Development of (quinolinyl)amido-based pincer palladium complexes: A robust and phosphine-free catalyst system for C-H arylation of benzothiazoles

Article abstract of DOI:10.1039/c7nj00452d

(Quinolinyl)amido-ligated palladium(ii) complexes have been synthesized and applied in the catalytic C-H bond arylation of benzothiazoles. The tridentate ligand precursors R₂N-C(O)CH₂-(NH)-C₉H₆N [(^R2NNN^8-Q)-H; R₂N = morpholinyl, Me-N-piperazinyl] and the pincer palladium complexes [κ^N,κ^N,κ^N-{R₂N-C(O)CH₂-(μ-N)-C₉H₆N}]PdX [(^R2NNN^8-Q)PdX {R₂N = Et₂N, morpholinyl, Me-N-piperazinyl; X = OAc or Cl}] were efficiently synthesized, and characterized by various analytical techniques. The iodo derivative (^Et2NNN^8-Q)PdI was obtained in excellent yield by the treatment of the complex (^Et2NNN^8-Q)PdCl with KI. The molecular structures of complexes (^Et2NNN^8-Q)Pd(OAc) (2a), (^Et2NNN^8-Q)PdCl (3a) and (^Et2NNN^8-Q)PdI (4a) were elucidated by X-ray crystallography. Complex 3a was found to be the most efficient catalyst for direct C-H bond arylation of substituted benzothiazoles with diverse aryl iodides using a mild base, K₂CO₃. The working catalyst system 3a is highly robust and can be recycled and reused several times for the arylation of benzothiazole without loss of catalytic activity. Preliminary mechanistic investigations using controlled studies and kinetic analysis have been performed, which greatly support a molecular mechanism for the arylation.

Full text of DOI:10.1039/c7nj00452d

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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
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PAPER
Development of (quinolinyl)amido-based pincer palladium
complexes: A robust and phosphine-free catalyst system for C‒H
arylation of benzothiazoles†
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Hanumanprasad Pandiri,a Vineeta Soni,a Rajesh G. Gonnadeb and Benudhar Punji*,a
(Quinolinyl)amido-ligated palladium(II) complexes have been synthesized and applied in the catalytic C‒H bond arylation
of benzothiazoles. The tridentate ligand precursors, R2N-C(O)CH2-(NH)-C9H6N [(R2NNN8-Q)‒H; R2N = morpholinyl, Me-N-
piperazinyl] and the pincer palladium complexes, [κN,κN,κN-{R2N-C(O)CH2-(μ-N)-C9H6N}]PdX [(R2NNN8-Q)PdX {R2N = Et2N,
morpholinyl, Me-N-piperazinyl; X = OAc or Cl}] were efficiently synthesized, and characterized by various analytical
techniques. The iodo-derivative, (Et2NNN8-Q)PdI was obtained in excellent yield by the treatment of complex (Et2NNN8-Q)PdCl
with KI. Molecular structures of complexes (Et2NNN8-Q)Pd(OAc) (2a), (Et2NNN8-Q)PdCl (3a) and (Et2NNN8-Q)PdI (4a) were
elucidated by the X-ray crystallography. The complex 3a was found to be the most efficient catalyst for direct C–H bond
arylation of substituted benzothiazoles with diverse aryl iodides using a mild base, K2CO3. The working catalyst system 3a is
highly robust that can be recycled and reused several times for the arylation of benzothiazole without loss in the catalytic
activity. Preliminary mechanistic investigations by the controlled studies and kinetic analysis have been performed, which
greatly support a molecular mechanism for the arylation.
is crucial, as they constitute the building blocks of various
biological and pharmaceutical compounds.9 For example, the
Thioflavin-T, which contain the C-2 arylated benzothiazole as
Introduction
Palladium complexes of tridentate pincer-ligands have been
widely explored for diverse catalytic transformations, by virtue
of their unusual thermal, moisture and air-stability.1 Among
various reactions, the pincer-palladium complexes as catalyst
are commonly exploited for the traditional cross-couplings,2
aldol and Michael reactions,3 allylation of aldehydes and
imines,4 hydrosilylation and borylation,5 and many other6
reactions. Most of these reactions were reported with high
turnover numbers and broad substrate scope. Additionally, the
pincer-ligated palladium complexes were demonstrated for
enantioselective synthesis.3a,3d,3i,4e,7 Conversely, the application
of robust pincer-ligated palladium complexesas catalysts in
core motif, is commonly used for histology staining and
biophysical studies for protein aggregation.9f,g Similarly, the
compound
2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-
thiazolecarboxylic acid (TEI-6720) based on aryl-thiazole is an
extremely potent inhibitor of xanthine oxidoreductase (XOR).9c
Considering the significant pharmaceutical conciliation of aryl-
benzothiazole motifs, it is worth exploring the design and
synthesis of new and robust catalyst system for the selective
C-2 arylation of benzothiazoles.
The selective C-2 arylation of substituted-benzothiazoles
with aryl halides to achieve the 2-arylated benzothiazole
derivatives has been established by various metal catalysts,
such as Ni,10 Cu,11 Ru,12 Rh13 or Pd14,15 with the added ligands.
Though, these metal catalysts efficiently perform the arylation
of benzothiazoles; very often harsh reaction conditions, strong
and expensive bases, costly phosphine-based ligands are
essential for the satisfactory conversion. Additionally, the
catalyst stability is a major concern, which enforces the usage
of high catalyst loading (more than 5 mol%) in many reactions.
