Palladium-catalysed amination of aryl- and heteroaryl halides using tert-butyl tetraisopropylphosphorodiamidite as an easily accessible and air-stable ligand

Article abstract of DOI:10.1002/ejoc.201301789

The phosphorus compound tert-butyl tetraisopropylphosphorodiamidite, prepared from bis(diisopropylamino)chlorophosphine, is an excellent ligand for palladium-catalysed Buchwald-Hartwig amination of aryl- and heteroaryl chlorides and bromides. Based on its ready accessibility and air-stability, this amination protocol is a practical approach to the synthesis of industrially important aryl- and heteroarylamines. Copyright

Full text of DOI:10.1002/ejoc.201301789

FULL PAPER
DOI: 10.1002/ejoc.201301789
Palladium-Catalysed Amination of Aryl- and Heteroaryl Halides Using tert-
Butyl Tetraisopropylphosphorodiamidite as an Easily Accessible and Air-Stable
Ligand
Gheorghe-Doru Roiban,[a,b] Gerlinde Mehler,[b] and Manfred T. Reetz*[a,b]
Keywords: Amines / Amination / P ligands / Palladium / Homogeneous catalysis
The phosphorus compound tert-butyl tetraisopropylphos-
phorodiamidite, prepared from bis(diisopropylamino)chloro-
phosphine, is an excellent ligand for palladium-catalysed
Buchwald–Hartwig amination of aryl- and heteroaryl chlor-
ides and bromides. Based on its ready accessibility and air-
stability, this amination protocol is a practical approach to the
synthesis of industrially important aryl- and heteroaryl-
amines.
Introduction
The Pd-catalysed Buchwald–Hartwig amination of aryl
and heteroaryl halides is a prominent transformation in
modern synthetic chemistry.[1] The efficiency of this indus-
trially important C–N bond-forming reaction is highly de-
pendent on the nature of the ligands. In contrast to the
“standard” phosphorus ligand, Ph3P, which leads to poor
yields, bulky tertiary phosphines such as 1,[2] 2,[3] 3,[3a,4] 4,[5]
5,[6] 6,[7] 7,[3b,8] and 8[9] ensure high yields for a variety of
structurally different substrates. N-Heterocyclic carbene
(NHC) ligands have also been used, phosphine-function-
alized NHC 9 being a recent example.[10] All of these li-
gands require multi-step syntheses. Phosphorus compounds
that lack P–C bonds are generally quite air-stable; ligands
9[10] and 10[11] are examples of such compounds that have
also been used in Buchwald–Hartwig aminations.
In a patent, we recently disclosed preliminary results re-
garding the use of P-ligands of type 13 bearing two bulky
amino groups and a sterically demanding alkoxy moiety at
phosphorus.[12] The synthesis of this compound, which was
originally used as a phosphorylating agent for biomolecules,
has been described briefly in the literature, but spectro-
scopic data are lacking.[13] Our synthetic strategy is
straightforward and is based on the reaction of commer-
cially available bis(diisopropylamino)chlorophosphine (11)
with potassium tert-butoxide (12) (Scheme 1). The fact that
the material is readily available in sufficiently large amounts
by this method, and the observation that it is easily handled
[a] Fachbereich Chemie, Philipps-Universität Marburg,
Hans-Meerwein Str., 35032 Marburg, Germany
[b] Max-Planck-Institut für Kohlenforschung,
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
E-mail: reetz@mpi-muelheim.mpg.de
http://www.kofo.mpg.de/de/forschung/organische-synthese
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301789.
Scheme 1. Synthesis of ligand 13.
