Design and development of POCN-pincer palladium catalysts for C-H bond arylation of azoles with aryl iodides

Article abstract of DOI:10.1039/c4dt01547a

Well-defined and efficient POCN-ligated palladium complexes have been developed for the direct C-H bond arylation of azoles with aryl iodides. The phosphinite-amine pincer ligands 1-(R₂PO)-C₆H₄-3-(CH₂NⁱPr₂) [^R2POCN^iPr2-H; R = ⁱPr (1a), R = ^tBu (1b)] and corresponding palladium complexes {2-(R₂PO)-C₆H₃-6-(CH₂NⁱPr₂)}PdCl [(^R2POCN^iPr2)PdCl; R = ⁱPr (2a), R = ^tBu (2b)] were synthesized in good yields. Treatment of palladium complex 2a with KI and AgOAc afforded the complexes (^iPr2POCN^iPr2)PdI (3a) and (^iPr2POCN^iPr2)Pd(OAc) (4a), respectively. Similarly, the reaction of 2a with benzothiazolyl-lithium produces the (^iPr2POCN^iPr2)Pd(benzothiazolyl) (5a) complex in a quantitative yield. The pincer palladium complex 2a efficiently catalyzes the C-H bond arylation of benzothiazole, substituted-benzoxazoles and 5-aryl oxazoles with diverse aryl iodides in the presence of CuI as a co-catalyst under mild reaction conditions. This represents the first example of a pincer palladium complex being applied for the direct C-H bond arylation of any heterocycle with low catalyst loading. A preliminary mechanistic investigation reveals that palladium nanoparticles are presumably not the catalytically active form of 2a and supports the direct involvement of the catalyst 2a, with complex 5a being a probable key intermediate in the catalytic reaction. This journal is

Full text of DOI:10.1039/c4dt01547a

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Design and development of POCN-pincer
palladium catalysts for C–H bond arylation of
azoles with aryl iodides†
Cite this: Dalton Trans., 2014, 43,
16084
Shrikant M. Khake,a Vineeta Soni,a Rajesh G. Gonnadeb and Benudhar Punji*a
Well-defined and efficient POCN-ligated palladium complexes have been developed for the direct C–H
bond arylation of azoles with aryl iodides. The phosphinite-amine pincer ligands 1-(R2PO)-C6H4-3-
i
t
(CH2NiPr2) [R2POCNiPr2-H; R = Pr (1a), R = Bu (1b)] and corresponding palladium complexes {2-(R2PO)-
C6H3-6-(CH2NiPr2)}PdCl [(R2POCNiPr2)PdCl; R = Pr (2a), R = Bu (2b)] were synthesized in good yields.
Treatment of palladium complex 2a with KI and AgOAc afforded the complexes (iPr2POCNiPr2)PdI (3a)
and (iPr2POCNiPr2)Pd(OAc) (4a), respectively. Similarly, the reaction of 2a with benzothiazolyl-lithium pro-
duces the (iPr2POCNiPr2)Pd(benzothiazolyl) (5a) complex in a quantitative yield. The pincer palladium
complex 2a efficiently catalyzes the C–H bond arylation of benzothiazole, substituted-benzoxazoles and
5-aryl oxazoles with diverse aryl iodides in the presence of CuI as a co-catalyst under mild reaction
conditions. This represents the first example of a pincer palladium complex being applied for the direct
C–H bond arylation of any heterocycle with low catalyst loading. A preliminary mechanistic investigation
reveals that palladium nanoparticles are presumably not the catalytically active form of 2a and supports
the direct involvement of the catalyst 2a, with complex 5a being a probable key intermediate in the cata-
lytic reaction.
i
t
Received 26th May 2014,
Accepted 19th August 2014
DOI: 10.1039/c4dt01547a
www.rsc.org/dalton
realized by the employment of various transition metal salts
with suitable ligand sets.4 Among them, the most convenient
Introduction
Direct C–H bond functionalization of heteroarenes has raised and inexpensive transition metal catalysts, such as complexes of
much interest as an alternative to traditional cross-coupling nickel5 and copper,6 represent a very important development for
reactions, because such a process bypasses pre-activation steps the arylation of azoles in terms of the catalyst cost for large scale
such as the halogenation or metallation of heteroarenes.1 The synthesis. However, in most cases the utilization of strong bases
transition metal-catalyzed C–H bond functionalizations, like ary- and harsh reaction conditions limits the further advancement
lation, alkenylation, alkynylation and alkylation, of various of those methodologies. The arylation of azoles has also been
heteroarenes have been widely explored over the last few years.2 reported under mild conditions employing precious metal cata-
Most importantly, the arylation of azoles has received particular lysts, like Ru,2j Rh,7 or Pd,8 where high loading of the catalyst
attention, as arylated azoles are essential building blocks of (>5 mol%) is essential for the completion of reactions. More-
diverse biological and pharmaceutical compounds.3 The C-2 over, many of these catalysts were generated in situ (not “well-
arylations of azoles to synthesize 2-arylated azoles have been defined”) with few exceptions;8l hence limiting the proper
understanding of the catalyst’s reactivity and reaction system.
Although many of these in situ generated catalysts are con-
venient for the arylation of various azoles, there is still a
demand to develop well-defined catalyst which can execute the
same tasks with minimal catalyst loading. Herein, our objective
aOrganometallic Synthesis and Catalysis Group, Chemical Engineering Division,
CSIR–National Chemical Laboratory (CSIR–NCL), Dr. Homi Bhabha Road,
Pune – 411 008, Maharashtra, India. E-mail: b.punji@ncl.res.in;
Fax: +91-20-25902621; Tel: +91-20-2590 2733
is to develop well-designed, well-characterized and competent
palladium catalysts for the direct C–H bond arylation of azoles,
as in many cases such catalysts are more efficient than the
transformations carried out by metal salts and added ligands.
Pincer-ligated transition metal catalysts have shown excep-
tionally high thermal stability and catalytic activity for various
important organic transformations in comparison with the tra-
bCentre for Material Characterization, CSIR–National Chemical Laboratory
(CSIR–NCL), Dr. Homi Bhabha Road, Pune – 411 008, Maharashtra, India
†Electronic supplementary information (ESI) available: Details of the experi-
mental data and NMR spectra of all compounds, crystal structure data of com-
plexes 2a and 2b, and the 31P{1H} NMR spectrum of the (iPr2POCNiPr2)Pd species
during the arylation of azole, demonstrating the catalyst resting state. CCDC
973533 and 973534. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4dt01547a
16084 | Dalton Trans., 2014, 43, 16084–16096
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Chart 1 General representation of pincer palladium complexes.
ditional mono- or bi-dentate ligated transition metal catalysts; bromide (Scheme 1). First, 3-hydroxy benzyl bromide was
as the tight tridentate coordination in the pincer system keeps treated with two equivalents of diisopropyl amine in acetone
the metal and ligand together in each catalytic step, where the to obtain the colorless product of 3-((diisopropylamino)-
ligand effects are conveniently transferred to the metal center methyl)phenol in 82% isolated yield. This compound was
(Chart 1).9 For example, the PCP pincer palladium complexes, characterized by 1H and 13C NMR spectroscopy as well as
[{2,6-(iPr2PCH2)2-C6H3}Pd(OCOCF3)] and [{2,6-(iPr2PCH2)2-3,5- HRMS. The treatment of 3-((diisopropylamino)methyl)phenol
(CH3)2-1-CH2-C6H}Pd(OCOCF3)], are highly active catalysts for with NaH, followed by reaction with dialkylchlorophosphine,
i
t
the Heck coupling reaction with bromo- and iodo-arene elec- R2PCl (R = Pr, Bu) produced the ligands {1-(R2PO)-C6H4-3-
trophiles;10 whereas a phosphinite-based POCOP pincer palla- (CH2NiPr2)}, R2POCNiPr2-H (R = Pr, 1a; R = Bu, 1b), as color-
dium catalyst, [{2,6-(iPr2PO)2-C6H3}PdCl], shows efficient less viscous liquids in excellent yields. The 31P{1H} NMR spec-
activity for the coupling of styrene with relatively difficult aryl trum of 1a displayed a peak at 148.8 ppm (for the O-PiPr2
chloride electrophiles.11 Similarly, aminophosphine-based moiety), whereas that of 1b displayed a peak at 154.3 ppm
pincer palladium complexes, [{2,6-(EP(piperidinyl)2)2-C6H3}PdCl] (for the O-PtBu2 moiety). These NMR values of 1a and 1b are
(E = NH, O), and an adamantyl core palladium complex, [{2,6- consistent with the 31P NMR data reported for similar
(Cy2PCH2)2-C10H13}PdCl], are extremely efficient catalysts for compounds i.e. iPr4POCOP-H16 (δ 149.0 ppm) and tBu4POCOP-H17
Suzuki cross-coupling reactions.12 Driven by the high thermal (δ 153.1 ppm), respectively. These crude viscous liquids were
stability and extraordinary catalytic efficiency of pincer palladium used for the metallation reactions without further purification.
