C-N Coupling of nitrogen nucleophiles with aryl and heteroaryl bromides using aminoarenethiolato-copper(I) (pre-)catalyst

Article abstract of DOI:10.1016/j.tet.2010.03.040

The activity of a library of 2-aminoarenethiolato-copper(I) (CuSAr) (pre-)catalyst was explored in the arylation reaction of amines and N-containing heterocycles with aryl and heteroaryl bromides, respectively. These CuSAr pre-catalysts are thermally stable, are soluble in common organic solvents and show good catalytic activities in these N-arylation reactions with catalyst loadings amounting to 2.5 mol %. The targeted C-N coupling products were obtained in moderate to good yields (40-97%) for a variety of substrates.

Full text of DOI:10.1016/j.tet.2010.03.040

Tetrahedron 66 (2010) 3478–3484
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Tetrahedron
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C–N Coupling of nitrogen nucleophiles with aryl and heteroaryl bromides using
aminoarenethiolato–copper(I) (pre-)catalyst
,
Elena Sperotto a, Gerard P.M. van Klink a, Johannes G. de Vries b, Gerard van Koten a
*
a Chemical Biology & Organic Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
b DSM Research, Life Science, Advanced Synthesis and Catalysis, P.O. Box 18, 6160 MD Geleen, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
The activity of a library of 2-aminoarenethiolato–copper(I) (CuSAr) (pre-)catalyst was explored in the
arylation reaction of amines and N-containing heterocycles with aryl and heteroaryl bromides,
respectively. These CuSAr pre-catalysts are thermally stable, are soluble in common organic solvents and
show good catalytic activities in these N-arylation reactions with catalyst loadings amounting to
2.5 mol %. The targeted C–N coupling products were obtained in moderate to good yields (40–97%) for
a variety of substrates.
Received 21 October 2009
Received in revised form 17 February 2010
Accepted 8 March 2010
Available online 17 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
maintain its importance in organic synthetic chemistry and it can
now also be utilized for the synthesis of N-arylated hetero-
Functionalized aromatic and heteroaromatic amines are im-
portant and widely employed building blocks for the synthesis of
pharmaceutical and natural products.1 Therefore, the development
of a mild and efficient method for the preparation of N-containing
aromatic compounds has received increasing interest. Recently,
a large number of elegant Pd-catalyzed C–N coupling reactions
have been reported,2 but the scope of these methods scarcely
include the arylation of, for example, N–H heterocycles.3 Besides
the use of palladium and copper (vide infra), also other metals have
recently been explored as catalyst for C–N bond forming reactions,
cycles.9,10 New approaches involving the use of milder reaction
conditions than the classical copper-mediated Ullmann coupling
employ catalytic amounts of copper and stoichiometric use of
transmetallating agents, such as aryllead triacetates,11 arylbor-
onic acids,12 triarylbismuths,13 hypervalent aryl siloxanes,14 and
arylstannanes.15 However, the application of the latter reagents
also represents a major shortcoming of these methods as they are
toxic and/or unstable reagents while their preparation usually
requires multistep synthesis. Thus, the use of readily available
aryl halides as the electrophilic coupling partner could overcome
these issues.
6
e.g., catalysts based on cadmium,4 ruthenium,5 nickel, or iron.7
Traditionally, the C–N coupling reaction is limited to aryl halides
bearing strongly electron-withdrawing substituents.8 Alternately,
the classical copper-mediated Ullmann coupling is a commonly
applied method for the coupling of a primary amine functionality
with an aromatic halide.9 This reaction, however has the disad-
vantage that it requires harsh reaction conditions, such as high
temperatures and the need of a stoichiometric amount of copper
catalyst. These facts and the moderate yields obtained have
undeniably prevented the Ullmann reaction from becoming
a broadly applied method.
Whilst some examples of ligand-free conditions are known,16 the
addition of mono- and bidentate ligands, such as phosphines,17
diamines,18 -diimines,19 diols and diketones,20 amino alcohols,21
a
amino acids,22 salicylamide derivatives,23 phosphoramidites,24
phosphine oxides,25 phosphinidenes26 and phenantroline
derivatives27 have shown to significantly increase the yield and
generality of the C–N coupling reaction. Through the use of these
additives/ligands the solubility and stability of the copper species
are improved, allowing the use of catalytic amounts of copper,
milder reaction conditions and wider reaction scope.
In spite of its limitations the Ullmann-type copper-catalyzed
coupling of aryl halides with amines is still recognized as an
attractive and, when compare to alternative metal protocols,
economic method providing easy access to aryl amine building
blocks. Recent developments have allowed this reaction to
An alternative to the addition of an external ligand for the in situ
formation of the complex is offered by modification of the catalyst,
in order to accomplish enhanced catalyst solubility, stability and
a well-defined structure. Recently, several single-component pre-
catalysts have been reported to be effective in catalytic aminations.
Examples of chemically well-defined, stable and soluble copper(I)
complexes have been reported by Snieckus et al.28 and Ven-
kataraman and Gujadhur,29 which have shown good activities in
catalyzed C–N and C–O bond formation.
* Corresponding author. Tel. þ31 30 2533120; fax: þ31 30 252 3615; e-mail
address: g.vankoten@uu.nl.
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.040

E. Sperotto et al. / Tetrahedron 66 (2010) 3478–3484
3479
Prompted by our interest in carbon–carbon30 and carbon–het-
eroatom coupling reactions,16a,31 and the availability of a class of
well-defined copper(I) complexes, which recently has successfully
been tested, as an alternative to the commonly used insoluble
copper halides, in C–C and C–O coupling reactions, we extended
our studies to the C–N bond formation reaction. Herein we reported
a library of 2-aminoarenethiolato–copper(I) complexes and its
application in the N-arylation reaction of diverse amines and N-
containing heterocycles with aryl and heteroaryl bromides, as an
extension of our preliminary work.31
The 2-[(dimethylamino)methyl]benzenethiolato-copper(I) (1c,
Scheme 1) pre-catalyst was used in the optimization of the reaction
conditions. Blank reactions in the absence of 1c did not give any
product showing that its use was essential for obtaining the C–N
coupling product.
