Selective palladium-catalysed arylation of 2,6-dibromopyridine using N-heterocyclic carbene ligands

Article abstract of DOI:10.1039/c5ra10561g

A selective palladium-catalysed arylation of 2,6-dibromopyridine has been developed by employing N-heterocyclic carbene ligands. Selective mono-arylation was performed in water/acetonitrile solvent system at ambient temperature with catalyst loading of 0.1 mol%. This reaction was also found to proceed smoothly in water although at a slightly elevated temperature of 80 °C. 2,6-Disubstituted and diversely substituted 2,6-pyridines were also obtained in high yields which will be of importance to organic and medicinal chemists.

Full text of DOI:10.1039/c5ra10561g

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DOI: 10.1039/C5RA10561G
A selective palladium-catalysed arylation of dihalopyridines as well as dihaloarenes has been developed
by employing N-heterocyclic carbene ligands. Selective mono-arylation was performed in
water/acetonitrile solvent system at ambient temperature with catalyst loading of 0.1 mol%. This
reaction was also found to proceed smoothly in water although at a slightly elevated temperature of 80
oC. Disubstituted and diversely substituted pyridines were also obtained in high yields which will be of
importance to organic and medicinal chemists.

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ARTICLE
Selective Palladium-Catalysed Arylation of 2,6-Dibromopyridine
Using N-Heterocyclic Carbene Ligands
D. Prajapatia, C. Schulzkeb, M. K. Kindermannb and A. R. Kapdia,*
Received 00th January 20xx,
Accepted 00th January 20xx
A selective palladium-catalysed arylation of 2,6-dibromopyridine has been developed by employing N-heterocyclic carbene
ligands. Selective mono-arylation was performed in water/acetonitrile solvent system at ambient temperature with
catalyst loading of 0.1 mol%. This reaction was also found to proceed smoothly in water although at a slightly elevated
temperature of 80 oC. 2,6-Disubstituted and diversely substituted 2,6-pyridines were also obtained in high yields which will
DOI: 10.1039/x0xx00000x
www.rsc.org/
be
of
importance
to
organic
and
medicinal
chemists.
1. Introduction
Pyridine as a structural motif has found wide applications in a
variety of natural products as well as pharmaceutical intermediates;
Palladiumꢀmediated CꢀC bond forming technologies are among the it has also proved to be one of the most useful building blocks.13
most applied processes in academia and industries.1 From the Polyhalogenated pyridines and their application in synthetic
synthesis of simple biaryls to complex synthetic targets this chemistry has been immense and in the last few years the selective
methodology has been employed successfully.2 This success can be functionalisation of such structural motifs has been carried out
attributed mainly to the rapid development of new ligand systems extensively via palladiumꢀcatalysed crossꢀcoupling reactions.14 In
which in combination with different palladium precursors have that respect the type of ligands employed have also been shown
resulted in a drastic improvement in reactivity.3 NꢀHeterocyclic to play an important role in deciding the outcome of such
carbenes (NHCs)4 comprise one such class of highly electronꢀrich, processes.15 NꢀHeterocyclic carbenes to that matter have
activating ligand systems that have found applications as ligands in seldom been used for selective palladiumꢀcatalysed crossꢀ
metalꢀmediated processes5 as well as organocatalytic carbene coupling of polyhalogenated pyridines as is evident from the
catalysis6 in recent years. Consequently, this field has emerged as a number of reports that have emerged in the last few years.16
highly useful area for organic synthesis.
Since the early independent reports of their isolation by Arduengo7,8
,
N
N
N
N
Nꢀheterocyclic carbenes have been used in a variety of synthetic
transformations, while recently their Pdꢀcomplexes have also
exhibited promising anticancer9 properties. Their use in palladiumꢀ
catalysed crossꢀcoupling reactions has also seen rapid growth and
has been employed extensively towards addressing a variety of
synthetic problems with valuable contributions from the groups of
Nolan and Organ.10 Site selectivity in crossꢀcoupling reactions is one
such challenge, which has attracted a lot of attention due to its large
synthetic applicability related to the selective activation of CꢀX
bonds in polyhalogenated heteroaryls.11 The development of
efficient synthetic processes to tackle such a problem would be
immensely beneficial towards their application for natural product
synthesis.12
N
N
N
N
N
N
N
N
N
O3S
SO3
O3S
SO3
N
SO3
O3S
1A
1B
N
1C
O3S
1D
N
N
O3S
1E
Figure 1: N-Heterocyclic Carbene ligands 1A-E employed for selective Suzuki-Miyaura
cross-coupling of dihalopyridines.
a Department of Chemistry, Institute of Chemical Technology, Matunga, Mumbai-
400019, India.
bInstitute fur Biochemie, Ernst-Moritz-Arndt Universität Greifswald, Felix-Hausdorff-
Straße 4, D-17487 Greifswald, Germany
To address this issue for assessing the utility of Nꢀheterocyclic
carbenes for selective coupling of 2,6ꢀdibromo(hetero)arenes,
in this study we have employed some of the previously
developed NHC ligands17ꢀ20 (see Figure 1) for the development
of efficient and selective arylation (monoarylation) procedures
of 2,6ꢀdibromopyridine21. The purpose for selecting 2,6ꢀ
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dibromopyridine especially as the substrate of choice is with Complete diarylation was also found to take place at higher
respect to its occurrence in a variety of natural products such as temperature. Sequential oneꢀpot and direct oneꢀpot arylation
Combretastatins Aꢀ4 analogues.21h,22 Previous reports on the protocols have also been developed and applied towards the
selective arylation of 2,6ꢀdibromopyridines21 have highlighted synthesis of diversely substituted 2,6ꢀdiarylpyridines.
the importance of such a methodology. However, a closer look Mechanistic studies have also been performed to get an insight
at these reports reveal several drawbacks such as high Pd into the possible coordination mode of the metal to the NHC
content, lower selectivity towards monoꢀarylated product and ligands by comparison against ligandꢀless system. Presence of a
higher temperature ranges.
homotopic catalyst has been proposed by subjecting the
catalytic reactions to mercuryꢀdrop test and CS2 addition tests
With this in mind we report herein the monoꢀarylation of 2,6ꢀ giving preliminary support for such a proposal.
dibromopyridine under relatively mild conditions at 0.1 mol%
catalyst loading in H2O/CH3CN system at room temperature.
Table 1: Screening studies.a
No.
Ligand
Temp (oC)
Catalyst (mol%)
%Yieldb
2a
55
21
18
17
57
21
19
16
26
12
9
4a
5a
10
<2
<2
<2
<2
<2
29
26
23
24
22
<2
<2
<5
<2
<2
<2
<2
30
26
<2
<2
1.
2.
-
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
100
80
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
1.0
0.1
0.1
0.01
0.01
0.001
35
1A
76
3.
1B
78
81 (80)c
4.
1C
5.
1D
40
6.
1E
75
7.
IMes.HCl
51
8.
IPr.HCl
57
9.
Pd(PPh3)4
PEPPSITM-IPr
49
63
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
SPhos-Pd G2
67
1C
1C
1C
1C
1C
1C
1C
-
52
45
43
17
17
16
16
29
39
28
87
45
51
60
50
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
81
81 (16)d
81 (81)d
80 (800)d
37
-
28
1C
1C
69 (6900)d
10
a1.0 mmol 2,6ꢀdibromopyridine, 1.2 mmol arylboronic acid, K2CO3 (2.0 mmol) in H2O/CH3CN 1:1 (3.0 mL) at 30 oC. bUnless otherwise stated are isolated yields after column
chromatography and characterized by LCMS and 1H NMR. cInstead of H2O/CH3CN, neat water was used as solvent. dValues in bracket are TON (mol product/ mol catalyst) secꢀ1
(r.t. is 30 oC)
2 | J. Name., 2012, 00, 1-3
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2. Palladium-catalysed selective mono-arylation of
ARTICLE
Scheme 1: Selective monoꢀarylation protocol.a,b
2,6-dibromopyridine
B(OH)2
Pd(OAc)2 (0.1 mol%)
Ligand 1C (0.1 mol%)
At the outset of our studies we performed screening of all
synthesised NHC ligands for the selective monoꢀarylation of
2,6ꢀdibromopyridine with 4ꢀchlorophenylboronic acid in
H2O/CH3CN solvent system. Pd(OAc)2 on its own without the
presence of the ligand led to poor yield of both mono as well as
diarylated products, possibly due to the formation of palladiumꢀ
black at higher concentrations of palladium (entry 1, Table 1).
Initial screening of different ligands revealed that ligand 1C
(entry 4, Table 1) possessing the pyridine backbone coupled
with butane sultone gave relatively better yield of the selective
monoꢀarylated product compared to other ligands, however
given the close reactivity pattern it should be noted that other
ligands too could perform at the same rate as 1C.The catalytic
system was also tested against some of the commercially
available NHC ligands as well as complexes such as IMes.HCl,
IPr.HCl, Pd(PPh3)4, PEPPSITMꢀIPr and SPhosꢀPd G2 catalysts
(entries 7ꢀ11, Table 1). Although, good conversion was
observed in the case of PEPPSITMꢀIPr and SPhosꢀPd G2,
selectivity for monoꢀarylated product was found to be poor as
compared to the 1C with larger quantity of diarylated product
also obtained (entry 10 and 11, Table 1).
