by
ammonia in the presence of the strong base NaO-t-Bu to form
aryl alcohols as the major product. In 2003, we showed that
the complex generated from Pd[P(o-tol)3]2 and CyPF-t-Bu
undergoes the oxidative addition of aryl tosylates rapidly at room
temperature.20 More recently, the authors’ laboratory showed
that the coupling of aryl tosylates with alkyl- and arylamines
occurs at room temperature when catalyzed by the species
generated from Pd[P(o-tol)3]2 and CyPF-t-Bu.22 The low tem-
peratures of the coupling of primary amines suggested that the
coupling of ammonia could occur faster than cleavage of aryl
sulfonates. Indeed, we found that the coupling of ammonia with
aryl sulfonates conducted with 2 mol % of catalyst, at a
temperature of 50 °C, and with a tosylate as the sulfonate group
occurred faster than S-O bond cleavage. Reactions of aryl
triflates led to the phenol as the major product from S-O bond
cleavage.
The results of our study on the scope of the coupling of aryl
tosylates with ammonia under these conditions are shown in
Table 7. Reactions of sterically hindered aryl tosylates with
ammonia produced primary arylamines in good to excellent
yields. For example, 2-methylphenyl p-toluenesulfonate and
2,4,6-trimethylphenyl p-toluenesulfonate coupled with ammonia
in the presence of 2 mol % of the catalyst at 50 °C for 24 h to
give primary arylamines in 65% and 86% yield, respectively
(Table 7, entries 1 and 2). Less sterically hindered aryl tosylates
reacted with ammonia to give slightly lower yields of the
arylamine than did ortho-substituted aryl tosylates. We attributed
this result to the faster rates of formation of aryl alcohols from
2.5. Coupling of Ammonia with Aryl Halides Containing
Base-Sensitive Functional Groups.
2.5.1. Identification of Reaction Conditions. The scope of the
palladium-catalyzed coupling of ammonia with aryl halides
containing base-sensitive functional groups, such as enoliazble
ketones, esters, and nitriles, has been limited. We presumed that
this limitation in scope results from the use of the strong base
NaO-t-Bu.
Thus, our initial attempts to expand the scope of the coupling
of ammonia to encompass base-sensitive functional groups focused
on conducting reactions with weak bases, such as Cs2CO3 and
K3PO4, that have helped to address issues of functional group
compatibility in the coupling of amines.43,44 We studied reactions
of ammonia with ethyl 4-bromobenzoate to evaluate conditions
required to obtain high yield and selectivity of the primary
arylamine from base-sensitive haloarenes.
The reaction of ethyl 4-bromobenzoate with ammonia con-
ducted in 0.5 M solutions of ammonia in dioxane in the presence
of 0.5 mol % of equimolar amounts of Pd[P(o-tol)3]2 and CyPF-
t-Bu and 5 equiv of K3PO4 occurred to full conversion, but only
the diarylamine product was observed. Apparently, the more
acidic arylamine product reacts faster than ammonia in reactions
9
11056 J. AM. CHEM. SOC. VOL. 131, NO. 31, 2009

Preparation of Primary Arylamines
A R T I C L E S
Table 8. Coupling of Ammonia with Aryl Halides and Sulfonates Containing Base-Sensitive Functional Groupsa
a Reactions conducted with 1:1 ratio of metal to ligand, 0.5 mmol aryl chloride, and 200 psi of ammonia in a 50 mL Parr bomb, and 1.4 equiv of
NaO-t-Bu in 1,4-dioxane. b Temperature of bath. c Isolated yield after purification by flash column chromatography. d Determined by 1H NMR
spectroscopy.
conducted with the weaker base. However, reactions conducted
with higher concentration of ammonia occurred with higher
selectivity for formation of the primary arylamine. For example,
the reaction of ethyl 4-bromobenzoate with 200 psi of ammonia
in the presence of 0.5 mol % of equimolar amounts of Pd[P(o-
tol)3]2 and CyPF-t-Bu and 5 equiv of K3PO4 occurred to full
conversion and gave a 30:1 ratio of the primary arylamine to
the diarylamine.
