Mechanistic Insights into Pincer-Ligated Palladium-Catalyzed Arylation of Azoles with Aryl Iodides: Evidence of a PdII-PdIV-PdII Pathway

Article abstract of DOI:10.1021/acs.organomet.6b00003

Pincer-based (^R2POCN^R′2)PdCl complexes along with CuI cocatalyst catalyze the arylation of azoles with aryl iodides to give the 2-arylated azole products. Herein, we report an extensive mechanistic investigation for the direct arylation of azoles involving a well-defined and highly efficient (^iPr2POCN^Et2)PdCl (2a) catalyst, which emphasizes a rare Pd^II-Pd^IV-Pd^II redox catalytic pathway. Kinetic studies and deuterium labeling experiments indicate that the C-H bond cleavage on azoles occurs via two distinct routes in a reversible manner. Controlled reactivity of the catalyst 2a underlines the iodo derivative (^iPr2POCN^Et2)PdI (3a) to be the resting state of the catalyst. The intermediate species (^iPr2POCN^Et2)Pd-benzothiazolyl (4a) has been isolated and structurally characterized. A determination of reaction rates of compound 4a with electronically different aryl iodides has revealed the kinetic significance of the oxidative addition of the C(sp²)-X electrophile, aryl iodide, to complex 4a. Furthermore, the reactivity behavior of 4a suggests that the arylation of benzothiazole proceeds via an oxidative addition/reductive elimination pathway involving a (^iPr2POCN^Et2)Pd^IV(benzothiazolyl)(Ar)I species, which is strongly supported by DFT calculations.

Full text of DOI:10.1021/acs.organomet.6b00003

Article
pubs.acs.org/Organometallics
Mechanistic Insights into Pincer-Ligated Palladium-Catalyzed
Arylation of Azoles with Aryl Iodides: Evidence of a PdII−PdIV−PdII
Pathway
Shrikant M. Khake,† Rahul A. Jagtap,† Yuvraj B. Dangat,‡ Rajesh G. Gonnade,§ Kumar Vanka,‡
and Benudhar Punji*,†
‡
†Organometallic Synthesis and Catalysis Group, Chemical Engineering Division, Physical and Materials Chemistry Division, and
§Centre for Material Characterization, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune 411 008,
Maharashtra India
S
* Supporting Information
ABSTRACT: Pincer-based (R2POCNR′2)PdCl complexes along with CuI cocatalyst catalyze the arylation of azoles with aryl
iodides to give the 2-arylated azole products. Herein, we report an extensive mechanistic investigation for the direct arylation of
azoles involving a well-defined and highly efficient (iPr2POCNEt2)PdCl (2a) catalyst, which emphasizes a rare PdII−PdIV−PdII
redox catalytic pathway. Kinetic studies and deuterium labeling experiments indicate that the C−H bond cleavage on azoles
occurs via two distinct routes in a reversible manner. Controlled reactivity of the catalyst 2a underlines the iodo derivative
(
iPr2POCNEt2)PdI (3a) to be the resting state of the catalyst. The intermediate species (iPr2POCNEt2)Pd-benzothiazolyl (4a) has
been isolated and structurally characterized. A determination of reaction rates of compound 4a with electronically different aryl
iodides has revealed the kinetic significance of the oxidative addition of the C(sp2)−X electrophile, aryl iodide, to complex 4a.
Furthermore, the reactivity behavior of 4a suggests that the arylation of benzothiazole proceeds via an oxidative addition/
reductive elimination pathway involving a (iPr2POCNEt2)PdIV(benzothiazolyl)(Ar)I species, which is strongly supported by DFT
calculations.
rich azoles and subsequent reductive elimination, has been
proposed (Figure 1A).4a,7 Similarly, Huang and co-workers, as
well as others, have described a crucial copper−benzothiazolyl
transmetalation to the oxidatively added product LnPdII(Ar)I,
before the occurrence of reductive elimination.4j In contrast to
other azoles, a ring-opening pathway in the Pd-catalyzed
arylation of benzoxazole has been proposed, which is limited
only to the benzoxazole system.8 In all of these proposed
mechanisms for the arylation of azoles, special attention has
been devoted to the C−H bond cleavage step, as the oxidative
addition of Ar−X was proposed to occur at the Pd(0) center
and the reaction was proposed to proceed via the classical
Pd(0)−Pd(II)−Pd(0) catalytic cycle.
INTRODUCTION
■
A plethora of transition-metal catalysts (nickel,1 copper,2
rhodium,3 palladium4) are known to catalyze the direct
arylation of azoles with aryl halides to give the 2-arylated
azoles.5 Among them, the palladium complexes as catalysts have
been predominantly utilized, because of the user-friendly nature
of palladium precursors and the mild reaction conditions.4
Despite the significant progress in palladium-catalyzed
methods, in-depth mechanistic studies for the palladium-
catalyzed arylation of azoles are unfortunately not available.6
An insightful mechanistic understanding of the direct arylation
of azoles is essential to the development of novel palladium
catalyst systems, which would show increased reactivity at lower
temperature and with low catalyst loadings. The absence of a
comprehensive mechanistic study for this reaction has led to
the consideration of diverse reaction pathways. For instance, an
initial oxidative addition of aryl halides to palladium(0),
followed by electrophilic aromatic substitution of electron-
In contrast to this, a Pd(II)−Pd(IV)−Pd(II) catalytic cycle
for the arylation of azoles can be envisioned if a suitable
Received: January 4, 2016
© XXXX American Chemical Society
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Figure 1. Palladium-catalyzed mechanisms for direct arylation of azoles: (A) previous reports by a classical Pd(0)−Pd(II)−Pd(0) pathway; (B)
description in this paper via a Pd(II)−Pd(IV)−Pd(II) pathway.
Scheme 1. Synthesis of POCN-H Ligand Precursors and (R2POCNEt2)PdCl Complexes
palladium catalyst system for the arylation reaction is applied.
