Ortho-(Dimesitylboryl)phenylphosphines: Positive boryl effect in the palladium-catalyzed suzuki-miyaura coupling of 2-chloropyridines

Article abstract of DOI:10.1002/adsc.201201100

Catalytic systems combining ortho-(dimesitylboryl) phenylphosphines and palladium precursors have been evaluated in the Suzuki-Miyaura couplings of chloro-N-heterocycles, in particular 2-chloro pyridines, with arylboronic acids. The Lewis basic character of the substrates does not interfere with the Lewis acidic site of the ligands, even for a substrate featuring free NH₂ groups. The influence of several reaction parameters has been studied and the ortho-dimesitylboryl moiety was actually found to substantially enhance the catalytic performance. The role of this group has been examined using preformed phosphine-borane/Pd complexes and the formation of an original phosphine/h4-boratabutadiene complex has been identified as a possible deactivation pathway. Regioselective coupling of 2,6-dichloro-3-nitropyridine with phosphine-borane/Pd catalysts has also been explored, and sequential double cross-couplings were found to give a direct and efficient access to unsymmetrical 2,6-diarylpyridines.

Full text of DOI:10.1002/adsc.201201100

FULL PAPERS
DOI: 10.1002/adsc.201201100
ortho-(Dimesitylboryl)phenylphosphines: Positive Boryl
Effect in the Palladium-Catalyzed Suzuki–Miyaura Coupling of
2-Chloropyridines
Raluca Malacea,a,b Faouzi Chahdoura,a Marc Devillard,a Nathalie Saffon,c
Montserrat Gꢀmez,a,* and Didier Bourissoua,*
a
Universitꢁ de Toulouse, UPS, LHFA, 118 route de Narbonne, F-31062 Toulouse Cedex 9, France and CNRS, LHFA UMR
5069, 31062 Toulouse Cedex 9, France
Fax : (+33)-56-155-8204; phone: (+33)-56-155-7738 or (+33)-56-155-8204; e-mail: gomez@chimie.ups-tlse.fr or
dbouriss@chimie.ups-tlse.fr
Current address: Universitꢁ de Bourgogne, Institut de Chimie Molꢁculaire de l’Universitꢁ de Bourgogne (ICMUB),
b
UMR CNRS 6302, 9 avenue Alain Savary, 21078 Dijon Cedex, France
Institut de Chimie de Toulouse, FR 2599, Universitꢁ Paul Sabatier, 118 route de Narbonne, 31062 Toulouse Cedex 9,
c
France
Received: December 17, 2012; Revised: June 11, 2013; Published online: August 9, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201201100.
Abstract: Catalytic systems combining ortho-(dimesi- formed phosphine-borane/Pd complexes and the for-
tylboryl)phenylphosphines and palladium precursors mation of an original phosphine/h4-boratabutadiene
have been evaluated in the Suzuki–Miyaura cou- complex has been identified as a possible deactiva-
plings of chloro-N-heterocycles, in particular 2- tion pathway. Regioselective coupling of 2,6-di-
chloroACHTUNGTRENNUNGpyridines, with arylboronic acids. The Lewis chloro-3-nitropyridine with phosphine-borane/Pd cat-
basic character of the substrates does not interfere alysts has also been explored, and sequential double
with the Lewis acidic site of the ligands, even for cross-couplings were found to give a direct and effi-
a substrate featuring free NH2 groups. The influence cient access to unsymmetrical 2,6-diarylpyridines.
of several reaction parameters has been studied and
ꢀ
the ortho-dimesitylboryl moiety was actually found Keywords: C Cl bond activation; N-heterocycles;
to substantially enhance the catalytic performance. palladium; phosphine-boranes; regioselective cou-
The role of this group has been examined using pre- pling; Suzuki–Miyaura cross-couplings
Introduction
anchor incoming substrates (in Rh-catalyzed hydroge-
nation, hydrosilylation and hydroformylation).[4]
Ligand modulation keeps playing a central role in the Quite disappointingly, the incorporation of boronates
development of organometallic catalysis in general or benzoxaborolidine fragments did not have a major
and of Pd-catalyzed cross-coupling reactions in partic- impact, and essentially identical catalytic behaviour
ular.[1] In that respect, phosphines are prominent scaf- was observed between A/B, and the corresponding
folds and subtle variations of the phosphorus environ- boron-free diphosphines (Figure 1). Over the last few
ment (modulation of the electronic properties and years, phosphine-boranes have attracted a surge of in-
steric shielding, incorporation of secondary coordina- terest, stimulated by their envisioned and now recog-
tion sites, etc.) have allowed significant progress to be nized ability to engage into unusual coordination
achieved in terms of activity and selectivity.[2]
Phosphine-boranes are archetypes of ambiphilic li- tion).[5,6]
modes (especially P!M!B bridging coordina-
gands combining a phosphine and a Lewis acid
The availability of a broad range of phosphine-bor-
moiety.[3] They have been very sporadically investigat- anes and their versatile coordination properties have
ed in transition metal catalysis, although the addition- stimulated renewed interest for their applications in
al borane group offers a true potential for catalytic catalysis. We have started to explore the use of ortho-
enhancement. In the 1990s, Kagan and Landis investi- (dimesitylboryl)phenylphosphines in model Rh-cata-
gated the possibility of the Lewis acid moiety to lyzed hydroformylation and Pd-catalyzed Suzuki–
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ortho-(Dimesitylboryl)phenylphosphines: Positive Boryl Effect
Results and Discussion
Cross-Couplings of Chloro-N-heterocycles and
Arylboronic Acids Catalyzed by Phosphine-Borane/
Pd Systems
With the aim to apply palladium catalytic systems
containing phosphine-boranes 1 and 2 in the synthesis
of functionalized heterocycles, we first studied the
cross-coupling of 2-chloropyridine with phenylboronic
acid as model reaction. Gratifyingly, the basic nitro-
gen atom of the substrate did not interfere with the
Lewis acidic site of the phosphine-borane ligand and
the cross-coupling reaction proceeded efficiently. The
catalytic species were generated in situ from the cor-
responding palladium precursor in the presence of the
appropriate phosphine-borane ligand. Using 1 and
Figure 1. Phosphine-borane ligands evaluated in transition
metal catalysis.