Recently, we have reported phosphine-amine based pincer
palladium system for the arylation of azoles, which catalyzes
the arylation with low catalyst loading.16 Moreover, the
described arylation by the pincer-palladium proceeded
more promising and ubiquitous C
remains scarce.5f,8
‒H bond functionalization
More specifically, the C‒H bond arylation of sulphur-
containing electron-rich heterocycles, such as benzothiazoles
a.Organometallic Synthesis and Catalysis Group, Chemical Engineering Division.
b.Centre for Material Characterization. CSIR–National Chemical Laboratory (CSIR–
NCL), Dr. Homi Bhabha Road, Pune – 411 008, Maharashtra, INDIA. Phone: + 91-
20-2590 2733, Fax: + 91-20-2590 2621. E-mail: b.punji@ncl.res.in
†Electronic Supplementary Information (ESI) available: 1H and 13C NMR spectra of
pincer precursors and palladium complexes, CIF files for 2a (CCDC-1487195), 3a
(CCDC-1487196) and 4a (CCDC-1502139). See DOI: 10.1039/x0xx00000x
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through a rare PdII-PdIV-PdII pathway, which has been validated
both by the experiments and by the theoretical calculations.16c
Motivated by these findings, we hypothesized that a pincer
Scheme 1. Synthesis of (8-quinolinyl)amido-ligands, (R2NNN8-Q
)‒H.
ligated palladium with the strong σ-donor nitrogen atoms on
The palladation reactions of ligand, Et2NNN8-Q
Pd(OAc)2 and PdCl2 in the presence of Et3N in THF under reflux
conditions gave {Et2N
CH2C(O)-(μ-N)-C9H6N}Pd(OAc) [(Et2NNN8-
Q)Pd(OAc); 2a] and {Et2N CH2C(O)-(μ-N)-C9H6N}PdCl [(Et2NNN8-
‒H (1a) with
ligand would enhance the oxidative addition of aryl halide
electrophile, and the resulting Pd(IV) intermediate would
suitably be stabilized, which in turn can act as a robust catalyst
system for the arylation.17
-
-
Q)PdCl; 3a], respectively (Scheme 2). These complexes were
obtained as yellow crystalline solids in moderate to good
yields. In the 1H NMR spectra of compounds 2a and 3a, the
disappearance of signal corresponds to –NH proton on ligand
indicative of the formation amido-palladium covalent bond.
Further, the methylene protons on –NEt2 group displayed two
sets of multiplets against a single set in 1a, which suggests the
coordination of –NEt2 arm to the Pd-center. Among two
multiplets for the methylene protons, one appeared in the
down-field region and the other in up-field region compared to
that observed in the free-ligand. The HRMS analysis of both
the compounds 2a and 3a showed the mass ion peaks
correspond to [2a–OAc]+ (m/z = 362.0493) and [3a–Cl]+ (m/z =
362.0474). These compounds were further characterized by
13C NMR spectroscopy and elemental analysis. The molecular
structures of 2a and 3a were determined by single crystal X-ray
diffraction study (Figures 1 and 2).
With the above assumption in mind, herein, we developed
the phosphine-free (quinolinyl)amido-based pincer ligands and
their palladium complexes, (R2NNN8-Q)PdX [κN,κN,κN-{R2N-
C(O)CH2-(μ-N)-C9H6N}PdX], and employed them for the
arylation of benzothiazoles. In fact, the synthesized palladium
catalyst system catalyzes the arylation of benzothiazoles with a
variety of aryl iodides employing low catalyst loading, and in
the presence of a mild base, K2CO3. Importantly, this catalyst
system demonstrated to be exceptionally robust, which was
recycled and reused for several rounds without loss in the
catalytic activity. Preliminary mechanistic experiments have
been performed to understand the working mode of catalyst.
Results and discussion
Synthesis and characterization of (R2NNN8-Q)‒H ligands and
palladium complexes
O
Recently, we have synthesized nickel complexes of Et2N
CH2C(O)N(H)C9H6N (Et2NNN8-Q
-
O
Pd(OAc)2
‒H; 1a) ligand and demonstrated
their application for the alkylation of indoles with diverse alkyl
N
Et3N, THF
70 oC, 3 h
N
R2N
N
Pd
H
R2N
N
halides.18 Similar to the synthesis of 1a, the quinolinyl-amide
CH2C(O)N(H)C9H6N [R2NNN8-Q
ligand precursors, R2N- ‒H; R2 = -
OAc
1a c
(
ꢀ
)
R2N = Et2N;
(2a)
(2b)
O
(CH2)2O(CH2)2- (morpholinyl; 1b) and -(CH2)2NMe(CH2)2- (Me-
N-piperazinyl; 1c)] were conveniently synthesized. Thus, the
reaction of 2-bromo-N-(quinolin-8-yl)acetamide with the cyclic
secondary amines, morpholine and N-methyl piperazine,
afforded the quinolinyl-amide ligands 1b and 1c, respectively,
in excellent yields (Scheme 1). Both the compounds 1b and 1c
were obtained as solids in analytical pure form. These ligands
were characterized by 1H and 13C NMR spectroscopy as well as
by the HRMS analysis. Notably, the morpholinyl methylene
protons in 1b resonate as two different sets to give two
PdCl2
Et3N, THF
70 oC, 3 h
R2N =
N
NMe
2c
)
R2N =
N
(
O
N
R2N
N
Pd
Cl
3a
)
R2N = Et2N;
R2N =
(
NMe
3c
)
(
N
Scheme 2. Synthesis of (8-quinolinyl)amido-based pincer palladium complexes.
multiplets (∼ 3.89 and ∼ 2.69 ppm), whereas those of
piperazinyl (eight protons) in 1c appeared as single multiplet (
∼
2.67 ppm).
The pincer palladium complex, (MorpNNN8-Q)Pd(OAc) (2b
)
was synthesized in good yield by the reaction of (MorpNNN8-Q)–
H (1b) with Pd(OAc)2 in the presence of Et3N. However, the
attempted synthesis of the corresponding chloro-derivative,
(
MorpNNN8-Q)PdCl (3b) was not successful. Compound 2b was
obtained as a yellow powder. The 1H NMR spectrum of 2b
displayed three sets of multiplet for the methylene protons on
morpholinyl moiety, in contrast to two sets in the free-ligand
1b. This suggests the coordination of morpholinyl-arm to the
Pd-center. The HRMS analysis of 2b showed mass peak m/z
376.0267 for the ion [2b–OAc]+. Pincer complexes, (PipNNN8-
Q)Pd(OAc) (2c) and (PipNNN8-Q)PdCl (3c) were obtained by the
treatment of 1c with Pd(OAc)2 and PdCl2, respectively, in the
O
O
R2NH
Br
acetone
65 oC, 24 h
N
N
H
H
R2N
N
N
ref.18
1a
)
R2N = Et2N;
(
O
1b
)
R2N =
N
(
NMe
1c
)
R2N =
N
(
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presence of Et3N base (Scheme 2). Both the compounds 2c and bigger size of iodide than that of chloride. In addition, a slight
3c were isolated in moderate to good yields as yellow shortening of the N(1) Pd N(2), N(1) Pd N(3) and
crystalline solids. Notably, the 1H NMR spectra of 2c and 3c N(2) N(3) bond angles (81.77(5), 83.88(5) and 165.64(4)o)
Pd
‒
‒
‒
‒
‒
‒
displayed four sets of signals each for the methylene protons in 4a was observed when compared to those in complex 3a
.
on piperazinyl-moiety, which could be due to the
O
O
diastereotopic nature of methylene protons, generated upon
the coordination of piperazinyl arm to the palladium center. All
KI
N
Pd
Cl
N
Pd
I
DCM/MeOH
r.t., 14 h
Et2N
N
Et2N
N
the three complexes 2b, 2c and 3c were further characterized
by the 13C NMR spectroscopy, HRMS and elemental analysis.
