Buchwald-Hartwig reactions in water using surfactants

Article abstract of DOI:10.1016/j.tet.2014.03.083

Examination of the scope and limitation of the Buchwald-Hartwig cross-coupling reaction in micellar medium is reported. An array of aryl or heteroaryl halides were coupled to diverse nitrogen coupling partners using a combination of [(allyl)PdCl]₂ and cBRIDP to afford the corresponding products in moderate to excellent yields. 30 examples are reported, including polar solid and fairly water-soluble organic substrates/reagents.

Full text of DOI:10.1016/j.tet.2014.03.083

Tetrahedron 70 (2014) 3413e3421
Contents lists available at ScienceDirect
Tetrahedron
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BuchwaldeHartwig reactions in water using surfactants
,
y,
z
z
*
ꢀ
ꢀ ꢀ
, Patrick Wagner , Maud Bollenbach, Frederic Bihel,
Christophe Salome
Jean-Jacques Bourguignon, Martine Schmitt
*
ꢀ
ꢀ
ꢀ
Laboratoire d’Innovation Therapeutique, UMR 7200, Faculte de pharmacie, Universite de Strasbourg, 74, route du Rhin, BP 60024, 67401 Illkirch, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Examination of the scope and limitation of the BuchwaldeHartwig cross-coupling reaction in micellar
medium is reported. An array of aryl or heteroaryl halides were coupled to diverse nitrogen coupling
partners using a combination of [(allyl)PdCl]2 and cBRIDP to afford the corresponding products in
moderate to excellent yields. 30 examples are reported, including polar solid and fairly water-soluble
organic substrates/reagents.
Received 15 February 2014
Received in revised form 24 March 2014
Accepted 25 March 2014
Available online 1 April 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
CeN cross coupling
Green chemistry
Surfactant
Palladium amination
1. Introduction
developed safer surfactants, e.g., polyoxyethanyl
a-tocopheryl
sebacate (PTS) and polyoxyethanyl- -tocopheryl succinate (TPGS-
a
Pd-catalyzed BuchwaldeHartwig cross-coupling reaction is one
of the most important methodologies in modern organic
synthesis,1 particularly in the synthesis of important intermediates
and building blocks for fine chemistry2 and pharmaceuticals.3 In
the past decade, research efforts led to the discovery of diverse
catalysts that are able to couple a wide scope of amines with
(hetero)aryl halides under mild reaction conditions. Convention-
ally, BuchwaldeHartwig cross-coupling reactions are carried out in
organic solvents (e.g., THF, dioxane, NMP) and often at above am-
bient temperatures. Although many attempts have been made to
perform these reactions under thermally mild conditions, the use of
potentially toxic organic solvents is common, which by definition
fails to meet the 12 Principles of Green Chemistry.
Typically, the use of water as the reaction medium often pro-
vides beneficial effect in rate enhancement, but, in some cases,
organic compounds (reactants) could be insoluble in water and
prevent the reactions due to heterogenous purposes (specially with
solid compounds).4 However, the commons apprehension of in-
solubility of organic substances in aqueous medium often becomes
deterrent for the use of water, which however may be circum-
vented by the use of surfactants.5 Recently, Lipshutz et al.
750-M), to serve as nanoreactors.6e9,10a,11 In particular, the second-
generation surfactant, TPGS-750-M, forms nanomicelles in water,
that are lipophilic on the inside and hydrophilic on the outside, and
allowed efficient Pd-catalyzed cross-coupling reactions at 40 ꢀC,
e.g., SuzukieMiyaura,7 Heck,8 BuchwaldeHartwig,9,10a or Sonoga-
shira reactions.11 The second-generation surfactant (TPGS-750-M)
is often a superior choice than the first-generation surfactant (PTS),
with respect to yields, economics of preparation, and levels of pu-
rity. Unfortunately, for the interesting BuchwaldeHartwig cross-
coupling reactions, only the N-arylation of aniline derivatives has
been reported (Scheme 1).6,9,10a Moreover, in the reported exam-
ples, the reactants used are relatively lipophilic compounds with
low molecular weights. Therefore, these reactants generally exist as
more or less viscous oils, thereby allowing their incorporations into
a micellar system. However, while this article was under review,
Lipshutz et al. enlarged the scope of the arylation reaction to urea,
carbamate, and sulfonamides derivatives and reported the efficacy
of these classes of nitrogen derivatives under micellar conditions.12
Herein, we report the scope and limitations of the Buch-
waldeHartwig reaction in a micellar medium, as described earlier
by Lipshutz’s catalyst system, [(allyl)PdCl]2 (1.1%), tBuONa
(1.5 equiv), TPGS-750-M-2% in water (1.0 mL), and cBRIDP (4.4%),
50 ꢀC,5 by reacting various (hetero)aryl halides with diverse ni-
trogen coupling partners. In particular, this study utilizes both
water-soluble amines, such as dimethylamine, and specific exam-
ples of fairly water-soluble polar solid organic substrates/reagents
with relatively high melting points.
* Corresponding authors. Tel.: þ33 (0)3 688 54 231; e-mail addresses: salome@
ꢀ
unistra.fr (C. Salome), mschmitt@unistra.fr (M. Schmitt).
y
ꢀ
Present address: Laboratoire de Biovectorologie, UMR 7199, Faculte de phar-
ꢀ
macie, Universite de Strasbourg, 74, route du Rhin, BP 60024, 67401 Illkirch, France.
z
These authors contributed equally to this work.
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.083

ꢀ
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C. Salome et al. / Tetrahedron 70 (2014) 3413e3421
Scheme 1. Pd-catalyzed amination reaction in water in presence of surfactants.
2. Results and discussion
arylation reaction of OTf derivative 1d resulted in a high isolated
yield (87% yield, Table 1, entry 5) even in the absence of NEt3. With
the O-tosyl derivative 1e, no reaction was observed even at high
micellar concentration (Table 1, entry 6). Similar reactivities have
been observed in the BuchwaldeHartwig reactions using classical
conditions.1f
First, the effect of the leaving group on the reaction rate and
yield was examined. In fact, Lipshutz et al. reported the reaction
with only aryl bromides and TPGS-750-M as the surfactant. In this
study, different leaving groups were chosen, e.g., I, Br, Cl, OTf, and
OTs. 3-Aminopyridine 2 was chosen as the representative of het-
eroaryl amines, and the results are summarized in Table 1. Bro-
motoluene 1b reacted efficiently in micellar medium, as observed
previously by Lipshutz (Table 1, entry 2, 2 h, 88% yield). Aryl iodide
1c afforded the product in 60% yield (Table 1, entry 3) after 2 h;
however, the reaction was quasi-complete (90% yield) after 16 h
(Table 1, entry 4). As expected, aryl chloride 1a was less reactive
(16 h, 40% yield, Table 1, entry 1), and 60% of the starting material
was recovered. This result is in accordance with the chemo-
selectivity observed for 1f (Table 1, entry 7). When a benzene ring
bearing both chlorine and bromine atoms was used as the sub-
strate, no reaction was observed on the chlorine position.