[PdCl2ACHTNUTRGNE(NUG cod)] as starting catalytic species, a good yield
of the desired product 2-phenylpyridine was obtained
(65%), higher in relation to that obtained from
[Pd(ma)
Miyaura cross-coupling reactions.[7] Thereby, unex- nadiene) (entries 1 and 2, Table 1). The catalytic
pected analogies were disclosed between ligands system based on [Pd2A(dba)3] was significantly less effi-
ACHTUNGTRENUN(NG nbd)] (ma=maleic anhydride; nbd=norbor-
CTHUNGTRENNUNG
1 and 2 (Figure 1), and Buchwald-type biarylphos- cient (entry 3, Table 1). No important differences
phines.[8] Complexes deriving from diphosphine-bor- were observed between Pd/2 and Pd/1 (entry 4 vs.
anes of type C have also been recently evaluated in entry 1, Table 1). The yield increased when the
transition metal catalysis (Figure 1).[9] Peters showed PhB(OH)2/substrate ratio was increased to 1.5/1 (en-
the ability of an Ni complex to activate reversibly H2 tries 5 and 6, Table 1), giving up to 94% of 2-phenyl-
and promote the catalytic hydrogenation of olefins.[9a] pyridine.
In addition, some “boron enhancement effect” has
been evidenced by Nakazawa with Rh (but not Ir) substrates using the [PdCl
complexes in the transfer hydrogenation of keto- (Table 2). Remarkably, no major difference was ob-
nes.[9b,10]
served between 2-, 3- or 4-chloropyridine and isolated
Some other chloro-N-heterocycles were tested as
CTHUNGTRENNUNG
Here we report an advanced evaluation of phos- yields higher than 90% were systematically obtained
phine-boranes 1 and 2 in Pd-catalyzed Suzuki– after 20 h (entries 1 and 2). Pyrimidine, pyrazine,
Miyaura reactions. Given the importance of this quinoline and quinazoline substrates were also effi-
cross-coupling for the preparation of heterobiaryl de- ciently coupled (as for 2-chloropyridine, yields reach
rivatives,[11] the reaction of chloro-N-heterocycles, in 90–93% after 20 h) (entries 3–6).
particular 2-chloropyridines, has been investigated.
The ability of our L/Pd catalytic systems to cross-
The Lewis acid moiety of the ligand proved to be couple N-heterocycles and Ph-B(OH)2 prompted us
compatible with the Lewis basic character of the sub-
strates, even those featuring free NH2 groups, and the
Table 1. Suzuki–Miyaura cross-coupling reactions of 2-
chloro
pyridine catalyzed by Pd/L systems (see Figure 1).[a]
ACHTUNGTRENNUNG
ortho-dimesitylboryl moiety was actually found to
have a very positive effect on the catalytic perfor-
mance. The influence of several reaction parameters
has been examined. Catalytic experiments with pre-
formed phosphine-borane/Pd complexes have provid-
ed some insight into the role of the BMes2 group and
Entry
Pd precursor
[PdCl2A(cod)]
Ligand
Yield[b] [%]
1
2
3
G
E
1
1
1
2
1
1
65 (46)
49 (19)
24 (10)
62 (44)
94 (77)
69 (21)
[Pd(ma)(nbd)]
[Pd2A(dba)3]
[PdCl2A(cod)]
[PdCl2A(cod)]
[Pd2A(dba)3]
ACHTUNGTRENNUNG
A
CHTUNGTRENNUNG
ꢀ
C H activation of one of the mesityl groups has been
4
A
CHTUNGTRENNUNG
5[c]
6[c]
A
CHTUNGTRENNUNG
identified as a possible deactivation pathway. The pos-
sibility to achieve regioselective couplings from 2,6-di-
chloro-3-nitropyridine has also been explored, and se-
quential double cross-couplings gave a direct and effi-
cient access to unsymmetrical 2,6-diarylpyridines.
A
CHTUNGTRENNUNG
[a]
Results from duplicate experiments. Reaction conditions:
1 mmol of substrate; 2 mL of toluene; K3PO4/Ph-
B(OH)2/I/Pd=2.1/1.1/1/0.01; L/Pd=2; 1008C; 20 h.
Determined by H NMR using 2-methoxynaphthalene as
internal standard; in brackets, yields at 5 h.
[b]
[c]
1
Ph-B(OH)2/I=1.5.
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Table 2. Suzuki–Miyaura cross-couplings of chloro-N-hetero-
cycles catalyzed by 1/Pd system.[a]
Table 3. Suzuki–Miyaura cross-coupling reactions of amino-
2-chloropyridines catalyzed by 1/Pd systems.[a]
Entry
Substrate
Product
Yield[b] [%]
1
93
2[c]
93
Entry Pd precursor
Substrate Conv.[b] [%] Yield[b] [%]
1
2
3
4
5
6
7
8
N
G
III
III
97
95
100
59
30
14
32
27
92
94
98
42
16
0
3
4
5
91
91
90
CHTUNGTRENNUNG
V
V
V
VII
C
21
21
[a]
6
93
Results from duplicate experiments. Reaction conditions:
1 mmol of substrate; 2 mL of toluene; K3PO4/Ph-
B(OH)2/substrate/Pd=2.1/1.1/1/0.01; 1/Pd=2.