The ORTEP diagrams of the complexes 2a and 3a are
shown in Figure 1 and Figure 2, respectively. Selected bond
lengths and bond angles are given in Table 1. In both the
complexes, ligand 1a provides a tridentate coordination to the
palladium through quinolinyl-N2, amido-N1 and amine-N3, and
the fourth site is occupied by anionic ligand –OAc (2a) or –Cl
(4a)
(3a)
Scheme 3. Synthesis of (R2NNN8-Q)PdI (4a) complex.
(
3a). The coordination geometry around palladium is slightly
distorted from the expected square-planar geometry in both
2a and 3a. The Pd N(1) bond lengths in 2a (1.936(5) Å) and 3a
(1.953(2) Å) are slightly longer than the Pd
(1.927(5)Å) in a similar amido-complex, {H2N
N)-C9H6N}PdCl;19 whereas the Pd
2.021(1) Å in 3a} and Pd
3a} bond lengths are comparable. The Pd
(2.314(1) Å) in 3a is slightly shorter than the analogous bond
length (Pd Cl = 2.322(1) Å) in the complex {H2N CH(Me)C(O)-
‒
‒
N bond length
-CH(Me)C(O)-(μ-
‒
N(2) {2.012(5) Å in 2a
N(3) {2.070(5) Å in 2a, 2.072(2) Å in
Cl bond length
,
‒
‒
‒
-
(μ-N)-C9H6N}PdCl. This slight difference in bond length could
be due to weaker σ-donor strength of amido-ligand moiety
Fig. 1 Thermal ellipsoid plot of (Et2NNNQ)Pd(OAc) (2a). All the hydrogen atoms are
omitted for clarity.
exerted towards palladium in 2a than the {H2N
CH(Me)C(O)NH-C9H6N} moiety in {H2N CH(Me)C(O)-(μ-N)-
C9H6N}PdCl. The N(2) Pd N(3) bond angles in 2a (166.8(2)°)
and 3a (166.99(7)°) are comparable with each other and
slightly more than that reported for {H2N CH(Me)C(O)-(μ-N)-
C9H6N}PdCl (N(2)-Pd-N(3) = 165.3(2)°). The N(1) Pd N(2) and
N(1) Pd N(3) bond angles in 2a and 3a are in the range of
82.35(7)-84.67(7)°. Notably, in the complex 3a the
N(1) Pd N(3) bond angle (84.67(7)°) is significantly larger than
the N(1) Pd N(2) bond angle (82.35(7)°). The five-membered
-
-
‒
‒
-
‒
‒
‒
‒
,
‒
‒
‒
‒
ring containing Pd, N(1), N(2) is almost planar with the
quinolinyl-moiety (Pd(1)-N(2)-C(9)-C(1) = 0.2(7)o), whereas the
other five-membered Pd-containing ring is slightly distorted
(Pd(1)-N(1)-C(10)-C(11) torsion angle 7.2(7)o) in the complex
2a.
Fig. 2 Thermal ellipsoid plot of (Et2NNNQ)PdCl (3a). All the hydrogen atoms are
omitted for clarity.
The iodo-derivative, (Et2NNN8-Q)PdI (4a) was synthesized by
the reaction of 3a with KI in DCM/MeOH (1:1, v:v) at ambient
temperature (Scheme 3). The complex 4a was obtained as a
1
brown solid in excellent yield. The H NMR spectrum of 4a has
similar splitting pattern to that observed for the complex 3a
.
The MALDI-TOF analysis of 4a showed the mass ion peaks
correspond to [4a + H]+ (m/z = 489.8192) and [4a – I]+ (m/z =
361.9155). The molecular structure of 4a was further
confirmed by single crystal X-ray diffraction analysis (Figure 3).
The coordination geometry around the palladium in 4a is
slightly distorted from the expected square-planar geometry.
The Pd‒N(1), Pd‒N(2) and Pd‒N(3) bond lengths (1.967(1),
2.030(1) and 2.079(1) Å, respectively) in 4a are slightly longer
than the corresponding bond lengths (1.953(2), 2.021(1) and
2.072(2) Å) in 3a, which is due to the larger trans effect and
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with 3a). This suggests that a catalyst stabilizing ligand is
essential for the better conversion in arylation reaction. After
investigating the various reaction parameters, we found that
the coupled product 2-(p-tolyl)benzothiazole (7aa) could be
obtained in 86% isolated yield, employing 0.5 mol% of catalyst
3a and 1.0 mol% of CuI in the presence of K2CO3 in DMSO.
Comparable yield of 7aa has previously been reported with the
catalyst Pd(OAc)2, however, a strong base LiOtBu along with
more loading of the catalyst and co-catalyst Cu(TFA)2 were
employed.14r
Fig. 3 Thermal ellipsoid plot of (Et2NNNQ)PdI (4a). All the hydrogen atoms are
omitted for clarity.