The screened reaction conditions31 revealed that the optimum
for product formation is at a reaction temperature of 160 ꢀC while
using N-methyl pyrrolidinone (NMP) as solvent. When dimethyl
sulfoxide (DMSO) was used, slightly lower yields were obtained,
while other solvents were tested without success. Potassium
carbonate (1.1 equiv) appeared to be the preferred base for the
coupling reaction whereas commonly used organic and inorganic
bases (e.g., caesium carbonate, potassium tert-butoxide, potassium
phosphate, triethylamine, 2,6-luitidine) did not give satisfactory
results. The amount of catalyst was optimized to 2.5 mol % with
respect to the arylating agent, which is quite low in comparison to
other protocols reported in literature, where the amount of copper
catalysts are in the range of 5–10 mol %.17–27
Subsequently, different phenyl halides were tested under the
developed reaction conditions. It clearly appeared from the results
that bromobenzene was the best coupling partner since reactions
with fluoro-, chloro- and iodobenzene hardly showed any conver-
sion to the C–N coupling product (Table 1).
The importance of using the aminoarenethiolato–copper(I)
complex was highlighted by the comparison of its reactivity with
those of simple ligand-free copper(I) salts. As previously repor-
ted16a the model reaction performed with only CuBr afforded
2. Results
A library of 2-aminoarenethiolato–copper(I) complexes (CuSAr,
Scheme 1), which exhibit good thermal stability and solubility in
common organic solvents, was achieved through a simple four-step
synthesis32 with overall yields of 67–85%.32c The different amines
of the monoanionic, S,N-coordinating 2-aminoarenethiolato ligand
were chosen to test the influence of the basicity and the steric
hindrance of the amino arm of the S,N-ligand on the catalyst
activity. The aryl ring could also be easily changed to the naphthyl
ring, in order to check a possible effect of the backbone connecting
the S and N donor atom sites. In addition, the trimethylsilyl and
tert-butyl groups were introduced on the aromatic backbone, to
possibly modify the solubility properties of the complexes in or-
ganic solvents.
Scheme 1. Library of 2-aminoarenethiolato–copper(I) complexes used in this study.
The prepared library of copper pre-catalysts was at first tested
in a model reaction, involving the N-arylation of benzylamine with
bromobenzene to give N-benzyl-aniline (Scheme 2).
Table 1
Effect of the nature of the aryl halide on the arylation of benzylamine
Haloarene
Amine
Yield%
Fluorobenzene
Chlorobenzene
Bromobenzene
Iodobenzene
Benzylamine
Benzylamine
Benzylamine
Benzylamine
0
1
61
9
Reaction conditions: aryl halide (5 mmol), amine (6.5 mmol), K2CO3 (5.5 mmol),
NMP (1 mL), complex 1 (0.125 mmol), 160 ꢀC, 16 h.
Scheme 2. Coupling reaction of bromobenzene with benzylamine.

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E. Sperotto et al. / Tetrahedron 66 (2010) 3478–3484
Figure 1. Screening of the CuSAr pre-catalyst library for N-arylation of benzylamine
with bromobenzene. Reaction conditions: bromobenzene (5 mmol), benzylamine
(6.5 mmol), K2CO3 (5.5 mmol), NMP (1 mL), Cu(I)-complex (0.125 mmol), 160 ꢀC, 16 h.
Figure 2. Screening of the CuSAr library for N-arylation of imidazole with bromo-
benzene. Reaction conditions: bromobenzene (5 mmol), imidazole (6.5 mmol), K2CO3
(5.5 mmol), NMP (1 mL), Cu(I)-complex (0.125 mmol), 160 ꢀC, 16 h.
pre-catalysts 9 showed a different activity that its parent 1c giving
a lower yield of 73%. Replacement of the NMe2 group in 9c by a more
basic one, 10c and 11c, respectively caused a slight improvement (cf.
3c and 4c, 79 and 86% yield, respectively). The last set, complexes
12c–14c bearing a TMS-group on the ring, reached slightly lower
results then complexes 1c and 5c (96, 77 and 88%).
In view of these results, diverse substrates were tested to
investigate the scope of the C–N coupling reaction using 1c as
pre-catalyst because of its simple preparation and good catalytic
performances (Table 2).
N-benzylaniline in 15% yield, whereas under the same reaction
conditions, the coupling with the CuSAr complex 1c reached a yield
of 61%. The positive influence of the aminoarenethiolato ligand
(vide infra) on the catalytic reaction is found to be a common
characteristic in the synthesised library (Fig. 1). Exception holds for
catalysts 2c–4c, 9c and 12c, which gave low yields of 25–41% of
coupling product. The best performances were given by complexes
1c, 5c, 10c, 13c, which reached 58–72% of N-benzylaniline.
The first four pre-catalysts have the unsubstituted arene-
backbone as a common structural element, while the amino-arm
was different (Scheme 1). Complex 1c gave a moderate yield of 58%,
whereas increasing the basicity of the nitrogen atom led to a signifi-
cant decrease of yield in product (see for 2c–4c, yields of 32–25%).
A parallel set of pre-catalyst bearing the naphthyl-backbone gave
higher yields (for 5c–8c 50–66%); with complex 5c the best outcome
of this set was obtained. It is obvious that introduction of a further
substituent (in 9c–11c a tert-butyl substituent wasintroduced inmeta
position) influenced considerably the activity of the pre-catalyst.
Complex 9c gave lower result with respect to complex 1c (41 vs
58%), while complexes 10c and 11c reached yields of 72 and 56%,
respectively, which is a clear improvement on the performances of
complexes 3c and 4c. The latter set of pre-catalyst corresponds to 1c
and 5c in which a Me3Si-(TMS) substituent was introduced in
different positions on the aromatic ring (Scheme 1). With the TMS
group in meta-position the coupling product was obtained in lower
amount, forCuSArwithbothareneand naphthyl backbones (complex
12c, yield 40% vs 58% with 1c; complex 14c, yield 45% vs 66% with 5c).
However, the 5-TMS-group induced a positive effect on the catalytic
reaction, (13c, yield 69% vs 1c, yield 58%).
