Efficient and versatile buchwald-hartwig amination of (hetero)aryl chlorides using the Pd-PEPPSI-IPr(NMe2)2 precatalyst in the presence of carbonate base

Article abstract of DOI:10.1002/ejoc.201500030

The precatalyst Pd-PEPPSI-IPr^(NMe2)2, in which the IPr ligand was modified by attachment of two dimethylamino groups on to the 4- and 5-positions of the imidazolyl heterocycle, was found to show high catalytic efficiency in the Buchwald-Hartwig amination under mild conditions using Cs₂CO₃ as a weak base, using a low catalyst loading of 1 mol-%. The protocol is applicable to aryl chlorides bearing base-sensitive substituents, as exemplified by the coupling of 4-chloroacetophenone with aniline. It can also be used with an unprecedentedly wide range of amines, including strongly basic secondary alkylamines, primary arylamines, and primary alkylamines. The Palladium precatalyst Pd-PEPPSI-IPr^(NMe2)2, whose supporting N-heterocyclic carbene ligand was decorated with two dimethylamino groups, was found to catalyse the Buchwald-Hartwig amination of aryl halides with a wide range of amines under mild conditions using cesium carbonate as base.

Full text of DOI:10.1002/ejoc.201500030

FULL PAPER
DOI: 10.1002/ejoc.201500030
Efficient and Versatile Buchwald–Hartwig Amination of (Hetero)aryl Chlorides
Using the Pd–PEPPSI-IPr(NMe2)2 Precatalyst in the Presence of Carbonate
Base
Yin Zhang,[a,b] Vincent César,*[a,b] and Guy Lavigne*[a,b]
Keywords: Homogeneous catalysis / Amination / Nitrogen heterocycles / Carbene ligands / Palladium
The precatalyst Pd–PEPPSI-IPr(NMe2)2, in which the IPr ligand
was modified by attachment of two dimethylamino groups on
to the 4- and 5-positions of the imidazolyl heterocycle, was
found to show high catalytic efficiency in the Buchwald–
Hartwig amination under mild conditions using Cs2CO3 as a
weak base, using a low catalyst loading of 1 mol-%. The
protocol is applicable to aryl chlorides bearing base-sensitive
substituents, as exemplified by the coupling of 4-chloroaceto-
phenone with aniline. It can also be used with an unprece-
dentedly wide range of amines, including strongly basic sec-
ondary alkylamines, primary arylamines, and primary alk-
ylamines.
Introduction
Arylamines are frequently encountered in natural and
pharmaceutical products,[1] as well as in materials with use-
ful physical properties.[2] The Pd-catalysed Buchwald–Hart-
wig amination (BHA) of aryl halides has become the most
valuable method for the formation of C(sp2)–N bonds in
contemporary organic synthesis, and it still receives much
interest from academic and industrial research groups.[3–5]
The development of customized ligands, and a better un-
derstanding of the mechanism and the special requirements
of the BHA, have resulted in this reaction becoming more
widely used.[6] A simplified catalytic cycle implying a mono-
dentate ligand is shown in Scheme 1. The active Pd0 species
is generated in situ from a ligand-stabilized PdII precatalyst.
Initially, the aryl halide (or pseudo-halide) undergoes oxi-
dative addition to the Pd0 centre to give unsaturated PdII
intermediate A. In a second step, coordination of the amine
HNR1R2 generates tetracoordinated PdII adduct B. Thirdly,
deprotonation of B with a base M+B– gives anionic amido
complex C, which then loses MX to give tricoordinate com-
plex D. Finally, reductive elimination from D produces the
target amine ArNR1R2, with concomitant regeneration of
the initial Pd0 species.
Scheme 1. Simplified catalytic cycle for the palladium-catalysed
Buchwald–Hartwig amination in the case of a monodentate sup-
porting ligand L.
Historically, development of the BHA reaction has
mainly focussed on the two redox steps, i.e., the oxidative
addition and the reductive elimination. It has been shown
that the rate of the oxidative addition is enhanced by an
electron-rich metal centre, and that a sterically hindered
ancillary ligand facilitates the reductive elimination. Such
findings have led to the advent of several powerful, bulky,
electron-rich phosphane ligands, such as BrettPhos,
RuPhos, XPhos,[4a,4c,7] JosiPhos,[4b,8] CM-Phos,[9] or Mor-
DalPhos.[10] In parallel, N-heterocyclic carbenes (NHCs),[11]
[a] CNRS, LCC (Laboratoire de Chimie de Coordination),
205 route de Narbonne, BP 44099, 31077 Toulouse Cedex 4,
France
E-mail: vincent.cesar@lcc-toulouse.fr,
guy.lavigne@lcc-toulouse.fr
http://www.lcc-toulouse.fr/lcc/spip.php?article24
[b] Université de Toulouse, UPS, INPT,
31077 Toulouse Cedex 4, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500030.
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Buchwald–Hartwig Amination of (Hetero)aryl Chlorides
which are stronger electron-donor ligands, and are even
more sterically hindered than phosphanes, have appeared
as complementary supporting ligands in Pd-catalysed cross-
coupling reactions,[12] and in particular in the Buchwald–
Hartwig amination.[13–15] As a result of these intense re-
search efforts, the most advanced ligand archetypes now al-
low the use of (hetero)aryl chlorides, which are challenging
substrates but are cheaper and more abundant than their
bromide analogues, and they can be used with various
“non-activated” reaction partners.[16]
Despite its popularity and widespread use, the BHA re-
action usually requires aggressive alkoxide bases such as
tert-butoxide for an efficient deprotonation of the Pd-coor-
dinated ammonium species in intermediate D. These
strongly basic reaction conditions still severely restrict the
applicability of the methodology, as they are incompatible
with base-sensitive functional groups, such as ketones, es-
ters, or nitro groups. To circumvent this problem, the use
of milder bases, and in particular of carbonate bases, has
been proposed, but reported examples are quite scarce, and
mainly concern phosphine-based catalysts.[7a,8a,9,17] The
most impressive breakthrough in this direction was recently
Figure 1. Palladium PEPPSI-type complexes considered in this
achieved by Organ and coworkers, with their Palladium study (PEPPSI = pyridine-enhanced precatalyst preparation stabili-
zation and initiation).