Br
N
H2O/CH3CN, 30 o
K2CO3 (2.0 Equiv.), 12 hr
C
Br
Br
N
Br
R
2a
3a-j
4a-l
R
N
Br
N
Br
N
Cl
4a 80% (<2%, 16%)
4b 80% (<2%, 17%)
4c 81% (<2%, 16%)
OMe
NH2
Br
N
Br
N
Br
N
OMe
CO2Me
4e
<2%
,9%)
4d 85% (<2%, 11%)
86% (
4f 80% (<5%, 12%)
OCF3
Br
N
Br
N
Br
N
4i 85% (0%, 13%)
4g 75% (<2%, 21%)
4h 77% (0%, 21%)
10%(0%, 88%)c
87%(0%, 10%)d
Br
N
O
O
Br
N
Br
N
The reaction proceeded smoothly at ambient temperature while
increase in temperature led to loss in reactivity (entries 12ꢀ15,
Table 1). We next turned our attention to catalyst loading
experiments to check the possibility of reducing the catalyst
concentration in order to make the protocol synthetically
attractive. Lowering the catalyst concentration did not affect the
catalytic activity and it was possible to reduce the loading to 0.1
mol% (entry 13, Table 1). The possibility of whether Pd(OAc)2
could catalyse the reaction at lower concentrations through
nanoparticular pathway23 without the ligand was not found to
be acting in such catalytic reaction as the reactivity and
selectivity suffered drastically compared to the one with ligand
(entry 14 & 15, Table 1). The reaction also proceeded smoothly
at 0.01 mol%, however a slight reduction in the monoarylated
product was observed (entry 16, Table 1).
4k 65% (<2%, 31%)
4j 83% (<2%, 13%)
4l 84% (<2%, 12%)
CO2Me
a1.0 mmol 2,6ꢀdibromopyridine, 1.2 mmol arylboronic acid, Pd(OAc)2 (0.1 mol%),
Ligand 1C (0.1 mol%), K2CO3 (2.0 mmol) in H2O/CH3CN 1:1 (3 mL) at 30 oC. for 12 h.
bIsolated yields (Values in bracket: bold numbers signify the amount of diarylated
product isolated, while the other part corresponds to the value related to the amount of
starting 2,6ꢀdibromopyridine isolated)ꢀcharacterised by LCMS and 1H NMR cInstead of
H2O/CH3CN, neat H2O was used (3 mL) at 30 oC. dInstead of H2O/CH3CN, H2O was
used (3 mL) at 80 oC.
The Xꢀray analysis of one of the monoꢀarylated product that
crystallised in CDCl3 (NMR tube) to give single crystals
suitable for Xꢀray characterisation revealed interesting details
regarding the positioning of different groups on the pyridine
ring.
With a highly active catalytic system in hand we then explored
its scope in the selective monoꢀarylation of 2,6ꢀ
dibromopyridine with different aryl boronic acids at 0.1 mol%
catalyst loading at ambient temperature in CH3CN/H2O solvent
system (Scheme 1). In most cases very good yields of the
monoꢀarylated product was obtained with no particular
electronic influence (effect of substituents on the arylboronic
acid) on the reactivity was observed. The coupling could also
be performed in water however at higher temperature (80 oC) as
poor yields were obtained at room temperature.
Single crystal X-ray for 4g
Figure 2 ORTEP representation of compounds 4g with atomic
labelling. Thermal ellipsoids are drawn at 50% probability. Selected
bond lengths (Å) for compound 4g: C(5)ꢀC(6) 1.482 (3), C(5)ꢀN(1)
1.344 (3), C(9)ꢀC(12) 1.483 (3), C(1)ꢀBr(1) 1.906 (2). Selected bond
angles for compound 4g: N(1)ꢀC(5)ꢀC(4) 121.7 (2), N(1)ꢀC(5)ꢀC(6)
116.79 (2), C(4)ꢀC(5)ꢀC(6) 121.5 (2), C(10)ꢀC(9)ꢀC(8) 116.4 (2).
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Monoꢀarylated product 4g obtained from the coupling of 2,6ꢀ
dibromopyridine 2a and 4ꢀbiphenyl boronic acid 3g (Scheme 1)
3. Palladium-catalysed
dibromopyridine:
diarylation
of
2,6-
crystallised to provide its Xꢀray crystal structure (Figure 2).24 Given the unique reactivity of the catalytic system we became
The torsion angle between the plane C6 to ꢀC17 and the plane interested in exploring it further towards the diarylation of 2,6ꢀ
N1ꢀC1 toꢀC5 was found to be 18.2° indicating that the dibromopyridine in H2O/CH3CN. In comparison to the monoꢀ
aromaticity between the biaryl part and the pyridine part is not arylation of 2,6ꢀdibromopyridine, the diarylation reaction when
perfectly in resonance, while the two planes itself are almost carried out at room temperature gave a mixture of monoꢀ
entirely flat.
arylated and diarylated products (Scheme 3). For improving the
selectivity towards achieving complete diarylation the reaction
o
In order to demonstrate the generality of the catalytic system, was performed at higher temperature (80 C) in H2O/CH3CN
other dibromoheteroarenes (although this is not the were also with a catalyst loading of 0.5 mol%. As expected the increase
subjected to the monoꢀarylation conditions using 0.1 mol% of the reaction temperature resulted in complete diarylation of
catalyst loading in H2O/CH3CN as solvent at ambient 2,6ꢀdibromopyridine with no monoꢀarylation observed. Good to
temperature. 2,4ꢀDibromopyridine in comparison to its 2,6ꢀ excellent yields of diarylated product was obtained regardless
dihalogenated analogue gave slightly lower yield of the monoꢀ of the type of substituent on the arylboronic acid.
arylated product (70%). The catalytic system was found to be
Scheme 3: Diarylation of 2,6ꢀdibromopyridine.a,b,c
quite selective towards arylation at the 4ꢀposition of the
pyridine ring (Scheme 2). Other unactivated substrates such as
1,3ꢀdibromobenzene and 1,4ꢀdibromobenzene when subjected
to monoarylation conditions also furnished the desired product
in good yields.
Scheme 2: Selective monoarylation of dibromo(hetero)arene.a,b,c
a1.0 mmol 2,6ꢀdibromopyridine, 1.2 mmol arylboronic acid, Pd(OAc)2
(0.1 mol%), Ligand 1C (0.1 mol%), K2CO3 (2.0 mmol) in H2O/CH3CN
b
1:1 (3 mL) at 30 oC for 12 hr. Isolated yields (Values in bracket: bold
numbers signify the amount of diraylated product isolated, while the
other part corresponds to the value related to the amount of starting
dibromo(hetero)arene isolated)ꢀcharacterised by LCMS and 1H NMR. c
Control experiment with Pd(OAc)2 used on its own.
This was also found to be the case with 2,5ꢀdibromopyridine
a1.0 mmol 2,6ꢀdibromopyridine, 2.0 mmol arylboronic acid, Pd(OAc)2 (0.1
and 9,10ꢀdibromoanthracene giving the monoarylated product
mol%), Ligand 1C (0.1 mol%), K2CO3 (4.0 mmol) in H2O/CH3CN 1:1 (3
mL) at 80 oC for 12 hr. bIsolated yields. cNo monoarylated product was
in good yield and slightly lower yields respectively, although
with good selectivity in both the cases. These results point
towards the general nature of the developed protocol which is
independent of the type of substrate employed.
d
observed and remaining was starting material. Reaction carried out only
with Pd(OAc)2 to give 37% of diarylated product
4 | J. Name., 2012, 00, 1-3
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ARTICLE
In the case of diarylated product 6d which was obtained by the
reaction of 2,6ꢀdibromopyridine 2a and 1ꢀnaphthyl boronic acid
4. Synthesis of diversely 2,6-disubstituted pyridines:
Sequential and direct one-pot synthesis
(2.0 equiv.), the xꢀray structure25 (Figure 3) revealed that the The above results demonstrate the powerful nature of the
two naphthalene rings are in an almost right angle to each other catalytic system which could be further employed towards
(89.8o). Naphthalene C1 toꢀC10 has an angle of 51.1o to the obtaining diversely 2,6ꢀdisubstituted pyridines in a sequential
central pyridine ring and the other naphthalene is at 112.2o. oneꢀpot manner without the isolation of the monoꢀarylated
There appears to be no πꢀπ stacking interactions in the crystal intermediate. Sequential oneꢀpot transformations26 have in
lattice, which is unusual given the molecule’s highly aromatic recent years gained a lot of interest and have emerged as a new
character.
and powerful technology in synthesis. One of the major
advantages of such methodology is the reduction of waste
leading to better reaction conditions.
Initially, for achieving monoꢀarylation 2,6ꢀdibrompyridine was
reacted with 4ꢀmethoxyphenylboronic acid at room temperature
in H2O/CH3CN and the reaction mixture was stirred for 12 hrs
after which the other arylboronic acid was added and the
reaction continued at 80 oC for 3 more hours (Scheme 4). At the
end of the reaction a differently substituted pyridine was
isolated in good yield. The methodology was demonstrated to
provide the 2,6ꢀdisubstituted pyridines (possible pyridineꢀbased
Combretastatin analogues21h,22) using 3 different arylboronic
acids with the best results obtained for the combination of two
electronꢀdonating substituents on the aryl boronic acids (4ꢀMeO
and 3ꢀMeO).
Figure 3 ORTEP representation of compound 6d with atomic labelling.