Conversions and yields determined by H NMR using 2-
methoxynaphthalene as internal standard.
[a]
Results from duplicate experiments. Reaction conditions:
1 mmol of substrate; 2 mL of toluene; K3PO4/Ph-
[b]
1
B(OH)2/substrate/Pd=2.1/1.5/1/0.01; 1/
1008C; 20 h.
Isolated yields.
ACHUTGTNRNE[NUG PdCl2HCATUNGTRENN(UGN cod)]=2;
[b]
[c]
steric shielding is also likely to play a significant role
for the 3-amino substrate V.
Substrate used as hydrochloride salt.
For the 4-amino substrate III, the catalytic influ-
to study Suzuki–Miyaura reactions using polysubsti- ence of various parameters was then studied, includ-
tuted pyridines and we turned our attention to amino- ing the metal precursor, the nature of the ligand, the
chloropyridines. The introduction of electron-rich sub- boronic acid/chloropyridine ratio and the ligand/Pd
stituents such as amino groups at the pyridine ring ratio (Table 4). With the diphenylphosphine-dimesi-
ꢀ
makes the C Cl bond activation more difficult. In ad- tylborane ligand 1, the nature of the organometallic
dition, it increases the basicity of the pyridine nitro- precursor, Pd(II) or Pd(0), had little influence and es-
gen and thus favours N coordination over oxidative sentially identical results were obtained with [PdCl2
ꢀ
addition of the C Cl bond. In this area, substrates
ACHUTGTNRENU(NG cod)] and [Pd2ACHTUNGTERN(NUGN dba)3] (entries 1 and 2). The related
featuring free NH2 groups are most challenging. Pro- di(isopropyl)phosphine-dimesitylborane ligand 2 be-
tection/deprotection is usually necessary to achieve haved somewhat differently (entries 3 and 4). It is less
efficient cross-coupling[12] and to avoid Buchwald– efficient (conversions of ca. 44% were obtained with
Hartwig amination of chloroaminopyridine sub- both Pd precursors), and in this case, the yield in cou-
strates.[13] So far, direct couplings of unprotected sub- pling product IV was higher with [Pd
CHTUNGTERN(NUNG dba)3] than
2A
strates remain rather scarce, although significant using [PdCl2AHCTUNGTERNGN(UN cod)] (41 vs. 26%, entries 3 and 4).
progress has been achieved recently in this area Whereas sterically demanding alkyl substituents usu-
thanks to the fine tuning of the ligand structure and ally increase the activity of phosphines in cross-cou-
reaction conditions.[14,15] The ability of 1/Pd systems to pling reactions, such an effect is not observed here
mediate the coupling of phenylboronic acid and ami- and the diphenylphosphine-borane 1 gives significant-
nochloropyridines III, V and VII was first evaluated ly better results.
with different Pd precursors (Table 3). For 4-amino-2-
chloropyridine, the coupling product IV was obtained onic acid and aminochloropyridine III was then evalu-
in high yields (up to 98%; entries 1–3), without signif- ated with two catalytic systems, namely 1/[PdCl2A(cod)]
icant formation of side-products (less than 5%). For or 2/[Pd2A(dba)3]. In both cases, no catalytic improve-
The influence of the ratio between the phenylbor-
A
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
3- and 5-amino substrates V and VII, conversions and ment was noticed with 1.5 equiv. of phenylboronic
yields were much lower (entries 4–6 and 7, 8, respec- acid (entries 6, 7 vs. 1, 4, respectively), probably due
tively). This indicates that 1/Pd systems are very sensi- to the high chemoselectivity of these phosphine-
tive to electronic and steric factors. When placed in borane/Pd systems for cross-coupling over undesirable
the ortho or para position to chlorine, the NH2 group processes (such as proto-deboronation, homo-cou-
disfavours the oxidative addition step (to an even pling, etc.). The effect of the ligand to Pd ratio was
greater extent in the 5-amino derivative VII), and also examined for the 1/ACHTNUGTRENN[UG Pd2ACHTUNTGERN(NGUN dba)3] system. Quite re-
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ortho-(Dimesitylboryl)phenylphosphines: Positive Boryl Effect
Table 4. Suzuki–Miyaura cross-coupling reactions between 4-amino-2-chloropyridine and aryl boronic acids catalyzed by L/
Pd systems.[a]
Entry
Pd precursor, L (L/Pd)
[PdCl2A(cod)], 1 (2/1)
ArB(OH)2/III[b]
Conv.[c] [%]
Yield[c] [%]
1
2
3
4
5
6
7
8
G
G
1.1 (R=H)
1.1 (R=H)
1.1 (R=H)
1.1 (R=H)
1.1 (R=H)
1.5 (R=H)
1.5 (R=H)
1.1 (R=H)
1.1 (R=H)
1.1 (R=H)
1.1 (R=Me)
1.1 (R=Me)
1.1 (R=Me)
1.5 (R=H)
1.5 (R=H)
97 (96)
95 (89)
42 (16)
46 (45)
24 (24)
97 (93)
42 (43)
94 (87)
93
92 (92)
92 (89)
81 (79)
100
92 (90)
94 (86)
26 (16)
41 (41)
11 (6)
95 (87)
38 (15)
92 (74)
81
79 (64)
86 (80)
75 (73)
91
A
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
9
A
CHTUNGTRENNUNG
10
11
12
13[e]
14[f]
15[f]
A
U
A
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
1-Pd
1’-Pd
96 (95)
40 (37)
92 (84)
33 (29)
[a]
Results from duplicate experiments. Reaction conditions: 1 mmol of III; 2 mL of toluene; K3PO4/III/Pd=2.1/1/0.01.