i
t
complexes for the Suzuki and Heck coupling reactions, we
The metallation of the ligand iPr2POCNiPr2-H with Pd(COD)-
became fascinated in developing a novel pincer palladium cata- Cl2 in the presence of K3PO4 in 1,4-dioxane under refluxing con-
lyst for C–C bond forming reactions via direct C–H bond ditions gave {2-(iPr2PO)-C6H3-6-(CH2NiPr2)}PdCl, (iPr2POCNiPr2)-
functionalization. As many of these pincer palladium catalysts PdCl (2a), as an air-stable light yellow solid. The 31P{1H} NMR
are assumed to follow a Pd(II)–Pd(IV)–Pd(II) catalytic pathway spectrum of 2a shows a singlet at δ 198.9 ppm (cf. (iPr4POCOP)-
1
during cross-coupling reactions,12b a pincer-ligated palladium PdCl,16 δ 187.7 ppm). The H NMR spectrum of compound 2a
complex with a strong σ-donor atom on the ligand would shows signals for only three protons in the aromatic region,
enhance the electrophilic oxidative addition at the Pd(II) center with the disappearance of the signal corresponding to the
and stabilize the Pd(IV) species.13 Furthermore, transmetallation apical proton, which clearly indicates the formation of the
and electrophilic attack have opposing electron demands during pincer palladium complex. Similarly, the complexation of
such catalysis. Hence, we envisioned that an amino-phosphinite tBu2POCNiPr2-H with Pd(COD)Cl2 in the presence of K3PO4 in
ligand,14 where the electron-rich hard donor amino side and toluene under refluxing conditions produced {2-(tBu2PO)-C6H3-
phosphinite segment would assist in electrophilic addition and 6-(CH2NiPr2)}PdCl, (tBu2POCNiPr2)PdCl (2b), as a yellow solid in
transmetallation, respectively, could be an ideal system to stabil-
ize the catalytically active palladium species in the higher oxi-
dation state,15 which can lead to a high conversion rate with low
catalyst loading. With these hypotheses, herein, we have syn-
thesized a “hybrid” pincer palladium catalyst system which
efficiently catalyzes the arylation of various azoles with aryl
iodides with low catalyst loading in the presence of CuI as a co-
catalyst. The preliminary mechanistic investigation has been
carried out to gain an insight into the catalyst’s behaviour and
reaction pathway.
Results and discussion
Synthesis of the POCN-H ligands and palladium complexes
The R2POCNiPr2-H {1-(R2PO)-C6H4-3-(CH2NiPr2)} ligands were
Scheme 1 Synthesis of the (R2POCNiPr2)-H ligands and (R2POCNiPr2
)
synthesized in two steps starting from 3-hydroxy benzyl PdCl complexes.
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than that of the (iPr4POCOP) moiety in the (iPr4POCOP)PdCl
complex. Interestingly, the Pd–P bond length (2.1890(6) Å) in
2a is significantly shorter than the corresponding Pd–P bond
lengths (2.276( 2) and 2.284( 2) Å) reported for (iPr4POCOP)-
PdCl. The Pd–N bond length (2.2204(17) Å) in 2a is slightly
longer than the Pd–N bond length (2.159( 2) Å) observed for a
similar palladium complex, (3-MeO-Ph2POCNMe2)PdCl.14h The
P–Pd–N bond angle (162.10(5)°) of 2a is slightly greater than
that observed for (3-MeO-Ph2POCNMe2)PdCl (P–Pd–N, 159.53(5)°).
The C–Pd–P bond angle (80.35(7)°) of 2a is comparable with
that observed for (iPr4POCOP)PdCl (C–Pd–P; 80.500( 2) and
79.920( 2)°). The C–Pd–N bond angle (81.84(8)°) is slightly
greater than the C–Pd–P bond angle (80.35(7)°) for 2a. For
compound 2b, two methyl groups (C15, C16 and C20, C21) of
each tert-butyl group showed large anisotropic displacement
parameters (ADP) due to orientational disorder. The Pd–
C(ipso) and Pd–Cl bond lengths in 2b are 1.958(4) and
2.3943(11) Å, respectively; which are comparable with the corres-
ponding bond lengths in 2a. The Pd–P bond length (2.2090(11)
Å) in 2b is slightly longer than the Pd–P bond length of 2a,
whereas the Pd–N bond length (2.229(3) Å) in 2b is comparable
with that observed for 2a. The P–Pd–N (161.65(9)°), C–Pd–P
(80.56(12)°) and C–Pd–N (81.35(15)°) bond angles of 2b are com-
parable with the corresponding bond angles in 2a.
Fig. 1 Thermal ellipsoid plot of (iPr2POCNiPr2)PdCl (2a). All the hydrogen
atoms are omitted for clarity. Selected bond lengths (Å): Pd(1)–C(1),
1.956(2); Pd(1)–P(1), 2.1890(6); Pd(1)–N(1), 2.2204(17); Pd(1)–Cl(1),
2.3922(6). Selected bond angles (°): C(1)–Pd(1)–P(1), 80.35(7); C(1)–
Pd(1)–N(1), 81.84(8); P(1)–Pd(1)–N(1), 162.10(5); C(1)–Pd(1)–Cl(1),
177.32(7); P(1)–Pd(1)–Cl(1), 97.04(2); N(1)–Pd(1)–Cl(1), 100.79(5).
89% yield. The 31P{1H} NMR spectrum of 2b shows a singlet at δ
204.9 ppm (cf. (tBu4POCOP)PdCl,18 δ 192.1 ppm). The complexes
2a and 2b were characterized well by 1H and 13C NMR spec-
troscopy as well as elemental analyses.
Compounds 2a and 2b were further characterized by single
X-ray crystallography (Fig. 1 and 2). For both compounds, the
coordination geometry around palladium is distorted square-
planar. Selected bond lengths and bond angles are given in
the respective figure captions. For 2a, the Pd–C(ipso) bond
length is 1.956(2) Å, slightly shorter than the Pd–C bond
length (1.974( 1) Å) of (iPr4POCOP)PdCl; whereas the Pd–
Cl bond length (2.3922(6) Å) is slightly longer than the corres-
Catalytic activity of (R2POCNiPr2)PdCl complexes for the C–H
bond arylation of azoles
The newly developed hybrid pincer complexes, (iPr2POCNiPr2
)
PdCl (2a) and (tBu2POCNiPr2)PdCl (2b), were optimized and
employed for the direct C–H bond arylation of azoles with aryl
iodides. Initially, the complex 2a was screened for the C–H
bond arylation of benzothiazole (6a, 0.50 mmol) with 4-iodo-
toluene (7a, 0.75 mmol) as the electrophile, employing CuI as
a co-catalyst. After investigating various reaction parameters,
we found that the coupled product 2-(p-tolyl)benzothiazole
(8aa) could be obtained in 97% isolated yield by employing
0.5 mol% of catalyst 2a and 5.0 mol% of CuI, in the presence
of Cs2CO3 (0.75 mmol) in DMF.19 Other carbonate bases like
Na2CO3 and K2CO3, as well as a cesium source like CsOAc,
were found to be less effective (5–34%). The use of a K3PO4
base also gave a good yield (88%) of 8aa. The polar aprotic
solvent DMF was found to be the solvent of choice,20 whereas
solvents like dioxane and toluene led to diminished yields.
The presence of CuI as a co-catalyst was very much essential
for obtaining a good conversion rate. Direct arylation pro-
ceeded even in the absence of a CuI co-catalyst, however with
low efficacy (21% of 8aa and a TON of 42). The CuI most likely
enhances the transmetallation of the azoles to the palladium
center.8l The presence of the palladium catalyst 2a under the
standard conditions (6a, 0.50 mmol; 7a, 0.75 mmol; Cs2CO3,
0.75 mmol; CuI, 5 mol% in DMF at 120 °C) was necessary; in
ponding bond length (2.371(2) Å) of
This could be due to the σ-donor strength exerted by the
iPr2POCNiPr2) moiety upon the palladium in 2a being stronger
(
iPr4POCOP)PdCl.16
(
Fig. 2 Thermal ellipsoid plot of (tBu2POCNiPr2)PdCl (2b). All the hydro-
gen atoms are omitted for clarity. Selected bond lengths (Å): Pd(1)–C(1),
1.958(4); Pd(1)–P(1), 2.2090(11); Pd(1)–N(1), 2.229(3); Pd(1)–Cl(1),
2.3943(11). Selected bond angles (°): C(1)–Pd(1)–P(1), 80.56(12); C(1)–
Pd(1)–N(1), 81.35(15); P(1)–Pd(1)–N(1), 161.65(9); C(1)–Pd(1)–Cl(1),
177.93(13); P(1)–Pd(1)–Cl(1), 99.18(4); N(1)–Pd(1)–Cl(1), 99.00(9).