PEPPSI-type precatalysts (PEPPSI = pyridine-enhanced
precatalyst preparation stabilization and initiation). Indeed,
the archetypal complex Pd–PEPPSI-IPr (1) (Figure 1) was
shown to catalyse the amination of certain electron-de- 80 °C). Based on these experimental observations, the incre-
ficient heteroaryl chlorides with secondary amines in the mental increases in catalytic efficiency of 3 and 4 was ra-
presence of Cs2CO3 as the base.[13f] Later, Organ disclosed tionalized in terms of i) an increase in the electron-donating
a second generation precatalyst, Pd–PEPPSI-IPent (2H), in abilities of the carbenes IPr(NMe2) and IPr(NMe2)2, and ii) a
which the incorporation of 2,6-di(3-pentyl)phenyl groups as slight increase of their steric bulk, which appears to be al-
nitrogen substituents in place of the 2,6-diisopropylphenyl ready maximized in complex 3. Keeping in mind Organ’s
groups was intended to impart bulkiness and flexibility to conclusions, we were thus prompted to study the catalytic
the NHC ligand.[18,19] In BHA, the bulkier precatalyst 2H efficiency of our precatalysts 3 and 4 in the BHA reaction
was shown to greatly outperform precatalyst 1 in the amin- with a mild base, and we report our results in this paper.
ation of secondary amines and anilines with a great variety
of aryl chlorides.[6b,6c] Finally, even the coupling of weakly
nucleophilic anilines with electron-rich aryl chlorides, which
represents the most challenging combination of coupling
Results and Discussion
partners, was recently and efficiently achieved by substitut-
In a first comparative evaluation of the precatalysts, the
ing the heterocyclic backbone of IPent with two chloride experimental conditions required to perform the Buch-
atoms to give precatalyst 2Cl.[13a] Most importantly, on the wald–Hartwig amination in the presence of a mild base like
basis of additional experiments, Organ and coworkers de- cesium carbonate were taken from the earlier recent report
duced that the observed enhancement of catalyst’s perform- by Organ, using the reaction between 4-chloroanisole and
ance is independent of the electronic nature of the back- morpholine as a standard model (Table 1). In a first cata-
bone substituents, and is the result of steric rather than elec- lytic test based on 4 mol-% of Organ’s precatalyst Pd–
tronic effects.[20]
PEPPSI-IPr (1) (Table 1, entry 1), we were able to repro-
Following our interest in the functionalization of the duce his previously reported result corresponding to 15%
skeleton of NHCs,[21] we recently reported that precatalysts conversion after 24 h.[13f] Under the same conditions, our
3 and 4, obtained by formal substitution of the imidazolyl precatalyst 3 (bearing one amino group on the heterocyclic
ring of the IPr ligand by one and two dimethylamino backbone) (Table 1, entry 2) led to an improved conversion
groups, respectively, show sequential enhanced catalytic of 75%, whereas 100% conversion was reached with precat-
efficiencies relative to 1 in the BHA.[22] Using KOtBu as the alyst 4 within an unoptimized time of 24 h (Table 1, en-
base, complex 4 was found to be particularly efficient for try 3). This result compares well with the 94% isolated yield
the coupling of various amines and aryl chlorides at room obtained by Organ’s group with catalyst 2H under the same
temperature using 2 mol-% of catalyst, and to be remarka- conditions.[13f] Gratifyingly, it was even possible to reduce
bly stable, allowing a decrease of the catalyst loading to as the loading of 4 down to 1 mol-% (Table 1, entry 5). The
little as 50 ppm for a range of challenging substrates (at lower limit of the catalyst’s efficiency was reached with
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Y. Zhang, V. César, G. Lavigne
FULL PAPER
0.5 mol-% of 4 (Table 1, entry 6), when a slight erosion of the aryl chloride component was noted in the coupling of
the conversion to 80% was observed. Finally, 3 equiv. of 2-chlorotoluene with morpholine, which proceeded cleanly
Cs2CO3 were found to be necessary for complete conver- to give 5g. The system was also found to be very efficient
sion, since decreasing to 1.5 equiv. led to an 80% conver- for the amination of heteroaryl chlorides such as 2-chloro-
sion of 4-chloroanisole after 24 h (Table 1, entry 10).
pyridine and 3-chloropyridine, which gave high yields of 5h
and 5i, respectively. Impressively, even 3-chlorothiophene,
which is considered to be quite a challenging coupling part-
ner,[3b] was also successfully coupled with morpholine to
give 5j in 84% yield.
Table 1. Optimization of the Pd-catalysed amination reaction using
complexes 3 and 4 vs. 1 in the presence of carbonate bases.[a]
Entry Pd cat. (mol-%)
Solvent
Base
Conv. [%][b]
1
2
3
4
5
6
7
8
9
1 (4)
3 (4)
4 (4)
4 (2)
4 (1)
4 (0.5)
4 (1)
4 (1)
4 (1)
4 (1)
DME
DME
DME
DME
DME
DME
dioxane
toluene
DME
DME
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Cs2CO3
15
75
100
100
100
80
92
90
45
10
80[c]
[a] Reaction conditions: 4-chloroanisole (0.5 mmol), amine
(0.75 mmol), base (1.5 mmol), solvent (0.5 mL), 80 °C. [b] Conver-
sion rates were determined by GC based on 4-chloroanisole with
dodecane as internal standard. [c] 1.5 equiv. of Cs2CO3 (0.75 mmol)
was used.
Consistent with our previous report,[22] these experimen-
tal observations provided convincing evidence that decora-
tion of the heterocyclic skeleton with two dimethylamino
groups imparts high stability to the catalyst, whose lifetime
then becomes much longer than that of the original un-
modified complex Pd–PEPPSI-IPr (1). Further experiments
focussing exclusively on the activity of 4, indicated that
DME (1,2-dimethoxyethane) is a better solvent than diox-
ane or toluene, and that Cs+ is a much better counter-cation
for the base than K+ (Table 1, entries 7–10). Such a prefer-
ence may be due either to the bigger size of Cs+, which
would more efficiently stabilize the large anionic complex
at the intermediate stage, or to the higher solubility of its
salts in the selected organic solvent.
Scheme 2. Scope of the Buchwald–Hartwig amination with second-
ary amines catalysed by 4, yields refer to the average of isolated
yields of two runs after column chromatography. Reaction condi-
tions: ArCl (0.5 mmol), amine (0.75 mmol), 4 (1.0 mol-%), Cs2CO3
(1.5 mmol), DME (0.5 mL), 80 °C, 24 h. [a] 0.2 mol-% of 4.
[b] 2.0 mol-% of 4. [c] 4.0 mol-% of 4. [d] 100 °C in dioxane.
The optimized conditions described above were sub-
sequently used as standard conditions in further attempts
to extend the application of 4 to a variety of (hetero)aryl
In further catalytic experiments, whose results are dis-
chlorides and secondary aliphatic amines as reaction part- played in the lower part of Scheme 2, we investigated the
ners (Scheme 2). We found that aryl chlorides bearing either coupling of aryl chlorides such as chlorobenzene with a
electron-donating (OMe or Me) or electron-withdrawing series of amines more basic than morpholine (pKa = 8.36),
substituents (CN, NO2, or Ac) in the para position could for which the deprotonation step is more difficult. Gratify-
be coupled with morpholine to give the desired products ingly, N-phenylpiperazine (pKa = 8.8) could be introduced
(i.e., 5a–5f) in excellent yields. In the most favourable cases as a coupling partner to give 5k in a satisfactory 81% yield.
of aryl chlorides bearing electron-withdrawing substituents, It was also still possible to activate piperidine, a strongly
even a drastic reduction of the catalyst loading down to basic amine (pKa = 11.22), but in that case, it was necessary
0.2 mol-% did not affect the high yields of the resulting cou- to increase the amount of precatalyst to 2.0 mol-% to ob-
pling products (i.e., 5d and 5e). This indicates that further tain 5n in 72% yield. The catalytic system also proved ef-
optimization of the reaction time might be possible in such ficient for the introduction of acyclic dialkylamines as cou-
favourable cases. A good tolerance of steric hindrance in pling partners (see the production of 5m and 5o). Dibut-
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Buchwald–Hartwig Amination of (Hetero)aryl Chlorides
ylamine, a highly challenging partner with both a high ba-
sicity and steric congestion, was successfully activated for
the first time by a Pd–NHC catalyst under slightly modified
standard conditions using a higher catalyst loading and
higher temperature to produce 5o in a reasonable 64%
yield. Finally, to our delight, N-methylaniline, regarded as
a much less nucleophilic amine, could be activated to pro-
duce 5p in an impressive 92% yield. Taken together, these
representative results establish the high efficiency of precat-
alyst 4, whose performance can be seen to match and even
sometimes surpass those of IPent derivative 2H.