[b]
[c]
In brackets the substituent on the arylboronic acid.
1
Conversions and yields determined by H NMR using 2-methoxynaphthalene as internal standard. In brackets, the results
obtained after 5 h of reaction.
3=(2’,4’,6’-triisopropyl-[1,1’-biphenyl]-2-yl)-diphenylphosphine.
After 5 h.
[d]
[e]
[f]
Preformed complex as catalytic precursor (Scheme 1).
markably, essentially identical results (94% conver- nylboronic acids was then examined. With 2-methyl-
sion, 92% yield) were obtained with only one equiva- phenylboronic acid, the coupling product IX was ob-
lent of phosphine-borane 1 per metal center (entry 8 tained in high yield (86%) and good chemoselectivity
vs. entry 2). On the other hand, the use of an excess (side-products <6%) using
1
and [Pd2ACHTUNGTRENNUNG(dba)3]
of phosphine-borane (5 equiv.) had a negative effect: (entry 11).[16] Here also, the dialkylphosphine ligand 2
the conversion was essentially the same, but the selec- proved to be less efficient than 1 (81% conversion,
tivity dropped and the yield in the coupling product 75% yield, entry 12), but the difference between the
IV was about 10% lower (entry 9 vs. entry 8).
two phosphine-boranes is smaller than that observed
A positive effect of the BMes2 moiety on catalytic with phenylboronic acid. In addition, the biarylphos-
activity was supported by comparing the catalytic be- phine 3 surpassed 1 in this case (100% conversion,
haviour of Pd/1 with that of related systems Pd/PPh3 91% yield, entry 13), suggesting that the phosphine-
and Pd/3. The Pd/PPh3 catalyst gave low activity in borane ligands are more sensitive to the steric shield-
contrast to Pd/1: only 11% yield of IV vs. more than ing of the substrates. Consistently, the 2,6-dimethyl-
92% (entry 5 vs. entries 1 and 2). The sterically de- phenylboronic acid could not be efficiently coupled
manding biarylphosphine 3 {(2’,4’,6’-triisopropyl-[1,1’- with either of the phosphine-borane 1 and 2.[17]
biphenyl]-2-yl)-diphenylphosphine} was chosen as
a representative member of the very efficient Buch-
wald-type ligands. The two catalytic systems Pd/1 and Synthesis and Catalytic Evaluation of Preformed
Pd/3 gave similar conversions (~93%, entries 8 and Phosphine-Borane Complexes: Towards a Better
10), but a significantly higher yield was obtained with Understanding of the Boryl Effect
the phosphine-borane 1 (92 vs. 79%, entry 8 vs
entry 10).
At this stage, the catalytic properties of preformed
To assess the influence of steric effects, the coupling complexes deriving from the phosphine-borane ligand
of 4-amino-2-chloropyridine III with substituted phe- 1 were also evaluated to better assess the contribution
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According to NMR spectroscopy, one of the Mes
ꢀ
group at boron underwent C H activation and diag-
nostic signals for a CH2 group are observed both in
1H (AB system, d=4.63 and 2.93 ppm, JH,H =2 Hz)
and 13C (d=62.49 ppm, JC,P =39 Hz) NMR spectra. In
addition, the 11B NMR resonance signal for 1’-Pd (d=
52.8 ppm) is shifted upfield by about 10 ppm (d=
69.4 ppm for 1-Pd), suggesting the presence of some
Pd!B interaction.[6] The precise structure of complex
1’-Pd was figured out by X-ray diffraction analysis.
Actually, one of the Mes groups at boron underwent
ꢀ
an original C H activation process. In addition to the
phosphorus and iodine atoms, the metal center is
bonded to a BCCCH2 fragment whose geometry re-
mains essentially planar. The Pd/C distances range
from 2.15 to 2.33 ꢃ, and the Pd/B distance is short
[2.395(4) ꢃ]. The overall structure of 1’-Pd is very
similar to that reported recently by Hoefelmeyer for
the compound obtained upon reacting 8-
(BMes2)quinoline with [PdCl2ACHTUNTRGNEUNG
(PhCN)2].[20] Complexes
featuring acyclic boron-containing p-ligands are rela-
tively scarce,[21] and complex 1’-Pd represents a rare
example of a h4-boratabutadiene complex.[22]
The exact mechanism for the transformation of 1-
Pd into 1’-Pd remains unclear at this stage,[23] but
ꢀ
there are a few precedents for such concomitant Ar
Scheme 1. Reaction of complex 1-Pd with iodobenzene
(ma=maleic anhydride); and molecular structure of the en-
suing complex 1’-Pd (ellipsoids drawn at 50% probability
and hydrogen atoms omitted for clarity, except for H on
CH2).
[24]
ꢀ
X and phosphine ligand C H activation.
In addi-
tion, the reaction of 1-Pd with p-nitroiodobenzene
also gave 1’-Pd, and the concomitant formation of p-
nitrobenzene could be unequivocally identified by gas
chromatography.