To further investigate the versatility of this method, we carried
out a second set of experiments: the cross-coupling reactions of
various aliphatic amines (primary amines, acyclic and cyclic
secondary amines, anilines, amidines, and heteroaryl amines) with
m-bromotoluene. The results are summarized in Table 2. The first
goal of this study was to investigate the reactivity of the most basic
nitrogen derivatives. With the primary amine n-BuNH2 (Table 2,
entry 1), no trace of the expected product was observed, and the
starting material 1b was recovered unchanged. With the more
lipophilic benzylamine, 25% yield of the product was observed by
HPLC analysis after 16 h (compare: Table 2, entries 1 and 4). In
contrast, the secondary aliphatic amines were found to be more
reactive than the primary aliphatic amines (compare: Table 2,
entries 1 and 2 and entries 4 and 5). In all these cases, the yields are
good. With this in mind, we tried the reactions successfully
with water-soluble secondary amines, N,N-dimethylamine
(log D¼ꢁ0.19,13 Table 2, entry 3) and N-methylpiperidine
(log D¼ꢁ0.35, Table 2, entry 6). With N,N-dimethylamine, no
reaction was observed under the standard stoichiometric condi-
tions (1.2 equiv of amine, Table 2, entry 3). However, when a large
excess of N,N-dimethylamine (40% in water, 9 equiv) was used, N,N-
dimethylanilino derivative 3b was obtained in 90% yield (Table 2,
entry 3). With 1.2 equiv of N-methylpiperidine, only 40% conver-
sion was observed after 16 h (Table 2, entry 6). The use of 5 equiv of
N-methylpiperidine increased the yield (55% isolated yield, Table 2,
entry 6). These results demonstrate that: (i) the N-arylation
reactions can be realized with the commercially available aqueous
solutions of amines; (ii) the log D of the amines does not play
a major role in the reaction; and (iii) even water-soluble com-
pounds can be incorporated inside the highly hydrophobic mi-
celles. These results are very interesting because in the classical
BuchwaldeHartwig cross-coupling reaction, the aqueous solutions
of amines are not tolerated. Instead, highly anhydrous conditions
are needed, and highly volatile amines available in aprotic solvents
(THF) or ether at low concentrations are used. Two others sec-
ondary cyclic amines were examined, N-benzylpiperazine (Table 2,
entry 7) and tetrahydroisoquinoline (THIQ, Table 2, entry 8). In both
the cases, the reactions afforded the corresponding products in
satisfactory yields (70e80% isolated yields). This can be explained
by the high lipophilicity of these compounds, favoring their rapid
concentrations in the micelles. However, the THIQ derivative took
Table 1
Study of amination of aryl halides in water in presence of TPGS-750-M
Entry
Nꢀ
R
X
Time (h)
Nꢀ
3 (%)
1
2
3
4
5
6
7
1a
1b
1c
1c
1d
1e
1f
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
4-Cl
Cl
Br
I
16
2
2
16
2
16
2
3h
3h
3h
3h
3h
3h
3n
40
88a,b
60
I
90
OTf
OTs
Br
87
n.r.c
72
a
Without TPGS only 15% of formation of 3h.
98% of 3h (previous work).9
n.r. no reaction even in 0.5 M concentration (1 mmol of 1e/2 mL of TPGS-750-
b
c
M-2%).
Aryl sulfonates were used owing to their ease of preparation
from readily available phenolic precursors. m-Tolyl tri-
fluoromethanesulfonate 1d and m-tolyl 4-methylbenzenesulfonate
1e were synthesized following the reported procedures. The Pd-
catalyzed amination of aryl triflates has been previously per-
formed by Lipshutz using the first-generation surfactant (TPS).
However, these reactions often resulted in low yields owing to the
tBuONa-catalyzed cleavage of the triflate. The use of NEt3 as the
additive improved the results (76% isolated yield, 0.5 h).
Interestingly, in our hands using TPGS-750-M micelles, the N-

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C. Salome et al. / Tetrahedron 70 (2014) 3413e3421
3415
Table 2
(Table 2, entry 11), only 9% of the corresponding product was iso-
lated after 1 h or 72 h, even with higher catalyst loadings (5% [(allyl)
PdCl]2 and 4.4% cBRIDP). Surprisingly, no trace of aryl bromide 1b
was recovered. This is probably because the guanidine moiety of
the 2-aminopyrimidine could coordinate to the Aryl Pd complex
and so catalyzes the reductive elimination leading in our case to
toluene as observed earlier by Buchwald with monodentate li-
gands.14 As shown in Table 2, entries 12e14, the amination process
was successfully applied to pyrrole or indole. For example, pyrrole
afforded the target N-arylation product in 60% yield after 2 h under
the standard conditions (Table 2, entry 12). With indole, the rate for
the amination reaction was slightly slower than that for the ami-
nation of pyrrole; moreover, this reaction required higher catalyst
loadings. However, the expected product was obtained in 86% yield
under the standard conditions (Table 2, entry 13). Finally, the re-
action yield was very low with indazole (14% yield, Table 2, entry
14) even with higher catalyst loadings.
Finally, we evaluated the efficacy of the amidation reaction of
3-bromotoluene under the micellar conditions. In particular, a set
of amides, carbamates, and ureas were selected for this purpose.
As expected from the previous results described by Buchwald, our
studies,15 and very recently by Lipshutz12 the reactions with car-
bamates (Table 3, entries 1 and 2), ureas (Table 3, entries 7 and 8),
and cyclic amide (Table 3, entry 6) in the micellar medium affor-
ded the corresponding products in satisfactory yields, whereas the
Palladium-cross coupling amination with TPGS and amine
Entry
Amine
Time (h)
Nꢀ
3 (%)a
1
2
3
4
n-BuNH2
n-Bu(Me)NH
Me2NH
16
16
2
d
3a
3b
3c
n.r.
66
n.r. (90)b
25
PhCH2NH2
16
5
16
3d
70
6
7
8
16
3
3e
3f
40c (55)d
80
16
3g
70e
9
2
3h
87
Table 3
Palladium-cross coupling N-arylation with TPGS
10
11
12
48
16
2
3i
65f
3j
9 (5)g
Entry
ReC(O)NHR1
Time (h)
Nꢀ
4 (%)a
1
2
t-BOCeNH2
Z-NH2
16
16
4a
4b
77
69
3k
60
3
4
16
4c
28b
13
24
40
3l
86f
14
16
16
4d
13
21c
14
3m
n.rd
a
Isolated yields.
(Me)2NH 40% in water was used as solvent.
Estimated by HPLC.
Amine (5 equiv).
Formation of 10% of 8.
5
16
4e
b
c
d
e
f
Second addition of 2% of [(allyl)PdCl]2 and 4.4% of cBRIDP after 16 h.
[(Allyl)PdCl]2 (5%) and 4.4% of cBRIDP.
6
7
16
18
4f
80
81
g
a longer period for the completion of the reaction (16 h). In the case
of tetrahydroisoquinoline, the oxidation of the resulting N-aryl
tetrahydroisoquinoline 3g afforded the corresponding N-aryl 3,4-
dihydroisoquinoline-1(2H)-one 8, as the side product (10% yield).
Next, the cross-coupling reactions of 3-bromotoluene with di-
verse nitrogen-containing heterocycles were carried out (Table 2).
With 3-aminopyridine (Table 2, entry 9), the reaction worked
pretty well, as described earlier by Lipshutz (88% yield, 2 h).6
However higher catalyst loadings (2% [(allyl)PdCl]2 and 4.4%
cBRIDP) were required for 2-aminopyridine (Table 2, entry 10). This
is probably because of the chelating properties of the
2-aminopyridine derivative. In contrast, with 2-aminopyrimidine
4g
8
24
4h
15
65e
a
Isolated yields.
Estimated by NMR.
b
c
[(Allyl)PdCl]2 (5%) and 4.4% of cBRIDP were used.
n.r. no reaction.
d
e
3-Bromotolyl (2 equiv) was used.

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C. Salome et al. / Tetrahedron 70 (2014) 3413e3421
3416
trans-secondary amide did not react (Table 3, entry 5). In-
terestingly, when other potentially reactive functional groups (e.g.,
hydroxyl) were present on the amide substrate, chemoselective
arylation on the nitrogen was observed (Table 3, entry 7). Sur-
prisingly primary amides afforded the corresponding products in
moderate yields (Table 3, entries 3 and 4), even when using higher
catalyst loading.
In continuation of our efforts, the N-arylation reaction was
studied with several unactivated azaheteroaryl halide coupling
partners (Table 4). In this study, we selected 3-aminopyridine as the
prototypical partner. Various chloroheterocyclic systems, such as
pyridine, pyrazine, pyridazine, pyrimidine (compounds 5aee and
6), and thiophene (compound 5f) were efficiently N-substituted
with 3-aminopyridine. In particular the reaction conditions were
effective for the 2,4-dichloropyrimidine derivative (Table 4, entry 7)
because 2,4-pyrimidinediamine 6 was obtained as the major
product. In contrast, the very low reactive 3-bromothiophene
reacted smoothly; however, it required higher catalyst loadings
(5% of [(allyl)PdCl]2). Surprisingly, the reaction of 6-phenyl-3-
chloropyridazine failed (Table 4, entry 5). This is probably
because of the very low solubility of 6-phenyl-3-chloropyridazine
in water (0.067 mg/mL compared to 0.255 mg/mL for the
5-phenyl analog)16 affording an insoluble precipitate.
Finally, owing to the observed poor reactivities of the primary
amines and primary amides, highly electron-deficient 2,6-dichloro-
5-methyl pyrimidine 7 was used as the substrate to facilitate the
reactions. With the benzamide derivative (Table 5, entry 1), the
reaction afforded a 3/1 regioisomeric mixture of 9a and 10a in 87%
isolated yield. Good results were also observed with benzylamine
(Table 5, entry 2). The structure of 2-amino-substituted pyrimidin-
4-ol 10b was established by the heteronuclear NMR experiments
(HMBC and HMQC, see the Supplementary data).