The arylations through the Pd(II)/Pd(IV) process will have
many advantages over that with Pd(0)/Pd(II), as in the former,
the active catalyst is expected to be highly air and moisture
stable and the reaction would exhibit complementary functional
group tolerance.9 Similar mechanistic observations have been
made for the arylation of other (hetero)arenes, wherein the
strongly electrophilic reagents [Ar2I]X10 or aryl halides with
stoichiometric amounts of external oxidants were employed.11
Vicente et al. have shown intramolecular C(sp2)−I oxidative
addition to a Pd(II) species during a Heck-type reaction,12 and
the intermediacy of similar Pd(IV) species is assumed in various
other arylation reactions.13 However, the arylation of azoles
involving the oxidative addition of C(sp2)−X electrophiles,
such as aryl halides, to a Pd(II) derivative has not been
documented, though the theoretical work on the Pd(II)/
Pd(IV) process indicates that the oxidative addition of Ph−I to
Pd(II) would be feasible if a suitable ligand system were
present.14 Recently, we have developed POCN-pincer-ligated
palladium catalyst systems for the arylation of azoles with aryl
iodides and we made a speculative assertion about the reaction
path.15 Herein, we describe an active, well-defined
(Figure 1B). In addition to the detailed kinetic and controlled
reactivity studies and isolation and reactivity of the intermediate
species, DFT calculations were performed for the key
elementary steps to obtain information about the energetically
feasible intermediates during the azole arylation. These
investigations have led us to introduce an advanced mechanistic
pathway for the direct arylation of azoles with aryl iodides
catalyzed by the (iPr2POCNEt2)Pd catalyst.
RESULTS AND DISCUSSION
■
Recently, we have synthesized two arene-based hybrid pincer
palladium complexes (iPr2POCNiPr2)PdCl and (tBu2POCNiPr2)-
PdCl and employed them for the arylation of azoles with aryl
iodides.15 These hybrid palladium systems were designed and
developed with the assumption that the hemilabile character of
the POCN backbone could provide suitable sterics, electronics,
and coordination demands that are needed along the different
steps of the arylation reaction. At the outset of our studies, we
found that the sterically less demanding catalyst (iPr2POCNiPr2)-
PdCl performed much better than the bulky analogue
(
tBu2POCNiPr2)PdCl for the direct arylation of azoles. We
(
iPr2POCNEt2)-pincer palladium derivative and have unraveled
considered that the sterically even less bulky and electronically
distinct complexes, such as (iPr2POCNEt2)PdCl and
the detailed mechanism of the (iPr2POCNEt2)Pd-catalyzed
arylation of azoles with aryl iodides, wherein a rare Pd(II)/
Pd(IV)/Pd(II) redox catalytic process has been revealed
(
Ph2POCNEt2)PdCl, might be superior to the previously
employed pincer complexes for the arylation of azoles.
B
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Synthesis and Characterization of POCN-Palladium
Complexes. The iPr2POCNEt2-H (3-(iPr2PO)-C6H4-1-
(CH2NEt2); 1a) ligand precursor was prepared by a slight
modification of the procedure described for the same species by
Zargarian and van der Est (Scheme 1).16 Initially, the 3-
hydroxybenzyl bromide was treated with 2 equiv of diethyl-
amine in acetone to obtain the colorless product of 3-
((diethylamino)methyl)phenol in excellent yield. 3-
1
((Diethylamino)methyl)phenol was well characterized by H
and 13C NMR spectroscopy. The treatment of 3-
((diethylamino)methyl)phenol with NaH at 70 °C, followed
by a reaction with diisopropylchlorophosphine (iPr2PCl),
produced the ligand iPr2POCNEt2-H as a viscous liquid in
86% yield. The 31P{1H} NMR spectrum of 1a showed a single
resonance at 146.6 ppm (for the O−PiPr2 moiety). Other NMR
data of compound 1a are in good agreement with those
reported for the same species by Zargarian and van der Est.16
Metalation of the crude ligand 1a with Pd(COD)Cl2 in the
presence of K3PO4 in 1,4-dioxane at 70 °C afforded the
complex (iPr2POCNEt2)PdCl ([2-(iPr2PO)-C6H3-6-
(CH2NEt2)]PdCl; 2a) as a light yellow solid after purification
by column chromatography on neutral alumina (Scheme 1).
The 31P{1H} NMR spectrum of 2a displayed a singlet at δ
199.3 ppm, which is comparable with the 31P NMR data
reported for the similar compound (iPr2POCNiPr2)PdCl (δP
Figure 2. Thermal ellipsoid plot of (iPr2POCNEt2)PdCl (2a). All
hydrogen atoms are omitted for clarity. Selected bond lengths (Å):
Pd(1)−C(1), 1.955(4); Pd(1)−P(1), 2.1895(12); Pd(1)−N(1),
2.192(4); Pd(1)−Cl(1), 2.3889(12). Selected bond angles (deg):
C(1)−Pd(1)−P(1), 80.08(18); C(1)−Pd(1)−N(1), 82.4(2); P(1)−
Pd(1)−N(1), 162.53(11); C(1)−Pd(1)−Cl(1), 175.41(13); P(1)−
Pd(1)−Cl(1), 100.30(5); N(1)−Pd(1)−Cl(1), 97.14(11).
The complex (Ph2POCNEt2)PdCl (2b) was previously
reported via a one-pot phosphorylation/palladation synthetic
route, starting from 3-((diethylamino)methyl)phenol, diphe-
nylchlorophosphine, and palladium chloride, by Song and co-
workers,17 without the isolation and characterization of the
ligand precursor Ph2POCNEt2-H (1b). However, we have
synthesized and characterized the ligand Ph2POCNEt2-H (1b),
and the complexation was carried out by the modification of the
reported procedure (Scheme 1). Similar to the synthesis of 1a,
the ligand precursor Ph2POCNEt2-H (1b) was synthesized from
the reaction of 3-((diethylamino)methyl)phenol with diphenyl-
chlorophosphine (Ph2PCl). The compound 1b was obtained as
a viscous liquid in 77% yield. The 31P{1H} NMR spectrum of
1b displayed a singlet at 110.1 ppm (for the O-PPh2 moiety),
which is consistent with the 31P NMR data reported for an
analogous compound: i.e., Ph4POCOP-H18 (δ 112.0 ppm).