1
its absence the arylation product 8aa formed in <2% H NMR
yield, which is non-catalytic with regard to CuI. To understand
the respective roles of the palladium catalyst 2a and CuI, a
number of experiments were carried out, which involved
decreased 2a loading and increased CuI loading. Hence, in the
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catalytic reactions using 0.5% of 2a + 5% of CuI, 0.25% of 2a + electrophiles like iodo-pyridine and iodo-pyrazine also reacted
10% of CuI and 0.125% of 2a + 20% of CuI under standard cata- with moderate to good conversion (8al and 8am). In contrast,
lytic conditions, the yields (TONs) of 8aa obtained were 97% the aryl bromide or chloride as the electrophilic coupling
(194), 76% (304) and 67% (536), respectively. Even a large partner did not produce arylated products satisfactorily under
amount of CuI could not replace 2a under the present catalytic standard catalytic conditions. Similar to benzothiazole, substi-
conditions. For example, when the standard catalytic reaction tuted-benzoxazoles also reacted smoothly, yielding the pro-
was carried out employing 20 mol% of CuI in the absence of 2a, ducts 8ba and 8ca in good yields.
only 8% 1H NMR yield of coupled product was formed. This
Furthermore, we tested the versatility of the catalyst 2a in
clearly indicates that both the palladium catalyst 2a and CuI are the arylation of various 5-substituted-oxazoles (Scheme 3).
essential for the catalytic reaction to occur, and CuI acts as a co- Hence, azoles containing both electron-donating as well as
catalyst for the reaction. The catalytic reaction also proceeded electron-withdrawing substituents (9a and 9c) on an aryl back-
with low catalyst loading (0.1 mol% of 2a and 5 mol% of CuI) bone reacted conveniently with aryl iodides to give the 2-aryl-
giving the product 8aa with a TON of 650 after 48 h. The employ- ated products in good yields. Functional groups like chloro
ment of the bulky pincer palladium catalyst, (tBu2POCNiPr2)PdCl and methoxy, as well as heteroarene substituents like pyridine,
(2b), was less efficient, giving the coupled product 8aa in 47% were tolerated well on azole substrates. Interestingly, the elec-
yield, which could be due to more steric constraint.
tron-deficient aryl iodides that showed moderate performance
Subsequently, the optimized reaction conditions were in coupling with benzothiazole reacted efficiently with 5-pyri-
applied to the C–H bond arylation of benzothiazole with dinyl azole, giving the arylated product 10ef in good yield.
diversely substituted aryl iodide electrophiles (Scheme 2). By
Although in situ generated palladium catalysts are known
employing only 0.5 mol% of the catalyst 2a and 5 mol% of for the C–H bond arylation of azoles, a minimum 5 mol%
CuI,21 benzothiazole was very efficiently arylated in DMF at loading of the precious palladium metal is required in many
120 °C. Thus, electron-rich aryl iodides were effectively cases.8a,c,h,k However, the well-characterized complex 2a cata-
employed as coupling partners, including the sterically lyzes the arylation of azoles with only 0.5 mol% of catalyst
demanding ortho-substituted partner (7j). The coupling of loading. In addition, we were particularly fascinated by the
electron-deficient aryl iodides with benzothiazole was less remarkable reactivity observed with the electron-rich aryl
effective, giving the products (8af and 8ag) in moderate to low iodides, which are generally considered as electronically de-
yields. A variety of functional groups, –OMe, –F, –Cl, –Br, –CF3 activated coupling partners in Pd(0)/Pd(II) redox catalysis.
and –COCH3, were tolerated on the aryl iodide moiety under
Synthesis of (iPr2POCNiPr2)PdX derivatives
like –Cl and –Br in the products (8ad and 8ai) is significant, as Having assumed the possible formation of (iPr2POCNiPr2)Pd(X)
the catalytic conditions. The tolerability of functional groups
they can be used for further functionalization. Heteroarene (X = I, OAc, benzothiazolyl) intermediates during the cata-
Scheme 2 Scope of the (iPr2POCNiPr2)PdCl (2a) catalyzed arylations of azoles with aryl iodides. Reagents and conditions: azole (0.5 mmol), aryl
iodide (0.75 mmol), Cs2CO3 (0.75 mmol), catalyst 2a (0.5 mol%), CuI (5.0 mol%) and DMF (1.0 mL), 120 °C, 16 h. Isolated yield after column chrom-
atography on silica gel.
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Scheme 3 Scope of the (iPr2POCNiPr2)PdCl (2a) catalyzed arylations of 5-arylated azoles with aryl iodides. Reagents and conditions: azole
(0.5 mmol), aryl iodide (0.75 mmol), Cs2CO3 (0.75 mmol), catalyst 2a (0.5 mol%), CuI (5.0 mol%) and DMF (1.0 mL), 120 °C, 16–24 h. Isolated yield
after column chromatography on silica gel.
Scheme 4 Synthesis of (iPr2POCNiPr2)Pd-derivatives.
lysis, we have independently synthesized these complexes Mechanistic aspects
to prove their authenticity (Scheme 4). Hence, the treatment
Considering the excellent catalytic activity of (iPr2POCNiPr2)-
PdCl (2a) for the arylation of azoles, we became interested in
looking at the working mode of the catalyst. The palladium
catalysts known for the arylation of azoles generally undergo a
classical redox process, such as the Pd(0)–Pd(II)–Pd(0) cycle.
However, a similar catalytic cycle for the complex 2a will
decompose the pincer catalyst when palladium enters the zero
oxidation state; and the catalyst might concurrently transform
into another active species, such as a palladium(0) nanoparti-
cle.22 In such cases, the pincer complex does not catalyze the
reaction directly, and instead serves as a precatalyst and
of (iPr2POCNiPr2)PdCl (2a) with KI in a dichloromethane
and methanol solvent mixture in a J-Young NMR tube
afforded (iPr2POCNiPr2)PdI (3a) at 40 °C. Similarly, the reac-
tion of (iPr2POCNiPr2)PdCl with AgOAc in THF at room temp-
erature gave (iPr2POCNiPr2)Pd(OAc) (4a) in 73% isolated yield.
The 31P NMR spectrum of 3a shows a single resonance
at 203.9 ppm, whereas that of 4a resonates at 196.7 ppm.
The treatment of complex 2a with a benzothiazolyl-lithium
compound at −78 °C afforded the product (iPr2POCNiPr2)-
Pd(benzothiazolyl) (5a) with quantitative conversion. The
31P NMR spectrum of complex 5a shows
a singlet at
releases the active palladium(0) species. Alternatively,
hypothetical Pd(II)–Pd(IV)–Pd(II) catalytic cycle is proposed for
a
194.4 ppm. The complexes 3a, 4a and 5a were further charac-
1
terized by H and 13C NMR spectroscopy as well as HRMS.
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cross-coupling reactions, where the pincer complexes directly NiPr2)PdCl (2a) (0.012 g, 0.025 mmol) and CuI (0.005 mmol)
catalyze the reaction, as palladium(IV) pincer complexes are were taken in a J-Young NMR tube along with benzothiazole
supposed to be stable species.12b In order to know the precise (0.25 mmol), 4-iodotoluene (0.375 mmol) and Cs2CO3 in DMF
catalytic cycle involved for 2a during the arylation of azoles, a and the reaction was monitored by 31P NMR at regular inter-
number of quantitative tests and NMR studies were carried vals. At room temperature, the reaction mixture exhibited two
out.
signals: a singlet at 198.8 ppm, which corresponds to 2a
The addition of Bu4NBr (10 mol%), a salt known to stabilize (89%), and another singlet at 204.5 ppm, which was assigned
palladium(0) nanoparticles,23 to the catalytic reaction did not to (iPr2POCNiPr2)PdI (3a, 11%). The (iPr2POCNiPr2)PdI obtained
enhance the rate of reaction as well as the yield of the product. from the halide exchange reaction of 2a with CuI was again
Instead, a low yield of isolated product (40% vs. 97% in the independently investigated. Upon heating the aforementioned
absence of Bu4NBr) was observed in the presence of the reaction mixture at 100 °C for 5 h, the two signals persisted at
Bu4NBr salt.24 Similarly, the addition of ligands suitable for 198.8 ppm (23%, 2a) and 204.5 ppm (72%, 3a) with the iodo-
poisoning the palladium(0) nanoparticles,25 such as PPh3 (2.0 derivative 3a being the major species.29 An additional phos-
equiv. w.r.t. 2a), to the standard catalytic reaction has no phorus signal appeared at 49.3 ppm (3%, unknown) and a
impact on the reaction, whereas the addition of molecular pyr- slight (<2% w.r.t. the external standard PMe3) disappearance
idine (150 equiv. w.r.t. 2a) to the catalytic reaction has a negli- of the catalyst from the total catalyst concentration (2a + 3a)
gible influence on overall conversion.26 The catalytic reaction was observed, which could be due to catalyst decomposition.