In the first series of reactions, bromobenzene was the arylating
partner, while the nucleophile was changed among primary and
secondary heterocyclic amines. Besides the model reaction with
benzylamine, 1,3-diaminopropane was tested, giving only a mod-
erate yield in diarylated product (Table 2, entry 2). The heterocyclic
amine imidazole was employed in the reaction with excellent result
of 97% yield (entry 3), whereas the substituted 4-methyl imidazole
and 4-phenyl imidazole lowered the yield in product to 59 and 54%,
respectively (entries 4 and 5), probably due to their higher steric
hindrance if compared to unsubstituted imidazole. The reaction
with pyrazole (entry 6) led to a 78% yield, slightly lower than re-
action with imidazole. Moderate yields of the corresponding cou-
pling products were obtained with two other nucleophiles, 2-
pyrrolidinone and indole, (entries 7–8, 40–48% yield, respectively).
In another series of reactions, the arylating agent was changed
to various bromopyridines and coupled with different nucleophiles.
Benzylamine and 4-methylbenzylamine showed good reactivity
towards the coupling with 2-bromopyridine (entries 9 and 10,
yields 70 and 90%, respectively). The same holds for imidazole used
as nucleophile, in the coupling with both 2- and 3-bromopyridines
(entries 11 and 12), which resulted for both reactions in a yield of
89%. An example of double arylation on 2,6-dibromopyridine was
performed with imidazole and the coupling product was achieved
in yield of 60%, a noteworthy result if one considers that no traces of
monoarylated product were found. Another interesting example
is the C–N coupling between 5-bromo-2-aminopyridine and im-
idazole. The arylation on imidazole occurs selectively and with
good yield (entry 14, yield 80%), bearing the NH2– functionality and
leaving it intact, with no need of group protection. Subsequently,
two different secondary amines, morpholine and piperidine, were
coupled to 2-bromopyridine, obtaining good results of the desired
products (entries 15 and 16, yields 91 and 71%). A catalytic test with
3-bromoquinoline is shown in entry 17, which reacted with imid-
azole affording the C–N coupling product in a moderate yield of
53%. Eventually, 2-bromothiazole was employed as heteroaryl ha-
lide and the arylated imidazole was obtained in modest yield.
The library of the CuSAr (pre-)catalysts was also screened for the
arylation of the heterocyclic amine imidazole, in order to evaluate
the effect of the nature of the catalyst on the C–N coupling reaction
with a different nucleophile (Fig. 2).
Asreported inanearliercommunication using a smaller setofpre-
catalysts,31 the C–N coupling between bromobenzene and imidazole
gave higher yields of the C–N coupling product compared to the
modelreactioninvolvingbenzylamine. Throughoutthewholelibrary,
good to excellent yields were obtained (72–97%). However, some
differences in reactivity between the various complexes could be
identified. Complex 1c led to almost quantitative yield in N-benzyli-
midazole (97%), while the complexes, bearing a different amino
group, again showed lower reactivity (complexes 2c–4c, yield
72–76%). Withthe secondset, i.e., complexes5c–8chavinga naphthyl
backbone, very good yields were obtained (78–97%) without sub-
stantial differences in reactivity among them. The t-Bu-substituted

E. Sperotto et al. / Tetrahedron 66 (2010) 3478–3484
3481
Table 2
situ formation of this modified ligand PhSAr for the copper centre,
positively influences its catalytic activity, i.e., the catalyst is
distinctly more active than CuBr itself33 and could act as a ligand
and induce a particular mechanistic pathway.
Amination of aryl and heteroaryl bromides catalyzed by aminoarenethiolato–
copper(I) complex 1c
Entry
ArX
Nucleophile
Product
Yield (%)
(isolated yield)
The results show that the 2-aminoarenethiolato–copper(I)
complexes of the library (Scheme 1) are all active as pre-catalysts in
the N-arylation of different amines, with a low loading of the
copper complex (2.5 mol %). The first characteristic of this library is
the decrease of the activity of the pre-catalyst with an increase of
the basicity of the amino arm of the complexes (see complexes
1c–4c in Fig. 1). This observation could be related to the above
mentioned conversion of the pre-catalyst CuSAr into PhSAr (and
CuBr). In this transformation a higher basicity of the amino donor,
which stabilizes the CuSAr species makes this first step, leading to
the actual active catalytic species, more difficult. In line with these
observations, the presence of the naphthalene backbone instead of
a phenyl one has a positive effect on the catalytic activity, probably
because it increases the nucleophilicity of the SAr-anion and
favours in this way the initial formation of PhSAr via the S-arylation
process. In both library screenings, the introduction of tert-butyl- or
TMS-group on the aryl ring resulted in an improvement of the
product yield. This effect can be attributed to an increased solubility
of the copper complexes (and the corresponding CuBr/PhSAr
complexes) in organic media when they bear a tert-butyl- or TMS-
substituent on the aryl ring. However, an additional observation
can be made on complexes 12c–14c, bearing a TMS-group, when
they are applied for the N-arylation of benzylamine (see Fig. 1). In
the case of 12c and 14c, the TMS-group is in ortho position to the
amine substituent and it can cause a lowering of the conforma-
tional flexibility of the amine substituent, i.e., buttressing effect,34
which is translated in a negative effect on the activity (to com-
pare to complex 13c). This result is therefore an indication that the
PhSAr-ligand is involved in the catalytic cycle and has an influence
on the rate determining step.
Aryl halides are the arylating agents frequently employed for
metal mediated C–X coupling reactions, and the commonly found
order of reactivity parallels the leaving group ability of the halide
ions (Iꢁ>Brꢁ>Clꢁ).9 However, in the presently developed protocol
wefind thatit isthe aryl bromidethat hasa higherreactivitythan the
corresponding iodide (and chloride). This could be possibly
explained by the fact the bromide ion would allow a change in
oxidation state of copper, permitting a feasible catalytic cycle, while
iodide ions would stabilize the copper atom in its þ1 oxidation state,
rendering the species stable and insoluble as CuI salt. This feature
indicates that the use of CuSAr, i.e., the PhSAr/CuBr, catalyst induces
a singular change in the mechanistic pathway of the C–N coupling
pathway, incomparisontopreviouslyreported couplingprocedures.