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2014, 2070–2076
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Palladium-Catalysed Amination of Aryl- and Heteroaryl Halides
in air, led us to consider it as a possible ligand in Buchwald– Table 2, entry 2). When the reaction was continued for 20 h
Hartwig amination. In this paper, we report the results of at this concentration, the amount of triarylamine increased,
a more extensive study.
but it stayed below 10%. Furthermore, the reaction could
even be performed under an atmosphere of air. Under such
conditions, full conversion was achieved at 105 °C within
Results and Discussion
Table 2. Exploratory experiments the Pd-catalysed amination 14a/
14b + 17Ǟ18.[a]
Optimization Experiments
Initial exploratory optimization experiments were carried
out using the amination of bromobenzene (14a) with
morpholine (15) to give 16 as the model reaction. As shown
in Table 1 (see also Tables S1 and S2 for additional exam-
ples), the reaction is best performed under an inert atmo-
sphere in toluene as the solvent. Various Pd sources may be
used. Other solvents such as THF, DME (dimethoxy-
ethane), or dioxane can also be used, but they seem to give
somewhat less efficient reactions. The best bases are Na-
OtBu and KOtBu.
Exploratory optimization experiments were also carried
out for the reaction between bromobenzene (14a) and anil-
ine (17) to give amination product 18 (Table 2; see also
Tables S2–S5 for additional examples). At a catalyst loading
of 5 mol-% and a reaction temperature of 105 °C, complete
conversion was observed after 30 min (Table 2, entry 1).
Therefore, the reaction was repeated, this time taking sam-
ples at two-minute intervals. We found that complete con-
version was reached within the first two minutes, with only
Entry Halide
Pd source
Pd
[mol-%]
t
Conv.
[%]
1
2
3
4
5
6
7
8
14a
14a
14a
14a
14a
14a
14a
14a
14a
14b
14b
14b
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(COD)Cl2
PdCl2
Pd(OAc)2
Pd(acac)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
5
5
5
30 min
2 min
1 h[b]
1 h[b]
20 h
20 h
20 h
20 h
20 h
24 h
24 h
24 h
100
100
100
100
54
19
7
10
8
63
91
1
0.5
0.5
0.5
0.5
0.5
1
9
10
11
12
2
3
100
[a] Same conditions as for Table 1. [b] Reactions carried out under
traces of the respective triarylamine being detected (Ͻ1%; an air atmosphere.
Table 1. Optimization experiments of the Pd-catalysed amination 14a + 15Ǟ16.[a]
Entry
Pd source
Pd
[mol-%]
Solvent
Base
t
Conv.[b]
[%]
1
2
3
4
5
6
7
8
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(COD)Cl2
PdCl2
Pd(OAc)2
Pd(acac)2
Pd(CH3CN)Cl2
Pd(dba)2
Pd(dba)2
Pd(dba)2
5
5
5
5
5
5
5
5
5
5
2
2
2
2
2
2
2
toluene
THF
DME
NaOtBu
NaOtBu
NaOtBu
NaOtBu
KOtBu
K2CO3
Cs2CO3
K3PO4
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
1 h
1 h
1 h
1 h
3 h
3 h
3 h
3 h
0.5 h
2 min
0.5 h
0.5 h
0.5 h
0.5 h
0.5 h
0.5 h
0.5 h
1 h
100
89
94
85
92
3
7
18
100
100
100
100
100
100
100
98
dioxane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
9
10
11
12
13
14
15
16
17
18
19
20
85
100
95
1
0.5
0.25
20 h
20 h
34
[a] Reaction conditions: 14a (1 mmol), 15 (2 mmol), base (2 mmol), Pd: tert-butyl tetraisopropylphosphorodiamidite (1:2), dry toluene
(3 mL), 105 °C, argon. [b] Conversions to coupling product, based on 14a, determined by GC. dba = dibenzylideneacetone, COD =
cyclooctadiene, acac = acetoacetate.
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G.-D. Roiban, G. Mehler, M. T. Reetz
FULL PAPER
1 h, provided 5 mol-% catalyst loading was used (Table 2, a higher catalyst loadings with 14b, but the reaction was
entries 3 and 4). Several experiments were also performed completely selective, and no triphenylamine as an undesired
with the cheaper chlorobenzene (14b), which also proved by-product was detected. In addition to further secondary
to be successful (Table 2, entries 10–12). In many previous amines 19–20, primary amines such as benzylamine (21)
amination studies, undesired reduction of the aryl halide similarly reacted readily (Table 3, entries 10 and 11). Even
was observed to a small extent, and this side-reaction also though the reactions went to completion, small amounts
occurs in the present catalyst system (typically Ͻ5%).
of the respective tertiary amines (9%) were formed as by-
products.