was slightly affected by the incorporation of 150 equiv. of basic In order to identify the origin of an iodide source other than
poison poly(vinyl pyridine) (PVPy), known to quench homo- CuI and to verify the possibility of using iodide from 4-iodo-
geneous Pd(0) nanoparticles.22b,c All these experimental find- toluene for the formation of 3a,29 a reaction was carried out by
ings support the possibility of 2a being directly involved in the replacing CuI with Cu(OAc). Hence, after heating the reaction
catalytic reaction27 and less likely to transform into another mixture in the presence of Cu(OAc) (0.016 mmol) at 100 °C for
active catalytic species (palladium nanoparticles). However, the
5
h, the 31P NMR spectrum exhibited four signals at
addition of 200 equiv. of mercury to the catalytic reaction 195.2 ppm (10%), 198.8 ppm (30%, 2a), 204.5 ppm (57%, 3a)
reduced the reaction yield remarkably, though it could not and 49.3 ppm (2%, unknown). The signal at 195.2 ppm was
quench the reaction completely. Generally, mercury causes the assigned to the (iPr2POCNiPr2)Pd(OAc) (4a) complex.30 The for-
reaction to cease completely if the catalyst is heterogeneous in mation of the iodo-derivative 3a from 2a in the absence of CuI
nature, by forming an amalgam with palladium nanoparticles.28 clearly demonstrates that 4-iodotoluene is the only iodide
Furthermore, to gain a greater insight into the nature of the source for the generation of 3a. To examine the contribution
active catalytic species, the catalytic reactions were probed of the pincer complex 2a and to rule out the possible indirect
using 31P NMR spectroscopy (Scheme 5). The catalyst (iPr2POC- involvement of Cu(OAc)31 in the generation of the iodo-deriva-
Scheme 5 Formation of different (iPr2POCNiPr2)Pd species during control experiments (% are w.r.t. the standard PMe3 capillary).
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tive 3a during the catalytic reaction, complex 2a was treated
with 4-iodotoluene and benzothiazole in the absence of a
copper source. The 31P NMR spectrum of the reaction mixture
shows the formation of 3a (23%), which indicates that CuX
was not necessarily required for the generation of 3a; and
(
iPr2POCNiPr2)Pd alone can generate 3a during the catalytic
reaction in the presence of 4-iodotoluene and benzothiazole.
Next, the probable route for the generation of complex 3a
from the complex 2a and 4-iodotoluene was investigated.
Milstein et al. have reported that a halide exchange reaction
between (pincer)Pd–Cl and Ar–I can occur via a redox induced
binuclear Pd(0) intermediate.32,33 However, the reactivity order
of the electronically different substituted aryl iodides in the
current system does not support the oxidative addition of Ar–I
to a Pd(0) species for the formation of 3a.34,35 To investigate
further, the complex 2a (0.025 mmol) was treated with 4-iodo-
toluene (0.375 mmol) in DMF at 100 °C. After heating the reac-
tion mixture at 100 °C for 5 h, the 31P NMR of the reaction did
not show the formation of 3a; and the complex 2a mostly
remained unreacted. This indicates that 4-iodotoluene does
not undergo a direct halide exchange reaction with 2a, either
via a concerted halide exchange or via an oxidative pathway
through a Pd(IV) intermediate. Alternatively, the 4-iodotoluene
can react with a (POCN)Pd(II) intermediate species (generated
from 2a), which can lead to the formation of complex 3a. To
test this hypothesis and to identify the formation of any
(POCN)Pd(II) intermediate species, 2a was treated with benzo-
thiazole in the absence of 4-iodotoluene and CuI. Hence, in
the treatment of 2a with benzothiazole in the presence of
Cs2CO3 at 100 °C for 5 h, a new peak was observed at
194.4 ppm, which corresponds to the (POCN)Pd-benzothiazolyl
(5a) complex. Though the formation of complex 5a was not
competitive enough in the reaction,36 it has been reacted with
4-iodotoluene and a new peak corresponding to 3a appeared.
Furthermore, a stoichiometric reaction of 5a with 4-iodo-
toluene in DMF at 100 °C for 5 h exclusively produced 3a and
the coupled product 8aa; and the amount of 3a generated was
roughly same as that of the starting complex 5a.37 This indi-
cates that complex 5a might be a possible intermediate during
Fig. 3 Possible mechanisms for the arylation of azoles catalyzed by 2a.
metallation with the palladium complex 2a to form an inter-
mediate complex, 5a. Subsequently, the oxidative addition of
aryl iodide to 5a could generate the neutral hexacoordinated
pincer Pd(IV) intermediate A, followed by the reductive elimin-
ation of the arylated azole product (Fig. 3, Path-I). Alternatively,
direct formation of the arylated azole product on the pincer
Pd(II) center of 5a via the four-centered concerted transition
state B (path-II) can be manifested. Although the experimental
evidence supports a homogeneous catalysis pathway, the
results of some standard tests to distinguish homogeneous
from heterogeneous catalysis were not conclusive. Hence,
parallel catalysis via trace amounts of highly active palladium
nanoparticles as well as a molecular catalyst cannot be ruled
out completely at this stage.
Experimental section
General information
the catalytic reaction. Even a catalytic reaction employing 5a as All manipulations were conducted in an argon atmosphere,
the catalyst under standard reaction conditions produces 8aa either in a glove box or using standard Schlenk techniques in
in 95% yield, which means that 5a is as active as the catalyst pre-dried glassware. The catalytic reactions were performed in
2a. This finding further supports 5a as a feasible active inter- flame-dried reaction vessels with Teflon screw caps. Solvents
mediate during the catalytic reaction and also in the formation were dried over Na/benzophenone or CaH2 and distilled prior
of 3a. Hence, in all the controlled experiments, the formation to use. DMF was dried over CaH2, distilled under vacuum and
of 3a from the concerted metathesis or oxidative addition of stored over 4 Å molecular sieves. Liquid reagents were flushed
4-iodotoluene to 5a followed by the reductive elimination of with argon prior to use. 3-Hydroxy benzyl bromide,38 5-methyl
8aa might be presumed.
benzoxazole,39 5-aryl azoles40 and benzothiazolyl lithium41
With these results, as well as following the previously were synthesized according to previously described pro-
reported mechanistic observations for the palladium/copper- cedures. All other chemicals were obtained from commercial
catalyzed azole arylation8l and pincer palladium-catalyzed sources and were used without further purification. The yields
Suzuki reaction,12b we have proposed a possible catalytic cycle refer to isolated compounds, estimated to be >95% pure as
1
for the arylation of azoles by complex 2a (Fig. 3). We assume determined by H NMR. TLC: TLC silica gel 60 F254. Detection
that the catalytic cycle begins with the important base-assisted under UV light at 254 nm. Chromatography: separations were
concerted metallation deprotonation of benzothiazole with carried out on Spectrochem silica gel (0.120–0.250 mm,
CuI. The benzothiazolyl-copper species then undergoes trans- 60–120 mesh). All IR spectra were recorded on a Bruker optics
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alpha-E Spectrometer. High resolution mass spectroscopy was taken in a J-Young NMR tube along with the PMe3 capil-
(HRMS) mass spectra were recorded on a Thermo Scientific lary (external standard), and DMF (0.5 mL) was added into it.
Q-Exactive, Accela 1250 pump. M.p.: Büchi 540 capillary The reaction mixtures were subsequently heated at 100 °C and
melting point apparatus, values are uncorrected. NMR (1H and the progress of the reaction was monitored by 31P NMR. The
13C) spectra were recorded at 400 or 500 MHz (1H), 100 or percentage of the different species formed was calculated w.r.t.