As presented in Table 2, moderate to good yields of coupling
products were obtained when bromobenzene was coupled to
primary amines, whereas also in this work (cf. Refs. 16,17) coupling
of secondary cyclic amines, like morpholine or piperidine appeared
to be impossible (results not shown here). Imidazole showed to be
a better nucleophile, but its reactivity decreased when the ring is
bearing a substituent on the fourth position (entries 4 and 5).
The relative reactivity for the azole series in the studied
N-arylation with bromobenzene appeared to be the following:
1
2
3
4
5
6
7
61 (57)
43a
Br
97
Br
HN
N
N
59
N
N
N
Br
Br
Br
N
N
54
HN
N
N
78 (75)
40
HN
O
N
N
H
O
Br
Br
N
8
48
70
N
H
9
N
10
11
12
13
14
15
16
90
89
89 (85)
60b
80
91 (87)
71 (68)
17
18
53
51(47)
Reaction conditions: aryl halide (5 mmol), amine (6.5 mmol), K2CO3 (5.5 mmol),
NMP (1 mL), complex 1 (0.125 mmol), 160 ꢀC, 16 h.
a
Bromobenzene (10 mmol).
b
Imidazole (13 mmol). Yield was calculated by GC measurements, and isolated
yields are reported in brackets.
3. Discussion
The CuSAr-catalytic system presented here allowed the forma-
tion of the C–N coupling product through a clean and selective
reaction. In the product solutions commonly found side pro-
ducts19a,27 like biaryl compounds or hydrodehalogenated arene
byproducts have not been detected, while the unreacted starting
material was found unaltered at the end of the reaction. However,
limitations of the protocol involve the rather high reaction tem-
perature and long reaction time, together with some restrictions on
the substrate side.
It is important to mention the fact that the CuSAr pre-catalyst is
converted, in the first stages of the reaction, into neutral 2-
[(dimethylamino)methyl]phenyl phenyl sulfide (PhSAr), through
S-arylation of the SAr-anion with bromobenzene.33 However, the in
This order of reactivity appears to be best related to the acidity
of the nucleophiles and therefore to the ease of deprotonation of
the azole by the base, since the pKHA values follow the same relative
trend (pKHA in DMSO: imidazole¼18.6; pyrazole¼19.8;
indole¼20.95; 2-pyrrolidinone¼24.2).35,19a For the first three

3482
E. Sperotto et al. / Tetrahedron 66 (2010) 3478–3484
azoles of the series, a linear relationship (R2¼0.9835) is found be-
tween their reactivity (expressed in yield % after 16 h) and their
acidity (expressed in pKHA values); after that, a further decrease of
acidity does not bring an additional decrease in reactivity but this
stays on the same level.
The reactivity of primary and heterocyclic amines is clearly
different as can be seen from the presented results. This most
probably reflects the fact that these reactions involve different
mechanisms. For the C–N bond formation with primary amines we
recently proposed a mechanistic pathway through electron transfer
and changes between þ1 and þ2 oxidation states of the copper
centre.31,33 However, in the case of heterocyclic amines it is more
filtered. The solvent of the filtrate was removed under vacuum. The
resulting residue was purified by chromatography on silica (hexane/
ethyl acetate 15:5) to obtain the pure product as a colourless oil.
Product N-benzyl-aniline:31 GC yield: 61%; isolated yield: 57%.
1H NMR (399.94 MHz, CDCl3):
d
4.33 (s, 2H, CH2), 6.74 (d. 2H, CH
Ar), 6.79 (t, 1H, CH Ar), 7.19 (t, 2H, CH Ar), 7.27 (m, 1H, CH Ar), 7.33–
7.38 (m, 4H, CH Ar). 13C NMR (100.576 MHz, CDCl3):
48.8 (CH2),
d
113.4, 118.2, 127.5, 127.9, 128.9, 129.5, 139.4, 148.0 (Ar). M/S (EI) m/z
(relative intensity): 184 (30), 183 (100), 106 (30), 91 (60).
Examples for isolation of known synthesized products (see
Table 2).
1-Phenyl-pyrazole: isolated as pale yellow oil.6 1H NMR
likely to presume
a
different catalytic cycle, most probably
(399.94 MHz, CDCl3):
(m, 2H, Ar), 7.65–7.70 (m, 3H, Ar), 7.87 (s, 1H, NCH). 13C NMR
(100.576 MHz, CDCl3): 107.8,119.4,126.6, 126.9, 129.6, 140.4,141.3.
d 6.41 (s, 1H, CH), 7.21 (s, 1H, NCH), 7.24–7.41
involving a s-bond metathesis type of mechanism, through a four-
centred intermediate.36,37,18b
d
The change of arylating reagent from aryl bromides to bromo-
pyridines brought about a considerable improvement of the yield in
product (see entry 9 compared to 1), which parallels the fact that
pyridines are activated substrates. Indeed bromo-pyridines couple
with a variety of amines, now also including secondary amines like
morpholine and piperidine (entries 15 and 16). Furthermore,
2-bromo quinoline showed to be less reactive than 2-bromo pyri-
dine when coupled to imidazole (entries 12 and 17).
In summary, the preparation of a new library of 2-amino-
arenethiolato–copper(I) complexes was described and tested in the
C–N bond formation reaction between (hetero)aryl bromides and
amines and N-containing heterocycles. Their versatility allow their
employment in the catalysis of a variety of C–X coupling reactions in
a cascade fashion, a subject, which is currently under investigation.
M/S (EI) m/z (relative intensity): 145 (35),144 (100),117 (40), 77 (38).
2-Pyridinyl-piperidine: isolated as pale yellow oil.38 1H NMR
(399.94 MHz, CDCl3):
d 1.60 (s, 6H, CH2), 3.48 (s, 4H, NCH2), 6.49–
6.52 (m, 1H, CHpyr), 6.58–6.61 (m, 1H, CHpyr), 7.38–7.41 (m, 1H,
CHpyr), 8.13–8.15 (1H, CHpyr). 13C NMR (100.576 MHz, CDCl3):
d
24.9, 25.7, 46.5 (Cpiperidine), 107.3, 112.6, 137.5, 148.1, 159.9
(Cpyridine). M/S (EI) m/z (relative intensity): 163 (20), 162 (100),
133 (38), 119 (55), 107 (47), 78 (70).