We then turned to other aryl halides 25a–34a, 25b–31b,
and 33b as reaction components, and discovered that these
also react smoothly with morpholine (15) and aniline (17)
(Table 4). Here again, in almost all reactions, minor
amounts of aromatic compounds corresponding to the re-
duction products (Ͻ5%) of the aryl halides were observed.
Unfortunately, in the case of sterically hindered halides 31
and 32, this side-reaction dominated, indicating the limita-
tions of the method (Table 4, entries 13–15). The reaction
between 1-bromo-4-(tert-butyl)benzene (28a) and morph-
oline (15) (Table 4, entry 7) was scaled up (10 mmol), and
the high yield of 95% obtained after column chromatog-
raphy demonstrates the feasibility of this method based on
ligand 13. Vinyl bromides could also be aminated similarly.
For example, (bromomethylene)cyclohexane (34a) reacted
smoothly with morpholine within 2 h at a catalyst loading
of 1 mol-%.
Scope and Limitations
Following the optimization experiments, other amines
19–21 were tested with phenyl halides 14a and 14b. Table 3
summarizes the best results using all amines tested to date.
Here and in subsequent tables, conversion values refer to
amination product formation based on ArX, as determined
by GC, taking into account dehalogenation (reduction) and
homocoupling reactions. It is clear that ligand 13 can be
used to make up a fairly effective and general catalyst sys-
tem. In the case of morpholine (15), a catalyst loading of
1 mol-% was sufficient to achieve complete conversion
within 1 h when using 14a, while in the case of chloroben-
zene (14b), complete conversion required 24 h at the same
catalyst loading (Table 3, entries 1 and 2). Aniline needed
When aniline (17) was used as the amine, higher amounts
of catalyst were required for good conversions, but the un-
desired reduction of the respective aryl halide was mini-
mized (Table 4, entries 31–33). In the case of the sterically
hindered aryl halide 2-bromo-1,3-dimethylbenzene (32a),
excellent results were observed (97% conversion to the de-
sired amine; Table 4, entry 33). Thus, halide 32a appears to
be more reactive than 2-bromo-1,3,5-trimethylbenzene
(31a) at the same catalyst loading. A similar reactivity
pattern was noticed in the reactions of aryl halides with
amines 19–21 (Table S6). In addition to the desired amin-
ation reaction, in some cases traces of C–C homocoupling
compounds derived from the aryl halides were observed
(Ͻ3%; see GC chromatograms in the Supporting Infor-
mation).
Table 3. Amination of phenyl halides 14a and 14b using amines
15,[a] 17, and 19–21.[b]
Finally, a few heteroaryl halides 54a–58a and 54b–58b
were tested. Table 5 shows that 2- and 3-bromosubstituted
pyridines have different reactivities in their reactions with
morpholine (15) and aniline (17). Unexpectedly, chloro-
substituted pyridines reacted faster than their bromo ana-
logues. For example, 3-bromopyridine (55a) reacted with
morpholine to give 4-(pyridin-3-yl)morpholine (60) with a
48% conversion after 24 h, whereas 3-chloropyridine was
completely converted into the desired amine (i.e., 60) within
4 h (Table 5, entries 3 and 4). The same behaviour was no-
ticed for 2-halo-substituted quinolines 57a and 57b
(Table 5, entries 6 and 7). A scaled-up procedure gave 4-
(quinolin-2-yl)morpholine (62) after column chromatog-
raphy in a very good yield (93%), underlining once more
the practical utility of ligand 13 (Table 5, entry 7). When
aniline (16) was used as the amine, increased catalyst load-
ings proved to be necessary, but even then the reactions did
not reach completion (Table 5, entries 10–14). Furthermore,
[a] Morpholine (2 mmol) was used. [b] Reaction conditions: ArX
(1 mmol), amine (1.2 mmol), NaOtBu (2 mmol), Pd(dba)2:13 (1:2),
dry toluene (3 mL), 105 °C, argon. [c] Conversions to amination
product based on ArX as determined by GC, taking into account
dehalogenation (reduction) and homocouping reactions. [d] Non-
optimized catalyst loadings. [e] Complete conversion, but with 9%
of the tertiary amine as by-product.