125 MHz (13C, DEPT (distortionless enhancement by polariz- the standard PMe3 capillary.
ation transfer)), 377 MHz (19F) and 162 or 202 MHz (31P{1H})
Reaction in the presence of CuI. Following the general pro-
on Bruker AV 400 and AV 500 spectrometers in CDCl3 solu- cedure and using a CuI co-catalyst, when the reaction mixture
tions, if not otherwise specified; the chemical shifts (δ) are was heated for 1 h, two signals appeared in the 31P NMR spec-
1
given in ppm. The H and 13C NMR spectra are referenced to trum at 198.8 and 204.5 ppm, which correspond to (iPr2POC-
the residual solvent signals (CDCl3: δ H = 7.26 ppm, δ C = NiPr2)PdCl (68%) and (iPr2POCNiPr2)PdI (30%), respectively. On
77.2 ppm) and the 31P{1H} NMR chemical shifts are referenced continuation of the same reaction for 5 h, the two signals per-
to an external standard, Me3P in p-xylene-d10 solvent sisted with a different intensity ratio, (iPr2POCNiPr2)PdCl (23%)
(δ −62.4 ppm) in a sealed capillary tube.
and (iPr2POCNiPr2)PdI (72%). An additional peak appeared
during the course of the reaction at 49.3 ppm (3%, unknown).
The total 31P NMR active product concentration dropped to
98% ((iPr2POCNiPr2)PdCl + (iPr2POCNiPr2)PdI + unknown) of the
Representative procedure for the arylation of azoles: synthesis
of 2-(p-tolyl)benzo[d]thiazole (8aa)
To a flame-dried screw-capped Schlenk tube equipped with a concentration from the beginning of reaction. The disappear-
magnetic stir bar were introduced 4-iodotoluene 7a (0.164 g, ance of this 2% from the original concentration might be due
0.75 mmol), Cs2CO3 (0.244 g, 0.75 mmol) and CuI (0.005 g, to minor catalyst decomposition. Even after heating the reac-
0.025 mmol, 5.0 mol%) under argon. The screw-capped tion mixture at 100 °C for 16 h, the total pincer catalytic
Schlenk tube with the mixture was then evacuated and refilled species observed were 82%. This indicates that the catalyst’s
with argon. To the above mixture were added benzothiazole 6a decomposition is not significantly high.
(0.068 g, 0.50 mmol) and (iPr2POCNiPr2)PdCl (0.0025 mmol,
Reaction in the presence of CuOAc. Following the general
0.5 mol%, 1.0 mL of a 0.0025 M stock solution) in DMF under procedure and using CuOAc, when the reaction mixture was
argon. The resultant reaction mixture was then degassed, heated at 100 °C for 1 h, three signals appear in the 31P NMR
refilled with argon and was stirred at 120 °C in a preheated oil at 195.2, 198.8 and 204.5 ppm, which represent (iPr2POCNiPr2)-
bath for 16 h. At ambient temperature, H2O (15 mL) was Pd(OAc) (5%), (iPr2POCNiPr2)PdCl (87%) and (iPr2POCNiPr2)PdI
added and the reaction mixture was extracted with t-BuOMe (8%), respectively. After heating for 5 h, the same three signals
(20 mL × 3). The combined organic layers were dried over persist with an intensity ratio of 10% (iPr2POCNiPr2)Pd(OAc),
MgSO4 and the solvent was evaporated in vacuo. The remaining 30%
(
iPr2POCNiPr2)PdCl and 57%
(
iPr2POCNiPr2)PdI. An
residue was purified using column chromatography on silica additional peak appeared during the course of the reaction at
gel (n-hexane–EtOAc 30/1 → 20/1) to yield 8aa (0.109 g, 97%) as 49.3 ppm (2%, unknown).
an off-white solid.
Reaction in the absence of CuX. Following the general pro-
cedure and without the addition of a Cu precursor, when the
reaction mixture was heated at 100 °C for 5 h, two signals
General procedure for the added ligand experiments
These reactions were carried out following the representative appeared in the 31P NMR at 204.5 and 198.8 ppm, which corre-
procedure for the synthesis of 2-(p-tolyl)benzo[d]thiazole (8aa); spond to
using 6a (0.068 g, 0.50 mmol), 7a (0.164 g, 0.75 mmol), (54%), respectively.
Cs2CO3 (0.244 g, 0.75 mmol), 2a (0.0025 mmol, 0.5 mol%), CuI Reaction with 4-iodotoluene. Following the general pro-
( (
iPr2POCNiPr2)PdI (23%) and iPr2POCNiPr2)PdCl
(0.025 mmol, 5.0 mol%) and an appropriate amount of the cedure and without the addition of CuX, benzothiazole and
external ligand, Bu4NBr (0.016 g, 0.05 mmol), Hg (0.1 g, Cs2CO3; the complex 2a (0.012 g, 0.025 mmol) was treated with
0.5 mmol), PPh3 (0.0013 g, 0.005 mmol), Py (0.03 g, 4-iodotoluene (0.083 g, 0.375 mmol) in DMF at 100 °C for 5 h.
0.375 mmol) or PVPy (0.04 g, 0.375 mmol). After stirring the The 31P NMR spectrum of the reaction mixture showed only
reaction mixtures at 120 °C for 16 h, the products were isolated the signal corresponding to 2a. The formation of the signal
using column chromatography.
corresponding to 3a was not observed.
The isolated yields of 8aa obtained in the presence of
Reaction with benzothiazole. Following the general pro-
Bu4NBr, Hg, PPh3, Py and PVPy in the reactions were 40%, cedure and without the addition of both CuX and 4-iodo-
42%, 94%, 76% and 80%, respectively.
toluene, the reaction mixture was heated at 100 °C for 5 h. The
31P NMR spectrum of the reaction mixture showed two signals
at 194.4 and 198.8 ppm, which correspond to (iPr2POCNiPr2)Pd-
benzothiazolyl (3%) and (iPr2POCNiPr2)PdCl (97%), respectively.
General procedure for the resting state study of (iPr2POCNiPr2)Pd
during azole arylation
A mixture of (iPr2POCNiPr2)PdCl (0.012 g, 0.025 mmol), CuX Upon the addition of 4-iodotoluene (0.083 g, 0.375 mmol) to
(for X = I, 0.001 g, 0.005 mmol or for X = OAc, 0.002 g, the resulting reaction mixture and further heating at 100 °C
0.016 mmol), Cs2CO3 (0.124 g, 0.38 mmol), benzothiazole for 1 h, the peak at 194.4 ppm disappeared and the peak
(0.034 g, 0.25 mmol) and 4-iodotoluene (0.083 g, 0.375 mmol) corresponding to (iPr2POCNiPr2)PdI (3a) formed.
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Reaction of (iPr2POCNiPr2)Pd-benzothiazolyl (5a) with 4-iodo- J = 6.5 Hz, 12H, N{CH(CH3)2}2). 13C NMR (100 MHz, CDCl3):
toluene. A mixture of
iPr2POCNiPr2)Pd-benzothiazolyl (5a) δ = 159.5 (d, JP–C = 8.4 Hz, Cq), 145.2 (Cq), 128.8 (CH), 121.2
(
(0.018 g, 0.031 mmol) and 4-iodotoluene (0.007 g, (CH), 118.2 (d, JP–C = 10.3 Hz, CH), 116.6 (d, JP–C = 9.9 Hz, CH),
0.031 mmol) was taken in a J-Young NMR tube and DMF 48.9 (CH2), 47.9 (2C, N{CH(CH3)2}2), 28.5 (d, JP–C = 17.6 Hz, 2C,
(0.5 mL) was added into it. The reaction mixture was sub- P{CH(CH3)2}2), 20.9 (4C, N{CH(CH3)2}2), 18.0 (d, JP–C = 20.5 Hz,
sequently heated at 100 °C for 2 h. The 31P NMR spectrum of 2C, PCH(CH3)2), 17.2 (d, JP–C = 8.4 Hz, 2C, PCH(CH3)2). 31P{1H}
the reaction mixture shows 57% conversion of 5a to (iPr2POC- NMR (162 MHz, CDCl3): δ = 148.8 (s).
NiPr2)PdI (3a). Upon the continuation of heating for 5 h, the
(
tBu2POCNiPr2)-H (1b). Yield: 4.58 g, (90%). 1H NMR
complete conversion of 5a to 3a was observed. The amount of (400 MHz, CDCl3): δ = 7.21 (br s, 1H, Ar–Hipso), 7.15 (t, J = 7.8
3a (92%) formed was roughly the same as that of the starting Hz, 1H, Ar–H), 6.98 (d, J = 7.8 Hz, 2H, Ar–H), 3.62 (s, 2H, CH2),
complex 5a (100%).