3-Imidazolinyl-pyridine: isolated as pale yellow oil.39 1H NMR
(399.94 MHz, CDCl3):
d 7.26–7.40 (m, 2H, NCH2), 7.42–7.42 (m, 1H,
CHpyridine), 7.70–7.73(m,1H, CHpyridine), 7.89(br s,1H, NCHN), 8.62
(s, 1H, NCHpyridine), 8.73 (s, 1H, NCHpyridine). M/S (EI) m/z (relative
intensity): 145 (100), 118 (37), 91 (32), 78 (22), 64 (15), 51 (38).
4-Pyperidinyl-morpholine: isolated as yellow oil.24 1H NMR
(399.94 MHz, CDCl3):
d
3.43–3.46 (t, J¼4.8 Hz, 4H, NCH2), 3.76–3.77
4. Experimental
(t, J¼4.4 Hz, 4H, OCH2), 6.57–6.62 (m, 2H, CHpyridine), 7.72–7.47
(m, 1H, CHpyridine), 8.15–8.17 (m, 1H, CHpyridine). 13C NMR
4.1. General remarks
(100.576 MHz, CDCl3): d 45.8 (NCH2), 66.9 (OCH2), 107.1, 114.0, 137.7,
148.2, 159.8 (Cpyridine). M/S (EI) m/z (relative intensity): 164 (447),
163 (62), 133 (59), 119 (35), 78 (100).
All reactions were performed using Schlenk techniques under
an inert atmosphere unless stated otherwise. Chemicals were
purchased from Across or Aldrich. Solvents used in the catalyst
syntheses were carefully dried and distilled prior to use. Solvents
used for catalytic tests were used as received. Chlorotrimethylsilane
was distilled and passed through basic alumina prior to use. 1H and
13C{1H} NMR spectra were recorded on a Varian Inova 300 MHz
spectrometer at 298 K unless stated otherwise. The chemicals shifts
2-Imidazolyl-thiazole: isolated as yellow oil.16d 1H NMR
(399.94 MHz, CDCl3):
7.445–7.453 (m, 1H, CH), 8.073 (s, 1H, NCHN). 13C NMR
(100.576 MHz, CDCl3): 115.9, 117.9, 131.0, 135.7, 140.8, 157.7. M/S
d 7.040–7.062 (m, 2H, CH), 7.393 (s, 1H, CH),
d
(EI) m/z (relative intensity): 153 (28), 152 (50), 124 (100), 97 (25), 79
(35), 57 (65).
Diethylbenzylamine 2a. Diethylamine (13.0 mL, 0.124 mol) was
added at 0 ꢀC to a solution of benzyl bromide (8.42 g, 49.2 mmol) in
dichloromethane. The mixture was allowed to reach room tem-
perature and was stirred overnight. All volatiles were removed in
vacuo and NaOH (100 mL of a 4 M aqueous solution) was added.
The mixture was extracted with hexane (3ꢂ80 mL). The aqueous
layer was made strongly basic by adding solid sodium hydroxide
and the resulting solution was extracted with diethyl ether
(3ꢂ80 mL). The combined organic layer was dried over magnesium
sulfate, filtered and solvents were removed in vacuo affording the
product as yellow oil (6.49 g, 39.8 mmol, 81%). 1H NMR (300.1 MHz,
(d) are presented in ppm (per million) referenced to residual sol-
vent resonances. Gas chromatography analyses were performed on
a Perkin–Elmer Clarus 500 GC equipped with an Alltech EC-5 col-
umn (30 mꢂ0.32 mm IDꢂ0.25
mm). GC–MS measurements were
performed using an HTÔ-50HT (30 mꢂ0.25 mm) column, and
using a Perkin Elmer turbomass spectrometer with an electro
ionization detector. Elemental analyses were performed by Kolbe,
Mikroanalytisches Laboratorium, Mu¨hlheim/Ruhr, Germany.
4.2. General procedure for catalyst testing
CD2Cl2):
d 7.36–7.32 (m, 5H, ArH), 3.59 (s, 2H, CH2N), 2.55 (q, 4H,
Preparation of N-benzyl-aniline. The catalytic tests were
performed using standard Schlenk techniques. Firstly the Schlenk
tube was charged with the solid base K2CO3 (5.5 mmol, 0.76 g).
3J¼7.2 Hz, N(CH2CH3)2), 1.07 (t, 6H, 3J¼7.2 Hz, N(CH2CH3)2).
4.2.1. {[2-(Diethylamino)methyl]thiophenyl}trimethyl-silane 2b. Proce-
Subsequently the liquid reagents (bromobenzene: 5 mmol, 527
m
L;
dure reported in Ref. 32c.
benzylamine: 6.5 mmol, 711 L) and solvent (1 mL) were added and
m
finally the (solid) aminoarenethiolat–copper(I) (2.5 mol %, 0.0288 g)
pre-catalyst. The filled Schlenk tube was flushed with nitrogen and
warmed at 160 ꢀC (in an oil bath) during 16 h. After that, the reaction
mixture was diluted with dichloromethane (5 mL) while dihexyl
4.2.2. [2-(Diethylamino)methyl]thiophenolato-copper(I)
2c. Procedure reported in Ref. 32c.
4.2.3. (Pyrrolidinylmethyl)benzene 3a. Same procedure as 2a
starting from benzyl bromide (5.05 g, 29.5 mmol) and pyrrolidine
(8.00 mL, 95.9 mmol), affording the initially impure product, which
was purified through column chromatography (SiO2, eluent hex-
ane/Et2O 1:1) as a yellow oil (3.59 g, 22.6 mmol, 75%). 1H NMR
ether (100 mL, 0.42 mmol) was added as standard.