Noteworthy, complex 1’-Pd proved to be signifi-
of the BMes2 group. We first used the previously de- cantly less active than 1-Pd in the cross-coupling of 4-
scribed complex 1-Pd featuring a weak p interaction amino-2-chloropyridine III with phenylboronic acid
between one of the Mes groups and Pd.[7b] Within the (37–40% conversion, compared with 95–96%; see en-
ꢀ
margin of error we obtained the same results as with tries 14 and 15, Table 4). The C H activation process
the related in situ generated catalytic system (96% undergone by the phosphine-borane ligand from 1-Pd
conversion, 92% yield of IV after 20 h, see entry 14, to 1’-Pd is thus detrimental to the catalytic efficiency
Table 4). This parallels what was observed with 4-bro- and may represent in that regard a deactivation path-
moanisole as model substrate[7b] and further support- way.[25]
ed the contribution of weak p-arene coordination
from BMes2 to Pd, akin to that commonly envisioned
with biarylphosphines.[18] With the aim of characteriz- Double Suzuki–Miyaura Cross-Coupling, Synthesis of
ing a more advanced catalytic intermediate, complex Unsymmetrical 2,6-Diarylpyridines
1-Pd
was
then
treated
with
iodobenzene
(1.25 equiv.).[19] The reaction proceeded only at high Polysubstituted pyridines are ubiquitous structural
temperature and was complete in ca. 1 h at 1008C motifs. They have found applications in many areas
(Scheme 1). Under these conditions, significant de- ranging from biologically active compounds,[26] coordi-
composition occurred (as apparent from the forma- nation complexes,[27] advanced functional materials,[28]
tion of black Pd and free ligand), but a new complex etc. This widespread interest prompts chemists to de-
1’-Pd was formed. After standard work-up and purifi- velop efficient synthetic routes and recently, regiose-
cation by column chromatography on silica gel, com- lective Pd-catalyzed coupling reactions have emerged
plex 1’-Pd was isolated in 26% yield as a yellow as a valuable and promising approach.[29,30] In this
powder. Mass spectrometry and elemental analysis context, selective functionalization of polyhalogenat-
are not consistent with simple oxidative addition of ed heteroaromatic compounds is most attractive as it
iodobenzene at palladium, but clearly indicate the in- may afford a straightforward access to polysubstituted
corporation of iodine and release of maleic anhydride. heterocycles.
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ortho-(Dimesitylboryl)phenylphosphines: Positive Boryl Effect
Table 5. Suzuki–Miyaura cross-coupling reactions between 2,6-dichloro-3-nitropyridine and phenylboronic acid (relative
ratio 1/2.2) catalyzed by L/Pd systems.[a]
Entry
Pd precursor, L
Time [h]
Yields[b] [%]
XI-C2
XI-C6
XI-C2,6
1
2
3
4
5
6
7
8
N
(cod)], 1
5
20
5
20
5
20
5
35.0
30.0
9.7
5.7
17.8
8.0
<1
<1
<1
0
<1
0
56.4
62.0
83.8
92.8
79.2
87.4
84.0
95.4
G
E
N
N
10.5
0.7
<1
0
20
[a]
Results from duplicate experiments, quantitative conversions. Reaction conditions: 1 mmol of X; 2 mL of toluene; K3PO4/
X/Ph-B(OH)2/Pd=2.1/1/2.2/0.01; L/Pd=2.
Determined by GC, based on calibration curves and using 2-methoxynaphthalene as internal standard. Less than 4% of
[b]
biphenyl was observed in any case.
In this respect and as an extension of the results de- (less than 1% of XI-C6 was observed),[32] and the ini-
scribed above on Suzuki–Miyaura cross-coupling of 2- tially formed mono-cross-coupled product XI-C2
chloropyridines, we became interested in using our evolves into XI-C2,6 at longer times (entry 1 vs.
phosphine-borane/Pd catalytic systems for the regio- entry 2 and entry 3 vs. entry 4). The catalytic trend
selective preparation of polyarylated pyridines. Adja- observed using [Pd
cent coordinating ester or amide groups have been observed with [PdCl
shown to impart good selectivity in the coupling of precursors gave about the same results with the phos-
2,6-chloropyridines.[31] We were keen to see whether phine-borane 2, while [Pd
2A(dba)3] showed slightly
the high sensitivity of phosphine-borane/Pd systems higher activity than [PdCl2A(cod)] with ligand 1. Ac-
towards substrate substitution may enable us to ach- cordingly, higher yields of the diphenylpyridine XI-
ieve selective couplings. For this purpose, we chose C2,6 were obtained with [Pd2A(dba)3] (88%, entry 6)
2,6-dichloro-3-nitropyridine X as a model of an un- than with [PdCl2A(cod)] (62%, entry 2). This suggests
symmetrically substituted substrate and investigated that the [Pd2A(dba)3]/1 catalytic system activates more
its cross-coupling with arylboronic acids. readily the C-6 Cl bond than [PdCl
First, we evaluated the activity of L/Pd systems consequence displays lower selectivity between the C-
(dba)3] was quite similar to that
CTHUNGTRENNUNG
CTHUNGTRENNUNG
CTHUNGTRENNUNG
CTHUNGTRENNUNG
CTHUNGTRENNUNG
CTHUNGTRENNUNG
ꢀ
2ACHTUNGTREN(NNUG cod)]/1 and in
ꢀ
ꢀ
(L=1 and 2) for the coupling of X with phenylboron- 2 Cl and C-6 Cl bonds of X.
ic acid [X/PhB(OH)2 =1/2.2] at 1008C (Table 5). The With the aim to achieve selective activation of the
ꢀ
reaction gave rise to three different coupling prod- most reactive C-2 Cl bond of X, coupling reactions
ucts: the two regioisomeric chlorophenylpyridines, re- were then carried out with only 1.1 equiv. of Ph-
ferred to as XI-C2 and XI-C6, and the diphenyl-sub- B(OH)2 (Table 6). In agreement with previous obser-
stituted pyridine XI-C2,6. An X-ray diffraction study vations, the 2/ACTHNUTRGENNUG[PdCl2ACHTUNGTRNE(NUGN cod)] catalytic system (entry 2)
was performed on XI-C6 in order to reliably assign was the most active (96% conversion). The chloro-
the regioisomeric structures of the mono-coupled phenylpyridine XI-C2 was obtained as major product
products (see Figure S1 in the Supporting Informa- (62.3% yield) along with small amounts of the regio-
tion).