Table 5
Palladium-catalyzed N-heteroarylation of the less reactive amines with 7
Entry
Nꢀ
R
9 (%)
10 (%)
1
2
a
b
4-MeOePheCO
PhCH2
65
72
22
14
Our great interest in medicinal heterocyclic chemistry prompted
us to evaluate the possible intramolecular cyclization of N-pro-
tected o-bromo-phenethylamine 11. Under the standard experi-
mental conditions, the expected N-Boc-indoline 12 was obtained in
excellent isolated yield (84%, Scheme 2). No side product (corre-
sponding indole) was detected by the LC/MS or 1H NMR analyses.
Table 4
Palladium-cross coupling N-arylation with TPGS-750-M on heterocyclic systems
Entry
1
Heterocycle
Time (h)
2
Nꢀ
5a (%)
5a
91
Scheme 2. Intramolecular cyclization of N-Boc-o-bromo-phenethylamine 11 under
micellar conditions.
2
3
2
2
5b
5c
71
75
3. Conclusions
We significantly expanded the substrate scope of the Pd-
catalyzed amination under micellar conditions (TPGS-750-M). In
particular, cyclic amides, anilines, carbamates, ureas, and various
nitrogen-containing heterocyclic derivatives were found to be re-
active and afforded the corresponding products in excellent yields.
We also demonstrated that various iminochlorides (pyridine and
pyrazine) and thiophene are largely tolerated in this aqueous mi-
cellar media. However, the yields directly depended on their in-
trinsic aqueous solubilities. In a few reactions, relatively higher
levels of catalyst loading (2% Pd) were required. The application of
the reaction to various heterocycles makes the method more at-
tractive because of their use in medicinal chemistry. Finally, two
chemoselective N-arylations (Br vs Cl, urea vs OH) were reported in
this study.
4
16
16
5d
5e
80
5
6
0
16
16
5f
60b
14c
The cross-coupling reactions with benzamide derivatives and
primary amines pose some challenges; therefore, further studies
are currently underway to overcome these problems.
7
5g
4. Experimental section
a
4.1. Solubility test using HPLC/UV
Isolated yields.
[(Allyl)PdCl]2 (5%) and 4.4% of cBRIDP were used.
b
c
In order to determine the solubility concentration of a sample
using HPLC/UV, a standard curve for each compound was prepared
Compound 6 (43%) was isolated.

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C. Salome et al. / Tetrahedron 70 (2014) 3413e3421
3417
from known concentration in DMSO (4.0, 1.5, 0.40, 0.15, and
0.040 mol/mL). The area under curve (AUC) was measured at the
maximum absorbance:
¼203 nm for 5-phenyl-3-chloropyzidazine
and
the line was then used to calculate the product concentration from
the absorbance of the sample. Probe (3.00 mg) was introduced in an
d
0.91e1.00 (3H, t, J¼7.2 Hz), 1.31e1.43 (2H, m), 1.53e1.63 (2H, m),
2.34 (3H, s), 2.94 (3H, s), 3.29e3.34 (2H, t, J¼7.5 Hz), 6.52e6.56 (3H,
m), 7.11e7.16 (1H, m); 13C NMR (101 MHz, CDCl3)
14.0, 20.4, 22.0,
m
l
d
l
¼200 nm for 6-phenyl-3-chloropyridazine. The equation of
29.0, 38.3, 52.6, 109.4, 112.9, 116.8, 129.0, 138.7, 149.6; HRMS
(MþHþ)(ESIþ) 178.1587 [MþHþ] (calcd for C12H20NHþ 178.1590).
Eppendorf tube. 600
mL of a saline solution (9 mg of NaCl dissolved
4.5. N,N,3-Trimethylaniline (3b)17
in 1 mL water) was added into the Eppendorf. The solution was
then stirred for 24 h at room temperature on an oscillating plate. In
order to improve the agitation, a little magnetic stirrer bar was
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), 3-bromotoluene
added. The mixture was then centrifuged. Supernatant (3.00
mL)
(121 mL, 1.0 mmol), TPGS-750M (20 mg), and NaO-t-Bu (144 mg,
was analyzed by HPLC. The solubility of each sample was then
obtained using the equation of the calibration curve: 0.067 mg/mL
for the 6-phenyl-3-chloropyridazine and 0.255 mg/mL for the 5-
phenyl-3-chloropyridazine.
1.5 mmol) in aqueous dimethylamine (40%, 1.0 mL), followed by
purification using column chromatography (SiO2) and cyclohexane/
ethyl acetate (9/1 to 5/5), yielded 3b as a brown oil (121 mg, 90%
yield). 1H NMR (300 MHz, CDCl3)
d
2.30 (3H, s), 2.91 (6H, s),
6.51e6.56 (3H, m), 7.09e7.13 (1H, m); 13C NMR (100 MHz, CDCl3)
d 21.9, 40.7, 109.9, 113.5, 117.6, 128.9, 138.7, 150.8.
4.2. Chemistry: general information
All reactions were carried out under a nitrogen atmosphere.
Chemicals and solvents were purchased from SigmaeAldrich and
were used without further purification. Analytical TLC was per-
formed using silica gel plates Merck 60F254 and plates were visu-
alized by exposure to ultraviolet light. Compounds were purified
using Armen spot flash chromatography on silica gel Merck 60
(particle size 0.040e0.063 mm). Yields refer to isolated com-
pounds, estimated to be >97% pure as determined by 1H NMR or
HPLC. 1H and 13C NMR spectra were recorded on Bruker Avance
Spectrometer operating at 300 MHz/400 MHz and 100 MHz, re-
4.6. N-Benzyl-3-methylaniline (3c)18
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), 3-bromotoluene
(121 mL, 1.0 mmol), benzylamine (130 mL, 1.2 mmol), and NaO-t-
Bu (144 mg, 1.5 mmol) in aqueous TPGS-750M (2%, 1.0 mL), fol-
lowed by purification using column chromatography (SiO2) and
cyclohexane/ethyl acetate (8/2), yielded 3c as a colorless oil (40 mg,
20% yield). 1H NMR (300 MHz, CDCl3)
d
2.30 (3H, s), 3.90e4.06 (1H,
br s), 4.34 (2H, s), 6.46e6.59 (3H, m), 7.09 (1H, J¼7.5 Hz), 7.27e7.41
(5H, m); 13C NMR (100 MHz, CDCl3)
21.7, 48.4, 110.0, 113.6, 118.6,
spectively. All chemical shift values
d
and coupling constants J are
d
quoted in parts per million and in hertz, respectively, multiplicity
(s¼singlet, d¼doublet, t¼triplet, m¼multiplet, br Broad). Analytical
RP-HPLC-MS was performed using an LC-MSD 1200SL Agilent with
127.2, 127.6, 128.6, 129.2, 139.1, 139.6, 148.3.
4.7. N-[(3-Methoxyphenyl)methyl]-N,3-dimethylaniline (3d)
a Thermo HypersilgoldÒ column (C18, 30 mmꢂ1 mm; 1.9
mm) using
the following parameters: (1) the solvent system: A (acetonitrile)
and B (0.05% TFA in H2O); (2) A linear gradient: t¼0 min, 98%B;
t¼5 min, 5% B; t¼6 min, 5%B; t¼7 min, 98%B; t¼9 min, 98%B; (3)
Flow rate of 0.3 mL/min; (4) Column temperature: 50 ꢀC; (5) The
ratio of products was determined by integration of spectra recorded
at 210 nm or 254 nm; (6) Ionization mode: MM-ESþAPCI. HPLC
were performed using a Dionex UltiMate 300 using the following
parameters: flow rate of 0.5 mL/min, column temperature: 30 ꢀC,
solvent system: A (MeOH) and B (0.05% TFA in H2O), t¼0e1 min:
50e60% of B then t¼1e10 min: 60e100% of B and t¼10e15 min:
100% of B. Infra-Red analyses were performed by FT-IR, on a Nicolet
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), 3-bromotoluene
(121
(179
m
L, 1.0 mmol), [(3-methoxyphenyl)methyl](methyl)amine
mL, 1.2 mmol), and NaO-t-Bu (144 mg, 1.5 mmol) in aqueous
TPGS-750M (2%, 1.0 mL), followed by purification using column
chromatography (SiO2) and cyclohexane/ethyl acetate (8/2), yiel-
ded 3d as a colorless oil (169 mg, 70% yield). HPLC rt 3.44; 1H NMR
(300 MHz, CDCl3, 25 ꢀC)
d 2.32 (3H, s), 3.00 (3H, s), 3.79 (3H, s), 4.50
(2H, s), 6.55e6.60 (3H, m), 6.78e6.86 (3H, m), 7.10e7.15 (1H, t,
J¼7.5 Hz), 7.22e7.25 (1H, t, J¼7.5 Hz); 13C NMR (101 MHz, CDCl3,
25 ꢀC)
d, 22.0, 38.5, 55.2, 56.7, 109.7, 112.1, 112.4, 113.2, 117.6, 119.1,
380 ATR from Thermo and wavenumber were expressed in cmꢁ1
.