2.5.2. Scope of the Coupling of Ammonia with Aryl Halides
and Sulfonates Containing Base-Sensitive Functional Groups.
Using the conditions described in section 2.5.1, we studied the
scope of the coupling of ammonia with aryl halides that contain
base-sensitive functional groups. The results of this study are
summarized in Table 8. Aryl halides and tosylates containing
base-sensitive, electron-withdrawing functional groups at the
para-position coupled with ammonia in high yields. For
example, reactions of ethyl 4-bromobenzoate and methyl
4-bromobenzoate with ammonia occurred with only 0.5 mol %
of the catalyst to give 94% and 83% yields of primary
arylamines, respectively (Table 8, entries 1 and 3). Aryl halides
containing enolizable ketones such as 4′-bromoacetophenone
and 4′-bromopropiophenone coupled with ammonia to give high
yields of coupled products (Table 8, entries 5 and 7).
The ability of the catalyst generated from Pd[P(o-tol)3]2 and
CyPF-t-Bu to add aryl halides under mild conditions and the
apparent stability of this catalyst toward iodide byproduct also
led to increases in reaction scope. For example, reactions of
ammonia with methyl 4-chlorobenzoate and 4-chlorobenzonitrile
occurred to give high yields of primary arylamines without
formation of amide or amidine side products (Table 8, entries
4 and 9). Moreover, the reaction of the electron-poor 4′-
iodoacetophenone with ammonia in the presence of 1 mol %
of Pd[P(o-tol)3]2 and CyPF-t-Bu afforded good yield of the
aniline product (Table 8, entry 6).
The ability to conduct these couplings with K3PO4 as base
also allowed us to develop the coupling of aryl tosylates
containing base-sensitive functionality. The rate of formation
of aryl alcohol side products should be slower in the presence
of ammonia and K3PO4 than in the presence of ammonia and
NaO-t-Bu, while the catalyst should add the electron-poor aryl
tosylate with a rate that is faster than it adds electron-neutral
and electron-rich aryl tosylates. Consistent with these expecta-
tions, reactions of ammonia with 4-cyanophenyl p-toluene-
sulfonate and ethyl 4-{[(4-methylphenyl)sulfonyl]oxy}benzoate
occurred with only 0.5 mol % of the catalyst to afford 73%
and 79% yields of coupled products, respectively (Table 8,
entries 2 and 10). Because the aryl halides shown in Table 8
are electron-poor, control reactions were conducted without the
palladium catalyst to determine if the reactions were truly metal-
catalyzed. No measurable quantity of primary arylamine product
was observed in the absence of palladium for reactions of any
of the aryl halides shown in Table 8. Some conversion was
observed during reactions of aryl tosylates with ammonia and
K3PO4 in the absence of catalyst at 80 °C, but these reactions
formed the corresponding aryl alcohols by S-O bond cleavage,
not the desired arylamines.
Cyano functionality is typically stable toward reactions in
the presence of NaO-t-Bu and either alkyl- or arylamine
nucleophiles,29,45 but 4-halobenzonitriles reacted with ammonia
in the presence of NaO-t-Bu with and without the palladium
catalyst to form multiple products. In contrast to the reactions
of ammonia in the presence of the strong alkoxide base, the
reaction of 4-bromobenzonitrile with ammonia and K3PO4 as
base catalyzed by Pd[P(o-tol)3]2 and CyPF-t-Bu occurred to give
71% yield of the coupled product (Table 8, entry 8).
(43) Åhman, J.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6363–6366.
(44) Wolfe, J. P.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6359–6362.
(45) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.;
Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575–5580.