Metalation of compound 1b with Pd(COD)Cl2 in the presence
of K3PO4 in 1,4-dioxane at 70 °C produced the complex
1
198.9 ppm). In the H NMR spectrum of 2a, the splitting
pattern in the aromatic region clearly suggested the formation
of a pincer-palladium complex, which is again evident from the
disappearance of the peak corresponding to the apical proton.
1
It is worth noting that, in the H NMR spectrum of 2a, four
protons on two −CH2 groups of −NEt2 appeared as a distinct
sextet and a septet, against a single quartet for the same protons
in the spectrum of the free ligand. This noticeable change in the
1
splitting pattern of the −CH2 peak in the H NMR spectrum
could be treated as evidence of the N-arm coordination of the
ligand to the palladium center. The 13C NMR, HRMS, and
elemental analysis data of 2a are in good agreement with the
assigned molecular structure.
Compound 2a was further characterized by X-ray crystallog-
raphy (Figure 2). The coordination geometry around the
palladium is approximately square planar. Selected bond lengths
and bond angles are given in the figure caption. The Pd−P
bond length in 2a is 2.1895(12) Å, almost the same as that
observed in (iPr2POCNiPr2)PdCl (Pd−P = 2.1890(6) Å). The
Pd−N bond length is 2.192(4) Å, slightly shorter than that
reported for (iPr2POCNiPr2)PdCl (Pd−N = 2.2204(17) Å). This
value suggests that a stronger coordination of the amino group
toward the Pd center in 2a in comparison to that of the same
group in the complex (iPr2POCNiPr2)PdCl. The Pd−C and Pd−
Cl bond lengths are 1.955(4) and 2.3889(12) Å, respectively,
which are comparable with the corresponding bond lengths in
(
Ph2POCNiPr2)PdCl ([2-(Ph2PO)-C6H3-6-(CH2NEt2)]PdCl;
2b). The 31P{1H} NMR spectrum of 2b showed a single
peak at δ 151.5 ppm. The H and 13C NMR data of 2b are
1
consistent with the data reported in the literature for the same
species.17
Catalytic Activity of Pincer-Ligated Palladium Com-
plexes for Arylation of Azoles. The sterically and
electronically distinct hybrid complexes (iPr2POCNEt2)PdCl
(2a) and (Ph2POCNEt2)PdCl (2b) along with the most
common symmetrical complexes (iPr4PCP)PdCl and
iPr2POCNiPr2)PdCl (Pd−C = 1.956(2), Pd−Cl = 2.3922(6)
(
iPr4POCOP)PdCl were screened and optimized for the direct
(
Å). The P(1)−Pd(1)−N(1) bond angle (162.53(11)°) of 2a is
comparable with that reported for (iPr2POCNiPr2)PdCl
(162.10(5)°). The C(1)−Pd−N(1) bond angle is 82.4(2)°,
slightly greater than that of (iPr2POCNiPr2)PdCl (81.84(8)°).
The N(1)−Pd−Cl(1) bond angle of 2a (97.14(11)°) is
significantly smaller than that reported for (iPr2POCNiPr2)PdCl
(100.79(5)°), which indicates that the Pd−Cl bond is aligned
more toward the amino group in 2a than is the Pd−Cl bond in
arylation of azoles with aryl iodides. After investigating various
reaction parameters (see Table S1 in the Supporting
Information for details), we found that 0.5 mol % of the
catalyst 2a along with CuI (1.0 mol %) catalyzed the arylation
of benzothiazole with 4-iodotoluene to produce the arylated
product 2-(p-tolyl)benzothiazole (7aa) in 98% yield in the
presence of K3PO4 in DMF. With the optimized catalytic
conditions, the initial rates for the arylation of benzothiazole
using different catalysts (iPr2POCNEt2)PdCl, (iPr2POCNiPr2)-
PdCl, (tBu2POCNiPr2)PdCl, and (Ph2POCNEt2)PdCl were
determined to be 16.0 × 10−4, 9.8 × 10−4, 2.2 × 10−4, and
(
iPr2POCNiPr2)PdCl. All of these bond angles seem consistent
with the steric impact exerted by the −NEt2 group in 2a being
less than that of the −NiPr2 group in (iPr2POCNiPr2)PdCl.
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6.2 × 10−4 M min−1, respectively (Figure 3), which strongly
supports the hypothesis that the activity of a less bulky
Figure 4. Reaction profile for the 2a-catalyzed arylation of
benzothiazole with 4-iodotoluene.
8 TONs, respectively, which suggests the absence of an
induction period for the arylation reaction. At the end of 90
min, the conversion of benzothiazole was 48% and the product
7aa formation was 44%.
The order in each component in the arylation of
benzothiazole with 4-iodotoluene was determined individually
at 120 °C in DMF using the initial rate approximation. Figure
S1 in the Supporting Information shows that the rate of the
arylation reaction is almost the same for the various
concentrations of the benzothiazole, suggesting that the
reaction is zeroth order in the concentration of benzothiazole.
Similarly, the rate of the arylation reaction is independent of the
concentration of 4-iodotoluene and establishes zeroth-order
behavior for this component (see Figure S2 in the Supporting
Information for details). Next, the dependence of the reaction
rate on the different loadings of the catalyst 2a was determined
by comparison of the initial rates of product formation. A slope
of 0.067 was obtained from the plot of log(rate) vs log(concn
of 2a), suggesting a zeroth-order reaction in the loading of 2a
(Figure S3 in the Supporting Information). The rate of the
arylation reaction increases upon higher loadings of K3PO4, and
a slope of 0.74 was obtained from the plot of log(rate) vs
log(equiv K3PO4), indicating a fractional order arylation
reaction in K3PO4 (Figure 5). The partial order in base
indicates that more than one pathway is operative for the
deprotonation of benzothiazole involving K3PO4 (most likely
via direct electrophilic C−H deprotonation of benzothiazole, as
well as from the CuI-coordinated benzothiazole). Figure S4 in
the Supporting Information shows that the rates of arylation
reactions slightly decelerate with an increase in the initial
concentration of CuI with a negative order of −0.15. The
fractional order of −0.15 indicates that the high concentration
of CuI actually retards the rate of the arylation reaction, which
might be due to the degradation of the active palladium catalyst
at higher concentrations of CuI. A plausible decoordination of
the N-arm of the pincer palladium and coordination of the
same to CuI can be assumed in the presence of excess CuI,
which would reduce the activity of the pincer Pd catalyst.19 On
the basis of all these results, the simple rate equation can be
written as shown in eq 1.