Thermal ellipsoids are drawn at 50% probability. Selected bond lengths (Å)
for compound 6d: C(1)ꢀC(10) 1.433 (3), C(15)ꢀC(16) 1.494 (3), C(15)ꢀN(1)
1.348 (3), C(11)ꢀN(1) 1.348 (3). Selected bond angles for compound 6d:
N(1)ꢀC(11)ꢀC(10) 116.97 (19), N(1)ꢀC(15)ꢀC(16) 115.6 (2), C(12)ꢀC(11)ꢀ
C(10) 121.0 (3), C(14)ꢀC(15)ꢀC(16) 121.8 (3).
Scheme 4: Sequential oneꢀpot arylation of 2,6ꢀdibromopyridine with different boronic acids.a
B(OH)2
R1
Pd(OAc)2 (0.5 mol%)
Ligand1C (0.5 mol%)
Br
N
R1
H2O/CH3CN, 30 o
C
Br
N
Br
K2CO3 (2.0 Equiv.)
12 hr
2a = 2,6-dibromopyridine
A (not isolated)
B(OH)2
Procedure A: Sequential one-pot
K2CO3 (2.0 Equiv.)
80 oC, 3 hr
R2
R1
R2
R1
R2
N
N
N
R1
R2
Homodiarylation B
Heterodiarylation C
Homodiarylation D
7a-d
No.
(hetero)arene
R1
R2
%Yieldb
(hetero)arene
A
B
C
D
-
1.
2.
3.
4.
2a
2a
2a
2a
4-MeO
4-MeO
4-MeO
4-MeO
1-Naphthyl
2-Naphthyl
3-MeO
<2% (2a)
<2% (2a)
<2% (2a)
<2% (2a)
7 (4d)
6 (4d)
10 (4d)
16 (4d)
10 (6f)
11 (6f)
13 (6f)
11 (6f)
79 (7a)
81 (7b)
74 (7c)
70 (7d)
-
-
3,4-(MeO)2
-
a1.0 mmol 2,6ꢀdibromopyridine, 1.2 mmol R1ꢀArB(OH)2, Pd(OAc)2 (0.5 mol%), Ligand 1C (0.5 mol%), K2CO3 (2.0 mmol) in H2O/CH3CN 1:1 (3
mL) at 30 o for 12 hr and then added K2CO3 (2.0 mmol), 1.2 mmol R2ꢀArB(OH)2 at 80 oC for 3 hr. bIsolated yields
C
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ARTICLE
In literature such a system has not been employed for the
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5. Mechanistic studies
substrates represented in this above scheme and gives the Given the reactivity of the catalytic system it was also
synthetic organic chemists and medicinal chemists a very good important to verify the possibility of a nanoparticular pathway
handle for obtaining diversely substituted pyridines and arenes. followed by the added Pd and whether the NHC ligands are
We next turned our attention to direct oneꢀpot procedure for acting as coordinating ligand29. To assess the nature of Pd
obtaining the diversely substituted 2,6ꢀdibromopyridine by the species that could be forming under the conditions a simple but
addition of both the arylboronic acids at the same time. Direct reliable Mercuryꢀdrop30 test method was employed. Catalytic
oneꢀpot synthetic procedures which involve a series of reactions reactions with and without ligand were performed, excess of
in an uninterrupted sequence27 has played a key role in mercury was added at the initial stages.
redefining synthetic organic chemistry through better waste
management and making the process energy intensive given the Presence of a nanoparticular pathway was evident for the
lesser number of steps required to obtain the desired product. reaction performed without the addition of the ligand as
One of the major applications of direct oneꢀpot reactions is the complete retardation of the catalytic reaction was observed. The
possibility to perform multicomponent processes28 in a more reaction failed to furnish any kind of product at the end of 12
selective manner to provide the product containing all the hrs. However, to our surprise the addition of the mercuryꢀdrop
components. To test our catalytic system for providing the failed to have any kind of effect on the catalytic activity of the
heterodiarylated product we subjected 2,6ꢀdibromopyridine to reaction involving the added ligand 1C furnishing the desired
the direct oneꢀpot procedure involving the addition of all the monoarylated product in good yield. Similar observations were
substrates at the same time in H2O/CH3CN solvent system at 80 made in the case of other catalyst poisons31 such as
oC for 12 hr (Scheme 5).
triphenylphosphine (PPh3) and carbon disulfide (CS2) where no
appreciable reduction in the yield of the crossꢀcoupled product
To our pleasant surprise the protocol furnished selectively the was observed. The employment of a nanoparticle stabilizer
desired heterodiarylated product in good yield with the tetraꢀnꢀbutylammonium bromide also failed to show any rate
remaining amount being that of starting material and small enhancement suggesting the lesser possibility for the
amount of homodiarylated product was observed.
involvement of a nanoparticular pathway and provide
preliminarily support for the presence of a homotopic catalyst
(active molecular catalyst).
Scheme 5: Direct oneꢀpot arylation of 2,6ꢀdibromopyridine with
different boronic acids.a
Scheme
6:
Homogeneity test for monoarylation of 2,6ꢀ
dibromopyridine.
Conditions
Additive
%Yield
0
A = Without Ligand
Mercury drop test
B = With added ligand 1C
B = With added ligand 1C
B = With added ligand 1C
B = With added ligand 1C
74
Triphenylphosphine
Carbon disulphide
Tetraꢀnꢀbutylammonium
bromide
67
62
79
These results were also supported by the fact that the reaction
solutions of these two catalytic systems showed a striking
contrast to each other. As depicted in Figure 4 the catalytic
solution containing Pd(OAc)2 and ligand 1C shows the possible
presence of homogeneous Pd species in the aqueous phase
a1.0 mmol 2,6ꢀdibromopyridine, 1.2 mmol R1ꢀArB(OH)2, 1.2 mmol R1ꢀ
ArB(OH)2, Pd(OAc)2 (0.5 mol%), Ligand 1C (0.5 mol%), K2CO3 (4.0
o
b
mmol) in H2O/CH3CN 1:2 (3 mL) at 80 C for 12 hr. Isolated yields
(remaining mass balance is starting material along with small amount of
homodiarylated products, monoarylated products were not observed).
while that of Pd(OAc)2 on its own (without added ligand 1C
)
showed colloidal Pd species in the organic phase.
No monoarylation products were obtained, confirming the
selective nature of the direct oneꢀpot method leading to the
minimisation of side products. These results also demonstrate
the powerful nature of the catalytic system in hand.
6 | J. Name., 2012, 00, 1-3
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Another important evidence for the presence of an active
molecular catalyst (Pd(OAc)2 with added ligand 1C) was the
observation of a linear reaction profile obtained on the injection
of aliquots of the reaction at regular intervals into Gas
ChromatographꢀMass Spectrometer (GCMS) (Figure 5). The
reaction was found to proceed smoothly towards the
predominant formation of the monoꢀarylated product after 12
hrs, although a slight induction period could be observed. In
comparison the catalytic reaction performed without the added
ligand 1C (only Pd(OAc)2 as catalyst) showed an initial
induction period extending upto 2 hrs after which the reaction
started to convert rapidly. However, the competing diarylation
process brings about the reduction in the overall yield of the
desired monoꢀarylated product.
Figure 4: Pictorial representation of catalytic solutions (upper layer
CH3CN and lower H2O)
.
Pd(OAc)2 with added ligand 1C
.
Pd(OAc)2 without added ligand
100
90
80
70
60
50
40
30
20
10
Pd(OAc)2
Pd(OAc)2 with 1D
0
0
1
2
3
6
9
12
Reaction time (Hrs)
Figure 5: GC reaction profile for catalytic reactions (Hexadecane added as internal standard).
6. Conclusion
All the above results point towards the involvement of
A
selective
palladiumꢀcatalysed
arylation
of
2,6ꢀ
molecular Pdꢀcatalyst32 in the SuzukiꢀMiyaura selective dibromopyridine has been developed by employing Nꢀ
coupling of 2,6ꢀdibromopyridine with arylboronic acids. At this heterocyclic carbene ligands. Selective monoꢀarylation was
moment the possibility of monoꢀPdꢀNHC coordinated species performed in water/acetonitrile solvent system at ambient
in solution compared to the doubly coordinated Pd species temperature with catalyst loading of 0.1 mol%. This reaction
(known to be formed at higher temperatures)19,33 is more was also found to proceed smoothly in water although at a
probable. Such a monomeric species has already been shown to slightly elevated temperature of 80 oC. Sequential and direct
form under relatively mild conditions (similar to the one we oneꢀpot synthetic procedure was also shown to furnish the
have developed for the monoarylation reaction) for ruthenium differently substituted 2,6ꢀdiarylpyridine in good yields. These
and osmium.17c Although, to verify such an assumption further molecules are of importance to organic as well as medicinal
studies are required to be undertaken which are underway in chemists and the protocol could provide an easy access to such
our group for getting an insight into the possible coordination molecules of synthetic relevance. The presence of a possible
mode of the ligand to the Pdꢀcentre and will be reported in due active molecular catalyst was found to be existent in the
course.
catalytic system and was confirmed by the catalyst poison
experiments (mercuryꢀdrop test, CS2 addition test) as well as on
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the basis of
a
nonꢀsigmoidal reaction profile for the 1H NMR (500 MHz, D2O): 9.31 (s, 2H), 7.81ꢀ7.79 (m, 2H),
monoarylation reactions.