For preparative runs, the reaction mixture was partitioned
between CH2Cl2 and NaHCO3 aq (1 N). The organic phase was washed
4–5 times with NaHCO3 aq to remove NMP, dried over MgSO4 and

E. Sperotto et al. / Tetrahedron 66 (2010) 3478–3484
3483
(300.1 MHz, CD2Cl2):
d
7.34–7.29 (m, 3H, ArH), 7.27–7.24 (m, 2H,
d 140.5, 136.2, 133.6, 133.5, 130.7, 129.0, 127.4, 136.7, 126.5 (Naph-
ArH), 3.63 (s, 2H, CH2N), 2.52 (m, 4H, N(CH2)2), 1.80 (m, 4H, (CH2)2).
tylC), 63.33 (CH2N), 46.04 (N(CH3)2), 1.4 (SSi(CH3)).
4.2.4. {[2-(Pyrrolidinyl)methyl]thiophenyl}trimethyl-silane 3b. Proce-
dure reported in Ref. 1, starting from 3a (3.61 g, 22.4 mmol) in hex-
ane, affording the product as a yellow oil (5.12 g, 21.9 mmol, 97%). 1H
4.2.11. [2-(Dimethylamino)methyl]thionaphtholato-copper(I) 5c. Proce-
dure reported in Ref. 1, starting from 5b (3.70 g, 12.78 mmol) and
CuCl (1.20 g, 12.16 mmol), affording the product as a yellowish
powder (2.28 g, 8.14 mmol, 67%). 1H NMR (300.105 MHz, C6D6,
NMR (300.1 MHz, C6D6):
d
7.62 (d, 1H, 3J¼7.2 Hz, ArH), 7.47 (d, 1H,
3J¼7.5 Hz, ArH), 7.07 (m, 1H, ArH), 6.9 (m, 1H, ArH), 3.93 (s, 2H,
358 K):
d
8.05 (s, 1H, ArH), 7.73 (d, 1H, 3J¼7.8 Hz, ArH), 7.62 (d, 1H,
CH2N), 2.46 (m, 4H, N(CH2)2), 1.56 (m, 2H, (CH2)2), 0.13 (s, 9H,
3J¼7.8 Hz, ArH), 7.48 (s, 1H, ArH), 7.40–7.27 (m, 2H, ArH), 3.87 (br s,
Si(CH3)3). 13C NMR (75.5 MHz, C6D6):
d
139.9, 138.6, 135.8, 132.7,
2H, CH2N), 2.43 (br s, 6H, N(CH3)2). 13C NMR (75.469 MHz, C6D6,
126.1, 123.3 (Aryl C), 65.6 (CH2N), 57.4 (N(CH2)2), 23.6 (–(CH2)2–).
358 K): d 138.6, 134.6, 134.0, 131.8, 131.2, 130.9, 127.6, 126.5, 126.2,
124.8 (NaphtylC), 67.7 (CH2N), 47.5 (N(CH3)2).
4.2.5. [2-(Pyrrolidinyl)methyl]thiophenolato-copper(I) 3c. Procedure
reported in Ref. 1, starting from 3b (5.12 g, 21.9 mmol) and CuCl
(1.96 g,19.8 mmol), affording the product a s a white powder (3.79 g,
4.2.12. 2-(Diethylaminomethyl)naphthalene 6a. Same procedure as
2a starting from 2-(bromomethyl)naphthalene (5.50 g, 24.8 mmol)
and diethylamine (7.00 mL, 67.0 mol), affording the product as or-
ange oil (4.96 g, 23.3 mmol, 93%). 1H NMR (300.1 MHz, CD2Cl2):
14.1 mmol, 75%). 1H NMR (300.1 MHz, C6D6, 358 K):
d 6.97 (m, 1H,
ArH), 6.91 (m, 1H, ArH), 6.8 (m, 1H, ArH), 6.73 (m, 1H, ArH), 3.82 (br,
2H, CH2N), 2.48 (br, 4H, N(CH2)2), 1.53 (br, 2H, (CH2)2). 13C NMR
d 7.82–7.76 (m, 3H, ArH), 7.57 (s, 1H, ArH), 7.47–7.4 (m, 3H, ArH),
(75.5 MHz, C6D6, 358 K):
d
139.7, 136.7, 134.8, 131.5, 124.1, 122.6
3.74 (s, 2H, CH2N), 2.59 (q, 4H, 3J¼7.02 Hz, N(CH2CH3)2), 1.09 (t, 6H,
(Aryl C), 64.3 (CH2N), 57.1 (N(CH2)2), 23.0 (–(CH2)2–). Anal. Calcd for
C11H14NSCu: C, 51.64; H, 5.52; N, 5.47. Found: C, 51.64; H, 5.22;
N, 5.47.
3J¼7.2 Hz, N(CH2CH3)2).
4.2.13. {[2-(Diethyl)methyl]thionaphtyl}trimethyl-silane 6b. Procedure
reported in Ref. 1, starting from 6a (4.07 g, 19.1 mmol) in hexane,
affording the product as an orange oil (5.53 g, 17.4 mmol, 91%). 1H
4.2.6. (Piperidinylmethyl)benzene 4a. Same procedure as 2a starting
from benzyl bromide (5.23 g, 30.6 mmol) and piperidine (10 mL, ex-
cess), affording the initially impure product, which was purified
throughcolumncromatography(SiO2, eluenthexane/Et2O1:1)giving
a yellow oil (5.28 g, 30.1 mmol, 98%). 1H NMR (300.1 MHz, CD2Cl2):
NMR (300.1 MHz, C6D6):
d 8.24 (br, 1H, ArH), 8.04 (br, 1H, ArH), 7.6
(m, 1H, ArH), 7.18–7.11 (m, 3H, ArH), 4.01 (s, 2H, CH2N), 2.53 (q, 4H,
N(CH2CH3)2), 1.01 (t, 6H, 3J¼6.9 Hz, N(CH2CH3)2), 0.15 (s, 9H,
3J¼6.9 Hz, Si(CH3)3). 13C NMR (75.469 MHz, C6D6):
d 139.9, 137.0,
d
7.33 (m, 3H, ArH), 7.29 (m, 2H, ArH), 3.49 (s, 2H, CH2N), 2.40 (t, 4H,
134.2, 133.7, 131.3, 128.0, 126.8, 126.5, 126.3, 125.8 (NaphtylC), 61.06
3J¼5.1 Hz, N(CH2)2), 1.60 (m, 4H, –(CH2)–), 1.46 (m, 2H, –CH2–).