Figure 3. Time-dependent formation of 7aa using different POCN-Pd
catalysts.
(POCN)Pd catalyst is higher than that of the sterically bulky
analogues. Though the previously reported catalyst
(
iPr2POCNiPr2)PdCl was very efficient in the arylation of azoles
in the presence of the expensive base Cs2CO3,15 it showed
slightly less activity under the current catalytic conditions. The
most common symmetrical pincer palladium complexes
(
iPr4PCP)PdCl and (iPr4POCOP)PdCl were shown to have
very poor catalytic performance for the arylation of
benzothiazole with 4-iodotoluene and produced the coupled
product 7aa in 54% and 22% yields, respectively (see Table S1
for details). With the optimized reaction conditions, the catalyst
2a was employed for the arylation of various substituted
benzothiazoles and azoles with diverse aryl iodides to obtain the
desired products in moderate to good yields (Table S2 in the
Supporting Information). This catalyst system is much more
efficient than the literature-reported palladium catalysts for the
arylation of azoles in terms of higher turnover numbers.4a,b,f,i In
addition, the advantage of the current system is the well-defined
nature of the catalyst, which makes it appropriate for an in-
depth mechanistic study.
Kinetic Analysis of Direct Arylation of Azoles
Catalyzed by 2a. All kinetic experiments were performed in
flame-dried screw-capped tubes under an argon atmosphere. In
the standard arylation experiment, 1.25 mM of 2a, 2.50 mM of
CuI, 0.108 M mesitylene (internal standard), benzothiazole
(0.25 M), 4-iodotoluene (0.375 M), and K3PO4 (0.75 mmol)
were used, and DMF was added to make the total volume 2.0
mL. All reactions were conducted at 120 °C, and the progress
of the reaction was monitored by gas chromatography (GC) at
regular intervals. The reported values represent the average of
three independent experiments. The reaction profile of the 2a-
catalyzed arylation of benzothiazole with 4-iodotoluene over a
period of 90 min is shown in Figure 4. The formation of
coupled product 7aa followed a linear plot, indicating a
constant reaction rate. After 5 and 10 min of the reaction, 4.0
and 10 mM of coupled product was formed amounting to 3 and
rate = k[K3PO ]0.74 [CuI]−0.15
4
(1)
overall reaction order = 0.6
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Figure 5. (A) Time-dependent formation of 7aa at different initial concentrations of K3PO4. (B) Plot of log(rate) vs log(equiv of K3PO4). The rates
are the average of three independent measurements.
In order to investigate the possible catalyst deactivation, the
recycling experiment of the catalytic reaction system was
conducted (section 5.1 in the Supporting Information). After
the first catalytic run between benzothiazole and 4-iodotoluene,
the yield of the coupled product observed was 98% (GC yield).
In the same reaction vessel were placed fresh benzothiazole, 4-
iodotoluene, and K3PO4, and the reaction was continued
further without addition of catalyst 2a and CuI. After 16 h, the
yield determined for the second cycle was 90%. Furthermore,
the possible catalyst deactivation was investigated by carrying
out four arylation reactions at the same [“excess”] but different
initial concentrations of the benzothiazole and 4-iodotoluene
(section 5.2 in the Supporting Information).20 As shown in
Table S9 in the Supporting Information, the rates of the
reactions are identical with different starting concentrations of
the benzothiazole and 4-iodotoluene, with identical values for
[“excess”]. All of these results suggest that there was no
significant catalyst deactivation during the arylation reaction of
benzothiazole.
Turnover-Limiting Step. The progress of the reaction
studied with the kinetic analyses reveals that the arylation
reaction is zeroth order in benzothiazole, 4-iodotoluene, and
the catalyst concentration, whereas a fractional order was
observed in K3PO4. Since the arylation reaction is of fractional
order in K3PO4, one can assume that the C−H bond cleavage is
the probable turnover-limiting step. To probe this possibility, a
kinetic isotope effect (KIE) study and a deuterium scrambling
experiment were carried out. The rates of the arylation
reactions employing 2-H-benzothiazole and 2-D-benzothiazole
with 4-iodotoluene were found to be almost consistent, and the
observed isotope effect (kH/kD) was approximately 1.0 (Figure
S7 in the Supporting Information), which indicates that C−H
bond cleavage is unlikely to be the turnover-determining step.
Furthermore, the treatment of 2-D-benzothiazole and 2-H-6-
ethoxybenzothiazole with the optimized catalytic system in the
absence of aryl iodide showed a significant H/D scrambling,
solely occurring at the C-2 position (section 6.2 and Figure S8
in the Supporting Information). This observation highlights the
C−H bond deprotonation to be reversible in nature and hence
indicates that it may not be involved in the turnover-limiting
step.