The reactions of ammonia with more electron-rich aryl halides
and sulfonates that contain base-sensitive functional groups gave
low yields of primary arylamines in the presence of Pd[P(o-tol)3]2
9
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A R T I C L E S
Vo and Hartwig
and CyPF-t-Bu as catalyst. A rationalization for this result will be
provided later in this paper. Despite this limitation, our method
allows for the coupling of ammonia with a set of aryl iodides,
bromides, chlorides, and sulfonates that contain base-sensitive
functional groups. The ability to conduct these reactions with this
range of halides and with sulfonates constitutes a significant
expansion of the scope of related reactions described previously
with other palladium or copper catalysts.10-14
2.6. Sequential Reactions Initiated by the Coupling of
Ammonia with Aryl Halides. Although primary arylamines are
often the desired end product, in many instances, the primary
arylamine would be used to generate diarylamines, amides,
sulfonamides, imides, or other products containing an aromatic
C-N bond. In some cases, the reagents that one would use for
the direct coupling to form these classes of products have not
been shown to undergo C-N coupling in a reliable fashion,
whereas in other cases, one might wish to generate the arylamine
as a means to generate a library of compounds derived from
the initial arylamine product. Having developed an efficient
synthesis of arylamines, we sought to demonstrate the utility
of the arylation of ammonia as a means to generate arylamine
derivatives. Two examples of such sequential reaction chemistry
are shown here.
2.6.1. Sequential Arylation of Ammonia by a Single Catalyst
in One Pot. Unsymmetrical diarylamines are intermediates to
unsymmetrical triarylamines, which have numerous applications
in photonic, organic polymers.46 The work described here has
demonstrated that the combination of Pd[P(o-tol)3]2 and CyPF-
t-Bu is a highly active catalyst for the coupling of aryl halides
and tosylates with ammonia to form primary arylamines, and
the authors’ group has recently shown that this same combina-
tion of metal and ligand catalyzes the coupling of aryl and
heteroaryl tosylates with arylamines at room temperature to form
mixed diarylamines.22 Thus, we sought to develop a sequential
coupling of ammonia with aryl halides and sulfonates in the
presence of a single catalyst to form mixed diarylamines.
The catalyst generated from Pd[P(o-tol)3]2 and CyPF-t-Bu
does allow the sequential coupling of ammonia with two
different aryl electrophiles to occur in one pot. As shown in eq
2, the arylation of ammonia with 4-bromo-tert-butylbenzene
occurs in the presence of 0.5 mol % of Pd[P(o-tol)3]2 and CyPF-
t-Bu and 3 equiv of NaO-t-Bu. After full conversion of the aryl
bromide, evaporation of the dioxane, followed by addition of
the aryl tosylate and toluene and heating, led to the formation
of the unsymmetrical diarylamine in high yield (eq 2). Sequential
coupling of two different aryl halides with ammonia can also
be conducted in one pot and will be reported in due course.
derivatives include amides, imides, and carbamates. The amide
moiety is present in many biologically active compounds, and
work has been conducted to develop methods to access libraries
of amides for studies on structure-reactivity relationships.47-50
Palladium-51,52 and copper-catalyzed53,54 amidations have limi-
tations in substrate scope, require high catalyst loadings, and
are sufficiently challenging in many cases that parallel synthesis
would require attention to the development of conditions for
individual substrate combinations.
N-Aryl imides, in particular, phthalimides, have been used
extensively as intermediates in the manufacture of dyes,55
polymers,56,57 and pesticides,58 and this class of compound has
also been shown to be biologically active.59,60 Amides and
imides are widely prepared by reactions between amines and
acid chlorides or anhydrides, but this procedure requires an
arylamine reagent. The N-arylation of imides has not been
reported with palladium catalysts and has not been reported with
modern copper catalysts.
The preparation of N-Boc-arylamines via palladium- or
copper-catalyzed coupling of aryl halides with tert-butyl car-
bamate is limited to a few examples conducted with palladium
catalysts generated from either xantphos, P(t-Bu)3, or tert-butyl
X-Phos as ligands.45,61-63 No reactions of aryl chlorides or
sulfonates have been reported, and the reactions of ortho-
substituted aryl halides were limited to one electron-poor62 and
two electron-neutral examples.45,63
Thus, the palladium-catalyzed coupling of an aryl halide with
ammonia, followed by the uncatalyzed reaction of the primary
amine product with an acid chloride, cyclic anhydide, or Boc
anhydride could provide a convenient route to a family of N-aryl
amides, imides, and carbamates from a single aryl halide. Our
demonstration of this sequence focused on reactions of ortho-
substituted aryl halides because of the direct coupling of this
class of aryl halides with primary aryl amides, tert-butyl
carbamate, and phthalimide has been challenging. Yet, a
sequence initiated with meta- or para-substituted aryl halides
would lead to analogous products.