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Palladium-Catalysed Amination of Aryl- and Heteroaryl Halides
Table 4. Amination of aryl halides 25a,b–34a.[a,b]
[a] Reaction conditions: aryl halide (1 mmol), amine (1.2 mmol), NaOtBu (2 mmol), Pd(dba)2:13 (1:2), dry toluene (3 mL), 105 °C, argon.
[b] In the case of morpholine (15), 2 mmol was used. [c] Conversions to coupling product based on aryl halide determined by GC.
Conversion values related to amination product are based on the reaction of ArX as determined by GC, taking into account dehalogena-
tion (reduction) and homocouping reactions (from average of at least three independent experiments). [d] Corrected GC conversion/yield
after column chromatography of scaled up reaction (10 mmol starting halide). [e] Ratio amination product/reduced substrate/starting aryl
halide. Selectivities were determined by GC, taking into account dehalogenation (reduction) and homocoupling reactions.
in the reactions of 2-bromo- and 2-chloroquinolines (57a ture of mono- (68) and diarylated (69) products in a 1:3
and 57b), different product ratios resulted. Optimized ex- ratio (Table 5, entry 15). The same trend was observed in
periments carried out with 2-bromoquinoline gave a mix- the reaction of 2-bromoisoquinoline, but in this case the
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G.-D. Roiban, G. Mehler, M. T. Reetz
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Table 5. Amination of heteroaryl halides 54a–58a and 54b–58b.[a]
[a] Similar conditions to Table 3. [b] MeONa was used as base in this case. [c] Corrected GC conversion/yield after column chromatog-
raphy, scaled up reaction (10 mmol starting halide). [d] Yield after column chromatography. [e] Ratio of diaryl- to triarylamine as deter-
mined by GC.
selectivity for the diarylated product (i.e., 71) was higher scribed in this paper using ligand 13 are also more efficient.
(1:5 ratio; Table 5, entry 17). Completely different behav- Limitations became apparent when more hindered sub-
iour was observed in the reactions of 2-chloroquinoline strates were tested, and in these cases, undesired reduction
(57b) and 2-chloroisoquinoline (58b). In these cases, mono- constitutes the major reaction pathway. Moreover, when the
arylation was preferred, and selectivities of 11:1 (68/69) and catalyst loading was lowered to Ͻ0.5 mol-%, the reactions
26:1 (70/71), respectively, were observed (Table 5, entries 16 did not reach completion, presumably due to catalyst deac-
and 18). In addition to the aminated quinolines, small tivation. Strangely enough, compound 13 has not been used
amounts of tert-butylated quinoline derivatives were de- in any transition-metal-catalysed reactions before. This
tected in some cases, in yields of up to 22%. Heteroaryl study demonstrates that Buchwald–Hartwig amination of
halides were found to behave similarly in their reactions aromatic and heteroaromatic halides using this sterically de-
with amines 19–21 (Table S6).
manding ligand is feasible, as shown, inter alia, by several
examples of scaled-up transformations. This procedure
competes well with many (but not all) previously reported
protocols for amination based on more difficult to prepare,
Conclusions
The P-ligand tert-butyl tetraisopropylphosphorodiamid- and thus more expensive, ligands such as 1–10. Industrial
ite (13) is an easily prepared air-stable compound, ac- applications appear to be possible, because ligand 13 (or its
cessible
from
bis(diisopropylamino)chlorophosphine analogues) has a relatively low molecular weight, it is easily
(Scheme 1). It is a useful ligand in Pd-catalysed Buchwald– stored and handled, and its undesired oxidation by air is a
Hartwig amination reactions. The compound is generically very slow process. In fact, the amination can be carried out
related to ligand 10, but the preparation of ligand 10 in- in air if a Pd catalyst loading of 5 mol-% is used. We also
volves the laborious synthesis of the intermediate N,N-bis- anticipate that this compound can serve as a useful ligand
(tert-butyl)ethylenediamine. The amination reactions de- in other transition-metal-catalysed reactions.