The role of a similar (POCN)Pd catalyst, as well as that of
CuI, in the arylation reaction has recently been established in
our group, wherein (POCN)Pd acts as a catalyst and CuI acts
as a cocatalyst.15 Further, the kinetic study for the arylation
with varying concentrations of CuI, as well as the control
experiments,21 suggest that complex 2a is the primary catalyst
and CuI behaves as a cocatalyst. Most likely, the CuI facilitates
the transmetalation of the benzothiazolyl moiety to the
palladium catalyst in the presence of a base. Furthermore, in
order to validate our assumption on the role of CuI,
benzothiazole was treated with CuI in acetonitrile, which
gave a white crystalline compound. The proton NMR spectrum
of the resulting compound displayed a peak at 9.59 ppm
corresponding to the C(2)−H proton of the N-coordinated
(benzothiazole)CuI moiety (0.18 ppm more deshielded than
the signal for free benzothiazole). This coordination could
enhance the acidity of the C(2)−H proton, which facilitates the
deprotonation/carbometalation of the benzothiazole with the
Cu metal followed by transmetalation with the palladium
catalyst. A similar role of the organo-copper intermediate has
been reported for the arylation of azoles as well as for other
coupling reactions.4j,22
Since the C−H bond cleavage/deprotonation was found to
be reversible in nature, the rates of the coupling of
benzothiazole, 6-ethoxybenzothiazole, and 6-fluorobenzothia-
zole with 4-iodotoluene were determined in order to
understand the electronic influence of the substrates on the
arylation reaction (Figure 6). These rates of the coupling
reaction were similar, though the substrates are electronically
different. Furthermore, the intermolecular competition experi-
ments between the differently substituted benzothiazoles with
4-iodotoluene concurrently furnished the arylation products
from both the electron-rich and electron-deficient substrates
(Figure S10 in the Supporting Information). These findings
indicate that the electronic property of the substituted
benzothiazole has negligible influence on the arylation reaction
and hence, the probability of transmetalation between
(benzothiazolyl)-K and CuX or between (benzothiazolyl)CuLn
and (iPr2POCNEt2)PdX being a turnover-limiting step is less
likely, because the more electron rich substrates with high
nucleophilicity would favor a transmetalation process. Further,
these experimental findings do not support reductive
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Further, the rates of the reaction of the presumed intermediate
species (iPr2POCNEt2)Pd(benzothiazolyl) (the synthesis and
observation of the same are discussed below) with 4-
methoxyiodobenzene and 4-acetyliodobenzene were deter-
mined by calculating the rate of the formation of
(
iPr2POCNEt2)PdI species at 100 °C. As shown in Figure 8,
Figure 6. Kinetics of the reactions of benzothiazole (5a), 6-
ethoxybenzothiazole (5b), and 6-fluorobenzothiazole (5c) with 4-
iodotoluene (6a).
elimination as a turnover-limiting step, as the reductive
elimination tends to be more favorable from electron-poor
metal centers.23 The interpretation of the reductive elimination
being not a turnover-limiting step was further supported by
DFT calculations (discussed below), which show a lower
energy barrier for this step.
Figure 8. Time-dependent formation of (iPr2POCNEt2)PdI for the
reaction of (iPr2POCNEt2)Pd(benzothiazolyl) with 4-methoxyiodoben-
zene and 4-acetyliodobenzene at 100 °C. The concentration of
(
iPr2POCNEt2)PdI was determined from the integration percentage of
Next, the initial rates for the arylation reaction of
benzothiazole with electronically different para-substituted
aryl iodides were determined (Figure 7). The Hammett plot
was drawn from a correlation between the initial rates and the
σp values, which resulted in an almost linear fit with a slope of
−0.777. The negative ρ value suggests that a positive charge is
being produced in the activated complex and that electron-
donating substituents on the aryl iodide will enhance the rate of
the arylation reaction. This is in support of the oxidative
addition of aryl iodides to a Pd(II) species rather than to a
Pd(0) species, as in the former an electron-donating substituent
would be expected to stabilize the resulting Pd(IV)
intermediate and hence lower the energy of the process.
the same with respect to PMe3 capillary.
the rate of the formation of (iPr2POCNEt2)PdI with use of the
electron-rich 4-methoxyiodobenzene is almost double that with
the electron-deficient electrophile 4-acetyliodobenzene. This
experimental finding further supports our notion that the
oxidative addition of aryl iodide occurs to a Pd(II) center, as an
electron-rich aryl iodide would favor oxidative addition to a
Pd(II) species, and this suggests that the oxidative addition step
is kinetically more significant.
Controlled Reactivity of Complex 2a. The status of the
catalyst 2a under the catalytic conditions was monitored by 31
P
Figure 7. (A) Time-dependent formation of arylation products for the coupling of benzothiazole with different para-substituted aryl iodides (4-R-
C6H4-I). (B) Hammett plot correlation using different aryl iodides.
F
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Scheme 2. Controlled Reactivity and Resting State of Catalyst 2a
NMR spectroscopy to determine the resting state of the catalyst
as well as to detect probable intermediate species during the
reaction. The 31P NMR experiments were carried out in J.
Young NMR tubes, and the yields of different (POCN)Pd
species were determined with reference to the external standard
(PMe3 capillary). Initially, the catalyst 2a (0.025 mmol), CuI
(0.0025 mmol), benzothiazole (0.25 mmol), 4-iodotoluene
(0.375 mmol), and K3PO4 (0.375 mmol) in DMF (0.5 mL)
were heated to 100 °C in an oil bath and the reaction was
monitored at regular intervals (Scheme 2a). After 3 h, the
reaction mixture showed 5% of 2a and 95% of (iPr2POCNEt2)-
PdI (3a) as the 31P NMR detectable species. The reaction
mixture was heated further for 40 h, wherein the complex 3a
persisted as the major species (91%) with the minor existence
of 2a (3%). Even from the 31P NMR measurement of the
reaction mixture at 100 °C in the NMR instrument, complex 3a
was detected as the major observable species. These
observations indicate that the catalyst decomposition was not
significant, and further, it demonstrates that the iodide species
3a could be the resting state of the catalyst.
significantly. The observed complex 4a could be a crucial
intermediate in the arylation of benzothiazole. This observation
further indicated that the reaction of 2a with benzothiazole is
most likely the first step of the catalytic reaction, rather than the
reaction of 2a with 4-iodotoluene.
Reactivity of Active Pd Intermediate 4a. In order to
understand the progress of the arylation reaction originating
from the intermediate species (iPr2POCNEt2)Pd-benzothiazolyl
(4a), the reactivity of 4a with various electrophiles was
investigated (Scheme 3). The reaction of 4a (0.013 g, 0.025
Scheme 3. Reactivity of (iPr2POCNEt2)Pd-benzothiazolyl (4a)
a
with Electrophiles
Further, with the anticipation of encountering any catalytic
intermediate species, we performed control experiments of
complex 2a. Hence, complex 2a was treated with 4-iodotoluene
(15 equiv) in DMF for 12 h (Scheme 2b). The 31P NMR
spectrum of the reaction mixture shows solely the starting
complex 2a without any decomposition or formation of the
iodide derivative 3a, which suggests that the oxidative addition
of 4-iodotoluene to the 16e species 2a might not be a feasible
process and such a reaction may not be involved in the first step
of the catalytic reaction.24 In another experiment, complex 2a
was treated with benzothiazole (10 equiv) in the presence of
K3PO4 (Scheme 2c). After the reaction mixture was heated to
100 °C for 3 h, the formation of the new complex
a
Complex yields are measured from the 31P NMR spectrum (PMe3
capillary as external standard) and coupled products yields are from
GC or H NMR analysis.