In a previous mechanistic investigation by Organ on the
catalysts Pd–PEPPSI-IPr and Pd–PEPPSI-IPent,[6b,6c] it
was proposed that the pKa of the palladium(II)–ammonium
species of type B (see Scheme 1) generated upon coordina-
tion of the amine might not only depend on the basicity of
the amine, but that it might also be influenced by the donor
properties of its coupling partner, namely, the aryl group in
the adjacent position in the metal’s coordination sphere. In
order to corroborate such a hypothesis in the case of our
modified precatalyst, two sets of parallel catalytic runs were
conducted with two aryl chlorides showing different donor
properties, namely, 4-chlorotoluene and 4-chloroanisole. In
each experiment, 1 equiv. of the aryl halide together with a
mixture of 1.5 equiv. of morpholine and 1.5 equiv. of piper-
idine was subjected to the reaction conditions. The first ex-
periment, carried out with 4-chlorotoluene, gave a 2:1 ratio
of N-(toluen-4-yl)morpholine and N-(toluen-4-yl)piper-
idine, whereas the second experiment (with 4-chloroanisole)
gave a 3:1 ratio of N-(4-methoxyphenyl)morpholine and N-
(4-methoxyphenyl)piperidine (see Supporting Information
for details). These results are consistent with the hypothesis
that variations in the electron-donating properties of the
aryl group derived from the aryl chloride may influence the
rate of deprotonation of the ammonium species, which is Scheme 3. Scope of the Buchwald–Hartwig amination with aniline
considered to be being rate determining in this case.[6c,23]
Based on the optimized results described above, we went
on to examine the scope of complex 4 in a series of even
more challenging amination reactions using anilines as sub-
strates, which show much lower nucleophilicities than alk-
ylamines (Scheme 3). The coupling reactions between aryl
chlorides (irrespective of whether they had electron-rich or
derivatives catalysed by 4, yields refer to the average of isolated
yields of two runs after column chromatography. Reaction condi-
tions: ArCl (0.5 mmol), aniline (0.75 mmol), 4 (1.0–4.0 mol-%,
specified in parentheses), Cs2CO3 (1.5 mmol), DME (0.5 mL),
80 °C, 24 h. [a] 100 °C in dioxane.
Next, we turned our attention to the coupling of elec-
electron-poor substituents) and various anilines proceeded tron-rich aryl chlorides with electron-poor anilines, which
smoothly to give the mono-arylamination products in excel- has previously been identified as one of the most challeng-
lent yields. Nevertheless, in the most difficult cases of aryl ing combinations in BHA. We were pleased to observe that
chlorides bearing an electron-donating substituent such as 4-chloroanisole could be efficiently coupled with 4-fluoro-
methoxy or methyl in the para position, it was necessary to aniline and 3-(trifluoromethyl)aniline in the presence of
increase the catalyst loading to 3.0 mol-% or 2.0 mol-% in precatalyst 4 (3.0 mol-% and 4.0 mol-%, respectively) to
order to achieve an almost quantitative production of the produce 6j in 97% yield, and 6k in 68% yield (the latter
corresponding amines (i.e., 6a and 6b, respectively). The or- reaction required a higher temperature). A test reaction
tho-methyl-substituted aryl chloride still gave an excellent using an aniline bearing an ester in the para position also
yield of the coupling product (i.e., 6h). Significantly, aryl gave a positive result, but required 4.0 mol-% of precatalyst
chlorides bearing sensitive para substituents, such as cyan- 4 and a higher temperature of 100 °C to produce 6l in an
ide or acetyl, were tolerated under these standard condi- acceptable 52% yield. In parallel, 3-chloropyridine, a het-
tions, and, using a low catalyst loading of 1.0 mol-%, it was eroaryl chloride, was tested in combination with aniline and
even possible to achieve a coupling reaction between unpro- para-fluoroaniline, and this led to the formation of 6m and
tected 4-chlorobenzaldehyde and aniline to produce 6g in 6n, respectively, in excellent yields. By comparing these re-
89% yield.
sults with those reported by Organ for the same cou-
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Y. Zhang, V. César, G. Lavigne
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plings,[6c,13a] the following qualitative ranking of the sup-
porting NHCs in the Pd–PEPPSI complexes could be
drawn: IPr ϽϽ IPent ≈ IPr(NMe2)2 Ͻ IPentCl. This led to
the conclusion that starting from the classical IPr ligand,
decorating the carbenic heterocycle is a viable and comple-
mentary alternative to the strategy of varying the nitrogen-
aryl substituents to optimize the catalyst efficiency in BHA.
Finally, we considered the case of primary alkylamines,
which often tend to undergo competitive β-hydride elimi-
nation from the corresponding amido–Pd complexes.[24]
This undesirable side-reaction (ending with the reduction
of aryl halides into arenes) is avoided by using sterically
demanding ligands. With this in mind, we were pleased to
observe that our precatalyst was highly active for the trans-
formation of primary alkylamines (Scheme 4). For example,
with 2 mol-% of 4, the reaction of 2-chlorotoluene or 2,6-
dimethylchlorobenzene and octylamine gave 97 and 92%
yields of the desired products (i.e., 7a and 7b, respectively).
Under the same conditions, N-(cyclohexyl)aniline (7c) was
obtained in a slightly reduced, but still satisfactory yield of
74%. Reactions of 4-chloroanisole and 3-chloropyridine
with octylamine also proceeded to completion, but ap-
peared to be less selective, and led to the formation of both
mono- and bis-arylated products. Finally benzylamine was
also tested, and was found to give two products. The ratio
of the mono- to bis-arylated products was found to depend
on the nature of both the aryl chloride and the amine.
Conclusions
In conclusion, the experimental results disclosed here re-
veal that the backbone-decorated precatalyst Pd–PEPPSI-
IPr(NMe2)2 4 shows high activity for the coupling between
various aryl chlorides and a broad range of amines, includ-
ing secondary amines, primary alkylamines, and primary
arylamines, in the presence of Cs2CO3 as a relatively weak
base. In particular, the performance of 4 in terms of activity,
low catalyst loading, and substrate scope, was found to be
greatly superior to that of the unmodified precatalyst Pd–
PEPPSI-IPr (1), and even slightly better than that of Or-
gan’s highly efficient second generation complex Pd–
PEPPSI-IPent when challenging alkylamines were used as
the coupling partners. The already spectacular results re-
ported by Organ with the IPent derivative were principally
ascribed to an increase in steric bulk, but the equally good
results reported here with our complex 4 can be attributed
to a synergy of steric and electronic effects. Both of these
complexes are very close to the optimum level of efficiency
and practical utility for the Buchwald–Hartwig amination.