Table 1 Selected bond lengths [Å] and angles [deg] for 2a, 3a and 4a
2a
3a
4a
Pd(1)–N(1)
1.936(5)
1.953(2)
1.967(1)
Pd(1)–N(2)
Pd(1)–N(3)
Pd(1)–O(2)
Pd(1)–Cl(1)
Pd(1)–I(1)
2.012(5)
2.021(1)
2.030(1)
2.070(5)
2.072(2)
2.079(1)
2.055(4)
-
-
Pdꢀcat.(0.5 mol%)
CuI (1.0 mol%)
N
S
N
S
-
-
2.314(1)
-
-
I
Me
Me
+
H
base (1.5 equiv)
solvent (1.0 mL)
temp. (oC), time (h)
2.624(1)
5a
6a
7aa
N(1)–Pd(1)–N(2)
N(1)–Pd(1)–N(3)
N(2)–Pd(1)–N(3)
N(1)–Pd(1)–O(2)
N(2)–Pd(1)–O(2)
N(1)–Pd(1)–Cl(1)
N(2)–Pd(1)–Cl(1)
N(3)–Pd(1)–Cl(1)
N(1)–Pd(1)–I(1)
N(2)–Pd(1)–I(1)
N(3)–Pd(1)–I(1)
83.1(2)
82.35(7)
84.67(7)
81.77(5)
83.88(5)
83.9(2)
Table 2 Optimization of reaction conditions for arylation of benzothiazolea
166.8(2)
166.99(7) 165.64(4)
176.4(2)
-
-
94.3(2)
-
-
Entry
Pd-
cat.
Base
Solvent
T (oC)/
time (h)
Yield
(%)b
-
-
-
-
-
-
175.82(5)
-
97.61(5)
-
95.40(5)
-
1
2a
2b
2c
3a
3c
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
-
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
K2CO3
K2CO3
Na2CO3
NOAc
KOAc
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
120/16
120/16
120/16
120/16
120/16
120/16
120/16
130/16
130/24
130/24
130/24
130/24
130/24
130/24
130/24
67
68
49
76
24c
78
49c
81
-
-
-
175.08(3)
97.71(3)
96.55(3)
2
DMF
3
DMF
4
DMF
5
DMF
6
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
NMP
Optimization of reaction conditions for (R2NNN8-Q)PdX catalyzed
arylation of benzothiazole
7
8
9
86 (99)c
53c
12c
25c
3c
Newly developed phosphine-free pincer palladium complexes
10
11
12
13
14
15
16
17
18
were screened, optimized and employed for the direct C
bond arylation of benzothiazoles with aryl iodides. Initially, all
the pincer complexes (R2NNN8-Q)PdX (2a
3c) were screened for
the coupling of benzothiazole (5a 0.30 mmol) with 4-
‒H
-
DMA
27
2c
10c
11c
16d
;
toluene
iodotoluene (6a; 0.45 mmol), employing CuI (1.0 mol%) co-
catalyst and K3PO4 base in DMF [standard conditions employed
with the (iPr2POCNiPr2)PdX catalyst]16c (Table 2). Among all the
complexes screened, 3a performed better and afforded the
1,4-dioxane 130/24
DMSO
DMSO
130/24
130/24
3a
coupled product 7aa in 76% isolated yield (Table 2, entries 1- aConditions: Benzothiazole (0.041 g, 0.30 mmol), 4-iodotoluene (0.098 g, 0.45
mmol), base (0.45 mmol), Pd-cat. (0.0015 mmol), CuI (0.0006 g, 0.003 mmol) and
5). The arylation reaction also proceeded equally in the polar
solvent (1.0 mL) were added inside the glove box. bIsolated yield. cG.C. yield. dCuI
aprotic DMSO solvent using catalyst 3a (entry 6). Interestingly,
was not employed.
the arylation in the presence of mild base, K2CO3 gave 86%
yield of 7aa; albeit slight elevated temperature of 130 oC is
essential (entries 7-9). Other bases like Na2CO3, NaOAc, KOAc
were found to be less effective (entries 10-12). Similarly, the
reaction was inefficient in other polar (NMP, DMA) and non-
polar (toluene, 1,4-dioxane) solvents (entries 13-16).
Employment of the palladium catalyst 3a under the standard
reaction conditions is essential, without which only 11% of
product 7aa was detected (entry 17). The presence of CuI as
co-catalyst was very much necessary to afford good yield.
Complex stability and catalyst recycling studies for arylation
Most likely, the CuI co-catalyst enhances the transmetalation
of benzothiazoles to the palladium center.16a A catalytic
Since the pincer-based complexes are presumed to be the
robust catalysts because of the strong and rigid pincer
reaction of the benzothiazole with iodide 6a employing PdCl2
coordination, we examined the stability of pincer complex 3a
.
as catalyst afforded 7aa in 46% yield (against 99% GC yield
4 | New J. Chem.
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For analysing air-stability, the complex (Et2NNN8-Q)PdCl (3a, in electronic features were coupled with the benzothiazole to
DMSO-d6) was exposed to air for 5 days. The 1H NMR was yield the desired arylated products in moderate to good yields.
recorded at regular intervals (1 day, 2 days, 3 days and 5 days) In general, with the current catalyst system, the electron-rich
and was analysed (using standard mesitylene in capillary), aryl iodides were more efficiently reacted than those with
which demonstrates that the complex 3a largely remained electron-deficient ones (Table 3, entries 1-9), which is contrary
intact. Neither the dissociation of ligand from 3a nor the to the Pd(0)-catalyzed coupling reactions, and similar to our
decomposition of 3a was occurred.
previous observations.16 Important functional groups, such as,
OMe, F, Cl, Br, NO2, CF3, CO2CH3 were tolerated on
‒
‒
‒
‒
‒
‒
‒
N
S
Cycle
Yield
7aa
a
Me
the aryl iodide backbone under the current catalytic
conditions, which is very crucial from the synthetic
1st
2nd
3rd
4th
5th
98%
7aa
+ volatiles
99%
98%
vacuum
distilation
96%
b
93% (87%
)
N
H
S
Cat. 3a (0.5 mol%)
CuI (1.0 mol%)
Pdꢀcat.
+
other leftover
7aa
+ Pdꢀcat.
+ others
Product
5a
+
K
2CO3 (1.5 equiv)
DMSO (2.0 mL)
130 oC, 24 h
I
Me
6a
5a
6a
+ substrate
substrate
Fig.
using para-xylene as internal standard.