129.0, 129.6, 138.8, 141.1, 150.0, 159.9; HRMS (MþHþ)(ESIþ)
242.1540 [MþHþ] (calcd for C16H19NOHþ 242.1539).
4.3. General procedure
4.8. 1-Methyl-4-(m-tolyl)piperazine (3e)19
Amine (1.2 equiv) and 3-bromotoluene (1 equiv) were added to
an aqueous solution of TPGS-750-M-2% (1 mL/mmol). The mixture
was degassed by bubbling Argon in through (5 min). NaO-t-Bu
(1.5 equiv), of [(allyl)PdCl]2 (1.1%) and cBridp (4.4%) were added
together to the previous solution. The mixture was stirred (at
1200 rpm) at 50 ꢀC (2e24 h). Volatiles were evaporated and the
crude residue was purified by chromatographic column on silica gel
using ethyl acetate and cyclohexane as solvent.
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), 3-bromotoluene
(121 mL, 1.0 mmol), N-methylpiperazine (133 mL, 1.2 mmol), and
NaO-t-Bu (144 mg, 1.5 mmol) in aqueous TPGS-750M (2%, 1.0 mL),
followed by purification using column chromatography (SiO2) and
ethyl acetate/methanol (10/0 to 8/2), yielded 3e as an orange oil
(71 mg, 40% yield). 1H NMR (400 MHz, CDCl3)
d 2.34 (3H, s), 2.49
(3H, s), 2.78 (4H, t, J¼4.8 Hz), 3.32 (4H, t, J¼4.8 Hz), 6.72e6.77 (3H,
4.4. N-Butyl-N,3-dimethylaniline (3a)
m), 7.18 (1H, J¼7.8 Hz); 13C NMR (100 MHz, CDCl3)
d 21.8, 45.4, 48.6,
54.7, 113.6, 117.2, 121.2, 129.0, 138.9, 139.6.
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), 3-bromotoluene
4.9. 1-Benzyl-4-(m-tolyl)piperazine (3f)
(121
mL, 1.0 mmol), N-methyl-1-butanamine (148 mL, 1.2 mmol),
and NaO-t-Bu (144 mg, 1.5 mmol) in aqueous TPGS-750M (2%,
1.0 mL), followed by purification using column chromatography
(SiO2) and n-heptane/ethyl acetate (9/1), yielded 3a as a colorless
oil (117 mg, 66% yield). HPLC rt 2.85; 1H NMR (300 MHz, CDCl3)
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), 3-bromotoluene
(121
mL, 1.0 mmol), N-benzylpiperazine (208 mL, 1.2 mmol), and
NaO-t-Bu (144 mg, 1.5 mmol) in aqueous TPGS-750M (2%, 1.0 mL),

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C. Salome et al. / Tetrahedron 70 (2014) 3413e3421
3418
followed by purification using column chromatography (SiO2) and
ethyl acetate/methanol (10/0 to 8/2), yielded 3f as an orange oil
139.2, 140.4, 148.5, 155.1; (MþHþ)(ESIþ) 185.1067 [MþHþ] (calcd
for C12H12N2Hþ 185.1078).
(212 mg, 80% yield). 1H NMR (400 MHz, CDCl3)
d 2.34 (3H, s), 2.63
(4H, t, J¼5.0 Hz), 3.22 (4H, t, J¼5.0 Hz), 3.60 (2H, s), 6.69e6.77
(3H, m), 7.17 (1H, J¼7.8 Hz), 7.28e7.40 (5H, m, H arom); 13C NMR
4.13. N-(3-Methylphenyl)pyrimidin-2-amine (3j)
(100 MHz, CDCl3)
d 21.8, 49.3, 53.2, 63.1, 113.6, 116.9, 121.2, 127.1,
128.3, 129.0, 129.2, 138.5, 138.7, 151.5. LRMS (MþHþ)(ESIþ) 267.1
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), 3-bromotoluene
(121 mL, 1.0 mmol), 2-aminopyrimidine (114 mg, 1.2 mmol), and
[MþHþ] (calcd for C18H22N2Hþ 267.0).
4.10. N-(m-Tolyl)tetrahydroisoquinoline (3g)20
NaO-t-Bu (144 mg, 1.5 mmol) in aqueous TPGS-750M (2%, 1.0 mL),
followed by purification using column chromatography (SiO2) and
ethyl acetate/n-heptane (1/3), yielded 3j as a white solid (17 mg, 9%
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), 3-bromotoluene
yield). HPLC rt 3.59; 1H NMR (400 MHz, CDCl3)
d 2.39 (3H, s),
6.68e6.72 (1H, t, J¼4.8 Hz), 6.89e6.92 (1H, d, J¼7.5 Hz), 7.23e7.29
(121
mL, 1.0 mmol), tetrahydroisoquinoline (138 mL, 1.2 mmol),
(1H, t, J¼7.8 Hz), 7.46e7.48 (2H, m), 8.29 (1H, s), 8.43e8.45 (2H, d,
and NaO-t-Bu (144 mg, 1.5 mmol) in aqueous TPGS-750M (2%,
1.0 mL), followed by purification using column chromatography
(SiO2) and heptane/ethyl acetate (9/1 to 7/3), yielded 3g (orange oil,
155 mg, 70% yield) and 8 (orange solid, 23.6 mg, 10%).
J¼4.8 Hz); 13C NMR (101 MHz, CDCl3)
d 21.7,112.3, 117.1,120.6,123.7,
128.8, 138.7, 139.5, 158.0, 160.5; HRMS (MþHþ)(ESIþ) 186.1027
[MþHþ] (calcd for C11H11N3Hþ 186.1026).
4.10.1. Compound 3g. 1H NMR (400 MHz, CDCl3)
d 2.36 (3H, s, CH3),
4.14. 1-(m-Tolyl)-1H-pyrrole (3k)21
3.00 (2H, t, J¼5.8 Hz, CH2), 3.56 (2H, t, J¼5.8 Hz, CH2), 4.41 (2H, s),
6.68 (1H, d, J¼7.4 Hz), 6.79e6.84 (2H, m), 7.14e7.22 (5H, m); 13C
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), 3-bromotoluene
NMR (100 MHz, CDCl3)
d 22.0, 29.3, 46.7, 51.0, 112.4, 116.1, 119.7,
126.1, 126.4, 126.7, 128.6, 129.2, 134.7, 135.0, 139.0, 150.8.
(121
mL, 1.0 mmol), pyrrole (82 mL, 1.2 mmol), and NaO-t-Bu
(144 mg, 1.5 mmol) in aqueous TPGS-750M (2%, 1.0 mL), followed
by purification using column chromatography (SiO2) and ethyl ac-
etate/cyclohexane (0/10 to 1/9), yielded 3f as a red oil (95 mg, 60%
4.10.2. 2-(3-Methylphenyl)-3,4-dihydroisoquinolin-1(2H)-one
(8). 1H NMR (400 MHz, CDCl3)
d 2.38 (3H, s, CH3), 3.14 (2H, t,
J¼6.4 Hz, CH2), 3.98 (2H, t, J¼6.4 Hz, CH2), 7.08 (1H, d, J¼7.5 Hz, H
arom), 7.17 (1H, d, J¼7.8 Hz, H arom), 7.20e7.27 (2H, m, H arom),
7.30 (1H, t, J¼7.8 Hz, H arom), 7.38 (1H, t, J¼7.5 Hz, H arom), 7.47
(1H, td, J¼7.5, 1.4 Hz, H arom), 8.16 (1H, dd, J¼7.7, 1.4 Hz, H arom).