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Palladium-Catalysed Amination of Aryl- and Heteroaryl Halides
organic phase was dried and evaporated to give tert-butyl tetraiso-
propylphosphorodiamidite (13; 0.984 g, 86%) as a white crystalline
solid. H NMR (300 MHz, CDCl3): δ = 3.64–3.47 (m, 4 H), 1.32
Experimental Section
1
General Remarks: Unless otherwise stated, the reactions were per-
formed under argon in a normal fume cupboard in 10 mL Schlenk
tubes sealed with PTFE septa, using an oil bath heated at 105 °C.
Reaction progress was monitored by GC, and compounds were
(m, 9 H), 1.23–1.08 (m, 24 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 74.86 [d, JP,C = 15.6 Hz, C(CH3)3], 44.88 [d, JP,C = 13.5 Hz, 4
C, CH(CH3)2], 30.97 [d, JP,C = 8.2 Hz, 3 C, C(CH3)3], 24.63 [d, JP,C
= 5.5 Hz, 4 C, CH(CH3)2], 24.23 [d, JP,C = 8.7 Hz, 4 C, CH(CH3)
2] ppm. 31P NMR (162 MHz, CDCl3): δ = 99.74 ppm. HRMS (EI):
calcd. for C16H37N2OP [M]+ 304.2644; found 304.2644.
1
identified by GC–MS or by H and 13C NMR spectroscopy using
authentic samples. Bis(diisopropylamino)chlorophosphine (11) was
bought from Sigma–Aldrich, and tert-butyl tetraisopropylphos-
phorodiamidite (13) was prepared as described below or was
bought from Sigma–Aldrich and used without further purification
(95%). Dry toluene was acquired from Sigma–Aldrich or TCI, and
was used without further drying. All other reagents were purchased
from Acros, Sigma–Aldrich, Alfa Aesar, and ABCR Chemicals,
and were used without further purification. NMR spectra were re-
corded with Bruker Avance 300 and DRX 400 (1H: 300 or
400 MHz, 13C: 75 or 101 MHz) spectrometers using tetramethylsil-
ane as internal standard (δ = 0 ppm). High-resolution EI mass
spectra were measured with a Finnigan MAT 95S spectrometer.
Conversions to the coupling product, based on aryl halide, were
determined by GC. Reported yields are an average of three or more
runs. Analytical thin-layer chromatography was carried out on
Merck silica gel 60 F254q plates, and column chromatography was
carried out using Merck silica gel 60 (230–400 mesh ASTM).
N-Phenyl-N-(pyrazin-2-yl)pyrazin-2-amine (67): Following the gene-
ral procedure, compound 67 was obtained as a white solid. Rf =
0.16 (EtOAc/petroleum ether, 1:1). 1H NMR (300 MHz, CDCl3): δ
= 8.41 (d, J = 1.3 Hz, 2 H), 8.27–8.17 (m, 4 H), 7.48 (t, J = 7.5 Hz,
2 H), 7.37 (t, J = 7.4 Hz, 1 H), 7.25 (d, J = 8.5 Hz, 2 H) ppm.
HRMS (EI): calcd. for C14H11N5 [M]+ 249.1014; found 249.1016.
N-Phenyl-N-(quinolin-2-yl)quinolin-2-amine (69): Following the ge-
neral procedure, compound 69 was obtained as colourless crystals.