4
Catalyst recycling experiment.
aGC
bIsolated yield.
yield
+ K2CO3 (1.5 equiv)
+ DMSO (2.0 mL)
Further, the catalyst performance was studied by
conducting recycling experiments (Figure 4). The recycling
experiment was performed by distilling out the product and
other volatiles after each experiment/cycle. In a Schlenk tube,
the standard catalytic experiment was performed using 5a (0.5
mmol), 6a (0.75 mmol), catalyst 3a (0.0025 mmol), CuI (0.005
mmol), K2CO3 (0.75 mmol) and DMSO (2.0 mL). After heating
the reaction mixture for 24 h (1st cycle), the internal standard
p-xylene (0.03 mL, 0.243 mmol) was added at ambient
temperature and the reaction mixture was subjected to GC
analysis, wherein the yield of the coupled product 7aa was
analyzed to be 98% (GC yield w.r.t. standard p-xylene). Then,
the product and other volatiles were distilled out under high
vacuum (5 × 10-5 bar) at 140 oC. The reaction vessel was
transferred in to the glove-box, and fresh 5a (0.5 mmol), 6a
(0.75 mmol), K2CO3 (0.75 mmol) and DMSO (2.0 mL) were
added. The reaction was continued for second cycle, wherein
the GC yield of the product 7aa was found to be 99%. Similarly,
in the 3rd, 4th and 5th cycles, the GC yields of the product 7aa
were observed to be 98%, 96% and 93%, respectively. At the
end of fifth cycle the product 7aa was isolated and the yield
was determined to be 87%. These experiments highlighted the
exceptional stability
and activity of the novel
(quinolinyl)amido-palladium catalyst system for the arylation
of benzothiazole.
Scope of the 3a-catalyzed arylation of benzothiazoles
The optimized reaction condition was applied to the
arylation of benzothiazoles with diversely substituted aryl
iodides. As listed in Table 3, aryl iodides with different
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Table 3 Scope for the 3a-catalyzed arylation of benzothiazoles with aryl halidesa
prospective. The para- and meta-substituted aryl iodides, as
well as di- and tri-substituted aryl iodides were coupled with
benzothiazole to deliver the desired C-2 arylated
benzothiazoles in good yields, though the coupling of sterically
demanding ortho-substituted aryl iodide resulted in slightly
lower yield (entries 10-13). Notably, the heteroaryl iodides,
such as pyridinyl and pyrazinyl iodides reacted with good
activity, whereas thiophenyl iodide gave poor yield of the
product (entries 15-17). Synthesis of these bis-heterocycles is
important, as they can be used as bidentate ligand system for
transition-metal-catalyzed reactions. Methyl- and ethoxy-
substituted-benzothiazoles reacted in moderate activity.
Unfortunately, the less expensive aryl bromides or chlorides as
electrophilic coupling partners reacted sluggishly and gave
unsatisfactory yield of the product. Though, many methods are
known for the arylation of azoles, the current process involves
a phosphine-free catalytic system, which represents a rare
example. More particularly, arylation methods of sulphur-
containing azoles, such as benzothiazole, are less precedented.
In addition, the contrasting reactivity of the electrophiles in
the 3a-catalyzed arylation reaction is interesting for detailed
mechanistic consideration.
entry
1
aryl halide (6)
product (7)
yield
(%)b
86
N
S
I
Me
Me
N
S
2
3
92
89
39
82
59
41
45
55
66
OMe
I
OMe
N
I
S
N
4
I
F
F
S
N
5
I
Cl
Cl
S
N
6
I
Br
Br
S
N
I
CF3
7
CF3
S
N
8
I
NO2
NO2
S
N
9
I
CO2Me
CO2Me
Mechanistic consideration
S
N
Pincer ligated palladium complexes are known for their
decomposition into Pd(0) nanoparticles during the coupling
reactions, and even a trace of such species can catalyze the
reaction and pincer complexes merely serve as the
precatalysts.20 To investigate the probable involvement of
Pd(0) nanoparticles during 3a-catalyzed arylation, the standard
catalytic reaction was performed in the presence of 300 and
1500 equiv (w.r.t catalyst 3a) of mercury (Hg),21 wherein the
yield of coupling product 7aa obtained was 72% and 63%,
respectively. The presence of mercury slightly suppressed the
arylation suggesting that minor Pd(0) particles might have
formed, and are responsible for at least some of the observed
reactivity. A filtration experiment was performed after the
initial heating (30 min, GC yield 34%) to remove all the
heterogeneous particles, and the reaction was subsequently
continued upon adding fresh K2CO3. The arylation proceeded
convincingly without much decline in the yield of 7aa (88%
yield), suggesting that the molecular palladium is responsible
for major activity. Furthermore, the addition of ligands, such as
PPh3 (3.0 equiv w.r.t 3a), poly(vinyl pyridine) (PVPy; 150 equiv
w.r.t 3a), known for poisoning the Pd(0) nanoparticles,21,22
afforded the arylated product 7aa in 98% and 78%,
respectively. Though, the arylation reaction remains
unaffected in the presence of PPh3, the presence of PVPy
slightly lowered the yield of 7aa. The Hg and PVPy addition
experiments indicate that at least some of the reactivity is
promoted by Pd(0)-nanoparticles, that might generate from
the partial decomposition of complex 3a. However, as the
arylation was only partially affected in the presence of Hg or
PVPy, the major arylation may not have solely emerged from
Pd(0) particles.23
I
10
S
Me
Me
N
S
I
11
12
88
88
Me
Me
Me
Me
N
S
I
Me
Me
OMe
OMe
N
S
13
14
73
76
OMe
I
OMe
OMe
OMe
N
S
I
I
N
S
15
16
17
18
19
64
65
20
64
57
N
N
N
N
N
S
N
S
N
S
I
N
S
N
S
I
I
Me
Me
Me
Me
N
I
Me
S
EtO
aConditions: Substrate 5 (0.3 mmol), iodide 6 (0.45 mmol), cat 3a (0.0015 mmol),
CuI (0.003 mmol), K2CO3 (0.45 mmol), DMSO (1.0 mL), 130 oC, 24 h. bIsolated
yields.