(MþHþ)(ESIþ) 238.0 [MþHþ] (calcd for C16H16N2OHþ 238.1).
yield). 1H NMR (400 MHz, CDCl3)
d 2.43 (3H, s), 6.37 (2H, t,
J¼2.2 Hz), 7.10e7.14 (3H, m), 7.22e7.30 (2H, m), 7.29e7.33 (1H, m);
13C NMR (100 MHz, CDCl3)
129.3, 139.5, 140.8.
d 21.4, 110.2, 117.7, 119.3, 121.3, 126.4,
4.11. N-(m-Tolyl)pyridin-3-amine (3h)11
4.15. 1-(m-Tolyl)-1H-indole (3l)22
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), 3-bromotoluene
Indole (135 mg, 1.2 mmol) and 3-bromotoluene (121
mL,
1.0 mmol) were added to an aqueous solution of TPGS (2%, 1 mL/
mmol). The mixture was degassed by bubbling Argon in through
(5 min). Pd2(allyl)2Cl2 (4.4 mg, 0.011 mmol), cBridp (15.5 mg,
0.044 mmol), and NaO-t-Bu (144 mg, 1.5 mmol) were added to-
gether to the previous solution. The mixture was stirred at 50 ꢀC
(16 h). After 16 h, Pd2(allyl)2Cl2 (4.4 mg, 0.011 mmol) and cBridp
(15.5 mg, 0.044 mmol) were added and the mixture was stirred as
indicated in Table 2. The residue was purified using column chro-
matography (SiO2) and ethyl acetate/cyclohexane (0/10 to 2/8), to
obtain 3l as colorless oil (180 mg, 86% yield). 1H NMR (400 MHz,
(121
mL, 1.0 mmol), 3-aminopyridine (113 mg, 1.2 mmol), and
NaO-t-Bu (144 mg, 1.5 mmol) in aqueous TPGS-750M (2%, 1.0 mL),
followed by purification using column chromatography (SiO2) and
cyclohexane/ethyl acetate (9/1 to 5/5), yielded 3h as a yellow solid
(160 mg, 87% yield). 1H NMR (400 MHz, CDCl3)
d 2.30 (3H, s),
5.64e6.70 (1H, br s), 6.80 (1H, d, J¼7.7 Hz), 6.84e6.90 (2H, m),
7.12e7.20 (2H, m), 7.38 (1H, ddd, J¼1.3, 2.6, 8.3 Hz), 8.13 (1H, dd,
J¼1.3, 4.8 Hz), 8.35 (1H, d, J¼2.6 Hz); 13C NMR (100 MHz, CDCl3)
d
21.7, 115.6, 119.2, 123.2,123.7, 123.9, 129.6, 139.7, 140.1, 140.4, 142.1,
one aromatic peak was not detected and is believed to overlap with
nearby signals.
CDCl3)
7.46e7.50 (1H, m), 7.58e7.61 (1H, m); 13C NMR (100 MHz, CDCl3)
21.5,103.6,110.6,120.3,121.1,121.5,122.3,125.1,127.3,128.0,123.2,
d
2.35 (3H, s), 6.58 (1H, t, J¼3.6 Hz), 7.07e7.32 (7H, m),
d
4.12. N-(m-Tolyl)pyridin-2-amine (3i)
129.5, 135.9, 139.7, 139.8.
2-Aminopyridine (112 mg, 1.2 mmol) and 3-bromotoluene
(121
m
L, 1.0 mmol) were added to an aqueous solution of TPGS
4.16. 1-(3-Methylphenyl)-1H-indazole (3m)
(2%, 1 mL/mmol). The mixture was degassed by bubbling Argon in
through (5 min). Pd2(allyl)2Cl2 (4.4 mg, 0.011 mmol), cBridp
(15.5 mg, 0.044 mmol), and NaO-t-Bu (144 mg, 1.5 mmol) were
added together to the previous solution. The mixture was stirred at
50 ꢀC (16 h). After 16 h, a second set of Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol) and cBridp (15.5 mg, 0.044 mmol) was added and the
mixture was stirred as indicated in Table 2. The residue was purified
using column chromatography (SiO2) and ethyl acetate/cyclohex-
ane (10/0 to 5/5), to obtain 3i as a brown oil (120 mg, 65% yield). 1H
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), 3-bromotoluene
(121
mL, 1.0 mmol), indazole (142 mg, 1.2 mmol), and NaO-t-Bu
(144 mg, 1.5 mmol) in aqueous TPGS-750M (2%, 1.0 mL), followed
by purification using column chromatography (SiO2) and CH2Cl2/n-
heptane (1/1), yielded 3m as a colorless oil (28 mg, 14% yield). 1H
NMR (400 MHz, CDCl3)
d 2.48 (3H, s), 7.18e7.27 (2H, m), 7.41e7.47
(2H, m), 7.53e7.57 (2H, m), 7.76e7.78 (1H, d, J¼8.6 Hz), 7.80e7.83
NMR (400 MHz, CDCl3)
d
2.27 (3H, s), 6.45e6.55 (1H, br s), 6.64 (1H,
(1H, d, J¼8.0 Hz), 8.2 (1H, s); 13C NMR (100 MHz, CDCl3)
d 21.5,
t, J¼6.2 Hz), 6.62e6.64 (2H, m), 7.04e7.06 (2H, m), 7.13 (1H, d,
110.5, 119.7, 121.3, 121.4, 123.6, 125.3, 127.1, 127.5, 129.2, 135.2, 138.8,
J¼8.0 Hz), 7.38e7.43 (1H, m), 8.12 (1H, J¼4.4 Hz); 13C NMR
139.6, 140.1; HRMS (MþHþ)(ESIþ) 209.1077 [MþHþ] (calcd for
(100 MHz, CDCl3)
d
21.5, 108.2, 115.0, 117.5, 121.1, 123.7, 129.1, 137.6,
C
14H12N2Hþ 209.1073).

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3419
4.17. N-(4-Chlorophenyl)pyridin-3-amine (3n)23
7.47e7.49 (1H, dd, J¼1.1, 5.0 Hz), 7.64e7.65 (1H, dd, J¼1.1, 3.7 Hz),
8.00 (1H, s); 13C NMR (101 MHz, CDCl3)
21.5, 117.6, 121.2, 125.4,
d
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), 1-bromo-4-
127.8, 128.6, 128.8, 130.8, 137.6, 138.9, 139.5, 160.3; HRMS
(MþHþ)(ESIþ) 218.0630 [MþHþ] (calcd for C12H11NOSHþ
218.0634).
chlorobenzene (121
mL, 1.0 mmol), 3-aminopyridine (142 mg,
1.2 mmol), and NaO-t-Bu (144 mg, 1.5 mmol) in aqueous TPGS-
750M (2%, 1.0 mL), followed by purification using column chro-
matography (SiO2) and CH2Cl2/n-heptane (1/1), yielded 3n as
4.22. (m-Tolyl)pyrrolidin-2-one (4f)27
a colorless oil (156 mg, 72% yield). 1H NMR (400 MHz, CDCl3)
d 5.80
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), 3-bromotoluene
(121 mL, 1.0 mmol), pyrrolidin-2-one (85 mL, 1.2 mmol), and NaO-
(1H, s), 7.03 (2H, d, J¼8.8 Hz), 7.21e7.28 (3H, m), 7.40 (1H, d,
J¼8.0 Hz), 8.15e8.25 (1H, br s), 8.36e8.46 (1H, br s); 13C NMR
(100 MHz, CDCl3) d 119.4,123.8,126.8,129.5,140.3,140.7,142.4; two
t-Bu (144 mg, 1.5 mmol) in aqueous TPGS-750M (2%, 1.0 mL), fol-
lowed by purification using column chromatography (SiO2) and
heptane/ethyl acetate (8/2 to 5/5), yielded 4f as a yellow solid
aromatic peaks were not detected and are believed to overlap with
nearby signals.