Rf = 0.54 (EtOAc/petroleum ether, 1:4). 1H NMR (300 MHz,
3
CDCl3): δ = 8.00 (d, J = 8.8 Hz, 2 H), 7.82–7.69 (m, 4 H), 7.62–
7.56 (m, 2 H), 7.48–7.35 (m, 4 H), 7.35–7.23 (m, 5 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 156.72, 147.50, 144.65, 137.11,
129.61, 129.50, 128.28, 128.02, 127.32, 126.01, 125.80, 124.92,
117.92 ppm. HRMS (EI): calcd. for C24H17N3 [M]+ 347.1422;
found 347.1423.
Catalyst Preparation: A stock solution of catalyst was prepared as
follows: Pd(dba)2 (1 equiv.) was added to a heat-gun-dried Schlenk
tube under argon, and then tert-butyl tetraisopropylphosphorodi-
amidite (95%; 2 equiv.) was added. The tube was evacuated and
backfilled with argon three times, and then dry toluene was added
by syringe. The Schlenk tube was then capped with a PTFE sep-
tum, the solution was homogenised using an IKA MS2 mini shaker
for 30 s, and then an argon-filled balloon was attached to the tube.
The solution was stirred for at least 10 min before the catalyst was
added to the reaction mixture. The calculated amount of freshly
prepared catalyst was added using a 1 mL syringe. For each set of
reactions, a new batch of the catalyst solution was prepared.
N-(iso-Quinolin-1-yl)-N-phenylisoquinolin-1-amine (71): Following
the general procedure, compound 71 was obtained as a white solid.
Rf = 0.10 (EtOAc/petroleum ether, 1:4). 1H NMR (300 MHz,
3
CDCl3): δ = 8.23 (d, J = 5.7 Hz, 2 H), 7.92–7.76 (m, 4 H), 7.58
(dt, 3J = 7.6 Hz, 2 H), 7.50–7.43 (m, 2 H), 7.37–7.20 (m, 4 H), 7.10
(dt, 3J = 7.4 Hz, 1 H), 7.00–6.90 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 158.69, 148.63, 141.93, 138.81, 129.98,
129.47, 127.31, 125.93, 124.54, 124.08, 118.67 ppm. HRMS (EI):
calcd. for C24H17N3 [M]+ 347.1422; found 347.1414.
Supporting Information (see footnote on the first page of this arti-
cle): Selected spectroscopic characterization of known amination
General Procedure for the Amination Reaction: NaOtBu (2 mmol)
and aryl halide (1 mmol; when solid) were added to an oven-dried
Schlenk tube. The tube was evacuated and backfilled with argon
three times, and then dry toluene, catalyst (volume calculated based
on the desired concentration of catalyst), and amine (1.20 mmol)
were added to reach a total volume of 3 mL. When an liquid aryl
halide was used, this was added after the addition of the catalyst.
The tube was then sealed with a PTFE septum, the suspension
homogenized using an IKA MS2 mini shaker for 10–30 s, and the
mixture was stirred in a preheated oil bath at 105 °C. Reaction
progress was monitored by GC. After all the starting materials had
been consumed, or when the reaction did not progress any more,
the mixture was cooled down to room temperature, and then di-
ethyl ether (7 mL) and saturated aqueous NaCl solution (10 mL)
were added. The resulting suspension was transferred into a separa-
tory funnel, the layers were separated, and the organic phase was
washed with water (4ϫ 10 mL). The organic layer was dried with
anhydrous Na2SO4, and then concentrated under reduced pressure.
The crude residue was purified by column chromatography. The
spectroscopic data of all known amination products are in agree-
ment with literature values.
1
products; copies of the H and 13C NMR spectra; GC chromato-
grams.
Acknowledgments
Financial support by the Max Planck Society and the Arthur C.
Cope Foundation is gratefully acknowledged. The authors thank
Stephanie Dehn for help with GC analysis.
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which was then degassed. Dry toluene (40 mL) was added under
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10029.
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Received: December 1, 2013
Published Online: January 31, 2014
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