Further structural variations of the decorating groups of N-
heterocyclic carbenes are under current investigation in our
laboratory, where we are also examining their potential ap-
plication to a wider range of transition-metal-catalysed re-
actions.
Experimental Section
Materials and Methods: All reactions were carried out under an
inert atmosphere of dry nitrogen using standard vacuum line and
Schlenk tube techniques. Glassware was dried at 120 °C in an oven
for at least 3 h. DME and 1,4-dioxane were distilled from sodium/
benzophenone, toluene was distilled from sodium, and [D]chloro-
form were dried with CaH2 and subsequently distilled. DMF was
degassed by bubbling N2 for 15 min, and was stored over activated
4 Å molecular sieves. NMR spectra were recorded with Bruker
AV300 or AV400 spectrometers. Chemical shifts are reported in
ppm (δ) relative to tetramethylsilane (1H and 13C), and the residual
peak of the deuterated solvent was used as an internal standard.[25]
Pd–PEPPSI-IPr (1),[26] Pd–PEPPSI-IPrNMe2 (3),[22] and Pd–
PEPPSI-IPr(NMe2)2 (4),[22] were synthesized according to literature
procedures. All other reagents were commercially available, and
were used as received, except for the liquid amines, which were
distilled before use. Cs2CO3 was purchased from Alfa Aesar. GC
analysis was carried out with a Shimadzu GC-2014 chromatograph
equipped with a 30 m capillary column (Supelco, SLB-5ms, fused-
silica capillary column, 30 mϫ0.32 mmϫ0.25 μm film thickness),
using helium as the vector gas. The following GC conditions were
used: Initial temperature 40 °C for 1 min; then temperature increase
at a rate of 30 °C min–1 until 250 °C; then 250 °C for 2 min; linear
velocity of carrier gas, 30 cms–1.
General Procedure for the Optimization of the Pd-Catalysed Amin-
ation with Carbonate Base: Base (1.5 mmol, 3.0 equiv.) and palla-
dium catalyst were put into a Schlenk tube under air. The tube
was then sealed with a septum, and purged with nitrogen (3ϫ).
4-Chloroanisole (55 μL, 0.5 mmol, 1.0 equiv.), morpholine (69 μL,
0.75 mmol, 1.5 equiv.), and solvent (0.5 mL) were then added by
syringe at room temperature. The mixture was stirred for about
1 min at room temperature, and was then transferred to a preheated
Scheme 4. Scope of the Buchwald–Hartwig amination with pri-
mary amine derivatives catalysed by precatalyst 4, yields refer to the
average of isolated yields of two runs after column chromatography.
Reaction conditions: ArCl (0.5 mmol), amine (0.75 mmol), 4
(2.0 mol-%), Cs2CO3 (1.5 mmol), DME (0.5 mL), 80 °C, 24 h.
[a] The yield was based on the aryl chloride. [b] Ratio between
mono- and bis-arylation product.
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Buchwald–Hartwig Amination of (Hetero)aryl Chlorides
1
oil bath (80 °C). The reaction was allowed to proceed for 24 h,
unless otherwise specified. The reaction mixture was diluted with
ethyl acetate (10 mL), and dodecane (112 μL, 0.5 mmol) was added
as internal standard. Conversions were measured by passing an ali-
quot of the solution through a plug of silica gel using EtOAc as
eluent, and monitoring the relative areas of the peaks compared to
that of dodecane in the GC chromatogram.
as a white solid. H NMR (400 MHz, CDCl3): δ = 7.32–7.27 (m,
2 H), 7.00–6.82 (m, 3 H), 3.91–3.83 (m, 4 H), 3.20–3.13 (m, 4 H)
ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 151.4, 129.3, 120.2,
115.9, 67.1, 49.6 ppm.
4-Morpholinobenzonitrile (5d): After flash chromatography on silica
gel (pentane/Et2O, 3:2), compound 5d (87.4 mg, 93%) was obtained
1
as a yellow solid. H NMR (400 MHz, CDCl3): δ = 7.52–7.48 (m,
2 H), 6.87–6.83 (m, 2 H), 3.86–3.82 (m, 4 H), 3.28–3.25 (m, 4 H)
ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 153.6, 133.6, 120.0,
114.1, 101.0, 66.5, 47.4 ppm.
Competitive Amination Experiments of 4-Chlorotoluene with Morph-
oline and Piperidine: Cesium carbonate (488 mg, 1.5 mmol,
3.0 equiv.) and complex 4 (3.9 mg, 0.005 mmol, 1.0 mol-%) were
put into a Schlenk tube under air. The tube was then sealed with
a septum, and purged with nitrogen (3ϫ). 4-Chlorotoluene (59 μL,
0.5 mmol, 1.0 equiv.), morpholine (69 μL, 0.75 mmol, 1.5 equiv.),
piperidine (59 μL, 0.75 mmol, 1.5 equiv.), and DME (0.5 mL) were
then added by syringe at room temperature. The mixture was
stirred for about 1 min at room temperature, and was then transfer-
red to a preheated oil bath (80 °C). The reaction was allowed to
proceed for 24 h. The ratio between the two products was deter-
mined from the NMR spectrum of the crude mixture.
4-(4-Nitrophenyl)morpholine (5e): After flash chromatography on
silica gel (pentane/Et2O, 4:1), compound 5e (103.0 mg, 99%) was
obtained as an orange solid. 1H NMR (400 MHz, CDCl3): δ = 8.12
(dd, J = 9.2, 3.7 Hz, 2 H), 6.82 (d, J = 9.3 Hz, 2 H), 3.94–3.76 (m,
4 H), 3.42–3.26 (m, 4 H) ppm. 13C{1H} NMR (101 MHz, CDCl3):
δ = 155.1, 139.1, 126.0, 112.7, 66.5, 47.2 ppm.
4-(4-Acetylphenyl)morpholine (5f): After flash chromatography on
silica gel (hexane/EtOAc, 1:1), compound 5f (102.0 mg, 99%) was
obtained as an orange solid. 1H NMR (400 MHz, CDCl3): δ =
7.93–7.83 (m, 2 H), 6.90–6.80 (m, 2 H), 3.92–3.77 (m, 4 H), 3.38–
3.16 (m, 4 H), 2.52 (s, 3 H) ppm. 13C{1H} NMR (101 MHz,
CDCl3): δ = 196.7, 154.3, 130.5, 128.3, 113.4, 66.7, 47.7, 26.3 ppm.