(140 mg, 80% yield). 1H NMR (400 MHz, CDCl3)
d 2.13 (2H, quint.,
4.18. tert-Butyl N-(m-tolyl)carbamate (4a)24
J¼7.8 Hz), 2.34 (3H, s), 2.58 (2H, t, J¼7.8 Hz), 3.83 (2H, t, J¼7.8 Hz),
6.94 (1H, d, J¼8.0 Hz), 7.23 (1H, t, J¼8.0 Hz), 7.35 (1H, d, J¼8.0 Hz),
7.42 (1H, s); 13C NMR (100 MHz, CDCl3)
120.8, 125.4, 128.6, 138.7, 139.3, 174.1.
d 16.1, 21.6, 32.8, 49.0, 117.2,
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), 3-bromotoluene
(121 mL, 1.0 mmol), tert-butyl carbamate (129 mg, 1.2 mmol), and
NaO-t-Bu (144 mg, 1.5 mmol) in aqueous TPGS-750M (2%, 1.0 mL),
followed by purification using column chromatography (SiO2) and
heptane/ethyl acetate (95/5 to 8/2), yielded 4a as a yellow solid
4.23. 1-(2-Hydroxyethyl)-3-(m-tolyl)imidazolidin-2-one (4g)
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), 3-bromotoluene
(160 mg, 77% yield). 1H NMR (400 MHz, CDCl3)
d 1.52 (9H, s), 2.33
(3H, s), 6.42 (1H, s), 6.85 (1H, d, J¼7.4 Hz), 7.09 (1H, d, J¼8.2 Hz), 7.16
(121
mL, 1.0 mmol), 1-(2-hydroxyethyl)imidazolidin-2-one
(1H, dd, J¼8.2, 7.4 Hz), 7.19 (1H, s); 13C NMR (100 MHz, CDCl3)
d 21.7,
(156 mg, 1.2 mmol), and NaO-t-Bu (144 mg, 1.5 mmol) in aqueous
TPGS-750M (2%, 1.0 mL), followed by purification using column
chromatography (SiO2) and ethyl acetate, yielded 4g as an orange
28.5, 80.5, 115.8, 119.3, 124.0, 128.9, 138.4, 139.1, 152.9.
4.19. Benzyl m-tolylcarbamate (4b)25
oil (180 mg, 81% yield). 1H NMR (400 MHz, CDCl3)
d 2.36 (3H, s),
3.43 (2H, t, J¼5.1 Hz), 3.57 (2H, t, J¼8.1 Hz), 3.79e3.83 (4H, m), 6.88
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), 3-bromotoluene
(1H, d, J¼7.2 Hz), 7.22 (1H, t, J¼7.8 Hz), 7.28e7.31 (1H, m), 7.38 (1H,
s); 13C NMR (100 MHz, CDCl3)
d 21.7, 43.0, 43.2, 47.5, 61.3, 114.7,
(121
mL, 1.0 mmol), benzyl carbamate (181 mg, 1.2 mmol), and
118.4, 123.5, 128.6, 138.6, 140.2, 159.1; HRMS (MþHþ)(ESIþ)
NaO-t-Bu (144 mg, 1.5 mmol) in aqueous TPGS-750M (2%, 1.0 mL),
followed by purification using column chromatography (SiO2) and
ethyl acetate/cyclohexane (2/8), yielded 4b as an orange oil
221.1290 [MþHþ] (calcd for C12H16N2O2Hþ 221.1284).
(165 mg, 69% yield). 1H NMR (400 MHz, CDCl3)
d
2.35 (3H, s), 5.22
(2H, s), 6.65e6.70 (1H, br s), 6.91 (1H, d, J¼6.4 Hz), 7.17e7.28 (4H,
m), 7.36e7.44 (4H, m); 13C NMR (100 MHz, CDCl3)
21.5, 67.0,124.4,
4.24. 1,3-Dimethyl-1-(3-methylphenyl)urea (4h)
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), 3-bromotoluene
d
128.3, 128.4, 128.6, 128.9, 136.1, 137.7, 139.0, 153.4 two peaks are
missing and are believed to overlap nearby; HRMS (MþHþ)(ESIþ)
242.1181 [MþHþ] (calcd for C15H15NO2Hþ 242.1175).
(242
mL, 2.0 mmol), 1,3-dimethylurea (88 mg, 1.0 mmol), and
NaO-t-Bu (144 mg, 1.5 mmol) in aqueous TPGS-750M (2%, 1.0 mL),
followed by purification using column chromatography (SiO2) and
n-heptane/ethyl acetate 3/7 to ethyl acetate, yielded 4h as
a brownish oil (115 mg, 65% yield). HPLC rt 3.15; 1H NMR (300 MHz,
4.20. N-(3-Methylphenyl)benzamide (4c)26
CDCl3)
d
2.33 (3H, s), 2.68 (3H, d, J¼4.8 Hz), 3.20 (3H, s), 4.29 (1H,
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), 3-bromotoluene
br), 6.99 (d, 2H, J¼7.8 Hz), 7.07 (d, 1H, J¼7.8 Hz), 7.25 (t, 1H,
J¼7.6 Hz); 13C NMR (101 MHz, CDCl3)
d 21.2, 27.4, 37.1, 124.3, 127.9,
(121
(144 mg, 1.5 mmol) in aqueous TPGS-750M (2%, 1.0 mL), yielded 4c
as a crude product (28% by NMR). 1H NMR (400 MHz, CDCl3)
2.34
mL, 1.0 mmol), benzamide (133 mg, 1.1 mmol), and NaO-t-Bu
128.0, 129.7, 140.0, 143.4, 158.0; HRMS (MþHþ)(ESIþ) 179.1180
[MþHþ] (calcd for C10H14N2OHþ 179.1179).
d
(3H, s), 6.95 (1H, d, J¼7.6 Hz), 7.23 (1H, dd, J¼7.6, 7.9 Hz), 7.40 (1H, d,
J¼7.9 Hz), 7.43e7.54 (4H, m), 7.83e7.85 (3H, m); 13C NMR
4.25. 4-Methyl-N-(pyridin-3-yl)pyridin-2-amine (5a)
(100 MHz, CDCl3) d 21.5, 117.3, 120.9, 125.4, 127.0, 128.8, 128.9, 131.8,
135.1, 137.9, 139.0, 165.7 (C(O)).
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), 2-chloropicoline
(111 mL, 1.0 mmol), 3-aminopyridine (113 mg, 1.2 mmol), and
4.21. N-(3-Methylphenyl)thiophene-2-carboxamide (4d)26
NaO-t-Bu (144 mg, 1.5 mmol) in aqueous TPGS-750M (2%, 1.0 mL),
followed by purification using column chromatography (SiO2) and
ethyl acetate/methanol(10/0 to 90/10), yielded 5a as a white solid
Following the general procedure, using Pd2(allyl)2Cl2 (18.3 mg,
0.05 mmol), cBridp (15.5 mg, 0.044 mmol), 3-bromotoluene
(121
mL, 1.0 mmol), 2-thienylamide (152 mg, 1.2 mmol), and NaO-
(180 mg, 92% yield). 1H NMR (400 MHz, CDCl3)
d 2.23 (3H, s),
t-Bu (144 mg, 1.5 mmol) in aqueous TPGS-750M (2%, 1.0 mL), fol-
lowed by purification using column chromatography (SiO2) and
ethyl acetate/n-heptane (1/9), yielded 4d as a brownish oil (46 mg,
6.57e6.63 (2H, m), 7.03e7.12 (1H, br s), 7.20 (1H, dd, J¼4.8, 8.3 Hz),
7.94 (1H, ddd, J¼1.2, 2.4, 8.3 Hz), 8.05 (1H, d, J¼5.9 Hz), 8.20 (1H, d,
J¼1.2, 4.6 Hz), 8.55 (1H, d, J¼2.4 Hz); 13C NMR (100 MHz, CDCl3)
21% yield). HPLC rt 3.97; 1H NMR (300 MHz, CDCl3)
d
2.28 (3H, s),
d 21.2,109.6,117.3,123.7,126.2,137.7,141.6,143.0,147.8,149.0,155.5;
6.90e6.92 (1H, d, J¼7.8 Hz), 7.03e7.05 (1H, dd, J¼3.7, 5.0 Hz),
HRMS (MþHþ)(ESIþ) 186.1024 [MþHþ] (calcd for C11H11N3Hþ
7.15e7.19 (1H, t, J¼7.8 Hz), 7.37e7.39 (1H, d, J¼7.8 Hz), 7.45 (1H, s),
186.1025).

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3420
4.26. Di(pyridin-3-yl)amine (5b)28
1.0 mmol), and NaO-t-Bu (144 mg, 1.5 mmol) in aqueous TPGS-
750M (2%, 1.0 mL), followed by purification using two column
chromatographies one (SiO2) and CH2Cl2/methanol(95/5 to 9/1),
yielded 5g (white solid, 33 mg, 14%) and (Si-C18) and waterþTFA
(0.05%)/methanol(9/1 to 0/1), 6 (white solid, 169 mg, 43%).