With [PdCl
ACHTUNGTRENNUNG(isopropyl)phosphine-borane ligand 2 afforded the
ACHTUNGTRENNUNG
2A
double cross-coupled product XI-C2,6 in very high Pd system (entry 3) proved to be less active (76%
yield (up to 93% yield based on X, see entries 3 and conversion) and less selective: in this case, the major
4). Under the same conditions, the diphenylphos- product was the diphenylpyridine XI-C2,6 (24.5%
phine-borane ligand 1 was less selective, giving ap- yield), and the mono-cross-coupled product XI-C2
proximately 60% of XI-C2,6 and 35% of the mono- represents only ca. 23% yield.[33] In all cases, only bi-
cross-coupled product XI-C2 (entries 1 and 2). Both phenyl was observed as by-product (less than 4% for
ꢀ
systems preferentially activated the C-2 Cl bond of X any of the three catalytic systems, Pd/1, Pd/2 and Pd/
Adv. Synth. Catal. 2013, 355, 2274 – 2284
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FULL PAPERS
Table 6. Suzuki–Miyaura cross-coupling reactions between
2,6-dichloro-3-nitropyridine and phenylboronic acid cata-
lyzed by Pd/L systems (see scheme of Table 5).[a]
Entry
L
Conv. [%][b]
Yields [%][b,c]
XI-C2
XI-C6
XI-C2,6
1
2
1
2
3
1
1
88
96
76
89
76
73.0
62.3
23.4
60.0
55.5
2.0
11.0
2.2
10.3
6.5
8.5
10.0
24.5
5.5
3[d]
4[e]
5[f]
3.3
[a]
Results from duplicate experiments. Reaction conditions:
1 mmol of X; 2 mL of toluene; K3PO4/X/Ph-
B(OH)2/ACHTUNGTRENNUNG[PdCl2ACHTUNGTRENNUNG(cod)]=2.1/1/1.1/0.01; L/Pd=2; [PdCl2
ACHTUNGTRENNUNG(cod)] as palladium precursor; reaction time: 20 h;
1008C. See Table S1 in the Supporting Information for
results at 5 h.
[b]
[c]
Determined by GC, based on calibration curves and
using 2-methoxynaphthalene as internal standard.
Yields were calculated on the basis of X; given that only
1.1 equiv. of Ph-B(OH)2 were employed, 50.5% is the
highest yield achievable for XI-C2,6.
Scheme 2. Synthesis of the unsymmetrical 2,6-diarylpyridine
XII by cross-coupling of XI-C2 with ortho-tolyl boronic
acid; and crystal structure of XII (ellipsoids drawn at 50%
probability and hydrogen atoms omitted for clarity).
[d]
3=(2’,4’,6’-triisopropyl-[1,1’-biphenyl]-2-yl)-diphenyl-
phosphine.
[e]
[f]
Pd
ACHTUNGTRENNUNG(OAc)2 as palladium precursor.
At 808C; data at 72 h.
XII was thereby obtained in 62% isolated yield and
3). The selectivity in mono-cross-coupled product XI- its molecular structure was secured by an X-ray dif-
C2 reached 73% yield with the diphenylphosphine- fraction study.
borane ligand 1, with only 8.5% of double cross-cou-
To further illustrate the synthetic interest of our ap-
pled product XI-C2,6 (entry 1). Lowering the reaction proach, we then prepared the regioisomeric unsym-
temperature from 100 to 808C (entry 5) triggered metrical 2,6-diarylpyridine XIII, simply by inverting
somewhat lower conversion and XI-C2 was obtained the order of reaction of the two boronic acids
in 55.5% yield (with 6.5 and 3.3% yields of XI-C6 (Scheme 3). Successive reactions of 2,6-dichloro sub-
and XI-C2,6 respectively). Replacing [PdCl
2ACHTUNGRTEN(NUNG cod)] for strate X with ortho-tolylboronic acid (1.1 equiv.) and
Pd(OAc)2, the conversion remains unchanged, but the phenylboronic acid (1.1 equiv.) afforded XIII with an
ACHTUNGTRENNUNG
selectivity towards the formation of XI-C2 slightly de- overall isolated yield of 57% (without optimization).
creases (entry 1 vs. entry 4) (see Table S1 in the Sup- The molecular structure of XIII was unambiguously
porting Information for catalytic experiments using ascertained by an X-ray diffraction analysis.
[Pd2ACHTUNGTRENNUNG(dba)3]).
This study reveals that Pd catalysts deriving from
the phosphine-boranes 1 and 2 are able to promote Conclusions
the cross-coupling of 2,6-dichloro-3-nitropyridine X
with relatively high selectivity for the activation of Palladium catalysts derived from the phosphine-
ꢀ
the C-2 Cl bond. Comparatively, the biarylphosphine borane ligands 1 and 2 have been successfully applied
3 does not enable us to discriminate efficiently the in the cross-coupling of N-heterocycles, including sub-
ꢀ
two C Cl bonds and the formation of the symmetrical strates featuring unprotected NH2 groups. The dimesi-
double cross-coupled product is favoured even with tylboryl group of the ligand is compatible with the
only one equivalent of phenylboronic acid.