(47) An, H.; Cook, P. D. Chem. ReV. 2000, 100, 3311–3340.
(48) Boger, D. L.; Tarby, C. M.; Myers, P. L.; Caporale, L. H. J. Am.
Chem. Soc. 1996, 118, 2109–2110.
(49) Kim, S.; Ko, H.; Kim, S.; Lee, T. J. Comb. Chem. 2002, 4, 549–551.
(50) Cheng, S.; Comer, D. D.; Williams, J. P.; Myers, P. L.; Boger, D. L.
J. Am. Chem. Soc. 1996, 118, 2567–2573.
(51) Hartwig, J. F. In Modern Amination Methods; Ricci, A., Ed.; Wiley-
VCH: Weinheim, Germany, 2000.
(52) Jiang, L.; Buchwald, S. L. In Metal-Catalyzed Cross-Coupling
Reactions; De Meijere, A., Diederich, F., Eds.; Wiley-VCH: Wein-
heim, Germany, 2004; Vol. 2, p 699.
(53) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–
5449.
(54) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 248,
2337–2364.
(55) Steffanut, P.; Klein, C.; Graciet, J. C.; Luecke, L.; Winter, M. A. PCT
Int. Appl. WO 2007118784 A2 20071025, 2007.
(56) Chae, K. H.; Kim, Y. H. AdV. Funct. Mater. 2007, 17, 3470.
(57) Chen, G.; Zhang, X.; Zhang, S.; Chen, T.; Wu, Y. J. Appl. Polym.
Sci. 2007, 106, 2808.
(58) Pawar, N. S.; Kapadi, U. R.; Hundiwale, D. G.; Kumbhar, P. P. Sci.
Ind. Res. 2002, 61, 454.
(59) Meng, X.-B.; Han, D.; Zhang, S.-N.; Guo, W.; Cui, J.-R.; Li, Z.-J.
Carbohydr. Res. 2007, 342, 1169.
2.6.2. One-Pot Synthesis of Amides and Imides from Aryl
Halides. The coupling of ammonia with aryl halides creates the
ability to conduct a one-pot synthesis of aniline derivatives that
are challenging to obtain directly by C-N coupling. These
(60) Balzarini, J.; Clercq, E. D.; Kaminska, B.; Orzeszko, A. AntiViral
Chem. Chemother. 2003, 14, 139.
(61) Wannberg, J.; Dallinger, D.; Kappe, C. O.; Larhed, M. J. Comb. Chem.
2005, 7, 574–583.
(62) Trabanco, A. A.; Vega, J. A.; Fernandez, M. A. J. Org. Chem. 2007,
72, 8146–8148.
(46) Thayumanavan, S.; Barlow, S.; Marder, S. R. Chem. Mater. 1997, 9,
(63) Bhagwanth, S.; Waterson, A. G.; Adjabeng, G. M.; Hornberger, K. R.
J. Org. Chem. 2009, 74, 4634–4637.
3231–3235.
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Preparation of Primary Arylamines
A R T I C L E S
Table 9. Synthesis of Amides and Imides from Aryl Bromides and Chloridesa
a Reactions conducted with 1:1 ratio of metal to ligand. b Temperature of bath. c Isolated yield after purification by flash column chromatography.
d One equivalent of Et3N was added.
Our data illustrating the two-step, one-pot synthesis of a
family of N-aryl amides, imides, and carbamates from a single
aryl halide are summarized in Table 9. The ortho-substituted
aryl halides, such as 2-bromo-N,N-dimethylaniline and 2-chlo-
roanisole, reacted with ammonia in the presence of only 0.1
mol % of the palladium catalyst. After evaporation of excess
ammonia under reduced pressure for 5 min, the addition of acid
chlorides that range from electron-rich to electron-poor, along
with 1 equiv of Et3N to neutralize the released HCl, afforded
the N-aryl amides in 70-94% yields (Table 9, entries 1, 3, 5,
and 6).
less hindered 4-bromothioanisole, followed by addition of
phthalic anhydride, gave 75% yield of the corresponding N-aryl
imide.