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), 3-chloropyridine
(113 mg, 1.0 mmol), 3-pyridinamine (113 mg, 1.2 mmol), and
NaO-t-Bu (144 mg, 1.5 mmol) in aqueous TPGS-750M (2%, 1.0 mL),
followed by purification using column chromatography (SiO2) and
ethyl acetate/methanol(10/0 to 9/1), yielded 5b as a white solid
4.30.1. Compound 5g. HPLC rt 2.44; 1H NMR (300 MHz, CDCl3)
d
2.11 (3H, s, CH3), 7.20e7.23 (1H, dd, J¼4.8, 8.4 Hz), 7.60e7.66 (1H,
(120 mg, 92% yield). 1H NMR (300 MHz, CDCl3)
d
5.99 (1H, s), 7.20
br s), 7.90 (1H, s), 8.10e8.13 (1H, ddd, J¼1.5, 2.5, 8.4 Hz), 8.21e8.22
(2H, dd, J¼4.6, 8.1 Hz), 7.41 (2H, d, J¼7.3 Hz), 8.20 (2H, d, J¼4.4 Hz),
(1H, dd, J¼1.5, 4.8 Hz), 8.62e8.63 (1H, d, J¼2.5 Hz); 13C NMR
8.39 (2H, d, J¼2.2 Hz); 13C NMR (100 MHz, CDCl3)
d
121.5, 123.7,
(100 MHz, CDCl3, 25 ꢀC)
d 13.6, 113.7, 123.7,129.0,135.3, 142.7, 144.8,
137.5, 139.9, 142.6.
156.6, 158.0, 160.1; HRMS (MþHþ)(ESIþ) 221.0588 [MþHþ] (calcd
for C10H9ClN4Hþ 221.0588);
4.27. N-(Pyridin-3-yl)pyrazin-2-amine (5c)29
4.30.2. Compound 6 (TFA salt). HPLC rt 2.63; 1H NMR (400 MHz,
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), 2-chloropyrazine
(89 mL, 1.0 mmol), 3-aminopyridine (113 mg, 1.2 mmol), and NaO-
DMSO-d6) d 2.22 (3H, s), 7.76e7.82 (2H, m), 8.15 (1H, s), 8.43 (1H, d,
J¼5.4 Hz), 8.45 (1H, d, J¼8.3 Hz), 8.53 (1H, dd, J¼1.3, 5.1 Hz), 8.55
(1H, d, J¼8.5 Hz), 9.15 (1H, d, J¼2.1 Hz), 9.19 (1H, d, J¼2.4 Hz),
9.40e9.46 (1H, br s), 10.35e10.38 (1H, br s), 13.40e13.55 (2H, br s);
t-Bu (144 mg, 1.5 mmol) in aqueous TPGS-750M (2%, 1.0 mL), fol-
lowed by purification using column chromatography (SiO2) and
ethyl acetate/methanol(10/0 to 90/10), yielded 5c as a white solid
13C NMR (100 MHz, CDCl3)
d
13.8, 109.6, 116.5 (q, J¼293 Hz), 126.2,
126.8, 132.7, 133.2, 134.8, 136.0, 138.1, 138.4, 126.8, 139.3, 139.8,
154.1, 155.9, 159.3 (q, J¼35 Hz), 159.5; HRMS (MþHþ)(ESIþ)
279.1348 [MþHþ] (calcd for C15H14N6Hþ 279.1353).
(130 mg, 75% yield). 1H NMR (400 MHz, CDCl3)
d
7.20 (1H, s),
7.28e7.33 (1H, m), 8.06 (1H, s), 8.17e8.33 (4H, m), 8.72 (1H, s); 13
C
NMR (100 MHz, CDCl3)
141.6, 143.8, 151.8.
d 123.7, 126.3, 133.9, 135.6, 136.5, 141.3,
4.31. N-(2-Chloro-5-methylpyrimidin-4-yl)-4-
methoxybenzamide (9a) and N-(4-hydroxy-5-
methylpyrimidin-2-yl)-4-methoxybenzamide (10a)
4.28. 5-Phenyl-N-(pyridin-3-yl)pyridazin-3-amine (5d)
Following the general procedure, using Pd2(allyl)2Cl2 (1.0 mg,
0,0027 mmol), cBridp (3.9 mg, 0.011 mmol), 3-chloro-5-
phenylpyridazine (48 mg, 0.25 mmol), 3-pyridinamine (28 mg,
0.3 mmol), and NaO-t-Bu (36 mg, 0.38 mmol) in aqueous TPGS-
750M (2%, 1.0 mL), followed by purification using column chro-
matography (SiO2) and n-heptane/ethyl acetate (1/3 to 1/1), yielded
5d as a pale yellow solid (50 mg, 80% yield). HPLC rt 3.06; 1H NMR
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), 2,4-dichloro-5-
methylpyrimidine (116
mL, 1.0 mmol), 4-methoxybenzamide
(181 mg, 1.2 mmol), and NaO-t-Bu (144 mg, 1.5 mmol) in aqueous
TPGS-750M (2%, 1.0 mL), followed by purification using column
chromatography (SiO2) and ethyl acetate/cyclohexane (80/20 to 10/
0), yielded 9a and 10a as a mixture (ratio: 66/34) as a white solid
(300 MHz, DMSO-d6)
d
7.51 (1H, d, J¼1.9 Hz), 7.56e7.62 (3H, m),
(240 mg, 87% yield). 1H NMR (400 MHz, CD3OD)
d 2.09 (2H, s), 3.83
7.89e7.85 (3H, m), 8.45 (1H, d, J¼5.3 Hz), 8.54 (1H, dd, J¼1.7,
(2H, s), 3.87 (1H, s), 3.97 (1H, s), 6.89 (0.7H, d, J¼8.9 Hz), 6.89 (1.2H,
d, J¼8.9 Hz), 7.32 (0.3H, s), 7.53 (0.7H, s), 7.87 (1.3H, d, J¼8.9 Hz),
7.91 (0.7H, d, J¼8.9 Hz), 7.98 (1H, s), 8.55 (0.3H, s), in DMSO-d6, the
8.7 Hz), 9.27e9.26 (1H, d, J¼1.9 Hz), 9.46e9.45 (1H, d, J¼1.7 Hz),
10.30e10.35 (1H, br s); 13C NMR (100 MHz, DMSO-d6)
d 113.9,126.9,
127.5, 130.0, 130.7, 131.8, 133.8, 134.4, 136.8, 139.6, 140.0, 144.9,
d of the two methyl groups bared by the pyrimidine cycle was 1.83
157.3; HRMS (MþHþ)(ESIþ) 249.1133 [MþHþ] (calcd for
for 9a and 1.94 for 10a; 13C NMR (100 MHz, CD3OD)
d 13.7, 55.3,
C
15H12N4Hþ 249.1135).
113.3, 117.5, 129.4, 151.4, 158.0, 161.6, 167.5, 173.6, one peak is
missing and is believed to relax badly; HRMS (MþHþ)(ESIþ) of 9a
166.9981 [MþHþ] (calcd for C5H5ClN2ONaþ 166.9988), amide was
hydrolyzed during the analysis.
4.29. N-(Thiophen-3-yl)pyridine-3-amine (5f)
Following the general procedure, using Pd2(allyl)2Cl2 (18.3 mg,
0.05 mmol), cBridp (15.5 mg, 0.044 mmol), 3-bromothiophene
4.32. N-Benzyl-2-chloro-5-methylpyrimidin-4-amine (9b)
(94
mL, 1.0 mmol), 3-pyridinamine (113 mg, 1.2 mmol), and NaO-t-
and 2-(benzylamino)-5-methylpyrimidin-4-ol (10b)
Bu (144 mg, 1.5 mmol) in aqueous TPGS-750M (2%, 1.0 mL), fol-
lowed by purification using column chromatography (Si-C18) and
waterþTFA (0.05%)/methanol(9/1 to 5/5), yielded 5f as a yellow
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), 2,4-dichloro-5-
methylpyrimidine (117 mL, 1.0 mmol), benzylamine (109 mL,
solid (105 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6)
d
7.10 (1H,
dd, J¼1.5, 5.1 Hz), 7.28 (1H, dd, J¼1.5, 3.0 Hz), 7.64 (1H, dd, J¼3.0,
5.1 Hz), 7.82 (1H, dd, J¼5.3, 8.5 Hz), 8.00 (1H, dd, J¼2.5, 8.7 Hz), 8.25
(1H, d, J¼5.3 Hz), 8.44 (1H, d, J¼2.6 Hz), 9.49 (1H, s); 13C NMR
1.0 mmol), and NaO-t-Bu (144 mg, 1.5 mmol) in aqueous TPGS-
750M (2%, 1.0 mL), followed by purification using (Si-C18) and
waterþTFA (0.05%)/methanol(9/1 to 0/1), and, yielded 9b as a white
solid (168 mg, 72% yield) and 10b as a white solid (33 mg,14% yield).