Lewis basic character of the substrates and, actually,
Taking advantage of the regioselective coupling of it enhances significantly the catalytic performance.
X achieved by phosphine-borane/Pd catalysts, we Experiments carried out with preformed phosphine-
then pursued the preparation of unsymmetrical 2,6-di- borane/Pd complexes further support the contribution
arylpyridines. Pure chlorophenylpyridine XI-C2 (ob- of weak p-arene coordination to Pd (akin to those en-
tained following entry 2 of Table 4 and isolated after countered with biarylphosphines). Upon reaction with
purification by column chromatography) was reacted iodobenzene, an original phosphine/h4-boratabuta-
ꢀ
with ortho-tolylboronic acid in the presence of diene complex could be isolated, substantiating C H
1/Pd
A
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Adv. Synth. Catal. 2013, 355, 2274 – 2284

ortho-(Dimesitylboryl)phenylphosphines: Positive Boryl Effect
with a flame ionization detector, using a SGE BPX5 column
comprising 5% phenylmethylsiloxane.
ꢀ
General Procedure for Catalytic Suzuki–Miyaura C
C Cross-Coupling
Palladium precursor {0.01 mmol, for Pd
ACHTUNGRTEN(NGNU OAc)2: 2.25 mg; for
[PdCl2A(cod)]: 2.9 mg; for [Pd2A(dba)3]: 9.1 mg} and the appro-
C
CHTUNGTRENNUNG
priate ligand (0.02 mmol, for 1: 10.2 mg; for 2: 6.5 mg; for 3:
6.7 mg; for PPh3: 5.2 mg) were transferred in a Schlenck
tube in the glove box. Toluene (2 mL), phenylboronic acid
(135 mg, 1.1 mmol), K3PO4 (445 mg, 2.1 mmol), 2-methoxy-
naphthalene as internal standard (30 mg, 0.19 mmol) and
1 mmol of substrate (for I, 113.5 mg; for III, V and VII,
128.6 mg; for X, 193 mg) were then successively added
under argon. The catalytic mixture was stirred at the desired
temperature (80 or 1008C) for some hours (from 2 to 72 h).
The mixture was then diluted with toluene (ca. 2 mL), fil-
tered and analyzed by GC to determine conversion, selectiv-
ity and yield.
Synthesis and Characterization of the Pd(II) Complex
1’-Pd
Scheme 3. Synthesis of the unsymmetrical 2,6-diarylpyridine
XIII by one-pot sequential double cross-coupling of 2,6-di-
chloro-3-nitropyridine X; and crystal structure of XIII (ellip-
soids drawn at 50% probability and hydrogen atoms omitted
for clarity).
207 mg (0.29 mmol) of the Pd complex [ortho-Ph2P-
AHCTNUGERTG(NNUN C6H4)BMes2]Pd(ma) 1-Pd were dissolved in toluene
(10 mL) under argon. Then 40 mL (0.36 mmol) of iodoben-
zene were added and the solution was stirred at 1008C for
1 h. The black palladium formed upon heating was removed
by filtration. The orange filtrate contains free ligand 1 along
with the new complex 1’-Pd (1:1 according to 31P NMR).
The volatiles were removed under vacuum. The brown solid
residue was washed with pentane (5 mL) and diethyl ether
(2.5 mL). Complex 1’-Pd was purified by column chroma-
tography (dichloromethane/pentane 1/1) and isolated as
a yellow powder; yield: 55 mg (26%); mp 248–2518C. Crys-
tals suitable for XRD analysis were obtained by slow evapo-
deactivation pathway for these catalytic systems. The
phosphine-borane ligands are more sensitive to sub-
strate substitution than biarylphosphines but, in turn,
they are able to achieve cross-couplings of 2,6-di-
chloro-3-nitropyridine with higher regioselectivities.
Accordingly, sequential double Suzuki–Miyaura reac-
1
ration from a toluene solution. H NMR (500 MHz, CDCl3):
tions provide a direct and efficient access to unsym- d=7.53 (m, 2H, Harom), 7.40 (m, 5H, Harom), 7.27 (m, 5H,
Harom), 7.53 (m, 2H, Harom), 6.81 (bs, 1H, mMes), 6.75 (bs,
metrical 2,6-diarylpyridines.
1H, mMes), 6.70 (bs, 1H, mMes), 6.55 (bs, 1H, mMes), 4.63
(dd, 1H, CH2-Pd, JH,H =2 Hz, JH,P =8 Hz), 2.93 (dd, 1H,
CH2-Pd, JH,H =2 Hz, JH,P =13 Hz), 2.45 (s, 3H, CH3), 2.26 (s,
3H, CH3), 2.25 (s, 3H, CH3), 1.79 (s, 3H, CH3), 1.40 (s, 3H,
CH3); 11B NMR (160.5 MHz, CDCl3): d=52.8; 31P NMR
(202.5 MHz, CDCl3): d=39.8; 13C{1H} NMR (125.8 MHz,
Future studies will seek to exploit the availability
and modularity of phosphine-boranes to tune and im-
prove the catalytic activity and selectivity of the ensu-
ing complexes.