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In order to identify the status of complex 3a during the into a new active catalyst species is unlikely, and 3a might
arylation, we have performed the catalytic reaction in a J- directly involve in the catalytic arylation. Further, the initial
Young NMR tube using 20 mol% of (Et2NNN8-Q)PdCl (3a) in rates for the arylation of benzothiazole with electronically
DMSO-d6 and the progress of the reaction was monitored by distinct para-substituted aryl iodides (4-R-C6H4-I) were
1H-NMR spectroscopy (mesitylene was used in toluene-d8 as determined (Figure 6). The Hammett plot was drawn from a
an internal standard in a sealed capillary). Thus, upon heating correlation between the initial rates and σp values, which
the reaction mixture at 130 oC in a pre-heated oil bath, the resulted in linear fit with a slope of
major palladium species observed were (Et2NNN8-Q)PdCl (3a
negative slope (
‒
0.853 (Figure 7). The
)
ρ value) indicates that a positive charge is
and (Et2NNN8-Q)PdI (4a) in 65% and 35% (12 h), 69% and 28% produced in the active catalyst species and hence, the
(24 h), and 68% and 28% (48 h), respectively. Further, an electron-donating substituents on the aryl iodide would
independent catalytic reaction employing the complex 4a enhance the rate of arylation.16c,25 This strongly supports the
afforded the coupled product 7aa in 95% yield. These findings reaction of aryl iodide to a Pd(II) species (oxidative addition or
indicate that either 3a or 4a is the resting state of the catalyst concerted path) rather to a Pd(0) center, because the electron-
during arylation reaction. The complex 4a might have donating substituent is expected to stabilize the resulting
generated by the halide exchange reaction between 3a and palladium species in higher oxidation state, and in turn would
CuI or KI (KI will produce during the course of catalytic lower the energy of the process.16c Additionally, the observed
reaction). Further, the catalyst decomposition was negligible reactivity order of aryl iodides goes against the conventional
even after 24 h (3%) or 48 h (4%) at 130 oC. This strongly Pd(0)-catalyzed coupling reaction,26 which further supports the
suggests that the catalyst mostly remains in molecular form above observation.
and highly stable under catalytic conditions.
cat. 3a (1.5 mM)
CuI (3.0 mM)
N
S
N
S
R
cat. 3a (1.5 mM)
CuI (3.0 mM)
I
+
R
H
K2CO3 (1.5 equiv)
Mesitylene (0.03 mL)
DMSO
N
S
N
S
Me
I
Me
H
+
K2CO3 (1.5 equiv)
Mesitylene (0.03 mL)
DMSO
0.3 M
0.45 M
7
(
)
(5a)
(6)
total volume (2.0 mL)
0.3 M
(5a)
0.45 M
(6a)
7aa
(
)
total volume (2.0 mL)
0.28
R = OMe
R = Me
R = H
R = Cl
R = C(O)OMe
y = 2.66 X 10ꢀ3x + 0.05614
R2 = 0.98345
Conc. of benzothiazole
Conc. of product 7aa
0.30
0.24
0.20
0.16
0.12
0.08
0.04
0.00
0.25
0.20
0.15
0.10
0.05
0.00
y = 1.82 X 10ꢀ3x + 0.0179
R2 = 0.97015
y = 1.53 X 10ꢀ3x + 0.0206
R2 = 0.99722
y = 1.01 X 10ꢀ3x + 0.01288
R2 = 0.90337
y = 0.58 X 10ꢀ3x + 0.00862
R2 = 0.91711
0
10
20
30
40
50
60
70
80
90
Time (min)
0
20
40
60
80 100 120 140 160 180 200
Fig. 6 Time-dependent formation of arylated products in the coupling of
benzothiazole with various para-substituted aryl iodides (4-R-C6H4-I).
Fig. 5 Reaction profile for 3a-catalyzed arylation of benzothiazole with 4-
iodotoluene.
Since the Hg and PVPy addition experiments were not
conclusive, we performed kinetic experiments to know the
progress of the arylation as well as to understand the reactivity
of electronically distinct electrophiles.24 In a standard kinetic
experiment, 1.5 mM of 3a, 3 mM of CuI, benzothiazole (0.3 M),
R-C6H4-I (0.45 M), K2CO3 (1.5 equiv) and mesitylene (0.03 mL,
internal standard) were used, and DMSO was added to make
total volume 2.0 mL. All the reactions were performed at 130
oC and the progress of the arylation was monitored by GC
analysis. As shown in Figure 5, the formation of arylated
product 7aa followed a linear plot and induction period is
absent. This suggests that decomposition of the complex 3a
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Conclusions
0.3
0.2
ꢀ OMe
ꢀ Me
In summary, we have synthesized (quinolinyl)amido-based
pincer palladium complexes and disclosed their catalytic
0.1
application in the C‒H bond arylation of benzothiazoles. All the
ꢀ H
pincer-palladium complexes were fully characterized by NMR
spectroscopy, HRMS and elemental analysis. The molecular
structures of three complexes were established by single
0.0
k
k
ꢀ0.1
ꢀ0.2
ꢀ0.3
ꢀ0.4
ꢀ0.5
ꢀ Cl
y = ꢀ0.85344x ꢀ 0.01626
R2 = 0.97266
crystal X-ray diffraction study. Complex
(
Et2NNN8-Q)PdCl
efficiently catalyzes the arylation of benzothiazoles with
substituted aryl iodides. This (quinolinyl)amido palladium
catalyst system demonstrated to be highly robust, and was
recycled for five rounds with consistent yield of the arylation
product. Mechanistic study by the kinetic analysis strongly
supports a molecular mechanism with the direct involvement
of catalyst 3a. However, a parallel reaction path by the minor
formation of active palladium nanoparticles, via the partial
decomposition of pincer-palladium complex cannot be
completely ruled out.
ꢀ C(O)OMe
ꢀ0.3 ꢀ0.2 ꢀ0.1
0.0
0.1
σp
0.2
0.3
0.4
0.5
Fig. 7 Hammett correlation plot using various aryl iodides (4-R-C6H4-I).
Based on the mechanistic findings described above, and
from the earlier observation of ours16a,c and others,2o,6i
a
probable catalytic cycle is shown in Figure 8. The catalytic cycle
begins with the base-assisted concerted metalation
deprotonation (CMD) of benzothiazole with CuI,16c followed by
Experimental section
the reaction with complex 3a to produce species
aryl iodide with via oxidative addition would give Pd(IV)
species (Path I). Reductive elimination of arylated couple
product from will regenerate the active Pd(II) catalyst.
Alternately, aryl iodide can react with via concerted process
) to deliver the product and regenerate the catalyst (Path
II). The MALDI-TOF-MS analysis of the reaction mixture
provided evidences for the formation of the intermediates
and . Kinetic analysis of the arylation strongly supports the
A. Reaction of
General experimental
A
All manipulations were conducted under an argon atmosphere
either in a glove box or using standard Schlenk techniques in
pre-dried glass wares. The catalytic reactions were performed
in the flame-dried reaction vessels with Teflon screw cap.