7. Experimental Section
7.1 General Remarks
7.70ꢀ7.68 (m, 2H), 6.68 (s, 2H), 4.43ꢀ4.41 (m, 4H), 2.93ꢀ2.91
(m, 4H), 2.33ꢀ2.31 (m, 4H); 13C NMR (125 MHz, D2O): 123.7,
122.1, 58.9, 48.4, 47.1, 24.7; ESIꢀMS (m/z): 415 (M+ + Na+);
All catalytic reactions were conducted under an inert Anal.Calcd (%) for C13H20N4S2O6: C, 39.79; H, 5.14; N, 14.28.
atmosphere of N2 on a Schlenk line. TLC analysis was Found: C, 39.69; H, 5.09; N, 14.21.
performed on Merck 5554 aluminium backed silica gel plates
and compounds visualized by ultraviolet light (254 nm), Ligand 1B
phosphomolybdic acid solution (5% in EtOH), or 1% ninhydrin A suspension of bis(imidazolyl)methane (1.0 g, 6.74 mmol) and
in EtOH. Aryl boronic acids and other chemicals were obtained 1,4ꢀbutane sultone (33.8 mmol) in CH3CN (25 mL) was heated
o
from commercial sources, and were used without further at 100 C during 12 h in a Pyrex tube. The soꢀgenerated solid
purification. PEPPSITMꢀIPr, SPhosꢀPd G2, IMes.HCl, IPr.HCl was collected by filtration and washed with CH2Cl2 and MeOH.
and Pd(PPh3)4 were obtained from Sigma Aldrich. Yields refer Compound 1B was isolated as a white, airꢀ and moistureꢀstable
to isolated compounds, estimated to be >95 % pure as solid in 81% yield.
determined by 1HꢀNMR. NMR data (1H, 13C) were recorded on 1H NMR (500 MHz, D2O): 7.79ꢀ7.77 (m, 2H), 7.68ꢀ7.66 (m,
Bruker 500 MHz spectrometer. Chemical shifts are reported in 2H), 6.69 (s, 2H), 4.34ꢀ4.31 (m, 4H), 2.96ꢀ2.92 (m, 4H), 2.07ꢀ
parts per million downfield from an internal tetramethylsilane 2.02 (m, 4H), 1.78ꢀ1.72 (m, 4H); 13C NMR (125 MHz, D2O): ,
reference. Coupling constants (J values) are reported in hertz 123.8, 122.2, 58.9, 49.8, 49.6, 27.6, 20.8; ESIꢀMS (m/z): 443
(Hz). LCꢀMS analyses were performed on an Agilent VL massꢀ (M+ + Na+); Anal.Calcd (%) for C15H24N4S2O6: C, 42.85; H,
spectrometer. Elemental analysis was performed using
ThermoꢀFischer Scientific.
a
5.75; N, 13.32. Found: C, 42.77; H, 5.69; N, 13.27.
Synthesis of Ligands 1C and 1D
:
Ligand 1C19
GC Parameters. GC analysis for the kinetic profile was done A suspension of 2,6ꢀbis(imidazolꢀ1ꢀyl)pyridine (1.06 g, 5.02
on Shimadzu GCꢀMS Parvum equipped with an mmol) and 1,3ꢀpropane sultone (3.06 g, 25.2 mmol) in CH3CN
autosampler. Separation was achieved using a Zebron ZBꢀ1 (20 mL) was heated at 100 C during 12 h in a Pyrex tube. The
capillary column, (I.d. 0.25 mm, length 30 m) with solid was collected by filtration and washed subsequently with
temperature ramp from 50 to 250 oC at 10 oC minꢀ1. The CH2Cl2 and MeOH. Compound 1C was isolated as a white, airꢀ
a
2
o
a
injection volume was 1µl with a split ratio of 50.
and moistureꢀstable solid in 72% yield.
1H NMR (500 MHz, D2O): 9.74 (s, 2H), 8.28ꢀ8.26 (m, 1H),
Xꢀray structural analysis45ꢀ36
low temperature (ꢀ103.0 °C) using
diffractometer with graphiteꢀmonochromated molybdenum Kα MHz, DMSOꢀd6): 147.2, 146.4, 136.7, 125.2, 121.4, 116.4,
radiation,
= 0.71073 Å. The structures were solved by direct 50.3, 48.8, 26.5; ESIꢀMS (m/z): 478 (M+ + Na+); Anal.Calcd
:
Diffraction data were collected at 8.24ꢀ8.21 (m, 2H), 7.88ꢀ7.85 (m, 2H), 7.69 (s, 2H), 4.42ꢀ4.40
STOEꢀIPDS 2T (m, 4H), 2.85ꢀ2.83 (m, 4H), 2.33ꢀ2.31 (m, 4H); 13C NMR (125
a
λ
methods (SHELXSꢀ97) and refined by fullꢀmatrix leastꢀsquares (%) for C17H21N5S2O6: C, 44.83; H, 4.65; N, 15.37. Found: C,
techniques (SHELXLꢀ97). All nonꢀhydrogenꢀatoms were 44.75; H, 4.61; N, 15.29.
refined with anisotropic displacement parameters. The
hydrogen atoms were refined isotropically on calculated Synthesis of Ligands 1D and 1E
positions using a riding model with their Uiso values constrained Ligand 1D20
:
to 1.5 Ueq of their pivot atoms for terminal sp3 carbon atoms 3ꢀ(1ꢀButylꢀ3ꢀimidazolio)propanesulfonate 1D was obtained by
and 1.2 times for all other carbon atoms. Copies of the data can refluxing 1ꢀbutylimidazole (5 mmol) with 1,3ꢀpropanesultone
be obtained free of charge by contacting the CCDC via eꢀmail: (25 mmol) in acetone (25 mL) under dry nitrogen at room
deposit@ccdc.cam.ac.uk.
temperature for 24 h. The insoluble precipitate was separated
by filtration. The product was washed with acetone several
times. The resultant product was obtained as a white powder in
Synthesis of Ligands 1A and 1B
:
The preparation of compound 1A and 1B was carried out by 82% yield.
reaction of bis(imidazolyl)methane and 1,3ꢀpropane sultone or 1H NMR (500 MHz, DMSOꢀd6): 9.20 (s, 1H), 7.81ꢀ7.79 (m,
1,4ꢀbutane sultone, under different reaction conditions than 2H), 4.31ꢀ4.28 (m, 2H), 4.17ꢀ4.14 (m, 2H), 2.41ꢀ2.39 (m, 2H),
those reported in the literature.
2.12ꢀ2.06 (m, 2H), 1.82ꢀ1.74 (m, 2H), 1.30ꢀ1.25 (m, 2H), 0.92
(t, 3H); 13C NMR (125 MHz, DMSOꢀd6): 136.4, 122.6, 48.5,
Ligand 1A18
47.8, 47.6, 31.3, 26.3, 18.7, 13.2; ESIꢀMS (m/z): 269 (M+
+
A suspension of bis(imidazolyl)methane (1.0 g, 6.74 mmol) and Na+); Anal.Calcd (%) for C10H18N2SO3: C, 48.76; H, 7.37; N,
1,3ꢀpropane sultone (4.12 g, 33.8 mmol) in CH3CN ( 25 mL) 11.37. Found: C, 48.69; H, 7.31; N, 11.32.
was heated at 100 oC during 12 h in a Pyrex tube. The
generated solid was collected by filtration and washed with Ligand 1E
CH2Cl2 and MeOH. Compound 1A was isolated as a white, airꢀ 3ꢀ(1ꢀButylꢀ3ꢀimidazolio)butaneulfonate 1E was obtained by
and moistureꢀstable solid in 75% yield.
refluxing 1ꢀbutylimidazole (5 mmol) with 1,3ꢀbutanesultone
(25 mmol) in acetone (25 mL) under dry nitrogen at room
8 | J. Name., 2012, 00, 1-3
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temperature for 24 h. The insoluble precipitate was separated 2-Bromo-6-(3-trifluoromethoxyphenyl)pyridine
(
4f): 1H
by filtration. The product was washed with acetone several NMR (500 MHz, DMSOꢀd6): 7.93ꢀ7.86 (m, 2H), 7.68ꢀ7.62 (m,
times. The resultant product was obtained as a white powder in 2H), 7.52ꢀ7.45 (m, 2H), 7.34ꢀ7.26 (m, 2H); 13C NMR (125
61% yield.
MHz, DMSOꢀd6): 156.8, 142.3, 139.7, 139.1, 130.1, 127.1,
1H NMR (500 MHz, DMSOꢀd6): 9.26 (s, 1H), 7.82 (s, 2H), 125.2, 121.8, 119.6, 119.1; MS (EI, m/z): 318 (100).
4.21ꢀ4.15 (m, 4H), 2.47ꢀ2.43 (m, 2H), 1.89ꢀ1.87 (m, 2H), 1.79ꢀ Anal.Calcd (%) for C12H7NOF3Br: C, 45.31; H, 2.22; N, 4.40.
1.76 (m, 2H), 1.55ꢀ1.52 (m, 2H), 1..27ꢀ1.25 (m, 2H), 0.90 (t, Found: C, 45.22; H, 2.19; N, 4.36.
3H); 13C NMR (125 MHz, DMSOꢀd6): 136.3, 122.5, 50.5, 48.5, 2-Bromo-6-(4-biphenyl)pyridine 4g): 1H NMR (500 MHz,
(
31.3, 28.6, 21.7, 18.7, 13.2; ESIꢀMS (m/z): 283 (M+ + Na+); CDCl3): 8.09ꢀ8.06 (m, 2H), 7.73ꢀ7.57 (m, 6H), 7.49ꢀ7.38 (m,
Anal.Calcd (%) for C11H20N2SO3: C, 50.75; H, 7.74; N, 10.76. 4H); 13C NMR (125 MHz, CDCl3): 158.1, 142.3, 142.2, 140.3,
Found: C, 50.70; H, 7.69; N, 10.69.