CDCl3): d=161.78 (d, JC,P =43 Hz, Cipso-P), 145.83 (d, JC,P
2 Hz, Cquat), 144.41 (d, JC,P =2 Hz, Cquat), 142.40 (s, Cquat),
141.60 (s, Cquat), 138.51 (s, Cquat), 134.79 (d, JC,P =43 Hz, Cipso
P), 133.88 (d, JC,P =14 Hz, CHarom), 133.62 (d, JC,P =20 Hz,
CHarom), 133.24 (d, JC,P =10 Hz, CHarom), 133.08 (d, JC,P
3 Hz, CHarom), 133.00 (d, JC,P =44 Hz, Cipso-P), 132.59 (bs,
CHarom), 131.19 (d, JC,P =3 Hz, CHarom), 130.81 (d, JC,P
2 Hz, CHarom), 130.43 (d, JC,P =6 Hz, CHarom), 129.96 (d,
C,P =2 Hz, CHarom), 129.04 (s, CHarom), 128.99 (d, JC,P
37 Hz, Cipso-B), 128.26 (d, JC,P =11 Hz, CHarom), 128.12 (d,
C,P =10 Hz, CHarom), 127.98 (s, CHarom), 126.18 (d, JC,P
3 Hz, Cquat), 123.81 (d, JC,P =3 Hz, CHarom), 107.90 (bs, Cipso
=
-
Experimental Section
=
General
All preparations and manipulations were performed using
standard Schlenk techniques under an argon atmosphere.
Toluene was distilled under argon from molten sodium.
Unless stated otherwise, commercially compounds were
used without further purification. Ligands 1, 2[34] and 3[35] as
=
J
=
J
=
-
well as precursor [Pd(ma)
N
to previously described procedures. NMR spectra were re-
corded on Bruker Avance 300 and 500 spectrometers at
293 K. GC analyses were carried out on an Agilent GC6890
B), 62.49 (d, JC,P =39 Hz, CH2-Pd), 25.81 (s, CH3), 25.67 (s,
CH3), 23.33 (s, CH3), 21.45 (s, CH3), 21.18 (s, CH3), (one of
the Cipso-B is not seen); MS (FAB): m/z=742.526, calculated
Adv. Synth. Catal. 2013, 355, 2274 – 2284
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2281

Raluca Malacea et al.
FULL PAPERS
for C36H35PBIPd: 742.772; elemental analysis: calculated: C
58.16%, H 4.71%; found: C 57.95%, H 4.55%.
mixture was filtered on celite. After solvent evaporation,
the crude was purified by column chromatography (silica,
using pentane/diethyl ether=95/5 as eluent). The product
XIII was isolated as white powder after two consecutive pu-
rifications by column chromatography; yield: 331 mg (57%).
Single crystals suitable for X-ray diffraction analysis were
Synthesis of 2-Phenyl-3-nitro-6-chloropyridine, XI-C2
0.01 mmol of [PdClACHTUNGTRENNUNG(cod)2] (3.1 mg) and 0.02 mmol of ligand
1
2 (8.8 mg) were transferred in a Schlenck tube in the glove
box. Toluene (2 mL), phenylboronic acid (135 mg,
1.1 mmol), K3PO4 (445 mg, 2.1 mmol), 2-methoxynaphtha-
lene as internal standard (30 mg, 0.19 mmol) and 1 mmol of
X (193 mg) were then successively added under argon. The
mixture was stirred at 1008C for 20 h. Toluene (ca. 2 mL)
was then added and the reaction mixture was filtered on
celite. After solvent evaporation, the crude was purified by
column chromatography (silica, using pentane/diethyl
ether=95/5 as eluent). The product XI-C2 was isolated as
a colourless oil after two consecutive purifications by
column chromatography; yield: 52 mg (26%). 1H NMR
obtained from a diethyl ether solution. H NMR (300 MHz,
CDCl3): d=8.31 (d, 3JH,H =8.8 Hz, H5-pyridine ring), 8.06
3
(m, 2H), 7.84 (d, JH,H =8.8 Hz, H4-pyridine ring), 7.43 (m,
4H), 7.22 (m, 3H), 2.70 (s, CH3).
CCDC 915133, CCDC 915134, CCDC 915135, and CCDC
915136, contain the supplementary crystallographic data for
compounds 1’-Pd, XI-C6, XII, and XIII, respectively.
These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
3
(300 MHz, CDCl3): d=8.06 (d, 1H, JH,H =8.4 Hz, H-5-pyri-
dine ring), 7.51 (m, 2H, phenyl group), 7.43 (m, 3H, phenyl
group), 7.38 (d, 1H, JH,H =8.4 Hz, H-4-pyridine ring).
Acknowledgements
3
Its regioisomer, 2-chloro-3-nitro-6-phenylpyridine XI-
C6,[37] was isolated from one of the separated fractions
during the purification of XI-C2. It was crystallized from
a diethyl ether/pentane solution and its structure was deter-
mined by X-ray diffraction analysis.
Financial support from the Centre National de la Recherche
Scientifique (CNRS) and the Universitꢀ Paul Sabatier is
gratefully acknowledged. R. M. thanks the CNRS for a post-
doctoral grant. We are grateful to Dr. Antonio L. Llamas-
Saiz (Unidade de Raios X, Universidade de Santiago de
Compostela, Spain) for the X-ray diffraction analysis of 1’-
Pd.
Synthesis of 2-Phenyl-3-nitro-6-(2’-methylphenyl)-
pyridine, XII
0.01 mmol of PdACHTUNGTRENNUNG(OAc)2 (2.25 mg) and 0.02 mmol of ligand
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1.1 mmol), K3PO4 (445 mg, 2.1 mmol), 2-methoxynaphtha-
lene as internal standard (30 mg, 0.19 mmol) and 1 mmol of
XI-C2 (222 mg) were then successively added under argon.
The mixture was stirred at 808C for 22 h. Toluene (ca.
2 mL) was then added and the reaction mixture was filtered
on celite. After solvent evaporation, the crude was purified
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white powder; yield: 180 mg (62%). Single crystals suitable
for X-ray diffraction analysis were obtained at 08C from
a diethyl ether solution. 1H NMR (300 MHz, CDCl3): d=
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