3.02 (sept, J = 6.4 Hz, 2H, N{CH(CH3)2}2), 1.17 (d, J = 11.5 Hz,
18H, P{C(CH3)3}2), 1.02 (d, J = 6.4 Hz, 12H, N{CH(CH3)2}2). 13C
NMR (100 MHz, CDCl3): δ = 160.0 (d, JP–C = 8.6 Hz, Cq), 145.2
Synthesis of 3-((diisopropylamino)methyl)phenol
To a solution of 3-hydroxy benzyl bromide (5.0 g, 26.73 mmol) (Cq), 128.8 (CH), 120.9 (CH), 118.0 (d, JP–C = 9.6 Hz, CH), 116.4
in acetone (50 mL) was added diisopropylamine (7.6 mL, (d, J = 10.5 Hz, CH), 48.9 (CH2), 47.9 (2C, N{CH(CH3)2}2), 35.8
53.46 mmol) at room temperature. The resultant reaction (d, JP–C = 25.9 Hz, 2C, P{C(CH3)3}2), 27.6 (d, JP–C = 15.3 Hz, 6C,
mixture was refluxed at 70 °C for 14 h under an argon atmos- P{C(CH3)3}2), 20.9 (4C, N{CH(CH3)2}2). 31P{1H} NMR (162 MHz,
phere. After cooling the reaction mixture to room temperature, CDCl3): δ = 154.3 (s).
the solvent was evaporated under reduced pressure and the
crude product obtained was treated with a 10% aqueous solu-
tion of NaHCO3 (70 mL). The product was extracted with Et2O
General procedure for the synthesis of the (R2POCNiPr2)PdCl
complexes
(20 mL × 3) and the combined extracts were dried over MgSO4. A mixture of Pd(COD)Cl2 (0.84 g, 2.94 mmol for compound 2a;
Filtration and evaporation of all the volatile species gave a col- 0.155 g, 0.54 mmol for compound 2b), an appropriate amount
orless viscous product. Yield: 4.52 g (82%). 1H NMR (200 MHz, of (R2POCNiPr2)-H (1.0 g, 3.09 mmol of 1a; 0.20 g, 0.568 mmol
CDCl3): δ = 7.14 (dd, J = 8.1, 7.8 Hz, 1H, Ar–H), 6.94–6.90 (m, of 1b) and K3PO4 (0.749 g, 3.53 mmol for compound 2a;
2H, Ar–H), 6.68 (dd, J = 8.1, 2.2 Hz, 1H, Ar–H), 3.59 (s, 2H, 0.137 g, 0.645 mmol for compound 2b) were taken in a
CH2), 3.02 (sept, J = 6.7 Hz, 2H, N{CH(CH3)2}2), 1.02 (d, J = 6.7 Schlenk flask and 1,4-dioxane (for compound 2a) or toluene
Hz, 12H, N{CH(CH3)2}2). 13C NMR (50 MHz, CDCl3): δ = 155.8 (for compound 2b) (30 mL) was added into it. The reaction
(Cq), 145.3 (Cq), 129.2 (CH), 120.4 (CH), 115.0 (CH), 113.5 mixture was heated under reflux (2a: 100 °C for 8 h or 2b:
(CH), 49.0 (CH2), 48.1 (2C, N{CH(CH3)2}2), 20.8 (4C, N{CH- 110 °C for 24 h) under an argon atmosphere. The yellowish-
(CH3)2}2). HR-MS (ESI) m/z calcd for C13H21NO + H+ [M + H]+ black suspension formed was cooled to room temperature and
208.1701, found 208.1694.
the volatile species were evaporated under reduced pressure.
The compound was extracted with n-hexane (30 mL × 6; for 2a)
or THF (40 mL × 2; for 2b) and the combined organic solutions
were evaporated under reduced pressure to obtain the respect-
General procedure for the synthesis of the R2POCNiPr2-H
ligands
To the suspension of NaH (0.56 g, 23.3 mmol for 1a; 0.42 g, ive complexes as light yellow crystalline solids. The compound
17.5 mmol for 1b) in THF (10 mL) was added a solution of the 2a was recrystallized from the n-hexane solution by slow evap-
appropriate amount of 3-((diisopropylamino)methyl)phenol oration, whereas compound 2b was recrystallized from the
(4.0 g, 19.3 mmol for 1a; 3.0 g, 14.5 mmol for 1b) in THF CH2Cl2–n-hexane solvent to obtain X-ray quality single crystals.
(20 mL) and the resulting mixture was refluxed at 70 °C for
(
iPr2POCNiPr2)PdCl (2a). Yield: 0.818 g, 60%. M.p.
=
1
3 h. After the reaction mixture was cooled to room tempera- 143–144 °C. H NMR (400 MHz, CDCl3): δ = 6.91 (t, J = 7.8 Hz,
ture, a solution of dialkylchlorophosphine, R2PCl, (for com- 1H, Ar–H), 6.62 (d, J = 7.3 Hz, 1H, Ar–H), 6.56 (d, J = 7.8 Hz,
i
pound 1a, R = Pr, 3.2 mL, 20.1 mmol; for compound 1b, R = 1H, Ar–H), 4.07 (s, 2H, CH2), 3.55 (apparent octet,42 J = 6.4 Hz,
tBu, 2.90 mL, 15.3 mmol) in THF (20 mL) was added and the 2H, N{CH(CH3)2}2), 2.43 (apparent octet,42 J = 7.0 Hz, 2H,
resulting reaction mixture was further refluxed at 70 °C for P{CH(CH3)2}2), 1.65 (d, J = 6.8 Hz, 6H, NCH(CH3)2), 1.42 (dd,
12 h. The reaction mixture was cooled to ambient temperature J = 18.8, 7.3 Hz, 6H, PCH(CH3)2), 1.30 (dd, J = 15.8, 7.1 Hz, 6H,
and volatile species were evaporated under reduced pressure. PCH(CH3)2), 1.21 (d, J = 6.4 Hz, 6H, NCH(CH3)2). 13C NMR
The compounds were extracted with n-hexane (60 mL × 3) and (100 MHz, CDCl3): δ = 163.6 (d, JP–C = 6.9 Hz, Cq), 153.5 (Cq),
the combined n-hexane solutions were evaporated under 143.2 (d, JP–C = 1.5 Hz, Cq), 126.3 (CH), 114.9 (CH), 108.2 (d,
vacuum to obtain the oily products of R2POCNiPr2-H.
iPr2POCNiPr2)-H (1a). Yield: 5.40 (87%). 1H NMR (d, JP–C = 25.4 Hz, 2C, P{CH(CH3)2}2), 22.5 (2C, NCH(CH3)2),
JP–C = 16.2 Hz, CH), 61.1 (CH2), 57.3 (2C, N{CH(CH3)2}2), 29.4
(
g
(400 MHz, CDCl3): δ = 7.20–7.16 (m, 2H, Ar–H), 7.01 (d, J = 7.3 19.4 (2C, NCH(CH3)2), 17.7 (d, J = 5.4 Hz, 2C, PCH(CH3)2), 16.9
Hz, 1H, Ar–H), 6.94 (d, J = 5.8 Hz, 1H, Ar–H), 3.64 (s, 2H, CH2), (2C, PCH(CH3)2). 31P{1H} NMR (162 MHz, CDCl3): δ = 198.9 (s).
3.04 (sept, J = 6.5 Hz, 2H, N{CH(CH3)2}2), 1.94 (d of sept, J = HR-MS (ESI) m/z calcd for C19H33ClNOPPd − Cl+ [M − Cl]+
6.8, 2.5 Hz, 2H, P{CH(CH3)2}2), 1.21 (dd, J = 10.5, 6.8 Hz, 6H, 428.1335, found 428.1331. Anal. calcd for C19H33ClNOPPd: C,
PCH(CH3)2), 1.14 (dd, J = 15.8, 7.3 Hz, 6H, PCH(CH3)2), 1.05 (d, 49.15; H, 7.16; N, 3.02. Found: C, 49.07; H, 7.16; N, 2.77.
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(
tBu2POCNiPr2)PdCl (2b). Yield: 0.237 g, 89%. M.p.
=
JP–C = 15.3 Hz, CH), 60.8 (CH2), 56.9 (2C, N{CH(CH3)2}2), 29.9
1
167–169 °C. H NMR (400 MHz, CDCl3): δ = 6.91 (t, J = 7.7 Hz, (d, JP–C = 25.8 Hz, 2C, P{CH(CH3)2}2), 24.2 (COCH3), 21.9 (2C,
1H, Ar–H), 6.59–6.57 (m, 2H, Ar–H), 4.04 (s, 2H, CH2), 3.58 NCH(CH3)2), 19.3 (2C, NCH(CH3)2), 18.1 (d, J = 6.7 Hz, 2C,
(apparent octet,42 J = 6.4 Hz, 2H, N{CH(CH3)2}2), 1.65 (d, J = 6.4 PCH(CH3)2), 16.9 (d, JP–C = 2.9 Hz, 2C, PCH(CH3)2). 31P{1H}
Hz, 6H, NCH(CH3)2), 1.46 (d, J = 15.3 Hz, 18H, P{C(CH3)3}2), NMR (162 MHz, CDCl3): δ = 196.7 (s). IR (neat): νmax/cm−1
1.19 (d, J = 6.4 Hz, 6H, NCH(CH3)2). 13C NMR (100 MHz, 1598 (CO). HR-MS (ESI) m/z calcd for C21H36NO3PPd −
+
CDCl3): δ = 164.3 (d, JP–C = 5.7 Hz, Cq), 153.5 (Cq), 143.4 (Cq), OCOCH3 [M − OCOCH3]+ 428.1335, found 428.1329. Anal.