Competitive Amination Experiments of 4-Chloroanisole with Morph-
oline and Piperidine: Cesium carbonate (488 mg, 1.5 mmol,
3.0 equiv.) and precatalyst 4 (3.9 mg, 0.005 mmol, 1.0 mol-%) were
put into a Schlenk tube under air. The tube was then sealed with
a septum, and purged with nitrogen (3ϫ). 4-Chlorotoluene (61 μL,
0.5 mmol, 1.0 equiv.), morpholine (69 μL, 0.75 mmol, 1.5 equiv.),
piperidine (68 μL, 0.75 mmol, 1.5 equiv.), and DME (0.5 mL) were
then added by syringe at room temperature. The mixture was
stirred for about 1 min at room temperature, and was then transfer-
red to a preheated oil bath (80 °C). The reaction was allowed to
proceed for 24 h. The ratio between the two products was deter-
mined from the NMR spectrum of the crude mixture.
4-(2-Methylphenyl)morpholine (5g): After flash chromatography on
silica gel (hexane/EtOAc, 10:1), compound 5g (76 mg, 86%) was
obtained as a colourless oil. 1H NMR (400 MHz, CDCl3): δ = 7.21
(t, J = 7.2 Hz, 2 H), 7.09–6.98 (m, 2 H), 3.88 (t, J = 4.5 Hz, 4 H),
2.94 (t, J = 4.6 Hz, 4 H), 2.35 (s, 3 H) ppm. 13C{1H} NMR
(101 MHz, CDCl3): δ = 151.4, 132.7, 131.3, 126.7, 123.5, 119.0,
67.6, 52.4, 18.0 ppm.
4-(Pyridin-2-yl)morpholine (5h): After flash chromatography on sil-
ica gel (pentane/Et2O, 2:1), compound 5h was obtained (81.9 mg,
General Procedure for the Palladium-Catalysed Buchwald–Hartwig
Amination with Cesium Carbonate: Cesium carbonate (488 mg,
1.5 mmol, 3.0 equiv.) and precatalyst 4 (1–4 mol-%) were put into
a Schlenk tube under air. The tube was then sealed with a septum
and purged with nitrogen, through three vacuum/nitrogen cycles.
The aryl halide (0.5 mmol), the amine (0.75 mmol, 1.5 equiv.), and
DME (0.5 mL) were then added by syringe at room temperature.
In cases where the aryl halide or the amine was solid at room tem-
perature, it was introduced into the tube before purging with nitro-
gen. The mixture was stirred for about 1 min at room temperature,
and was then transferred to a preheated oil bath at 80 °C. The
reaction was allowed to proceed for 24 h. The reaction mixture was
diluted with ethyl acetate (10 mL), then it was filtered through a
small plug of silica gel, which was washed with ethyl acetate. The
filtrate was concentrated under reduced pressure, and the residue
was purified by silica gel flash chromatography.
1
100%) as a colourless oil. H NMR (400 MHz, CDCl3): δ = 8.16
(ddd, J = 5.0, 2.0, 0.9 Hz, 1 H), 7.45 (ddd, J = 8.5, 7.2, 2.0 Hz, 1
H), 6.64–6.54 (m, 2 H), 3.82–3.71 (m, 4 H), 3.49–3.40 (m, 4 H)
ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 159.6, 148.0, 137.5,
113.8, 106.9, 66.8, 45.6 ppm.
4-(Pyridin-3-yl)morpholine (5i): After flash chromatography on sil-
ica gel (EtOAc), compound 5i (70.2 mg, 86%) was obtained as a
1
yellow oil. H NMR (400 MHz, CDCl3): δ = 8.34–8.19 (m, 1 H),
8.19–7.98 (m, 1 H), 7.0–7.07 (m, 2 H), 3.94–3.67 (m, 4 H), 3.24–
3.04 (m, 4 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 147.0,
141.2, 141.2, 138.4, 123.6, 122.2, 66.8, 48.7 ppm.
4-(Thiophen-3-yl)morpholine (5j): After flash chromatography on
silica gel (pentane/EtOAc, 3:1), compound 5j (71.2 mg, 84%) was
1
obtained as a yellow solid. H NMR (400 MHz, CDCl3): δ = 7.25
(dd, J = 5.2, 3.1 Hz, 1 H), 6.86 (dd, J = 5.2, 1.5 Hz, 1 H), 6.21 (dd,
J = 2.9, 1.5 Hz, 1 H), 3.91–3.72 (m, 4 H), 3.18–2.96 (m, 4 H) ppm.
13C{1H} NMR (101 MHz, CDCl3): δ = 152.5, 125.7, 119.7, 100.6,
66.8, 50.9 ppm.
4-(4-Methoxylphenyl)morpholine (5a): After flash chromatography
on silica gel (pentane/Et2O, 4:1), compound 5a (94.0 mg, 97%) was
1
obtained as a white solid. H NMR (400 MHz, CDCl3): δ = 6.94–
6.82 (m, 4 H), 3.90–3.82 (m, 4 H), 3.77 (s, 3 H), 3.09–3.02 (m, 4
H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 154.1, 145.7,
117.9, 114.6, 67.2, 55.7, 50.9 ppm.
1,4-Diphenylpiperazine (5k): After flash chromatography on silica
gel (pentane/Et2O, 95:5), compound 5k (95.9 mg, 81%) was ob-
tained as shiny white crystals. 1H NMR (400 MHz, CDCl3): δ =
7.37–7.28 (m, 4 H), 7.05–6.98 (m, 4 H), 6.96–6.87 (m, 2 H), 3.37
(d, J = 1.4 Hz, 8 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ =
151.4, 129.3, 120.2, 116.5, 49.6 ppm.
4-(4-Methylphenyl)morpholine (5b): After flash chromatography on
silica gel (pentane/Et2O, 4:1), compound 5b (88.0 mg, 99%) was
1
obtained as a white solid. H NMR (400 MHz, CDCl3): δ = 7.10
(d, J = 8.7 Hz, 2 H), 6.85 (d, J = 8.4 Hz, 2 H), 3.96–3.77 (m, 4 H),
3.20–3.03 (m, 4 H), 2.29 (s, 3 H) ppm. 13C{1H} NMR (101 MHz,
CDCl3): δ = 149.3, 129.8, 129.7, 116.2, 67.1, 50.1, 20.5 ppm.
1-Ethyl-4-phenylpiperazine (5l): After flash chromatography on sil-
ica gel (CH2Cl2/MeOH, 90:10), compound 5l (86.4 mg, 91%) was
obtained as an orange oil. H NMR (400 MHz, CDCl3): δ = 7.31–
1
4-Phenylmorpholine (5c): After flash chromatography on silica gel
(pentane/Et2O, 10:1), compound 5c (79.9 mg, 98%) was obtained
7.20 (m, 2 H), 6.98–6.91 (m, 2 H), 6.90–6.81 (m, 1 H), 3.23 (t, J =
5.0 Hz, 4 H), 2.63 (t, J = 5.2 Hz, 4 H), 2.49 (q, J = 7.2 Hz, 2 H),
Eur. J. Org. Chem. 2015, 2042–2050
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2047

Y. Zhang, V. César, G. Lavigne
1.14 (t, J = 7.2 Hz, 3 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): (m, 2 H), 6.30 (br. s, 1 H) ppm. 13C{1H} NMR (101 MHz, CDCl3):
FULL PAPER
δ = 151.4, 129.2, 119.8, 116.2, 53.0, 52.5, 49.2, 12.1 ppm.