(CH2N), 46.73 (N(CH2CH3)2), 12.69 (N(CH2CH3)2), 1.32 (SSi(CH3)).
4.2.7. {[2-(Piperidinyl)methyl]thiophenyl}trimethyl-silane 4b. Proce-
dure reported in Ref. 1, starting from 4a (1.91 g, 10.9 mmol) in pen-
tane, affording the product as a yellow oil (2.58 g, 10.5 mmol, 96%).
4.2.14. [2-(Diethylamino)methyl]thionaphtolato-copper(I) 6c. Proce-
dure reported in Ref. 1, starting from 6b (5.53 g, 17.4 mmol) and
CuCl (1.38 g, 13.9 mmol), affording the product as an orange pow-
der (3.47 g, 11.3 mmol, 81%). 1H NMR (300.1 MHz, C6D6, 358 K):
1H NMR (300.1 MHz, C6D6):
d
7.63 (d, 1H, 3J¼7.5 Hz, ArH), 7.43 (d, 1H,
3J¼8.1 Hz, ArH), 7.07 (m, 1H, ArH), 6.91 (m, 1H, ArH), 3.73 (s, 2H,
CH2N), 2.36 (t, 4H, 3J¼5.7 Hz, N(CH2)2), 1.44 (m, 4 Hz, –(CH2)–), 1.27
(m, 2H, CH2), 0.13 (s, 9H, SSi(CH3)3). 13C NMR (75.5 MHz, C6D6):
d 7.71 (br, 1H, ArH), 7.52 (br, 1H, ArH), 7.37 (br, 1H, ArH), 7.21 (br, 1H,
ArH), 7.05 (br, 1H, ArH), 6.98 (br, 1H, ArH), 3.82 (br, 2H, CH2N), 2.49
(q, 4H, 3J¼6.5 Hz, N(CH2CH3)2), 0.93 (t, 6H, 3J¼6.5 Hz, N(CH2CH3)2).
d
143.2, 136.7, 132.6, 131.7, 127.4, 126.9 (Aryl C), 62.2 (CH2N), 55.1
13C NMR (75.5 MHz, C6D6, 358 K):
d 137.9, 136.7, 134.5, 133.2, 131.0,
(N(CH2)2), 26.6 (–(CH2)–), 24.9 (–CH2–), 1.3 SSi(CH3)3.
129.6, 125.8, 125.5, 124.3, 1232.8 (Naphthyl C), 61.90 (CH2N), 48.93
(N(CH2CH3)2), 11.73 (N(CH2CH3)2). Anal. Calcd for C15H18NSCu: C,
58.51; H, 5.89; N, 4.55. Found: C, 58.20; H, 5.77; N, 4.50.
4.2.8. [2-(Piperidinyl)methyl]thiophenolato-copper(I) 4c. Procedure
reported in Ref. 1, starting from 4b (2.58 g, 10.5 mmol) and CuCl
(0.93 g, 9.4 mmol), affording the product as a light brown powder
4.2.15. 2-(Pyrrolidinylmethyl)naphthalene 7a. Same procedure as
2a starting from 2-(bromomethyl)naphthalene (6.53 g, 29.5 mmol)
and pyrrolidine (13.0 mL, 0.155 mol), affording the impure product,
which was purified through column chromatography (SiO2, eluent
hexane/methanol/Et3N 100:15:2) as a yellow oil (5.34 g, 25.3 mmol,
(2.01 g, 7.45 mmol, 79%). 1H NMR (300.1 MHz, C6D6, 358 K):
d 7.98
(br, 1H, ArH), 7.11 (br, 1H, ArH), 6.95 (m, 1H, ArH), 6.78 (m, 1H, ArH),
3.82 (br, 1H, CH2N), 2.28 (br, 3H, N(CH2)2), 1.40 (br, 4H, –(CH2)–),
1.06 (br, 2H, CH2). 13C NMR (75.5 MHz, C6D6):
d 142.3, 134.6, 132.8,
130.8, 126.5, 125.8 (Aryl C), 60.2 (CH2N), 57.1 (N(CH2)2), 27.2
(–(CH2)–), 25.0 (–CH2–). Anal. Calcd for C12H16NSCu: C, 53.41; H,
5.98; N, 5.19. Found: C, 53.20; H, 5.91; N, 5.06.
85%). 1H NMR (300.1 MHz, CD2Cl2):
d 7.84–7.77 (m, 4H, ArH), 7.53–
7.44 (m, 3H, ArH), 3.79 (s, 2H, CH2N), 2.59–2.54 (m, 4H, N(CH2)2),
1.84–1.79 (m, 4H, (CH2)2).
4.2.9. 2-(Dimethylamino)methylnaphthalene 5a. Same procedure as
2a starting from 2-bromomethylnaphthalene (5.50 g, 24.87 mmol)
and dimethylamine (50 mL, excess), affording the product as a yellow
oil (3.29 g, 17.76 mmol, 92%). 1H NMR (300.105 MHz, CD2Cl2, 358 K):
4.2.16. {[2-(Pyrrolidinl)methyl]thionaphtyl}trimethyl-silane 7b. Proce-
dure reported in Ref. 1, starting from 7a (5.11 g, 24.2 mmol) in
hexane, affording the product as an yellow oil (6.89 g, 21.8 mmol,
90%). 1H NMR (300.1 MHz, C6D6):
d
8.12 (br, 1H, ArH), 8.04 (br, 1H,
ArH), 7.6 (m, 1H, ArH), 7.18–7.15 (m, 3H, ArH), 4.09 (s, 2H, CH2N),
2.53 (m, 4H, N(CH2)2), 1.59 (m, 4H, (CH2)2), 0.15 (s, 9H, Si(CH3)3). 13
NMR (75.469 MHz, C6D6): 140.2, 138.6, 137.5, 135.3, 133.8, 131.9,
d
7.86–7.82 (m, 3H, ArH), 7.76 (s,1H, ArH), 7.50–7.47 (m, 3H, ArH), 3.60
(s, 2H, CH2N), 2.32 (s, 6H, N(CH3)2).