Solvents were dried over Na/benzophenone or CaH2 and
distilled prior to use. Liquid reagents were flushed with argon
prior to use. The 2-bromo-N-(quinolin-8-yl)acetamide,28
B
B
A
(C
7
A
B
compound 1a 18 and 6-substituted benzothiazoles29 were
,
reaction of aryl iodide to a Pd(II) species, hence a molecular
catalytic pathway is assumed. But, the standard tests
performed to distinguish between homogeneous and
heterogeneous catalysis, particularly Hg test, was not
conclusive; thus, a parallel catalytic reaction by the trace
amount of Pd(0) nanoparticles may be operative in addition to
the arylation by a molecular Pd(II) species.27
synthesized according to previously described procedures. All
other chemicals were obtained from commercial sources and
were used without further purification. Yields refer to isolated
1
compounds, estimated to be > 95% pure as determined by H-
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, 100-200 mesh). High
resolution mass spectroscopy (HRMS) mass spectra were
recorded on a Thermo Scientific Q-Exactive, Accela 1250
pump. M. p.: Büchi 540 capillary melting point apparatus,
values are uncorrected. NMR (1H and 13C) spectra were
recorded at 400 or 500 MHz (1H) and 100 or 125 MHz {13C,
DEPT (distortionless enhancement by polarization transfer)} on
Bruker AV 200, AV 400 and AV 500 spectrometers in CDCl3
solutions, if not then specified; chemical shifts (δ) are given in
O
N
CuX
+
+
N
Pd
X
S
N
S
Et2N
N
K2CO3
Ar
3a
X = Cl (
)
= I (4a)
7
KHCO3 + KX
+
CuX
O
N
Et2N
N
Pd
S
O
1
ppm. The H and 13C NMR spectra are referenced to residual
I
O
N
N
N
Ar
I
solvent signals (CDCl3: δ H = 7.26 ppm, δ C = 77.2 ppm).
Et2N
N
Pd
N
PathꢀII
C
(
)
Ar
Et2N
N
S
Pd
N
GC Method
S
Ar
I
B
(
)
Gas Chromatography analyses were performed using
Shimadzu GC-2010 gas chromatograph equipped with
a
a
A
(
)
(Ar = 4ꢀMeꢀC 6H4)
detected by
MALDIꢀTOFꢀMS
PathꢀI
Shimadzu AOC-20s autosampler and a Restek RTX-5 capillary
column (30 m x 250 μm). The instrument was set to an
injection volume of 1 μL, an inlet split ratio of 10:1, and inlet
and detector temperatures of 250 and 320 °C, respectively.
Fig. 8 Plausible mechanism for 3a-catalyzed arylation of benzothiazole.
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UHP-grade argon was used as carrier gas with a flow rate of 30 8.26 (d, J = 8.3 Hz, 1H, Ar–H), 8.21 (d, J = 5.1 Hz, 1H, Ar–H),
mL/min. The temperature program used for all the analyses is 7.49 (vt, J = 7.7 Hz, 1H, Ar–H), 7.39 (dd, J = 7.8, 4.9 Hz, 1H, Ar–
as follows: 80 °C, 1 min; 30 °C/min to 200 °C, 2 min; 30 °C/min H), 7.33 (d, J = 8.1 Hz, 1H, Ar–H), 3.69 (s, 2H, CH2), 3.19-3.11
to 260 °C, 3 min; 30 °C/min to 300 °C, 3 min.
(m, 2H, CH2), 2.66-2.58 (m, 2H, CH2), 2.10 (s, 3H, CH3), 1.80 (t, J
Response factors for all the required compounds were = 7.3 Hz, 6H, CH3). 13C NMR (125 MHz, CDCl3): δ 178.2 (CO),
calculated with respect to standard para-xylene or mesitylene 175.4 (CO), 149.1 (CH), 146.8 (Cq), 145.2 (Cq), 139.1 (CH), 129.9
from the average of three independent GC runs.
(Cq), 129.5 (CH), 121.2 (CH), 120.8 (CH), 120.2 (CH), 65.9 (CH2),
57.5 (2C, CH2), 24.1 (CH3), 12.8 (2C, CH3). HRMS (ESI): m/z
Synthesis of (MorpNNN8-Q H (1b). A mixture of 2-bromo-N- calcd. for C17H21N3O3Pd – OAc+ [M – OAc]+ 362.0479, found
)‒
(quinolin-8-yl)acetamide (0.5 g, 1.89 mmol) and morpholine 362.0493. Anal. Calcd. for C17H21N3O3Pd: C, 48.41; H, 5.02; N,
(0.49 g, 5.6 mmol) in acetone (15 mL) was refluxed for 24 h. 9.96. Found: C, 47.98; H, 4.73; N, 9.71.30
The reaction mixture was then cooled to ambient temperature
and the volatiles were evaporated under vacuum. The crude Synthesis of (MorpNNN8-Q)Pd(OAc) (2b). To a Schlenk flask
mixture was quenched with distilled H2O (20 mL) and the equipped with magnetic stir bar was introduced ligand 1b
aminated product was extracted with EtOAc (15 mL x 3). The (0.05 g, 0.184 mmol) and Pd(OAc)2 (0.041 g, 0.183 mmol). To
combined organic extract was dried over Na2SO4. After the resultant reaction mixture, freshly distilled THF (10 mL)
filtration and evaporation of the volatiles in vacuo pure and Et3N (0.032 mL, 0.229 mmol) were added, and the
product of 1b was obtained as brown solid. Yield = 0.51 g, 99%. reaction mixture was heated to reflux for 3 h. The reaction
o
1
M. p. = 122-124 C. H-NMR (500 MHz, CDCl3): δ = 11.46 (br s, mixture was cooled to ambient temperature, filtered through
1H, N H), 8.85 (dd, J = 4.2, 1.6 Hz, 1H, Ar H), 8.76 (dd, J = 5.9, cannula and the volatiles were evaporated under vacuum. The
3.1 Hz, 1H, Ar H), 8.14 (dd, J = 8.3, 1.6 Hz, 1H, Ar H), 7.55-- product was then washed with Et2O (6.0 mL x 3) and dried
7.49 (m, 2H, Ar H), 7.44 (dd, J = 8.3, 4.3 Hz, 1H, Ar H), 3.92- under high vacuum to obtain a yellow solid compound 2b.