δ = 150.3, 139.9, 139.6, 129.9, 126.4, 124.8, 122.1, 113.8 ppm.
N-(4-Acetylphenyl)aniline (6f): After flash chromatography on silica
gel (hexane/EtOAc, 7:3), compound 6f (99.7 mg, 94%) was ob-
tained as a yellow solid. H NMR (400 MHz, CDCl3): δ = 7.91–
7.82 (m, 2 H), 7.39–7.30 (m, 2 H), 7.22–7.14 (m, 2 H), 7.13–7.04
(m, 1 H), 7.03–6.94 (m, 2 H), 2.53 (s, 3 H) ppm. 13C{1H} NMR
(101 MHz, CDCl3): δ = 196.5, 148.5, 140.7, 130.7, 129.7, 129.2,
123.5, 120.8, 114.6, 26.3 ppm.
N-Benzyl-N-ethylpyridin-3-amine (5m): After flash chromatography
on silica gel (EtOAc/pentane, 3:7), compound 5m (97.5 mg, 92%)
was obtained as a yellow oil. 1H NMR (400 MHz, CDCl3): δ =
8.14 (d, J = 3.1 Hz, 1 H), 7.92 (dd, J = 4.7, 1.3 Hz, 1 H), 7.37–7.15
(m, 5 H), 7.05 (dd, J = 8.5, 4.5 Hz, 1 H), 6.97–6.84 (m, 1 H), 4.51
(s, 2 H), 3.50 (q, J = 7.1 Hz, 2 H), 1.22 (t, J = 7.1 Hz, 3 H) ppm.
13C{1H} NMR (101 MHz, CDCl3): δ = 144.4, 138.1, 137.2, 134.5,
128.9, 127.2, 126.5, 123.8, 118.9, 53.8, 45.3, 12.1 ppm.
1
4-(Phenylamino)benzaldehyde (6g): After flash chromatography on
silica gel (pentane/Et2O, 8:1), compound 6g (88.1 mg, 89%) was
1-Phenylpiperidine (5n): After flash chromatography on silica gel
(pentane/Et2O, 95:5), compound 5n (57.4 mg, 71%) was obtained
as a colourless oil. 1H NMR (400 MHz, CDCl3): δ = 7.33–7.21 (m,
2 H), 6.97 (d, J = 7.9 Hz, 2 H), 6.85 (t, J = 7.3 Hz, 1 H), 3.18 (t,
J = 5.4 Hz, 4 H), 1.80–1.70 (m, 4 H), 1.65–1.56 (m, 2 H) ppm.
13C{1H} NMR (101 MHz, CDCl3): δ = 152.4, 129.1, 119.3, 116.6,
50.8, 26.0, 24.5 ppm.
1
obtained as a yellow solid. H NMR (400 MHz, CDCl3): δ = 9.79
(s, 1 H), 7.81–7.68 (m, 2 H), 7.43–7.30 (m, 2 H), 7.23–7.18 (m, 2
H), 7.16–7.08 (m, 1 H), 7.06–6.99 (m, 2 H), 6.40 (br. s, 1 H) ppm.
13C{1H} NMR (101 MHz, CDCl3): δ = 190.5, 150.0, 140.2, 132.2,
129.7, 128.6, 124.0, 121.4, 114.6 ppm.
N-Phenyl-2-methylaniline (6h): After flash chromatography on sil-
ica gel (hexane/EtOAc, 20:1), compound 6h (91.0 mg, 99%) was
obtained as a colourless oil. 1H NMR (400 MHz, CDCl3): δ =
7.37–7.26 (m, 4 H), 7.22 (td, J = 7.8, 1.4 Hz, 1 H), 7.06–6.95 (m,
4 H), 5.43 (br. s, 1 H), 2.33 (s, 3 H) ppm. 13C{1H} NMR (101 MHz,
CDCl3): δ = 144.1, 141.3, 131.0, 129.4, 128.4, 126.8, 122.1, 120.5,
118.9, 117.5, 18.0 ppm.
N,N-Dibutylaniline (5o): After flash chromatography on silica gel
(hexane/EtOAc, 20:1), compound 5o (65.8 mg, 64%) was obtained
as a colourless oil. 1H NMR (400 MHz, CDCl3): δ = 7.25–7.18 (m,
2 H), 6.73–6.57 (m, 3 H), 3.32–3.23 (m, 4 H), 1.66–1.52 (m, 4 H),
1.44–1.31 (m, 4 H), 1.02–0.94 (m, 6 H) ppm. 13C{1H} NMR
(101 MHz, CDCl3): δ = 148.3, 129.3, 115.2, 111.8, 50.9, 29.6, 20.5,
14.2 ppm.
N-(4-Methylphenyl)-4-methoxyaniline (6i): After flash chromatog-
raphy on silica gel (hexane/EtOAc, 8:1), compound 6i (97.4 mg,
N-Methyl-N-phenylamine (5p): After flash chromatography on sil-
ica gel (hexane/EtOAc, 99:1), compound 5p (84.5 mg, 92%) was
obtained as a colourless oil. 1H NMR (400 MHz, CDCl3): δ = 7.34
(t, J = 7.5 Hz, 4 H), 7.09 (d, J = 7.7 Hz, 4 H), 7.02 (t, J = 7.3 Hz,
2 H), 3.38 (s, 3 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ =
149.1, 129.3, 121.4, 120.6, 40.3 ppm.
1
91%) was obtained as a white solid. H NMR (300 MHz, CDCl3):
δ = 7.06–7.01 (m, 4 H), 6.88–6.83 (m, 4 H), 5.42 (br. s, 1 H), 3.80
(s, 3 H), 2.2 (s, 3 H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ =
154.9, 142.5, 136.7, 129.9, 129.5, 121.2, 116.7, 114.8, 55.7,
20.7 ppm.
N-(4-Methoxyphenyl)-4-fluoroaniline (6j): After flash chromatog-
raphy on silica gel (pentane/Et2O, 9:1), compound 6j was obtained
as a grey solid: 105.5 mg (97% yield). 1H NMR (400 MHz,
CDCl3): δ = 7.05–6.98 (m, 2 H), 6.97–6.81 (m, 6 H), 5.39 (br. s, 1
H), 3.80 (s, 3 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ =
157.3 (d, J = 238 Hz), 155.1, 141.2 (d, J = 2 Hz), 136.6, 121.3,
117.9 (d, J = 7 Hz), 115.9 (d, J = 22 Hz), 114.9, 55.7 ppm.
N-Phenyl-4-methoxyaniline (6a): After flash chromatography on sil-
ica gel (pentane/Et2O, 95:5), compound 6a (86.1 mg, 86%) was ob-
tained as a beige solid. 1H NMR (300 MHz, CDCl3): δ = 7.32–7.20
(m, 2 H), 7.17–7.06 (m, 2 H), 7.00–6.83 (m, 5 H), 5.52 (br. s, 1 H),
3.84 (s, 3 H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ = 155.4,
145.3, 135.8, 129.4, 122.3, 119.7, 115.8, 114.8, 55.7 ppm.