1
mmol) with 1 equiv of 4-iodotoluene in DMF at elevated
temperature exclusively produced the complex (iPr2POCNEt2)-
PdI (3a) and the coupled product 2-(p-tolyl)benzo[d]thiazole
(7aa). This observation again confirmed the intermediacy of 4a
during the arylation of benzothiazole with 4-iodotoluene.
Further, in order to know the possible pathway in which 4a
reacts with 4-iodotoluene, the complex 4a was treated with
other strong oxidants, such as I2. Hence, the treatment of 4a
with molecular I2 solely produced the complex 3a and 2-
(
iPr2POCNEt2)Pd-benzothiazolyl (4a) was observed in 19%
yield. The authenticity of 4a was established by an independent
synthesis and characterization of the same (discussed below).
Though the species (iPr2POCNEt2)PdX is significantly stable
under standard catalytic conditions, under the aforementioned
noncatalytic conditions the palladium species decomposed
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iodobenzo[d]thiazole at room temperature. All of these
experimental findings highlight the involvement of a transient
Pd(IV) intermediate during the reaction of 4a with 4-
iodotoluene or molecular iodine, before reductive elimination
of the coupled products and generation of the active
palladium(II) catalyst. This represents unique experimental
evidence, where the oxidative addition of C(sp2)−X electro-
phile to a Pd(II) center is unequivocally shown. Though the
formation of such Pd(IV) species involving C(sp3)−X
electrophiles are well documented both experimentally and
theoretically,9,25 similar oxidative addition of the C(sp2)−X
electrophiles to Pd(II) complexes is rare.12,13 We have further
carried out DFT calculations to validate our experimental
observations on the probable transient species, which is
discussed below.
iPr2POCNEt2)PdX Derivatives. The derivatives of
Figure 9. Thermal ellipsoid plot of (iPr2POCNEt2)PdI (3a). All
hydrogen atoms are omitted for clarity. Selected bond lengths (Å):
Pd(1)−C(1), 1.965(2); Pd(1)−P(1), 2.1959(7); Pd(1)−N(1),
2.185(2); Pd(1)−I(1), 2.6825(2). Selected bond angles (deg):
C(1)−Pd(1)−P(1), 80.21(7); C(1)−Pd(1)−N(1), 82.25(9); P(1)−
Pd(1)−N(1), 162.45(6); C(1)−Pd(1)−I(1), 172.74(7); P(1)−
Pd(1)−I(1), 99.531(18); N(1)−Pd(1)−I(1), 97.92(6).
(
(
iPr2POCNEt2)Pd were synthesized and characterized to
authenticate their presence during the mechanistic investigation
(Scheme 4). The reaction of (iPr2POCNEt2)PdCl (2a) with KI
Scheme 4. Synthesis of (iPr2POCNEt2)Pd Derivatives
in the dichloromethane/methanol solvent mixture at room
temperature afforded the complex (iPr2POCNEt2)PdI (3a). The
31P NMR spectrum of 3a showed a single peak at 205.4 ppm.
The complex (iPr2POCNEt2)Pd(benzothiazolyl) (4a) was
synthesized by the treatment of 2a with 5 equiv of
benzothiazolyllithium at −78 °C. The 31P NMR spectrum of
complex 4a showed a singlet at 196.0 ppm. The HRMS-ESI
mass spectrum of 4a displayed a peak at m/z 535.1169
corresponding to the [4a + H]+ ion. The 1H and 13C NMR and
elemental analysis data of complexes 3a and 4a are in good
agreement with the assigned molecular structures.
Molecular structures of complexes 3a and 4a were also
determined by X-ray single-crystal analysis. The thermal
ellipsoid plots of the molecules are shown in Figures 9 and
10. The selected bond lengths and bond angles are given in the
respective figure captions. In general, the structural parameters
of 3a and 4a are quite similar to those of 2a. The Pd−C(ipso)
bond lengths in 3a and 4a are 1.965(2) and 1.985(2) Å,
respectively. The differences in Pd−C(ipso) bond lengths are
indicative of the different trans influences of X ligands on the
complex, and they are in the order benzothiazolyl (4a) > I (3a)
> Cl (2a). The C−Pd−P and C−Pd−N bond angles in all the
complexes are almost similar, except that a slightly smaller P−
Pd−N bond angle (161.6°) was observed in 4a. In complex 4a,
the benzothiazolyl moiety is almost perpendicular to the
POCN-pincer ring, having both N(1)−Pd(1)−C(18)−N(2)
and P(1)−Pd(1)−C(18)−S(1) torsion angles of around 70°.
Figure 10. Thermal ellipsoid plot of (iPr2POCNEt2)Pd(benzothiazolyl)
(4a). All hydrogen atoms are omitted for clarity. Selected bond lengths
(Å): Pd(1)−C(1), 1.985(2); Pd(1)−P(1), 2.1953(6); Pd(1)−N(1),
2.181(2); Pd(1)−C(18), 2.072(2). Selected bond angles (deg):
C(1)−Pd(1)−P(1), 80.30(7); C(1)−Pd(1)−N(1), 81.31(9); P(1)−
Pd(1)−N(1), 161.60(6); C(1)−Pd(1)−C(18), 174.46(10); P(1)−
Pd(1)−C(18), 99.70(7); N(1)−Pd(1)−C(18), 98.58(8).
Quantum-Chemical Calculations. In order to get more
insight into the reactivity pattern of aryl iodide with the
intermediate palladium complex 4a, the reaction of iodoben-
zene (RC1) with the square planar palladium complex 4a has
been investigated through density functional theory (DFT).
The two steps (i) oxidative addition and (ii) reductive
elimination have been considered.