2.7. Mechanistic Studies. Although a full evaluation of the
mechanism of the coupling of ammonia with aryl halides
requires further study, several initial mechanistic experiments
provide insight into the factors that differentiate the current
catalyst from those used previously containing the CyPF-t-Bu
ligand and that differentiate the reactivity of aryl halides
containing electron-withdrawing groups in the para- and meta-
positions. These experiments evaluated the efficiency of the
generation of the active palladium(0) catalyst from the palla-
dium(II) precursors and identified the turnover-limiting steps
of the reactions of electron-poor aryl halides.
2.7.1. Studies on the Reactions of Palladium(II) Precursors
with Ammonia and Base. To address the origin of the higher
reactivity of complexes generated from Pd[P(o-tol)3]2 than those
generated from Pd(OAc)2 or (CyPF-t-Bu)PdCl2, we studied the
catalytic reactions of 4-bromo-tert-butylbenzene with ammonia
catalyzed by (CyPF-t-Bu)PdCl2 or the combination of CyPF-
t-Bu and Pd(OAc)2. 31P NMR spectra of reactions conducted
with (CyPF-t-Bu)PdCl2 or the combination of CyPF-t-Bu and
This one-pot method also formed N-aryl carbamates in good
yield. The conversion of 2-bromo-N,N-dimethylaniline and
2-chloroanisole with low loading of the palladium catalyst (0.1
mol %), followed by addition of Boc-anhydride, formed the
corresponding N-Boc-protected anilines in 75% and 68% yields,
respectively (Table 9, entries 4 and 7).
Finally, this sequence conducted with phthalic anhydride in
the second step occurred to form N-aryl imides. The reactions
of phthalic anhydride with sterically hindered arylamines formed
by the C-N coupling of ortho-substituted aryl halides gave
lower yields of N-aryl phthalimide than did those of sterically
unhindered arylamines. However, the imide derived from
2-bromo-N,N-dimethylaniline was formed by the two-step, one-
pot protocol in 51% yield. The coupling of ammonia with the
(64) The pKa value obtained from ionization of liquid ammonia: Coulter,
L. V.; Sinclair, J. R.; Cole, A. G.; Roper, G. C. J. Am. Chem. Soc.
1959, 81, 2986–2989.
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J. AM. CHEM. SOC. VOL. 131, NO. 31, 2009 11059

A R T I C L E S
Vo and Hartwig
Scheme 1
arylpalladium bromide complex by comparison of the 31P NMR
chemical shifts of the species in the catalytic reaction to those
of the species formed from the reaction of Pd[P(o-tol)3]2 and
CyPF-t-Bu with 4′-bromoacetophenone. This result indicates that
transmetalation is, indeed, the turnover-limiting step in the
reactions of aryl bromides with ammonia in the presence of
the weak base K3PO4.
Scheme 2
The same experiment was conducted on reactions of aryl
halides containing electron-withdrawing groups in the meta-
position, such as 3′-bromopropiophenone. Again, the arylpal-
ladium halide complex was observed. Because catalytic
reactions of the meta-substituted, electron-poor aryl halides
occur in much lower yields than those of the para-substituted
analogues, it appears that the rates of the transmetalation and
reductive elimination portion of the catalytic cycle are
affected strongly by the relative electron-withdrawing ability
of the aryl group in the meta- or para-position. Because the
pKa values of ammonia and monohydrogen phosphate are so
Pd(OAc)2 produced complex mixtures of palladium species,
whereas the reaction catalyzed by the combination of Pd[P(o-
tol)3]2 and CyPF-t-Bu generated a single major species. From
this observation, we concluded that the combination of Pd[P(o-
tol)3]2 and CyPF-t-Bu generates a higher concentration of active
catalyst than do other catalyst precursors.
65
different (33 for ammonia64 and 12 for HPO4
,
respec-
2-
tively), we assume that the formation of the amido complex
is facilitated by coordination of ammonia to palladium to
increase the acidity of the ammonia, and the aryl group bound
to palladium affects the Lewis acidity of the metal center
(Scheme 2).