138.9, 136.4, 128.8, 127.6, 127.4, 127.3, 127.0, 126.3, 118.8;
MS (EI, m/z): 310 (100). Anal.Calcd (%) for C17H12NBr: C,
Representative procedure for palladium-catalysed selective 65.83; H, 3.90; N, 4.52. Found: C, 65.72; H, 3.86; N, 4.54.
mono-arylation of 2,6-dibromopyridine: 2-Bromo-6-(2-naphthyl)pyridine
4h): 1H NMR (500 MHz,
(
In a dry Schlenk tube, Pd(OAc)2/ligand 1C (0.1 mol% in 3 mL CDCl3): 8.50 (s, 1H), 8.13ꢀ8.10 (m, 1H), 7.95ꢀ7.81 (m, 4H),
1:1 H2O:CH3CN) solution was stirred under N2 atmosphere. To 7.65ꢀ7.63 (m, 1H), 7.54ꢀ7.50 (m, 2H), 7.45ꢀ7.42 (m, 1H); 13C
this was added 2,6ꢀdibromopyridine 2a (0.5 mmol, 0.118 g), NMR (125 MHz, CDCl3): 158.5, 142.2, 139.0, 134.9, 133.9,
K2CO3 (1.0 mmol, 0.138 g) and the resultant solution was 133.3, 128.8, 128.5, 127.6, 126.8, 126.7, 126.4, 126.3, 124.2,
stirred at room temperature for 10 mins. To this was added 4ꢀ 119.2; MS (EI, m/z): 284 (100). Anal.Calcd (%) for
chlorophenyl boronic acid 3a (0.6 mmol, 0.093 g) and the C15H10NBr: C, 63.40; H, 3.55; N, 4.93. Found: C, 63.31; H,
o
resultant solution was stirred at 30 C for 12 hr. At the end of 3.54; N, 4.89.
the reaction, solvent was removed under vacuo and the resultant 2-Bromo-6-(9-phenanthrenyl)pyridine
crude product was purified using column chromatography (95:5 MHz, CDCl3): 8.81ꢀ8.79 (m, 1H), 8.75ꢀ8.73 (m, 1H), 8.10ꢀ8.07
(
4i): 1H NMR (500
Hexane:EtOAc) to give the product 4a in 80% yield.
(m, 1H), 7.97ꢀ7.95 (m, 1H), 7.90 (s, 1H), 7.75ꢀ7.70 (m, 3H),
7.67ꢀ7.59 (m, 4H); 13C NMR (125 MHz, CDCl3): 160.2, 141.7,
2-Bromo-6-(4-chlorophenyl)pyridine
MHz, CDCl3): 8.08ꢀ8.05 (m, 1H), 7.94 (d,
7.64ꢀ7.59 (m, 2H), 7.44 (d,
= 7.7 Hz, 2H); 13C NMR (125 334 (100). Anal.Calcd (%) for C19H12NBr: C, 68.28; H, 3.62;
MHz, CDCl3): 157.2, 142.2, 139.0, 135.8, 128.9, 128.8, 128.2, N, 4.19. Found: C, 68.22; H, 3.59; N, 4.15.
(
4a):37a 1H NMR (500 138.6, 135.4, 131.0, 130.7, 130.5, 129.8, 129.1, 128.9, 127.3,
J
= 7.8 Hz, 2H), 126.8, 126.7, 126.5, 126.0, 123.9, 122.9, 122.5; MS (EI, m/z):
J
1
126.6, 118.7; MS (EI, m/z): 268 (100).
Methyl 3-(6-bromopyridin-2-yl)benzoate
4b): 1H NMR (500 MHz, CDCl3): 8.56 (s, 1H), 8.21ꢀ8.19 (m, 1H), 8.08ꢀ8.06 (m,
= 7.8 Hz, 1H), 7.59 (t, = 7.6 Hz, 1H), 7.52 (t, J
7.55 (m, 1H), 7.29 (s, 1H), 7.17ꢀ7.14 (m, 2H), 6.68ꢀ6.65 (m, = 7.6 Hz, 1H), 7.41 (d,
= 7.8 Hz, 1H), 3.93 (s, 3H); 13C NMR
(4j): H NMR (500
2-Bromo-6-(3-aminophenyl)pyridine
(
MHz, DMSOꢀd6): 7.70ꢀ7.68 (m, 1H), 7.82ꢀ7.79 (m, 1H), 7.57ꢀ 1H), 7.71 (d,
J
J
J
1H), 5.29 (s, 2H); 13C NMR (125 MHz, DMSOꢀd6): 158.6, (125 MHz, CDCl3): 166.7, 157.3, 142.2, 139.1, 137.9, 131.4,
149.6, 141.5, 140.7, 137.8, 129.7, 126.6, 119.6, 115.8, 114.5, 130.7, 130.5, 128.9, 127.8, 126.8, 119.1, 52.2; MS (EI, m/z):
112.2; MS (EI, m/z): 249 (100). Anal.Calcd (%) for 292 (100). Anal.Calcd (%) for C13H10NO2Br: C, 53.45; H, 3.45;
C11H9N2Br: C, 53.04; H, 3.64; N, 11.25. Found: C, 52.91; H, N, 4.79. Found: C, 53.41; H, 3.43; N, 4.77.
3.60; N, 11.20.
2-Bromo-6-(3-methoxyphenyl)pyridine
MHz, DMSOꢀd6): 7.87ꢀ7.85 (m, 1H), 7.60ꢀ7.52 (m, 3H), 7.42ꢀ 2H), 7.62ꢀ7.57 (m, 5H); 13C NMR (125 MHz, CDCl3): 160.1,
7.37 (m, 1H), 7.00ꢀ6.95 (m, 1H), 3.89 (s, 3H); 13C NMR (125 141.7, 138.6, 136.7, 133.8, 130.8, 129.4, 128.4, 127.7, 126.7,
2-Bromo-6-(1-naphthyl)pyridine
(
4c): 1H NMR (500 CDCl3): 8.16ꢀ8.14 (m, 1H), 7.99ꢀ7.96 (m, 2H), 7.73ꢀ7.70 (m,
(
4k):37d 1H NMR (500 MHz,
MHz, DMSOꢀd6): 160.0, 158.3, 142.0, 138.9, 127.9, 126.4, 126.3, 126.0, 125.2, 125.1, 123.8; MS (EI, m/z): 284 (100).
1
119.3, 115.5, 112.2, 55.4; MS (EI, m/z): 264 (100). Anal.Calcd 2-Bromo-6-(5-methylenedioxyphenyl)pyridine
(
4l): H NMR
(%) for C12H10NBrO: C, 54.57; H, 3.82; N, 5.30. Found: C, (500 MHz, CDCl3): 7.60ꢀ7.56 (m, 2H), 7.54ꢀ7.52 (m, 2H),
54.51; H, 3.79; N, 5.26.
2-Bromo-6-(4-methoxyphenyl)pyridine
7.39ꢀ7.37 (m, 1H), 6.92ꢀ6.89 (m, 1H), 6.05 (s, 2H); 13C NMR
4d):37b 1H NMR (125 MHz, CDCl3): 157.9, 148.9, 148.2, 141.8, 138.8, 131.9,
(
(500 MHz, CDCl3): 7.96 (d,
J = 7.6 Hz, 2H), 7.59ꢀ7.54 (m, 125.6, 121.1, 118.2, 108.4, 107.2, 101.4; MS (EI, m/z): 278
2H), 7.32ꢀ7.29 (m, 1H), 6.99 (d,
J
= 7.7 Hz, 2H), 3.86 (s, 3H); (100). Anal.Calcd (%) for C12H8NO2Br: C, 51.83; H, 2.90; N,
13C NMR (125 MHz, CDCl3): 160.9, 158.2, 142.0, 138.8, 5.04. Found: C, 51.79; H, 2.87; N, 5.00.
130.2, 128.3, 125.4, 118.0, 114.1, 110.9, 55.3; MS (EI, m/z):
264 (100).
Representative procedure for palladium-catalysed selective
4e):37c 1H NMR mono-arylation of dibromo(hetero)arenes
Methyl 4-(6-bromopyridin-2-yl)benzoate
(
:
(500 MHz, CDCl3): 8.11ꢀ8.05 (m, 4H), 7.72ꢀ7.70 (m, 1H), In a dry Schlenk tube, Pd(OAc)2/ligand 1C (0.1 mol% in 3 mL
7.63ꢀ7.61 (m, 1H), 7.45ꢀ7.43 (m, 1H), 3.93 (s, 3H); 13C NMR 1:1 H2O:CH3CN) solution was stirred under N2 atmosphere. To
(125 MHz, CDCl3): 166.7, 157.2, 142.3, 141.5, 139.1, 130.8, this was added dibromo(hetero)arene 2b-e (0.5 mmol), K2CO3
130.0, 127.1, 126.8, 119.5, 52.2; MS (EI, m/z): 292 (100).