N-Phenyl-4-methylaniline (6b): After flash chromatography on sil-
ica gel (hexane/EtOAc, 97:3), compound 6b (91.4 mg, 99%) was
N-(4-Methoxyphenyl)-3-(trifluoromethyl)aniline (6k): After flash
chromatography on silica gel (pentane/Et2O, 7:1), compound 6k
(90.3 mg, 68%) was obtained as a beige solid. 1H NMR (400 MHz,
CDCl3): δ = 7.28 (t, J = 8.2 Hz, 1 H), 7.14–7.06 (m, 3 H), 7.06–
6.96 (m, 2 H), 6.95–6.85 (m, 2 H), 5.62 (br. s, 1 H), 3.82 (s, 3 H)
ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 156.3, 146.1, 134.4,
131.8 (q, J = 32 Hz), 129.9, 124.3 (q, J = 273 Hz), 123.6, 118.0,
115.7 (q, J = 4 Hz), 115.0, 111.4 (q, J = 4 Hz), 55.7 ppm.
1
obtained as a white solid. H NMR (400 MHz, CDCl3): δ = 7.33–
7.26 (m, 2 H), 7.15 (d, J = 8.1 Hz, 2 H), 7.09–7.03 (m, 4 H), 6.94
(tt, J = 7.8, 1.0 Hz, 1 H), 5.63 (br. s, 1 H), 2.37 (s, 3 H) ppm.
13C{1H} NMR (101 MHz, CDCl3): δ = 144.1, 140.4, 131.0, 130.0,
129.4, 120.5, 119.1, 117.0, 20.8 ppm.
Diphenylamine (6c): After flash chromatography on silica gel (pent-
ane/EtOAc, 95:5), compound 6c (80.0 mg, 95%) was obtained as a
Methyl 4-(4-Methoxyphenylamino)benzoate (6l): After flash
chromatography on silica gel (pentane/Et2O, 7:1), compound 6l
(67.2 mg, 52%) was obtained as a beige solid. 1H NMR (400 MHz,
CDCl3): δ = 7.87 (d, J = 8.4 Hz, 2 H), 7.12 (d, J = 8.5 Hz, 2 H),
6.90 (d, J = 8.6 Hz, 2 H), 6.81 (d, J = 8.5 Hz, 2 H), 5.99 (s, 1 H),
3.85 (s, 3 H), 3.81 (s, 3 H) ppm. 13C{1H} NMR (101 MHz, CDCl3):
δ = 167.2, 156.5, 150.0, 133.5, 131.6, 124.4, 119.9, 114.8, 113.3,
55.6, 51.7 ppm.
1
white solid. H NMR (400 MHz, CDCl3): δ = 7.31 (t, J = 7.9 Hz,
4 H), 7.11 (d, J = 8.4 Hz, 4 H), 6.98 (t, J = 7.3 Hz, 2 H), 5.73 (br.
s, 1 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 143.2, 129.5,
121.1, 117.9 ppm.
4-(Phenylamino)benzonitrile (6d): After flash chromatography on
silica gel (hexane/EtOAc, 4:1), compound 6d (93.4 mg, 96%) was
1
obtained as a beige solid. H NMR (400 MHz, CDCl3): δ = 7.50
(d, J = 8.6 Hz, 2 H), 7.43–7.32 (m, 2 H), 7.23–7.17 (m, 2 H), 7.17–
7.10 (m, 1 H), 7.04–6.94 (m, 2 H), 6.13 (br. s, 1 H) ppm. 13C{1H}
NMR (101 MHz, CDCl3): δ = 148.1, 140.1, 133.9, 129.8, 124.1,
121.4, 120.0, 115.0, 101.6 ppm.
N-Phenylpyridin-3-amine (6m): After flash chromatography on sil-
ica gel (hexane/EtOAc, 1:4), compound 6m (70.6 mg, 83%) was
obtained as a white solid. H NMR (400 MHz, CDCl3): δ = 8.39
1
(s, 1 H), 8.16 (d, J = 3.9 Hz, 1 H), 7.41 (ddd, J = 8.2, 2.5, 1.2 Hz,
N-Phenyl-4-nitroaniline (6e): After flash chromatography on silica 1 H), 7.30 (t, J = 7.9 Hz, 2 H), 7.17 (dd, J = 8.2, 4.7 Hz, 1 H), 7.08
gel (pentane/Et2O, 7:3), compound 6e (104.2 mg, 97%) was ob-
tained as a yellow solid. H NMR (400 MHz, CDCl3): δ = 8.15–
8.06 (m, 2 H), 7.44–7.35 (m, 2 H), 7.24–7.12 (m, 3 H), 6.97–6.87
(d, J = 7.6 Hz, 2 H), 6.99 (t, J = 7.4 Hz, 1 H), 5.89 (d, J = 14.3 Hz,
1 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 142.1, 142.0,
140.3, 140.0, 129.7, 123.8, 123.5, 122.1, 118.4 ppm.
1
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 2042–2050

Buchwald–Hartwig Amination of (Hetero)aryl Chlorides
N-(4-Fluorophenyl)pyridin-3-amine (6n): After flash chromatog-
2.4 Hz, 2 H), 8.23 (d, J = 3.8 Hz, 2 H), 7.30–7.25 (m, 2 H), 7.19
(dd, J = 8.3, 4.6 Hz, 2 H), 3.70 (t, J = 7.7 Hz, 2 H), 1.66 (pent, J
raphy on silica gel (EtOAc), compound 6n (82.3 mg, 88%) was ob-
1
tained as a white solid. H NMR (400 MHz, CDCl3): δ = 8.31 (d, = 7.6 Hz, 2 H), 1.33–1.21 (m, 10 H), 0.86 (t, J = 6.9 Hz, 3 H) ppm.
J = 2.7 Hz, 1 H), 8.13 (d, J = 4.6 Hz, 1 H), 7.28 (ddd, J = 8.3, 2.8, 13C{1H} NMR (101 MHz, CDCl3): δ = 143.6, 143.1, 127.7, 124.0,
1.4 Hz, 1 H), 7.14 (dd, J = 8.3, 4.7 Hz, 1 H), 7.10–6.95 (m, 4 H), 52.4, 31.9, 29.5, 29.4, 27.4, 27.1, 22.7, 14.2 ppm.
5.81 (d, J = 38.2 Hz, 1 H) ppm. 13C{1H} NMR (101 MHz, CDCl3):
N-Benzyl-4-methoxyaniline (7f): After flash chromatography on sil-
δ = 158.7 (d, J = 242 Hz), 141.7 (d, J = 3 Hz), 140.7, 139.4, 123.9,
ica gel (hexane/EtOAc, 20:1), compound 7f (52.4 mg, 49%) was
122.5, 121.4 (d, J = 8 Hz), 116.3 (d, J = 22 Hz) ppm.