(i). Oxidative Addition. The oxidative addition of aryl iodide
(RC1) can occur through four different possibilities. The
transition states for these different possibilities have been
explored. As shown in Figure 11, out of the four different
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Article
Figure 11. Four different possible transition states for the oxidative addition of RC1 to 4a. All values are in kcal/mol and are with respect to
(RC1+4a). Hydrogen atoms are omitted for the purpose of clarity. The color scheme is as follows: palladium, brown; iodide, maroon; sulfur, dark
yellow; phosphorus, light yellow; nitrogen, blue; oxygen, red; carbon, black.
Figure 12. Free energy profile for the reaction of phenyl iodide (RC1) with 4a. All values are in kcal/mol. Hydrogen atoms are omitted for the
purpose of clarity. The color scheme is as follows: palladium, brown; iodide, maroon; sulfur, dark yellow; phosphorus, light yellow; nitrogen, blue;
oxygen, red; carbon, black.
transition states the transition state TS1 is lower in energy than
the transition states TS1a, TS1b, and TS1c by 3.1, 10.7, and
15.6 kcal/mol, respectively. Thus, the addition of aryl iodide
(RC1) to 4a proceeds via TS1, leading to the octahedral
intermediate IM, which is endergonic by 20.0 kcal/mol, as
shown in Figure 12.
(ii). Reductive Elimination. The octahedral intermediate
(IM) is an unstable species (20.0 kcal/mol endergonic). The
formation of a C−C bond is feasible through the transition
state TS2 via a barrier of 12.9 kcal/mol. This reductive
elimination process yields the iodated Pd complex 3a and the
C−C coupled product 7as, with the reaction being exergonic by
45.8 kcal/mol with respect to the starting reactant, as shown in
Figure 12. It is also clear from the figure that the barrier for the
key step of the overall reaction of RC1 with 4a is 32.9 kcal/mol.
Therefore, under the given experimental conditions of elevated
temperature (120 °C), this process would be expected to be
feasible. The HOMO−LUMO gap and the energy values of the
frontier orbitals for all the intermediates and transition states
(shown in Figure 12) are presented in Table S11 in the
Supporting Information.
The possibility of a concerted pathway for the formation of
3a and 7as from the reaction of phenyl iodide (RC1) with 4a
has also been investigated. All attempts to find the concerted
transition state led either to the formation of IM or back to the
reactants. The concerted pathway is likely to be an energetically
unfavorable process, due to steric hindrance. Hence, our
calculations suggest a stepwise pathway.
Therefore, the corroboration with experimental results
suggests that the palladium complex is able to go through
oxidative addition and reductive elimination reactions, with the
formation of a stable octahedral Pd complex (IM), where the
palladium exists in the +4 oxidation state. A similar observation
of the palladium being in the +4 oxidation state via the C(sp2)−
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Figure 13. Proposed arylation pathway for benzothiazole with aryl iodides catalyzed by (POCN)PdX.
X electrophilic oxidative addition to a Pd(II) center has rarely
been documented.12,13
Probable Catalytic Cycle. On the basis of the
arylation of azoles with aryl iodides involving a well-defined
hybrid POCN-pincer palladium catalyst. Kinetic measurements,
reactivity studies, and DFT calculations on the arylation
reaction strongly support a Pd(II)/Pd(IV)/Pd(II) redox
process for the reaction, which occurs via the oxidative addition
of the C(sp2)−X electrophile, aryl iodide, to the (POCN)PdII
species. Intermolecular competition experiments between the
electronically distinct azoles and their comparative kinetic
studies for the arylation reaction establish that the electronic
properties on azoles are kinetically not relevant. The isolation
and characterization of a catalytically pertinent intermediate
experimental results and DFT studies described above, and
from the earlier observations of our group15 and others,4a,j
a
validated catalytic cycle can be drawn for the (iPr2POCNEt2)-
PdCl (2a) catalyzed arylation of azoles with aryl iodides (Figure
13). First, the benzothiazole coordinates to CuX to form the
copper complex A, followed by deprotonation and rearrange-
ment to generate the species B. K3PO4 most likely
deprotonates the free benzothiazole, in addition to the
benzothiazole coordinated to CuX, because the reaction is of
a fractional order with respect to the concentration of K3PO4.
This is also evident from the deuterium scrambling between 2-
D-benzothiazole and 2-H-6-ethoxybenzothiazole, which occurs
even in the absence of CuI. The copper−benzothiazolyl species
B then undergoes transmetalation with the (iPr2POCNEt2)PdX,
leading to complex 4a. The generated palladium−benzothia-
zolyl complex 4a then oxidatively reacts with the aryl iodide to
(
iPr2POCNEt2)Pd(benzothiazolyl) complex allowed the explicit
demonstration of the mechanistic pathway. Kinetic and
reactivity studies of this species are consistent with the
oxidative addition of aryl iodide electrophile to the Pd(II)
species being a kinetically important step for the arylation
reaction. All these studies provided a significant mechanistic
insight into the direct arylation of azoles with aryl iodides,
which could shed light into the palladium-catalyzed C−H bond
arylation of other arenes and heteroarenes.
produce the octahedral species
(
i P r 2 POCNE t 2 )-
PdIV(benzothiazolyl)(Ar)I (C). The reductive elimination of
the coupled product from species C will regenerate the catalyst
EXPERIMENTAL SECTION
■
iPr2POCNEt2)PdX. DFT calculations, as well as the exper-
General Experimental Considerations. All manipulations were
conducted under an argon atmosphere either in a glovebox or using
standard Schlenk techniques in predried glassware. The catalytic
reactions were performed in flame-dried reaction vessels with a Teflon
screw cap. Solvents were dried over Na/benzophenone or CaH2 and
distilled prior to use. DMF was dried over CaH2, distilled under
vacuum, and stored over 4 Å molecular sieves. Liquid reagents were
(
imental results, strongly support the involvement of a transient
(
iPr2POCNEt2)PdIV intermediate via the oxidative addition of
aryl iodide to the (iPr2POCNEt2)PdII species. Though there exist
a number of reports on the arylation of azoles by palladium
catalysts, all of them have shown a conventional Pd(0)/Pd(II)
redox process with little experimental input. We have, on the
other hand, elaborately demonstrated here a new mechanistic
avenue for the arylation of azoles by installing a suitable ligand
on the palladium. The reactions occurs via a Pd(II)−Pd(IV)−
Pd(II) pathway with C(sp2)−X aryl iodide oxidative addition to
the Pd(II) species. Though our experimental findings strongly
support the Pd(II)/Pd(IV) redox process for the arylation
reaction, a parallel Pd(0)/Pd(II) cycle via the decomposition of
a small amount of 2a to Pd(0) cannot be completely ruled out.
flushed with argon prior to use. (iPr2PCPiPr2)PdCl,26 iPr2POCOPiPr2)-
(
PdCl,27 3-hydroxybenzyl bromide,28 5-methylbenzoxazole,29 5-aryla-
zoles,30 and 6-substituted benzothiazole31 were synthesized according
to previously described procedures. All other chemicals were obtained
from commercial sources and were used without further purification.