126.1 (CH), 114.7 (CH), 108.2 (d, JP–C = 16.2 Hz, CH), 61.1 calcd for C21H36NO3PPd: C, 51.70; H, 7.44; N, 2.87. Found: C,
(CH2), 57.2 (2C, N{CH(CH3)2}2), 40.1 (d, JP–C = 16.2 Hz, 2C, 51.29; H, 7.46; N, 1.91.43
P{C(CH3)3}2), 28.1 (d, JP–C = 4.5 Hz, 6C, P{C(CH3)3)}2), 22.6 (2C,
Synthesis of (iPr2POCNiPr2)Pd-benzothiazolyl (5a)
NCH(CH3)2), 19.4 (2C, NCH(CH3)2). 31P{1H} NMR (162 MHz,
CDCl3):
δ
=
204.9 (s). HR-MS (ESI) m/z calcd for
To a stirred solution of benzothiazole (0.043 g, 0.323 mmol) in
THF (10 mL) was added n-BuLi (0.22 mL, 1.6 M in hexane) at
−78 °C. After stirring the resultant light yellow lithiated ben-
zothiazole solution at −78 °C for 20 min, a cold (−78 °C) solu-
tion of 2a (0.03 g, 0.065 mmol) in THF (10 mL) was added via
a cannula. The reaction mixture was stirred at −78 °C for 1 h.
The volatile species were evaporated under reduced pressure
and the product was extracted with n-hexane (20 mL). The n-
hexane extract was evaporated to dryness to obtain the crude
product, which shows a mixture of 5a (88%) and 2a (12%) in
C21H37ClNOPPd − Cl+ [M − Cl]+ 456.1648, found 456.1643.
Anal. calcd for C21H37ClNOPPd: C, 51.23; H, 7.57; N, 2.84.
Found: C, 49.87; H, 7.26; N, 1.96.43
Synthesis of (iPr2POCNiPr2)PdI (3a)
To the mixture of 2,6-(iPr2PO)(C6H3)(CH2-NiPr2)PdCl (2a)
(0.015 g, 0.032 mmol) and KI (0.008 g, 0.048 mmol) in a
J-Young NMR tube were added CH2Cl2 (0.3 mL) and methanol
(0.3 mL). Upon warming the reaction mixture at 40 °C for 14 h,
the chloro-derivative 2a is completely converted to the iodo-
derivative (iPr2POCNiPr2)PdI (3a). At ambient temperature the
volatile species were removed under vacuum to obtain a light
yellow compound. M.p. = 159–160 °C. 1H NMR (400 MHz,
CDCl3): δ = 6.94 (t, J = 7.8 Hz, 1H, Ar–H), 6.64 (d, J = 7.5 Hz,
1H, Ar–H), 6.61 (d, J = 8.0 Hz, 1H, Ar–H), 4.09 (s, 2H, CH2),
3.61 (apparent octet,42 J = 6.3 Hz, 2H, N{CH(CH3)2}2), 2.54
(apparent octet,42 J = 7.0 Hz, 2H, P{CH(CH3)2}2), 1.66 (d, J = 6.3
Hz, 6H, NCH(CH3)2), 1.45 (dd, J = 18.8, 7.3 Hz, 6H, PCH
(CH3)2), 1.28 (dd, J = 15.8, 7.0 Hz, 6H, PCH(CH3)2), 1.19 (d, J =
6.3 Hz, 6H, NCH(CH3)2). 13C NMR (100 MHz, CDCl3): δ = 162.9
(d, JP–C = 6.2 Hz, Cq), 153.8 (Cq), 147.1 (d, J = 6.9 Hz, Cq), 126.4
(CH), 115.1 (CH), 108.1 (d, JP–C = 16.9 Hz, CH), 61.1 (CH2), 58.2
(2C, N{CH(CH3)2}2), 30.3 (d, JP–C = 26.9 Hz, 2C, P{CH(CH3)2}2),
23.7 (2C, NCH(CH3)2), 19.5 (2C, NCH(CH3)2), 18.8 (d, J = 3.9
Hz, 2C, PCH(CH3)2), 16.9 (s, 2C, PCH(CH3)2). 31P{1H} NMR
(162 MHz, CDCl3): δ 203.9 (s). HR-MS (ESI) m/z calcd for
C19H33INOPPd − I+ [M − I]+ 428.1335, found 428.1330.
31P NMR spectroscopy. Characterization data of (iPr2POCNiPr2
)
1
Pd-benzothiazolyl (5a): H NMR (500 MHz, C6D6): δ = 8.34 (d,
J = 7.9 Hz, 1H, Ar–H), 7.95 (d, J = 7.6 Hz, 1H, Ar–H), 7.24 (t, J =
7.6 Hz, 1H, Ar–H), 7.08 (vt, J = 6.9 Hz, 1H, Ar–H), 7.00 (t, J = 8.2
Hz, 1H, Ar–H), 6.83 (d, J = 7.9 Hz, 1H, Ar–H), 6.63 (d, J = 7.6
Hz, 1H, Ar–H), 3.84 (s, 2H, CH2), 3.20 (apparent octet,42 J = 6.4
Hz, 2H, N{CH(CH3)2}2), 2.26 (apparent octet,42 J = 6.7 Hz, 2H,
P{CH(CH3)2}2), 1.43 (d, J = 6.0 Hz, 6H, NCH(CH3)2), 1.11 (dd,
J = 7.0, 1.8 Hz, 6H, PCH(CH3)2), 1.07 (dd, J = 7.0, 6.7 Hz, 6H,
PCH(CH3)2), 0.94 (d, J = 6.4 Hz, 6H, NCH(CH3)2). 13C NMR
(100 MHz, C6D6): δ = 163.9 (d, JP–C = 6.7 Hz, Cq), 158.4 (Cq),
154.8 (Cq), 152.6 (Cq), 139.0 (Cq), 136.4 (Cq), 127.1 (CH), 126.4
(CH), 125.2 (CH), 124.6 (CH), 122.6 (CH), 114.9 (CH), 108.1 (d,
JP–C = 15.3 Hz, CH), 64.7 (CH2), 58.2 (2C, N{CH(CH3)2}2), 29.2
(d, JP–C = 28.6 Hz, 2C, P{CH(CH3)2}2), 23.0 (2C, NCH(CH3)2),
19.4 (2C, NCH(CH3)2), 17.5 (d, JP–C = 4.8 Hz, 2C, PCH(CH3)2),
16.9 (2C, PCH(CH3)2). 31P{1H} NMR (202 MHz, C6D6): δ = 194.4
(s). HR-MS (ESI): m/z calcd for C26H37N2OPSPd + H+ [M + H]+
563.1477, found 563.1468.