1
obtained as a white solid. H NMR (400 MHz, CDCl3): δ = 7.40–
N-Octyl-2-methylaniline (7a): After flash chromatography on silica
gel (hexane/EtOAc, 20:1), compound 7a (106 mg, 97%) was ob-
tained as a colourless oil. H NMR (400 MHz, CDCl3): δ = 7.23
(td, J = 7.6, 1.2 Hz, 1 H), 7.15 (d, J = 7.7 Hz, 1 H), 6.79–6.64 (m,
2 H), 3.52 (br. s, 1 H), 3.24 (t, J = 7.1 Hz, 2 H), 2.23 (s, 3 H), 1.76
(pent, J = 7.1 Hz, 2 H), 1.57–1.33 (m, 10 H), 1.06–0.95 (m, 3 H)
ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 146.5, 130.1, 127.2,
121.7, 116.7, 109.7, 44.1, 32.0, 29.7, 29.6, 29.4, 27.4, 22.8, 17.5,
14.2 ppm.
7.27 (m, 4 H), 7.31–7.27 (m, 1 H), 6.82–6.78 (m, 2 H), 6.64–6.60
(m, 2 H), 4.30 (s, 2 H), 3.79 (br. s, 1 H), 3.76 (s, 3 H) ppm. 13C{1H}
NMR (101 MHz, CDCl3): δ = 152.3, 142.6, 139.8, 128.7, 127.7,
127.3, 115.0, 114.2, 55.9, 49.4 ppm.
1
N,N-Bis(4-methoxyphenyl)benzylamine
(7fЈ):
After
flash
chromatography on silica gel (hexane/EtOAc, 20:1), compound 7fЈ
(35.1 mg, 44%) was obtained as a white solid. 1H NMR (400 MHz,
CDCl3): δ = 7.40–7.27 (m, 4 H), 7.22 (t, J = 7.1 Hz, 1 H), 7.00–
6.91 (m, 4 H), 6.84–6.75 (m, 4 H), 4.89 (s, 2 H), 3.77 (s, 6 H) ppm.
13C{1H} NMR (101 MHz, CDCl3): δ = 154.4, 142.6, 139.7, 128.6,
126.8, 126.8, 121.9, 114.7, 57.2, 55.7 ppm.
N-Octyl-2,6-dimethylaniline (7b): After flash chromatography on
silica gel (pentane/EtOAc, 20:1), compound 7b (109.6 mg, 94%)
was obtained as a colourless oil. 1H NMR (400 MHz, CDCl3): δ =
7.00 (d, J = 7.4 Hz, 2 H), 6.81 (t, J = 7.4 Hz, 1 H), 3.07–2.90 (m,
3 H), 2.30 (s, 6 H), 1.64–1.52 (m, 2 H), 1.46–1.24 (m, 10 H), 0.95–
0.84 (m, 3 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 146.6,
129.2, 128.9, 121.6, 48.8, 32.0, 31.4, 29.7, 29.4, 27.3, 22.8, 18.7,
14.2 ppm.
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra of products 5a–5p, 6a–6n, 7a–7f,
and 7dЈ–7fЈ.
Acknowledgments
N-Cyclohexylaniline (7c): After flash chromatography on silica gel
(hexane/EtOAc, 10:1), compound 7c (64.5 mg, 74%) was obtained
as a colourless oil. 1H NMR (400 MHz, CDCl3): δ = 7.23–7.13 (m,
2 H), 6.73–6.65 (m, 1 H), 6.65–6.55 (m, 2 H), 3.53 (br. s, 1 H),
3.35–3.22 (m, 1 H), 2.08 (d, J = 12.6 Hz, 2 H), 1.86–1.73 (m, 2 H),
1.74–1.61 (m, 1 H), 1.48–1.33 (m, 2 H), 1.32–1.10 (m, 3 H) ppm.
13C{1H} NMR (101 MHz, CDCl3): δ = 147.5, 129.4, 116.9, 113.2,
51.8, 33.6, 26.1, 25.2 ppm.
The authors thank the Centre National de la Recherche Sci-
entifique (CNRS) for financial support, and the Chinese Scholar-
ship Council (CSC) for a Ph. D. grant to Y. Z.
[1] a) D. A. Horton, G. T. Bourne, M. L. Smythe, Chem. Rev.
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N-Octyl-4-methoxy-aniline (7d): After flash chromatography on sil-
ica gel (hexane/EtOAc, 20:1), compound 7d (51.6 mg, 44%) was
1
obtained as a white solid. H NMR (400 MHz, CDCl3): δ = 6.82–
6.76 (m, 2 H), 6.62–6.55 (m, 2 H), 3.75 (s, 3 H), 3.12 (br. s, 1 H),
3.06 (t, J = 7.1 Hz, 2 H), 1.61 (pent, J = 7.0 Hz, 2 H), 1.44–1.23
(m, 10 H), 0.90 (t, J = 6.7 Hz, 3 H) ppm. 13C{1H} NMR
(101 MHz, CDCl3): δ = 152.1, 143.0, 115.0, 114.1, 56.0, 45.2, 32.0,
29.8, 29.6, 29.4, 27.4, 22.8, 14.2 ppm.
N,N-Bis(4-methoxyphenyl)octylamine (7dЈ): After flash chromatog-
raphy on silica gel (hexane/EtOAc, 20:1), compound 7dЈ (48.6 mg,
1
57%) was obtained as a white solid. H NMR (400 MHz, CDCl3):
δ = 6.92–6.86 (m, 4 H), 6.86–6.80 (m, 4 H), 3.79 (s, 6 H), 3.60–3.52
(m, 2 H), 1.62 (pent, J = 7.6 Hz, 2 H), 1.35–1.23 (m, 10 H), 0.89
(t, J = 6.6 Hz, 3 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ =
154.3, 142.7, 122.2, 114.7, 55.7, 53.0, 32.0, 29.6, 29.5, 27.7, 27.3,
22.8, 14.2 ppm.
N-Octyl-pyridin-3-amine (7e): After flash chromatography on silica
gel (EtOAc), compound 7e (72 mg, 70%) was obtained as a white
1
solid. H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 2.8 Hz, 1 H),
7.93 (dd, J = 4.7, 1.2 Hz, 1 H), 7.10–7.01 (m, 1 H), 6.84 (ddd, J =
8.3, 2.9, 1.4 Hz, 1 H), 3.66 (br. s, 1 H), 3.10 (t, J = 7.0 Hz, 2 H),
1.62 (pent, J = 7.1 Hz, 2 H), 1.44–1.22 (m, 10 H), 0.93–0.82 (m, 3
H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 144.5, 138.6,
136.2, 123.8, 118.4, 43.7, 31.9, 29.6, 29.5, 29.4, 27.2, 22.8,
14.2 ppm.
N,N-Bis(pyridin-3-yl)octylamine (7eЈ): After flash chromatography
on silica gel (EtOAc), compound 7eЈ (14 mg, 20%) was obtained
as a white solid. 1H NMR (400 MHz, CDCl3): δ = 8.35 (d, J =
Eur. J. Org. Chem. 2015, 2042–2050
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2049

Y. Zhang, V. César, G. Lavigne
FULL PAPER
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Received: January 9, 2015
Published Online: February 9, 2015
2050
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 2042–2050