To address the fate of the Pd(II) species in the presence of
ammonia and base in more detail, we determined the amount
of (CyPF-t-Bu)Pd(0) species generated from the reaction of
(CyPF-t-Bu)PdCl2 with ammonia and base. (CyPF-t-Bu)PdCl2
was treated with NaO-t-Bu and ammonia in the presence of
P(o-tol)3 to trap any Pd(0) complex formed. This reaction
generated a complex mixture of products that contained less
than 10% of the Pd(0) species. Because the alkoxide base and
ammonia both lack hydrogens R to the heteroatom, the Pd(II)
species cannot be reduced to Pd(0) by the combination of
ꢀ-hydrogen elimination from an alkoxo or amido intermediate
and reductive elimination of amine or alcohol. Because the aryl
group serves as the electrophilic component, rather than the
nucleophilic component, formation of a bisaryl complex and
reductive elimination of an organic biaryl product also does not
lead to formation of Pd(0) in high yield. In contrast, the
combination of Pd[P(o-tol)3]2 and CyPF-t-Bu generates P(o-
tol)3 and (CyPF-t-Bu)Pd[P(o-tol)3], which adds aryl halides and
sulfonates rapidly.20,23
2.7.2. Studies on the Turnover-Limiting Step of Reactions
with Weak Base. We also conducted studies to determine
whether the use of a weak base would cause transmetalation to
be the turnover-limiting step. The reaction of 4′-bromoacetophe-
none with ammonia at 200 psi in the presence of 5 equiv of
K3PO4 was monitored by 31P NMR spectroscopy after ap-
proximately 50% conversion of the aryl bromide (Scheme 1).
The resting state of the catalyst was identified to be the
3. Conclusions
We have shown that the catalyst generated from the
combination of Pd[P(o-tol)3]2 and the sterically hindered alkyl
bisphosphine ligand CyPF-t-Bu is highly active and selective
for the coupling of ammonia with aryl halides and sulfonates
to form primary arylamine products. For example, reactions
of ortho-substituted aryl bromides and chlorides occurred
with only 0.1 mol % of catalyst loading. This catalyst leads
to a reaction scope that is expanded over that of couplings
conducted with previous catalysts. This scope now encom-
passes aryl chlorides, bromides, and iodides that possess or
lack an ortho-substituent and, for the first time, encompasses
aryl sulfonates. Moreover, this scope now includes reactions
of certain aryl halides containing base-sensitive functional
groups, such as ketones, esters, and nitriles. The utility of
this coupling process to form not only primary arylamines
but also mixed secondary arylamines, N-aryl amides, N-aryl
imides, and N-aryl carbamates by a one-pot procedure has
also been demonstrated.
The efficiency of the catalyst arises from the favorable
generation of a reactive (CyPF-t-Bu)Pd fragment from equimolar
(65) Perrin, D. D. Ionization Constants for Inorganic Acids and Bases in
Aqueous Solutions; Pergamon: Oxford, 1982; p 84.
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11060 J. AM. CHEM. SOC. VOL. 131, NO. 31, 2009

Preparation of Primary Arylamines
A R T I C L E S
amounts of Pd[P(o-tol)3]2 and CyPF-t-Bu. Preliminary studies
on the generation of the active catalyst suggest that low yields
of the active palladium(0) species are generated from palla-
dium(II) precursors, ammonia, and sodium tert-butoxide base.
Additional studies imply that the reactions with weak base occur
by turnover-limiting transmetalation and that the rate of this
step depends on the position of the electron-withdrawing group
on the aryl ligand. Detailed mechanistic studies on the catalyst
generated from Pd[P(o-tol)3]2 and CyPF-t-Bu will be reported
in due course.
Acknowledgment. We thank the NIH NIGMS for support of
this work (GM-55382), Johnson-Matthey for gifts of palladium
complexes, and Solvias AG for gifts of the Josiphos ligand.
Note Added after ASAP Publication. The products in Table
6, entry 7, and Table 9, entry 7, were incorrect in the version
published ASAP July 10, 2009. The corrected version was published
July 17, 2009.
Supporting Information Available: Full experimental proce-
dures and characterizations of reaction products. This material
is available free of charge via the Internet at http://pubs.acs.org.
JA903049Z
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J. AM. CHEM. SOC. VOL. 131, NO. 31, 2009 11061