C
d
4.2.10. {[2-(Dimethyl)methyl]thionaphthyl}trimethyl-silane
5b. Procedure reported in Ref. 1, starting from 5a (3.80 g,
20.50 mmol) in hexane, affording the product as an orange oil
131.1, 127.7, 126.2, 125.1 (Naphthyl C), 67.02 (CH2N), 56.7 (N(CH2)2),
23.8 ((CH2)2), 1.31 (SSi(CH3)).
(5.22 g, 18.03 mmol, 88%). 1H NMR (300.105 MHz, C6D6):
d
8.06 (s,
4.2.17. [2-(Pyrrolidinyl)methyl]thionaphtolato-copper(I) 7c. Proce-
dure reported in Ref. 1, starting from 7b (3.44 g, 10.9 mmol) and
CuCl (0.97 g, 9.80 mmol), affording the product as a yellow powder
1H, ArH), 8.03 (s, 1H, ArH), 7.63–7.59 (m, 1H, ArH), 7.51–7.47 (m, 1H,
ArH), 7.17–7.11 (m, 2H, ArH), 3.83 (s, 2H, CH2N), 2.21 (s, 6H,
N(CH3)2), 0.14 (s, 9H, Si(CH3)3). 13C NMR (75.469 MHz, C6D6):
(2.39 g, 7.84 mmol, 80%). 1H NMR (300.1 MHz, C6D6, 358 K):
d 8.30

3484
E. Sperotto et al. / Tetrahedron 66 (2010) 3478–3484
Taillefer, M.; Xia, N.; Ouali, A. Angew. Chem., Int. Ed. 2007, 46, 934; (h) Cristau, H.-J.;
Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Eur. J. Org. Chem. 2004, 695.
(br, 1H, ArH), 7.7 (m, 2H, ArH), 7.35 (m, 1H, ArH), 7.20 (m, 2H, ArH),
3.88 (br, 2H, CH2N), 2.3 (br, 4H, N(CH2)2), 1.51 (br, 4H, (CH2)2). 13
NMR (75.5 MHz, C6D6, 358 K): 139.8, 135.9, 134.5, 134.3, 133.6,
131.1, 130.1, 127.5, 126.4, 125.4 (Naphthyl C), 65.07 (CH2N), 56.9
(N(CH2)2), 23.1 ((CH2)2). Anal. Calcd for C15H16NSCu: C, 58.89; H,
5.27; N, 4.58. Found: C, 58.94; H, 5.35; N, 4.50.
C
10. (a) Jitchati, R.; Batsanov, A. S.; Bryce, M. R. Tetrahedron 2009, 65, 855; (b)
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d
11. (a) Elliot, G. I.; Konopelski, J. P. Org. Lett. 2000, 2, 3055; (b) Alvarado, L. L.;
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4.2.18. 2-(Piperidinylmethyl)naphthalene 8a. Same procedure as 2a
starting from 2-(bromomethyl)naphthalene (6.50 g, 29.4 mmol)
and piperidine (15.0 mL, 0.151 mol), affording the impure product,
which was purified through column chromatography (SiO2, eluent
hexane/methanol/Et3N 100:15:2) as
a
yellow solid (4.91 g,
7.82–7.78 (m, 3H,
21.8 mmol, 74%). 1H NMR (300.1 MHz, CD2Cl2):
d
ArH), 7.74 (br, 1H, ArH), 7.52–7.43 (3H, ArH), 3.65 (s, 2H, CH2N), 2.46
(m, 4H, N(CH2)-), 1.61 (m, 4H, –(CH2)–), 1.46 (m, 2H, CH2).
4.2.19. {[2-(Piperidinyl)methyl]thionaphtyl}trimethyl-silane 8b. Proce-
dure reported in Ref. 1, starting from 8a (4.91 g, 21.8 mmol) in
hexane, affording the product as a yellow oil (6.80 g, 20.6 mmol,
95%). 1H NMR (300.1 MHz, C6D6):
d 8.16 (br, 1H, ArH), 8.03 (br, 1H,
ArH), 7.6 (m,1H, ArH), 7.20–7.14 (m, 3H, ArH), 3.9 (s, 2H, CH2N), 2.42
(m, 4H, N(CH2)–), 1.50 (m, 4H, –(CH2)–), 1.34 (m, 2H, CH2), 0.15 (s,
9H, Si(CH3)3). 13C NMR (75.5 MHz, C6D6):
d 142.3, 137.8, 136.4, 133.7,
133.2, 132.2, 128.4, 127.5, 126.9, 126.0 (Naphthyl C), 62.5 (CH2N),
54.4 (N(CH2)2), 26.3 (–(CH2)–), 24.7 (CH2), 1.4 (Si(CH3)3).
4.2.20. [2-(Piperidinyl)methyl]thionaphtolato-copper(I) 8c. Proce-
dure reported in Ref. 1, starting from 8b (1.70 g, 5.16 mmol) and
CuCl (0.45 g, 4.54 mmol), affording the product as a yellow powder
(1.13 g, 3.53 mmol, 78%). 1H NMR (300.1 MHz, C6D6, 358 K):
d 8.35
(br, 1H, ArH), 7.57(m, 3H, ArH), 7.30 (m, 3H, ArH), 3.88 (br, 2H,
CH2N), 2.28 (br, 4H, N(CH2)–), 1.33 (br, 4H, –(CH2)–), 0.85 (m, 2H,
CH2). 13C NMR (75.5 MHz, C6D6, 358 K):
d 140.5, 134.6, 134.4, 132.2,
131.0,129.8,128.1,127.4,125.4,125.9 (Naphthyl C), 69.7 (CH2N), 56.9
(N(CH2)2), 24.6 (–(CH2)–), 24.03 (CH2). Anal. Calcd for C16H18NSCu:
C, 60.07; H, 5.67; N, 4.38. Found: C, 60.18; H, 5.79; N, 4.33.
For compounds 9a–c, 10a–c, 11a–c, 12a–c, see Ref. 31.
For compounds 13a–c, 14a–c, see Ref. 30b.
Acknowledgements
We thank the Dutch Ministry of Economic Affairs, NWO/CW,
NRSC-C and Chemspeed Technologies for the financial support
given to the CW/CombiChem programme.
References and notes
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