(100 MHz, DMSO-d6)
d 109.0, 122.8, 126.5, 127.2, 127.4, 127.7, 131.1,
138.0, 143.9. HRMS (MþHþ)(ESIþ) 177.0480 [MþH]þ (calcd for
C9H8N2SHþ 177.0481).
4.32.1. Compound 9b. 1H NMR (300 MHz, CDCl3)
4.79e4.81 (2H, d, J¼2.4 Hz), 7.31e7.34 (5H, m), 7.80 (1H, s),
d 2.13 (3H, s),
4.30. 2-Chloro-5-methyl-N-(pyridin-3-yl)pyrimidin-4-amine
(5g) and 5-ethyl-2-N,4-N-bis(pyridin-3-yl)pyrimidine-2,4-
diamine, 2TFA (6)
7.90e7.96 (1H, br s); 13C NMR (100 MHz, CDCl3)
d 13.0, 46.1, 114.1,
128.3, 128.3, 128.9, 135.9, 143.1, 152.0, 162.6; HRMS (MþHþ)(ESIþ)
234.0791 [MþHþ] (calcd for C12H12ClN3Hþ 234.0793).
Following the general procedure, using Pd2(allyl)2Cl2 (18.3 mg,
0.05 mmol), cBridp (15.5 mg, 0.044 mmol), 2,4-dichloro-5-
methylpyrimidine (163 mg, 1.0 mmol), 3-pyridinamine (94 mg,
4.32.2. Compound 10b. 1H NMR (300 MHz, CDCl3)
4.70e4.74 (2H, br s), 7.33e7.373 (5H, m), 8.06 (1H, s), 9.86e9.92
(1H, br s), 12.57 (1H, br s); 13C NMR (100 MHz, CDCl3)
15.5, 45.6,
d 2.27 (3H, s),
d

ꢀ
C. Salome et al. / Tetrahedron 70 (2014) 3413e3421
3421
114.0, 118.6, 128.1, 128.9, 136.1, 146.2, 153.8; HRMS (MþHþ)(ESIþ)
216.1127 [MþHþ] (calcd for C12H13N3OHþ 216.1131).
4. (a) Li, C. J.; Trost, B. M. Chem. Rev. 2005, 105, 3095; (b) Butler, R. N.; Coyne, A. G.
Chem. Rev. 2010, 110, 6302; (c) Kommi, D. N.; Kumar, D.; Seth, K.; Chakraborti,
A. K. Org. Lett. 2013, 15, 1158; (d) Kommi, D. N.; Jadhavar, D. K.; Chakraborti, A. K.
Green Chem. 2013, 15, 798; (e) Kommi, D. N.; Kumar, D.; Chakraborti, A. K. Green
Chem. 2013, 15, 756; (f) Seth, K.; Roy, S. R.; Pipaliya, B. V.; Chakraborti, A. K.
Chem. Commun. 2013, 5886; (g) Kommi, D. N.; Kumar, D.; Bansal, R.; Chebolu,
R.; Chakraborti, A. K. Green Chem. 2012, 14, 3329; (h) Chakraborti, A. K.; Ru-
drawar, S.; Jadhav, K. B.; Kaur, G.; Chankeshwara, S. V. Green Chem. 2007, 9,
1335; (i) Chankeshwara, S. V.; Chakraborti, A. K. Org. Lett. 2006, 3259; (j) Khatik,
G. L.; Kumar, R.; Chakraborti, A. K. Org. Lett. 2006, 2433; (k) Azizi, N.; Saidi, M. R.
Org. Lett. 2005, 7, 3649; (l) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.;
Kolb, H. C.; Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275.
5. (a) Kumar, D.; Seth, K.; Kommi, D. N.; Bhagat, S.; Chakraborti, A. K. RSC Adv.
2013, 3, 15157; (b) Parikh, N.; Kumar, D.; Roy, S. R.; Chakraborti, A. K. Chem.
Commun. 2011, 1797; (c) Sharma, G.; Kumar, R.; Chakraborti, A. K. Tetrahedron
Lett. 2008, 49, 4269; (d) Manabe, K.; Sun, X. M.; Kobayashi, J. S. J. Am. Chem. Soc.
2001, 123, 10101; (e) Breslow, R. Acc. Chem. Res. 1991, 24, 159.
4.33. tert-Butyl indoline-1-carboxylate (12)30
Following the general procedure, using Pd2(allyl)2Cl2 (4.4 mg,
0.011 mmol), cBridp (15.5 mg, 0.044 mmol), tert-butyl N-[2-(2-
bromophenyl)ethyl]carbamate (300 mg, 1.0 mmol), and NaO-t-Bu
(144 mg, 1.5 mmol) in aqueous TPGS-750M (2%, 1.0 mL), followed
by purification using column chromatography (SiO2) and EtOAc/n-
heptane (1/9), yielded 12 as a yellow oil (185 mg, 84%); HPLC rt
4.41; 1H NMR (300 MHz, CDCl3)
3.94 (2H, t, J¼8.7 Hz), 6.92 (2H, t, J¼7.6 Hz), 7.10e7.9 (2H, m),
7.75e7.84 (1H, br s); 13C NMR (100 MHz, CDCl3)
27.3, 28.5, 47.6,
d
1.57 (9H, s), 3.09 (2H, t, J¼8.7 Hz),
6. (a) Lipshutz, B. H.; Ghoraib, S. Aldrichimica Acta 2008, 41, 59; (b) Lipshutz, B. H.;
Ghoraib, S. Aldrichimica Acta 2012, 45, 3.
7. (a) Lipshutz, B. H.; Abela, A. R. Org. Lett. 2008, 10, 5329; (b) Lipshutz, B. H.;
Petersen, T. B.; Abela, A. R. Org. Lett. 2008, 10, 1333; (c) Nishikata, T.; Lipshutz, B.
H. J. Am. Chem. Soc. 2009, 131, 12103; (d) Isley, N. A.; Gallou, F.; Lipshutz, B. H. J.
Am. Chem. Soc. 2013, 135, 17707.
d
80.4 (br), 114.7, 122.1, 124.7 (br), 127.4, 130.9 (br), 143.0 (br), 152.6.
Acknowledgements
8. (a) Lipshutz, B. H.; Taft, B. R. Org. Lett. 2008, 10, 1329; (b) Lipshutz, B. H.; Ghorai,
S.; Leong, W. W. Y.; Benjamin, R.; Krogstadt, D. V. J. Org. Chem. 2011, 76, 5061.
9. Lipshutz, B. H.; Ghorai, S.; Abela, A. R.; Moser, R.; Nishikata, T.; Duplais, C.;
Krasovskiy, A.; Gaston, R. D.; Gadwood, R. J. Org. Chem. 2011, 76, 4379.
10. (a) Lipshutz, B. H.; Chung, D. W.; Rich, B. Org. Lett. 2008, 10, 3793.
11. Lipshutz, B. H.; Chung, D. W.; Rich, B. Adv. Synth. Catal. 2009, 351, 1717 Il faut
inverser 10 et 11.
This project was supported by the University of Strasbourg
(UdS), and the National Center of Scientific Research (CNRS).
Supplementary data
1H and 13C NMR charts of the reported compounds, solubility
graphs. Supplementary data associated with this article can be
found in the online version, at http://dx.doi.org/10.1016/
j.tet.2014.03.083.
12. Isley, N. A.; Dobarco, S.; Lipshutz, B. H. Green Chem. 2014, 16, 1480.
13. Calculated by chemaxonÒ
.
14. Kevin, W.; Anderson, K. W.; Tundel, R. E.; Ikawa, T. R.; Altman, A.; Buchwald, S.
L. Angew. Chem., Int. Ed. 2006, 45, 6523.
15. (a) Salome, C.; Schmitt, M.; Bourguignon, J. J. Tetrahedron Lett. 2009, 50, 3798;
(b) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101.
16. Experimental results: see Supplementary data.
References and notes
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