(1.0 mmol, 0.138 g) and the resultant solution was stirred at 30
oC for 10 mins. To this was added 4ꢀchlorophenyl boronic acid
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3d (0.6 mmol, 0.093 g) and the resultant solution was stirred at Representative
procedure
for
palladium-catalysed
room temperature for 12 hr. At the end of the reaction, solvent diarylation of 2,6-dibromopyridine
:
was removed under vacuo and the resultant crude product was In a dry Schlenk tube, Pd(OAc)2/ligand 1C (0.5 mol% in 3 mL
purified using column chromatography (95:5 Hexane:EtOAc) 1:1 H2O:CH3CN) solution was stirred under N2 atmosphere. To
to give the products 5a-d
2-Bromo-4-(2-naphthyl)pyridine
.
this was added 2,6ꢀdibromopyridine 2a (0.5 mmol, 0.118 g),
5a): 1H NMR (500 MHz, K2CO3 (2.0 mmol, 0.138 g) and the resultant solution was
(
CDCl3): 8.48ꢀ8.467 (m, 1H), 8.13 (s, 1H), 8.00ꢀ7.91 (m, 4H), stirred at room temperature for 10 mins. To this was added 4ꢀ
7.87 (s, 1H), 7.74ꢀ7.72 (m, 1H), 7.63ꢀ7.58 (m, 2H); 13C NMR chlorophenyl boronic acid (1.0 mmol, 0.155 g) and the resultant
(125 MHz, CDCl3): 151.2, 150.5, 142.9, 133.8, 133.6, 133.2, solution was stirred at 80 oC for 12 hr. At the end of the
129.1, 128.4, 127.7, 127.1, 126.8, 126.7, 126.0, 124.2, 121.0; reaction, solvent was removed under vacuo and the resultant
MS (EI, m/z): 331 (100). Anal.Calcd (%) for C15H10NBr: C, crude product was purified using column chromatography
63.40; H, 3.55; N, 4.93. Found: C, 63.36; H, 3.54; N, 4.91.
(90:10 Hexane:EtOAc) to give the product 6a in 70% yield.
5b):37e 1H NMR (500 2,6-Di-(4-chlorophenyl)pyridine 6a): 1H NMR (500 MHz,
= 7.8 Hz, 2H), 7.45ꢀ7.41 CDCl3): 8.01 (d, = 7.8 Hz, 4H), 7.72ꢀ7.69 (m, 1H), 7.60ꢀ7.57
= 7.8 Hz, 2H), 3.84 (s, (m, 2H), 7.43 (d,
= 7.7 Hz, 4H); 13C NMR (125 MHz,
3-Bromo-4'-methoxy-1,1'-biphenyl
MHz, CDCl3): 7.69 (s, 1H), 7.49 (d,
(m, 2H), 7.28ꢀ7.26 (m, 1H), 6.96 (d,
3H); 13C NMR (125 MHz, CDCl3): 159.5, 142.9, 132.1, 130.2, CDCl3): 155.7, 137.7, 137.6, 135.2, 128.9, 128.2, 118.6; MS
129.7, 129.5, 128.1, 125.2, 122.8, 114.3, 55.3; MS (EI, m/z): (EI, m/z): 300 (100). Anal.Calcd (%) for C17H11NCl2: C, 68.02;
(
(
J
J
J
J
263 (100).
4-Bromo-4'-methoxy-1,1'-biphenyl
H, 3.69; N, 4.67. Found: C, 67.95; H, 3.66; N, 4.63.
(
5c):37f 1H NMR (500 2,6-Di-(2-naphthyl)pyridine
(
6b): 1H NMR (500 MHz,
MHz, CDCl3): 7.51ꢀ7.47 (m, 4H), 7.40 (d,
(d,
159.3, 139.6, 132.4, 131.7, 128.2 127.9, 120.7, 114.2, 55.3; MS CDCl3): 156.6, 138.3, 135.6, 133.8, 133.4, 128.8, 128.4, 127.6,
J
= 7.6 Hz, 2H), 6.96 CDCl3): 8.59 (s, 2H), 8.29ꢀ8.25 (m, 2H), 7.98ꢀ7.92 (m, 4H),
J
= 7.6 Hz, 2H), 3.84 (s, 3H); 13C NMR (125 MHz, CDCl3): 7.88ꢀ7.80 (m, 5H), 7.52ꢀ7.45 (m, 4H); 13C NMR (125 MHz,
(EI, m/z): 263 (100).
9-Bromo-10-(4-methoxyphenyl)anthracene
127.0, 126.7, 126.3, 124.8, 119.6, 110.8; MS (EI, m/z): 331
5d):37g 1H NMR (100). Anal.Calcd (%) for C25H17N: C, 90.60; H, 5.17; N, 4.23.
(
(500 MHz, CDCl3): 8.60 (d,
Hz, 2H), 7.59ꢀ7.56 (m, 2H), 7.38ꢀ7.34 (m, 2H), 7.30 (d,
Hz, 2H), 7.11 (d,
J
= 7.6 Hz, 2H), 7.70 (d,
J
J
= 8.9 Found: C, 90.53; H, 5.14; N, 4.20.
= 7.6 2,6-Di-(3-trifluoromethoxyphenyl)pyridine (
6c): 1H NMR
J
= 8.6 Hz, 2H), 3.94 (s, 3H); 13C NMR (125 (500 MHz, CDCl3): 8.08ꢀ8.01 (m, 4H), 7.90ꢀ7.84 (m, 1H),
MHz, CDCl3): 159.1, 137.6, 132.1, 131.3, 130.3, 130.2, 127.7, 7.73ꢀ7.70 (m, 2H), 7.55ꢀ7.50 (m, 2H), 7.32ꢀ7.28 (m, 2H); 13C
127.4, 126.8, 125.4, 122.5, 113.8, 55.3; MS (EI, m/z): 363 NMR (125 MHz, CDCl3): 155.3, 149.8, 141.2, 137.9, 130.0,
(100).
125.1, 121.3, 119.5, 119.3; MS (EI, m/z): 399 (100).
1H NMR (500 MHz, Anal.Calcd (%) for C19H11NO2F6: C, 57.15; H, 2.78; N, 3.51.
37h
5-Bromo-2-phenylpyridine
(
5e)
:
CDCl3): 8.78ꢀ8.74 (m, 1H), 8.01ꢀ7.97 (m, 2H), 7.90ꢀ7.87 (m, Found: C, 57.12; H, 2.75; N, 3.48.
1H), 7.67ꢀ7.64 (m, 1H), 7.51ꢀ7.42 (m, 4H); 13C NMR (125 2,6-Di-(1-naphthyl)pyridine 6d): 1H NMR (500 MHz,
(
MHz, CDCl3): 155.4, 150.3, 138.9, 137.7, 129.1, 126.4, 121.4, CDCl3): 8.25ꢀ8.20 (m, 2H), 7.97ꢀ7.87 (m, 5H), 7.73ꢀ7.70 (m,
119.4; MS (EI, m/z): 234 (100).
5-Bromo-2-(4-methoxyphenyl)pyridine
2H), 7.65ꢀ7.55 (m, 4H), 7.52ꢀ7.46 (m, 4H); 13C NMR (125
5f): 1H NMR (500 MHz, CDCl3): 159.0, 138.6, 136.5, 133.9, 131.2, 128.8, 128.3,
(
MHz, CDCl3): 8.87 (s, 1H), 7.91ꢀ7.88 (m, 2H), 7.81ꢀ7.78 (m, 127.6, 126.3, 125.8, 125.7, 125.3, 123.4; MS (EI, m/z): 331
1H), 7.55ꢀ7.53 (m, 1H), 6.98ꢀ6.95 (m, 2H), 3.84 (s, 3H); 13C (100). Anal.Calcd (%) for C25H17N: C, 90.60; H, 5.17; N, 4.23.
NMR (125 MHz, CDCl3): 160.9, 155.5, 150.5, 139.1, 130.8, Found: C, 90.54; H, 5.15; N, 4.21.
1
128.0, 120.8, 118.3, 114.2, 55.3; MS (EI, m/z): 263 (100).
Methyl 4-(5-bromopyridin-2-yl)benzoate
2,6-Di-(9-phenanthrenyl)pyridine
(
6e): H NMR (500 MHz,
(
5g): 1H NMR (500 CDCl3): 8.82ꢀ8.75 (m, 4H), 8.30ꢀ8.27 (m, 2H), 8.07ꢀ8.04 (m,
MHz, CDCl3): 8.73 (s, 1H), 8.11ꢀ8.09 (m, 2H), 8.02ꢀ7.99 (m, 1H), 8.03ꢀ7.97 (m, 5H), 7.76ꢀ7.64 (m, 10H); 13C NMR (125
2H), 7.88ꢀ7.85 (m, 1H), 7.65ꢀ7.63 (m, 1H), 3.92 (s, 3H); 13C MHz, CDCl3): 159.1, 137.2, 136.7, 131.3, 130.8, 130.4, 129.0,
NMR (125 MHz, CDCl3): 166.7, 154.5, 150.9, 142.2, 139.4, 128.6, 126.9, 126.7, 126.6, 126.5, 123.6, 122.9, 122.5; MS (EI,
130.6, 130.1, 126.6, 121.9, 120.2, 52.2; MS (EI, m/z): 291 m/z): 431 (100). Anal.Calcd (%) for C33H21N: C, 91.85; H,
(100).
4.91; N, 3.25. Found: C, 91.76; H, 4.87; N, 3.23.