Yields refer to isolated compounds, estimated to be >95% pure as
determined by 1H NMR. TLC: TLC silica gel 60 F254, detection under
UV light at 254 nm. Chromatography: separations were carried out on
Spectrochem silica gel (0.120−0.250 mm, 60−120 mesh) or neutral
alumina (Al2O3). High-resolution mass spectroscopy (HRMS) was
carried out on a Thermo Scientific Q-Exactive, Accela 1250 pump.
Melting points were determined on a Buchi 540 capillary melting point
̈
CONCLUSION
apparatus; values are uncorrected. NMR (1H and 13C) spectra were
recorded at 400 or 500 MHz (1H), 100 or 125 MHz (13C, DEPT
(distortionless enhancement by polarization transfer)), 377 MHz
■
In summary, we have performed an in-depth mechanistic study
and demonstrated an unusual mechanistic avenue for the direct
J
DOI: 10.1021/acs.organomet.6b00003
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Article
(19F), and 162 or 202 MHz (31P{1H}) on Bruker AV 400 and AV 500
spectrometers in CDCl3 solutions, if not otherwise specified; chemical
shifts (δ) are given in ppm. The 1H and 13C NMR spectra are
referenced to residual solvent signals (CDCl3: δ(H) 7.26 ppm, δ(C)
77.2 ppm), and 31P{1H} NMR chemical shifts are referenced to an
external standard, Me3P in p-xylene-d10 solvent (δ −62.4 ppm), in a
sealed capillary tube. The synthesis and characterization data of the
pincer precursors 3-((diethylamino)methyl)phenol, (iPr2POCNEt2)-H
(1a) and (Ph2POCNEt2)-H (1b) and palladium complexes
Chem., Int. Ed. 2010, 49, 2202−2205. (d) Hachiya, H.; Hirano, K.;
Satoh, T.; Miura, M. ChemCatChem 2010, 2, 1403−1406.
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(2) Fox examples of Cu-catalyzed arylation, see: (a) Do, H.-Q.;
Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404−12405. (b) Kulkarni,
A. A.; Daugulis, O. Synthesis 2009, 4087−4109. (c) Han, Y.; Wang, X.;
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(
iPr2POCNEt2)PdCl (2a), (Ph2POCNEt2)PdCl (2b), (iPr2POCNEt2)PdI
(3a), and (iPr2POCNEt2)Pd-benzothiazolyl (4a) are given in the
Supporting Information.
Computational Details. All DFT calculations were carried out
using the Turbomole 6.0 suite of programs.32 Geometry optimizations
were performed using the dispersion corrected Perdew, Burke, and
Erzenhof density functional (PBE).33 The TZVP basis set was
employed for the calculations.34 The resolution of identity (ri),35 along
with the multipole accelerated resolution of identity (marij)36
approximations were employed for an accurate and efficient treatment
of the electronic Coulomb term in the density functional calculations.
Solvent effects were incorporated with the COSMO model,37 with ε =
2.25 for 1,4-dioxane. The contributions of internal energy and entropy
were obtained from frequency calculations done on the DFT
structures at 298.15 K. Therefore, the energies reported in the figures
are the ΔG values. It was ensured that the obtained transition state
structures possessed only one imaginary frequency corresponding to
the correct normal mode. The translational entropy term in the
calculated structures was corrected through a free volume correction
introduced by Mammen et al.38 This procedure of correcting the
translational entropy term has also been followed by other groups.39
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.6b00003.
Detailed experimental procedures, analytical data for
compounds, and 1H and 13C NMR spectra of new
compounds (PDF)
Crystallographic data for 2a (CCDC-1423294) (CIF)
Crystallographic data for 3a (CCDC-1423296) (CIF)
Crystallographic data for 4a (CCDC-1423295) (CIF)
(5) For selected reviews of the direct arylation, see: (a) Alberico, D.;
Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174−238.
(b) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed.
2009, 48, 9792−9826. (c) McGlacken, G. P.; Bateman, L. M. Chem.
Soc. Rev. 2009, 38, 2447−2464. (d) Lyons, T. W.; Sanford, M. S.
Chem. Rev. 2010, 110, 1147−1169. (e) Colby, D. A.; Bergman, R. G.;
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(h) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112,
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J. 2014, 9, 26−47. (j) Zhang, F.; Spring, D. R. Chem. Soc. Rev. 2014,
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AUTHOR INFORMATION
Corresponding Author
*B.P.: tel, +91-20-2590 2733; fax, +91-20-2590 2621; e-mail, b.
punji@ncl.res.in.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(6) (a) Bellina, F.; Cauteruccio, S.; Rossi, R. Curr. Org. Chem. 2008,
12, 774−790. (b) Verrier, C.; Lassalas, P.; Theveau, L.; Queguiner, G.;
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Trecourt, F.; Marsais, F.; Hoarau, C. Beilstein J. Org. Chem. 2011, 7,
This work was financially supported by the SERB, New Delhi,
India (SR/S1/IC-42/2012). We are grateful to the Alexander
von Humboldt Foundation of Germany for an equipment
grant. S.M.K. and R.A.J. thank the CSIR -New Delhi and UGC-
New Delhi, respectively, for research fellowships. We are
grateful to Dr. P. R. Rajmohanan for NMR facilities, Dr. (Mrs.)
Shanthakumari for HRMS analyses, and Dr. S. P. Borikar for
GC-MS analyses.
1584−1601. (c) Wakioka, M.; Nakamura, Y.; Hihara, Y.; Ozawa, F.;
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