Synthesis of (iPr2POCNiPr2)Pd(OCOCH3) (4a)
The mixture of 2,6-(iPr2PO)(C6H3)(CH2-NiPr2)PdCl (0.03 g,
0.065 mmol) and AgOAc (0.012 g, 0.072 mmol) in THF (10 mL)
was stirred at room temperature for 12 h. The resultant sus-
Conclusion
pension was filtered through celite and the volatile species In summary, new unsymmetrical pincer palladium complexes,
were evaporated under reduced pressure to obtain the light
iPr2POCNiPr2)PdCl and (tBu2POCNiPr2)PdCl, have been syn-
(
yellow compound 4a. Yield: 0.023 g, 73%. M.p. = 134–135 °C. thesized and demonstrated to catalyze the C–H bond arylation
1H NMR (400 MHz, CDCl3): δ 6.89 (t, J = 7.7 Hz, 1H, Ar–H), of azoles; the first time that any pincer-ligated palladium cata-
6.56 (d, J = 7.5 Hz, 1H, Ar–H), 6.52 (d, J = 7.8 Hz, 1H, Ar–H), lyst has been employed for such a reaction. In particular, the
4.05 (s, 2H, CH2), 3.43 (apparent octet,42 J = 6.3 Hz, 2H, N{CH sterically less demanding catalyst (iPr2POCNiPr2)PdCl enables
(CH3)2}2), 2.66 (apparent octet,42 J = 7.0 Hz, 2H, P{CH(CH3)2}2), the efficient coupling of a variety of activated, deactivated and
1.92 (s, 3H, COCH3), 1.55 (d, J = 6.3 Hz, 6H, NCH(CH3)2), 1.32 functionalized azoles with diverse aryl iodides with very low
(dd, J = 19.6, 7.3 Hz, 6H, PCH(CH3)2), 1.26 (dd, J = 14.7, 7.0 Hz, catalyst loading and TONs of up to 650. Numerous functional
6H, PCH(CH3)2), 1.23 (d, J = 6.3 Hz, 6H, NCH(CH3)2). 13C NMR groups, such as F, Cl, Br, OMe, COCH3, etc., were tolerated on
(100 MHz, CDCl3): δ = 176.5 (COCH3), 164.2 (d, JP–C = 7.6 Hz, the aryl backbone to give the coupled products in moderate to
Cq), 153.4 (Cq), 140.7 (Cq), 126.0 (CH), 114.4 (CH), 107.9 (d, excellent yields. Notably, the electron-rich aryl iodide electro-
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philes perform better than the electron-poor counterparts, a
result complementary to the traditional Pd(0)-catalyzed reac-
tions. Furthermore, the employment of less expensive and easily
available aryl chloride and bromide electrophiles for azole aryla-
tion by catalyst modification is currently under investigation in
our group. Although the mechanistic investigations accom-
plished were not conclusive, the experimental findings are
indicative of a homogeneous reaction mechanism with the
direct involvement of 2a in catalysis; however, the partial gene-
ration of another catalytic active species (palladium nanoparti-
cles) from 2a cannot be completely ruled out at this stage. The
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(
iPr2POCNiPr2)Pd-benzothiazolyl complex, 5a, is assumed to be a
key intermediate in the catalytic reaction. Hence, the reaction
mechanism is predicted to proceed via concerted metathesis or
the oxidative addition of aryl iodide to 5a, followed by the reduc-
tive elimination of the coupled product.
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Acknowledgements
This work was financially supported by CSIR-NCL (start-up
grant, MLP025926), CSIR-New Delhi (Network project ORIGIN,
CSC0108) and DST, New Delhi (SR/S1/IC-42/2012). S.M.K. and
V.S. thank CSIR, New Delhi for their research fellowship. We
thank a reviewer for useful suggestions during the review
process.
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14 For POCN-type amino-phosphinite ligands and their com-
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Bu4NBr during the catalytic reaction was monitored using
31P NMR spectroscopy. Hence, in the treatment of catalyst
2a (0.025 mmol) with benzothiazole (0.25 mmol) and
4-iodotoluene (0.375 mmol) in the presence of Bu4NBr
(0.05 mmol) under catalytic conditions at 100 °C for 3 h,
the three major species observed in the solution are
(
iPr2POCNiPr2)PdI (204.5 ppm, 43%), iPr2POCNiPr2)PdCl
(
(198.8 ppm, 24%) and a peak at 201.1 ppm (29%). The
peak at 201.1 ppm is most likely from the (iPr2POCNiPr2)-
PdBr compound (which has been independently investi-
gated by reacting
(
iPr2POCNiPr2)PdCl with Bu4NBr
(5 equiv.)). The observed low yield of the product in the
presence of Bu4NBr may be due to the impact of Bu4NBr on
CuX. The possible formation of coordinatively saturated
Cu(I) or Cu(II) species in equilibrium with CuX can be envi-
saged; a scenario which might hinder the action of Cu(I).
25 (a) Y. Lin and R. G. Finke, Inorg. Chem., 1994, 33, 4891–
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17 I. Göttker-Schnetmann, P. White and M. Brookhart, J. Am. 26 The catalytic reactions employing CuI (5 mol%)/PPh3
Chem. Soc., 2004, 126, 1804–1811.
(0.007 g, 0.025 mmol, 5 mol%) or CuI (5 mol%)/Py (0.03 g,
18 A. V. Polukeev, S. A. Kuklin, P. V. Petrovskii, S. M. Peregudova,
A. F. Smolyakov, F. M. Dolgushin and A. A. Koridze, Dalton
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19 See the Experimental section and ESI (Table S1†) for
details.
20 The standard catalytic reaction employing crude DMF as
well as DMF with added water (5 equiv. w.r.t. the catalyst
2a) has been investigated and both gave less than 2% of
the desired product 8aa at 120 °C. To know the status of
0.375 mmol) in the absence of 2a yielded the coupled
product 8aa in <5% and <1% H NMR yields, respectively.
This indicates that the actual catalytic reactions were not
promoted by CuI/PPh3 or CuI/Py-catalysis alone.
1
27 The status of the catalytic species was monitored by 31P
NMR in the presence of PPh3, pyridine and poly(vinyl pyri-
dine) during the catalytic reactions. The major pincer-palla-
dium species observed in all the cases were (iPr2POCNiPr2)-
PdI and (iPr2POCNiPr2)PdCl.
the catalyst under such conditions, the catalytic reaction 28 (a) P. Foley, R. DiCosimo and G. M. Whitesides, J. Am.
was monitored by 31P NMR. Hence, in the treatment of
catalyst 2a (0.025 mmol) with benzothiazole (0.25 mmol)
Chem. Soc., 1980, 102, 6713–6725; (b) D. R. Anton and
R. H. Crabtree, Organometallics, 1983, 2, 855–859.
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29 The reaction mixture contained 20% of CuI w.r.t. 2a;
however, the iodide-derivative 3a formed was 72%. This
suggests that the additional 52% of iodide is coming from
4-iodotoluene.
formation of 5a was not observed in this case. In addition,
the aim of this controlled experiment was also to check the
feasibility of transmetallation in the absence of CuI.
37 The reaction of (POCN)Pd-benzothiazolyl (5a) (100%) with
4-bromotoluene and 4-chlorotoluene in DMF at 100 °C for
5 h produced (POCN)Pd–Br (75%) and (POCN)Pd–Cl (16%),
respectively. This shows that the reactions of 4-bromo-
toluene and 4-chlorotoluene with 5a were resilient compared
to that shown with 4-iodotoluene. Though the stoichio-
metric reactions of 4-bromotoluene and 4-chlorotoluene
with 5a are feasible, we did not get convincing catalysis
while employing Ar–Cl and Ar–Br as electrophiles, which
might be due to the low catalyst concentration during cata-
lysis (substrate/catalyst ratio is 200/1 in catalysis).
30 The (iPr2POCNiPr2)Pd(OAc) (4a) complex might have formed
via the ligand (chloride/acetate) exchange reaction of
(
iPr2POCNiPr2)PdCl with CuOAc.
31 A probable ligand exchange between Cu(OAc) and 4-iodo-
toluene might produce CuI, which in turn can react with
2a to generate the complex 3a.
32 C. M. Frech, L. J. W. Shimon and D. Milstein, Angew.
Chem., Int. Ed., 2005, 44, 1709–1711.
33 Though Milstein et al. demonstrated that the halide
exchange reaction (pincer-Pd–Cl/Ar–I) is possible through a
redox induced Pd(0) intermediate, they have ruled out the 38 K. J. Przybilla and F. Vögtle, Chem. Ber., 1989, 122, 347–
intermediacy of such a species during the cross-coupling
355.
reaction.
39 K. R. Kunz, E. W. Taylor, H. M. Hutton and B. J. Blackburn,
Org. Prep. Proced. Int., 1990, 22, 613–618.
40 A. M. van Leusen, B. E. Hoogenboom and H. Siderius,
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35 The observed catalytic reactions were faster with aryl iodide
bearing electron-donating groups (Scheme 2), which goes 41 H. Chikashita, M. Ishibaba, K. Ori and K. Itoh, Bull. Chem.
against the conventional Pd(0)-mediated coupling reaction Soc. Jpn., 1988, 61, 3637–3648.
and is consistent with the probability of a transient Pd(IV) 42 In principle, the CH of –N{CH(CH3)2}2 should show a
species.
septet (if both CH groups are equivalent) or two separate
septets (if the CH groups are non-equivalent); however, an
apparent octet is observed, most likely due to the partial
overlapping of two septets for each CH of –N{CH(CH3)2}2.
36 Trivial formation of the (POCN)Pd-benzothiazolyl (5a)
species is most likely due to the absence of the transmetal-
lating reagent CuI in this reaction. The same reaction in
the presence of CuI produces (POCN)PdI as the major 43 A satisfactory elemental analysis is not observed for this
species in addition to unreacted 2a, and unfortunately the compound.
16096 | Dalton Trans., 2014, 43, 16084–16096
This journal is © The Royal Society of Chemistry 2014