5h): 1H 2,6-Di-(4-methoxyphenyl)pyridine 6f):37i 1H NMR (500
= 8.8 Hz, 4H), 7.77ꢀ7.65 (m, 1H),
= 8.7 Hz, 4H); 13C NMR (125
Methyl 2'-bromo-[1,1'-biphenyl]-4-carboxylate
NMR (500 MHz, CDCl3): 8.09ꢀ8.07 (m, 2H), 7.67ꢀ7.65 (m, MHz, CDCl3): 8.13 (d,
(
(
J
1H), 7.48ꢀ7.45 (m, 2H), 7.38ꢀ7.34 (m, 1H), 7.31ꢀ7.28 (m, 1H), 7.61ꢀ7.59 (m, 2H), 7.05 (d,
J
7.25ꢀ7.22 (m, 1H), 3.93 (s, 3H); 13C NMR (125 MHz, CDCl3): MHz, CDCl3): 160.3, 156.2, 137.2, 132.1, 128.1, 117.1 113.9,
166.8, 145.5, 141.5, 133.2, 131.0, 129.4, 129.2, 127.4, 122.2, 55.28; MS (EI, m/z): 292 (100).
52.1; MS (EI, m/z): 290 (100).
2-Bromo-4'-methoxy-1,1'-biphenyl
CDCl3): 7.67ꢀ7.65 (m, 1H), 7.38ꢀ7.33 (m, 4H), 7.19ꢀ7.15 (m, 7.78ꢀ7.74 (m, 6H); 13C NMR (125 MHz, CDCl3): 155.5, 142.3,
1H), 6.99ꢀ6.96 (m, 2H), 3.86 (s, 3H); 13C NMR (125 MHz, 137.9, 130.7, 127.2, 125.6, 120.7, 119.7; MS (EI, m/z): 367
CDCl3): 159.0, 142.2, 133.5, 133.1, 131.3, 130.5, 128.4, 127.4, (100).
2,6-Di-(4-trifluoromethylphenyl)pyridine
(5i): H NMR (500 MHz, (500 MHz, CDCl3): 8.24ꢀ8.22 (m, 4H), 7.91ꢀ7.87 (m, 1H),
(
6g):37j 1H NMR
1
122.9, 113.3, 55.2; MS (EI, m/z): 262 (100).
10 | J. Name., 2012, 00, 1-3
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ARTICLE
Dimethyl 4,4'-(pyridine-2,6-diyl)dibenzoate (
6h):37k 1H NMR (m, 1H), 7.55ꢀ7.52 (m, 2H), 7.10ꢀ7.07 (m, 2H), 3.92 (s, 3H);
(500 MHz, CDCl3): 8.21ꢀ8.19 (m, 4H), 8.16ꢀ8.14 (m, 4H), 13C NMR (125 MHz, DMSOꢀd6): 160.4, 156.4, 137.4, 136.8,
7.87ꢀ7.83 (m, 1H), 7.77ꢀ7.75 (m, 2H), 3.94 (s, 6H).; 13C NMR 133.6, 133.4, 132.1, 128.6, 128.2, 127.6, 126.3, 126.2, 126.1,
(125 MHz, CDCl3): 166.8, 155.7, 143.2, 137.8, 130.4, 130.0, 124.7, 118.2, 117.9, 114.0, 55.3; MS (EI, m/z): 311 (100).
126.8, 119.8, 52.2; MS (EI, m/z): 347 (100).
Dimethyl 3,3'-(pyridine-2,6-diyl)dibenzoate
(500 MHz, CDCl3): 8.73ꢀ8.71 (m, 2H), 8.43ꢀ8.41 (m, 2H), 2-(3-Methoxyphenyl)-6-(4-methoxyphenyl)pyridine (
7c): 1H
Anal.Calcd (%) for C22H17NO: C, 84.86; H, 5.50; N, 4.50.
(
6i):37l 1H NMR Found: C, 84.80; H, 5.45; N, 4.47.
8.11ꢀ8.09 (m, 2H), 7.86ꢀ7.84 (m, 1H), 7.78ꢀ7.75 (m, 2H),7.60ꢀ NMR (500 MHz, DMSOꢀd6): 8.16ꢀ8.14 (m, 2H), 7.81ꢀ7.78 (m,
7.56 (m, 2H), 3.96 (s, 6H); 13C NMR (125 MHz, CDCl3): 2H), 7.72ꢀ7.70 (m, 1H), 7.67ꢀ7.64 (m, 2H), 7.45ꢀ7.42 (m, 1H),
167.0, 155.8, 139.5, 137.8, 131.5, 130.5, 130.0, 128.9, 127.9, 7.06ꢀ7.04 (m, 2H), 7.02ꢀ7.00 (m, 1H), 3.95 (s, 3H), 3.91 (s,
119.2, 52.2; MS (EI, m/z): 347 (100).
2,6-Di-(4-trifluoromethoxyphenyl)pyridine
3H); 13C NMR (125 MHz, DMSOꢀd6): 160.4, 159.9, 156.3,
6j): 1H NMR 141.0, 137.3, 131.9, 129.5, 128.2, 119.3, 118.0, 114.4, 114.0,
(
(500 MHz, CDCl3): 8.16ꢀ8.14 (m, 4H), 7.84ꢀ7.80 (m, 1H), 7.67 112.5, 55.3; MS (EI, m/z): 291 (100). Anal.Calcd (%) for
(d,
= 7.9 Hz, 2H), 7.34ꢀ7.32 (m, 4H); 13C NMR (125 MHz, C19H17NO2: C, 78.33; H, 5.88; N, 4.81. Found: C, 78.25; H,
J
CDCl3): 155.5, 149.9, 137.8, 128.3, 121.7, 121.0, 119.1, 118.8; 5.84; N, 4.79.
MS (EI, m/z): 399 (100). Anal.Calcd (%) for C19H11NO2F6: C, 2-(3,4-Dimethoxyphenyl)-6-(4-methoxyphenyl)pyridine
57.15; H, 2.78; N, 3.51. Found: C, 57.09; H, 2.75; N, 3.49.
2,6-Di-(3-methylphenyl)pyridine
6k): 1H NMR (500 MHz, 2H), 7.80 (s, 1H), 7.75ꢀ7.71 (m, 1H), 7.64ꢀ7.62 (m, 1H), 7.57
DMSOꢀd6): 8.03ꢀ7.99 (m, 4H), 7.95ꢀ7.85 (m, 3H), 7.45ꢀ7.39 (d, = 7.8 Hz, 2H), 7.01 (d, = 8.6 Hz, 2H), 6.96 (d, = 8.2
( J = 8.6 Hz,
7d):37n 1H NMR (500 MHz, DMSOꢀd6): 8.09 (d,
(
J
J
J
(m, 2H), 7.30ꢀ7.24 (m, 2H), 2.43 (s, 6H); 13C NMR (125 MHz, Hz, 1H), 4.01 (s, 3H), 3.93 (s, 3H), 3.86 (s, 3H); 13C NMR
DMSOꢀd6): 155.9, 138.8, 138.2, 137.9, 129.8, 128.7, 127.2, (125 MHz, DMSOꢀd6): 160.4, 156.2, 149.8, 149.1, 137.2,
123.9, 118.8, 21.1; MS (EI, m/z): 259 (100). Anal.Calcd (%) 132.5, 132.1, 128.1, 119.4, 117.3, 114.0, 110.9, 110.0, 55.9,
for C19H17N: C, 87.99; H, 6.61; N, 5.40. Found: C, 87.94; H, 55.3; MS (EI, m/z): 321 (100).
6.57; N, 5.37.
2,6-Bis-(3,5-dimethylphenyl)pyridine
Representative procedure for palladium-catalysed synthesis
6l): 1H NMR (500 of diversely substituted pyridines from 2,6-dibromopyridine
(
MHz, DMSOꢀd6): 7.94ꢀ7.91 (m, 1H), 7.86ꢀ7.84 (m, 2H), 7.78 by direct one-pot method
:
(s, 4H), 7.10 (s, 2H), 2.39 (s, 12H); 13C NMR (125 MHz, In a dry Schlenk tube, Pd(OAc)2/ligand 1C (0.5 mol% in 3 mL
DMSOꢀd6): 156.1, 138.9, 138.1, 137.8, 130.6, 124.5, 118.9, 1:1 H2O:CH3CN) solution was stirred under N2 atmosphere. To
21.0; MS (EI, m/z): 287 (100). Anal.Calcd (%) for C21H21N: C, this was added 2,6ꢀdibromopyridine 2a (0.5 mmol), K2CO3 (2.0
87.76; H, 7.37; N, 4.87. Found: C, 87.71; H, 7.33; N, 4.86.
mmol) and the resultant mixture was stirred at room
temperature for 10 minutes after which 4ꢀmethoxyphenyl
Representative procedure for palladium-catalysed synthesis boronic acid 3d (0.6 mmol) and 1ꢀnaphthyl boronic acid (0.6
of diversely substituted pyridines from 2,6-dibromopyridine mmol) 3i were subsequently added and the solution was stirred
by sequential one-pot method
:
at 30 oC for 12 hrs. On completion of the reaction, the resultant
In a dry Schlenk tube, Pd(OAc)2/ligand 1C (0.5 mol% in 3 mL mixture was evaporated under vacuo and the crude product was
1:1 H2O:CH3CN) solution was stirred under N2 atmosphere. To purified using column chromatography (Hexane:EtOAc 90:10)
this was added 2,6ꢀdibromopyridine 2a (0.5 mmol), K2CO3 (1.0 to furnish the diversely arylated pyridine 6d as a colourless
mmol) and the resultant solution was stirred at room solid in 45% yield.
temperature for 10 mins. To this was added 4ꢀmethoxyphenyl 2-(4-Methoxyphenyl)-6-(1-naphthyl)pyridine 8a:
37o 1H NMR
boronic acid 3d (0.6 mmol) and the resultant solution was (500 MHz, DMSOꢀd6): 8.31ꢀ8.28 (m, 1H), 8.12ꢀ8.10 (m, 2H),
o
stirred at 30 C for 12 hrs. After this the reaction mixture was 7.96ꢀ7.95 (m, 2H), 7.90ꢀ7.87 (m, 1H), 7.78ꢀ7.75 (m, 1H), 7.73ꢀ
cooled and to this was added K2CO3 (1.0 mmol) and aryl 7.71 (m, 1H), 7.62ꢀ7.59 (m, 1H), 7.56ꢀ7.49 (m, 3H), 7.04ꢀ7.02
boronic acid (0.6 mmol) and the solution was stirred for further (m, 2H), 3.89 (s, 3H); 13C NMR (125 MHz, DMSOꢀd6): 160.4,
3 hrs at 80 oC. On completion of the reaction, the resultant 158.6, 156.4, 138.8, 137.0, 133.9, 131.9, 131.2, 128.7, 128.3,
mixture was evaporated under vacuo and the crude product was 127.5, 126.2, 125.9, 125.7, 125.2, 122.6, 117.7, 114.0, 55.2;
purified using column chromatography (Hexane:EtOAc 90:10). MS (EI, m/z): 311 (100).
2-(4-Methoxyphenyl)-6-(1-naphthyl)pyridine
(
7a):37m 1H 2-(5-Methylenedioxyphenyl)-6-(4-methoxyphenyl)pyridine
1
NMR (500 MHz, DMSOꢀd6): 8.31ꢀ8.28 (m, 1H), 8.12ꢀ8.10 (m, 8b: H NMR (500 MHz, DMSOꢀd6): 8.13ꢀ8.11 (m, 2H), 7.78ꢀ
2H), 7.96ꢀ7.95 (m, 2H), 7.90ꢀ7.87 (m, 1H), 7.78ꢀ7.75 (m, 1H), 7.74 (m, 2H), 7.67ꢀ7.65 (m, 1H), 7.62ꢀ7.60 (m, 1H), 7.57ꢀ7.55
7.73ꢀ7.71 (m, 1H), 7.62ꢀ7.59 (m, 1H), 7.56ꢀ7.49 (m, 3H), 7.04ꢀ (m, 1H), 7.05ꢀ7.02 (m, 2H), 6.95ꢀ6.93 (m, 1H), 6.06 (s, 2H),
7.02 (m, 2H), 3.89 (s, 3H); 13C NMR (125 MHz, DMSOꢀd6): 3.91 (s, 3H); 13C NMR (125 MHz, DMSOꢀd6): 160.4, 156.1,
160.4, 158.6, 156.4, 138.8, 137.0, 133.9, 131.9, 131.2, 128.7, 155.9, 148.1, 137.3, 134.0, 132.0, 128.1, 120.8, 117.3, 113.9,
128.3, 127.5, 126.2, 125.9, 125.7, 125.2, 122.6, 117.7, 114.0, 108.2, 107.4, 101.1, 55.2; MS (EI, m/z): 305 (100). Anal.Calcd
55.2; MS (EI, m/z): 311 (100).
2-(4-Methoxyphenyl)-6-(2-naphthyl)pyridine
(500 MHz, DMSOꢀd6): 8.63 (s, 1H), 8.35ꢀ8.33 (m, 1H), 8.20ꢀ 2-(4-Methoxyphenyl)-6-(9-phenanthrenyl)pyridine 8c
8.17 (m, 2H), 8.02ꢀ7.98 (m, 2H), 7.92ꢀ7.81 (m, 3H), 7.70ꢀ7.68 NMR (500 MHz, DMSOꢀd6): 8.83ꢀ8.80 (m, 1H), 8.78ꢀ8.75 (m,
(%) for C19H15NO3: C, 74.74; H, 4.95; N, 4.59. Found: C,
(7b): H NMR 74.72; H, 4.91; N, 4.55.
1
:
1H
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1H), 8.27ꢀ8.24 (m, 1H), 8.13ꢀ8.10 (m, 2H), 7.98ꢀ7.96 (m 2H), 1. R. F. Heck, Palladium Reagents in Organic Syntheses
;
7.93ꢀ7.90 (m, 1H), 7.80ꢀ7.77 (m, 1H), 7.73ꢀ7.70 (m 1H), 7.67ꢀ Academic: New York, 1985. b) J. Tsuji, Palladium Reagents
7.59 (m, 2H), 7.56ꢀ7.53 (m 1H), 7.04ꢀ7.02 (m, 2H), 3.89 (s, and Catalysts; Wiley: Chichester, 1995. c) F. Diedrich and P. J.
3H); 13C NMR (125 MHz, DMSOꢀd6): 160.4, 158.9, 156.5, Stang, Metalꢀcatalyzed Crossꢀcoupling Reactions; WileyꢀVCH,
137.5, 137.1, 131.9, 131.4, 130.8, 130.4, 128.9, 128.4, 128.3, New York, 1998
.
126.9, 126.8, 126.7, 126.6, 126.4, 122.8, 122.7, 122.5, 117.9, 2. a) K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem.
114.0, 55.3; MS (EI, m/z): 361 (100). Anal.Calcd (%) for Int. Ed., 2005, 44, 4442. b) K. C. Majumdar, B. Sinha,
C26H19NO: C, 86.40; H, 5.30; N, 3.88. Found: C, 86.35; H, Synthesis, 2013, 45, 1271. c) J. Yamaguchi, A. D. Yamaguchi,
5.28; N, 3.85.
K. Itami, Angew. Chem. Int. Ed., 2012, 51, 8960.
Catalyst Poisoning Experiments
:
3. A. Molnar, (Ed.) In PalladiumꢀCatalysed Coupling
Reactions: Practical Aspects and Future Developments; Wileyꢀ
a) Hg drop experiments
:
To a 3.0 ml (0.1 mol%) of catalyst stock solution, 0.235 g (1.0 VCH, Weinheim, 2013
.
mmol) of 2,6ꢀdibromopyridine and 0.152 g (1.0 mmol) of 4ꢀ 4. a) K. Öfele, J. Organomet. Chem., 1968, 12, 42. b) H. W.
methoxy phenylborornic acid and potassium carbonate (2.0 Wanzlick, H. J. Schonherr, Angew. Chem. Int. Ed., 1968,
mmol, 0.276 g) were added at 30 C followed by a drop of 141.
7
,
o
Mercury (300 Equiv.).
5. a) W. A. Herrmann, C. Kocher, Angew. Chem. Int. Ed., 1997,
36, 2162. b) W. A. Herrmann, Angew. Chem. Int. Ed., 2002, 41
1290. c) R. Visbal, M. C. Gimeno, Chem. Soc. Rev., 2014, 43
,
,
b) CS2 poisoning test
:
To a 3.0 ml (0.1 mol%) of catalyst stock solution, 0.235 g 3551. d) M. N. Hopkinson, C. Richter, M. Schedler, F. Glorius,
(1.0 mmol,1.0 equiv.) of 2,6ꢀdibromopyridine and 0.152 g (1.0 Nature, 2014, 510, 485.
mmol, 1.0 equiv.) of 4ꢀmethoxy phenylborornic acid and 6. a) D. Enders, O. Niemeier, A. Henseler, Chem. Rev., 2007,
potassium carbonate (2.0 mmol, 0.276 g) were added and then 107, 5606. b) M. Fevre, J. Pinaud, Y. Gnanou, J. Viqnolle, D.
0.1 mol% (1 ml from stock solution) of carbon disulfide (CS2) Taton, Chem. Soc. Rev., 2013, 42, 2142.
was added.
7. A. J. Arduengo, R. L. Harlow, M. Kline, J. Am. Chem. Soc.,
1991, 113, 361.
[stock solution: 0.0076g(0.006ml) of CS2 in 100 ml of MeCN]
8. A. J. Arduengo, Acc. Chem. Res., 1999, 32, 913.
To a 3.0 ml (0.1 mol%) of catalyst stock solution, 0.235 g (1.0 9. a) L. Mercs, M. Albrecht, Chem. Soc. Rev., 2010, 39, 1903.
mmol, 1.0 equiv.) of 2,6ꢀdibromopyridine and 0.152 g (1.0 b) W. Li and R. Gust, Chem. Soc. Rev., 2013, 42, 755. c) D. C.
mmol 1.0 equiv.) of 4ꢀmethoxy phenylborornic acid and F. Monteiro, R. M. Phillips, B. D. Crossley, J. Fielden, C. E.
potassium carbonate (2.0 mmol, 0.276 g) were added and then Willans, Dalton Trans., 2012, 41, 3720. d) A. R. Kapdi, I. J. S.
1.0 mmol (0.076 g, 1.0 equiv.) of carbon disulfide (CS2) was Fairlamb, Chem. Soc. Rev., 2014, 43, 4751.
added at 30 oC.
10. a) E. A. Kantchev, C. J. Obrien, M. G. Organ, Angew.
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A.R.K. would like to acknowledge the Department of Science Takeuchi, N. Fujikawa, T. Fukuda, F. Ishibashi, Tetrahedron
and Technology for the DST Inspire Faculty award (IFA12- Lett. 2003, 44, 4443. e) Y. Zhang, S. T. Handy, The Open
CH-22) providing Ph.D. fellowship to D.P. Alexander von Organic Chemistry Journal, 2008,
2, 58. f) C. Sicre, J. L.
Humboldt Foundation is also thanked for the equipment grant AlonsoꢀGomez, M. M. Cid, Tetrahedron, 2006, 62, 11063. g)
to A. R. K.
S. Theeramunkong, A. Caldarelli, A. Massarotti, S. Aprile, D.
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