‒
‒
‒
‒
‒
‒
3.87 (m, 4H, CH2), 3.28 (s, 2H, CH2), 2.71-2.66 (m, 4H, CH2). 13C- Yield: 0.048 g, 60%. M. p. = 230 C (dec.). H NMR (500 MHz,
NMR (100 MHz, CDCl3): δ = 168.9 (CO), 148.7 (CH), 139.1 (Cq), CDCl3): δ 8.61 (dd, J = 7.6, 0.9 Hz, 1H, Ar–H), 8.27 (dd, J = 8.2,
136.3 (CH), 134.4 (Cq), 128.2 (Cq), 127.4 (CH), 121.9 (CH), 121.7 1.2 Hz, 1H, Ar–H), 8.15 (dd, J = 5.2, 1.5 Hz, 1H, Ar–H), 7.50 (vt, J
(CH), 116.7 (CH), 67.4 (2C, CH2), 62.9 (CH2), 53.9 (2C, CH2). = 7.9 Hz, 1H, Ar–H), 7.40 (dd, J = 8.2, 5.2 Hz, 1H, Ar–H), 7.35 (d,
HRMS (ESI): m/z calcd for C15H17N3O2 + H+ [M + H]+ 272.1394, J = 7.9 Hz, 1H, Ar–H), 4.02 (s, 2H, CH2), 3.94-3.85 (m, 4H, CH2),
o
1
found 272.1391.
3.83-3.79 (m, 2H, CH2), 2.99-2.96 (m, 2H, CH2), 2.17 (s, 3H,
COCH3). 13C NMR (100 MHz, CDCl3): δ 178.6 (CO), 172.9 (CO),
Synthesis of (PipNNN8-Q
)‒
H (1c). Procedure similar to the 148.7 (CH), 146.6 (Cq), 145.0 (Cq), 139.4 (CH), 129.9 (Cq), 129.6
synthesis of 1b was followed, using 2-bromo-N-(quinolin-8- (CH), 121.3 (CH), 121.0 (CH), 120.5 (CH), 69.4 (CH2), 62.4 (2C,
yl)acetamide (0.5 g, 1.89 mmol) and 1-methylpiperazine (0.56 CH2), 59.3 (2C, CH2), 24.4 (CH3). HRMS (ESI): m/z calcd. for
g, 5.6 mmol). The compound 1c was obtained as brown solid. C17H19N3O4Pd – OAc+ [M – OAc]+ 376.0272, found 376.0267.
Yield = 0.52 g, 97%. M. p. = 106-108 oC. 1H-NMR (400 MHz, Anal. Calcd. for C17H19N3O4Pd: C, 46.86; H, 4.39; N, 9.64.
CDCl3): δ = 11.45 (br s, 1H, N
Ar H), 8.77 (dd, J = 6.1, 2.8 Hz, 1H, Ar
Hz, 1H, Ar H), 7.54-7.48 (m, 2H, Ar
H), 7.44 (dd, J = 8.3, 4.3 Synthesis of (PipNNN8-Q)Pd(OAc) (2c). Procedure similar to the
Hz, 1H, Ar
‒
H), 8.85 (dd, J = 4.3, 1.8 Hz, 1H, Found: C, 46.93; H, 4.36; N, 9.68.
‒
‒
H), 8.14 (dd, J = 8.3, 1.8
‒
‒
‒
H), 3.28 (s, 2H, CH2), 2.72-2.62 (m, 8H, CH2), 2.37 (s, synthesis of 2b was followed, using 1c (0.05 g, 0.176 mmol),
3H, CH3). 13C-NMR (100 MHz, CDCl3): δ = 169.3 (CO), 148.6 Pd(OAc)2 (0.04 g, 0.178 mmol) and Et3N (0.033 mL, 0.237
(CH), 139.2 (Cq), 136.3 (CH), 134.5 (Cq), 128.2 (Cq), 127.5 (CH), mmol). The compound 2c was obtained as a yellow solid. Yield:
121.8 (CH), 121.7 (CH), 116.7 (CH), 62.5 (CH2), 55.5 (2C, CH2), 0.062 g, 78%. M. p. = 170 oC (dec.). H NMR (500 MHz, CDCl3):
1
53.5 (2C, CH2), 46.2 (CH3). HRMS (ESI): m/z calcd for C16H20N4O δ 8.62 (d, J = 7.6 Hz, 1H, Ar–H), 8.26 (d, J = 8.2 Hz, 1H, Ar–H),
+ H+ [M + H]+ 285.1710, found 285.1708.
8.16 (d, J = 4.3 Hz, 1H, Ar–H), 7.49 (vt, J = 7.8 Hz, 1H, Ar–H),
7.39 (dd, J = 7.9, 5.5 Hz, 1H, Ar–H), 7.34 (d, J = 7.9 Hz, 1H, Ar–
Synthesis of (Et2NNN8-Q)Pd(OAc) (2a). To a Schlenk flask H ), 3.94 (s, 2H, CH2), 3.75 (vt, J = 10.4 Hz, 2H, CH2), 3.23 (br s,
equipped with magnetic stir bar was introduced ligand 1a 2H, CH2), 2.62 (br s, 2H, CH2), 2.47 (br s, 2H, CH2), 2.29 (s, 3H,
(0.167 g, 0.649 mmol) and Pd(OAc)2 (0.146 g, 0.650 mmol). To CH3), 2.16 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): δ 178.5
the resultant reaction mixture, freshly distilled THF (15 mL) (CO), 173.6 (CO), 148.9 (CH), 146.7 (Cq), 145.0 (Cq), 139.3 (CH),
and Et3N (0.12 mL, 0.860 mmol) were added, and the reaction 129.9 (Cq), 129.6 (CH), 121.2 (CH), 120.9 (CH), 120.4 (CH), 58.7
mixture was heated to reflux for 3 h. The reaction mixture was (CH2), 49.6 (4C, CH2), 46.1 (CH3), 24.5 (CH3). HRMS (ESI): m/z
cooled to ambient temperature and the volatiles were calcd. for C18H22N4O3Pd – OAc+ [M – OAc]+ 389.0588, found
evaporated under vacuum. The crude compound was 389.0576. Anal. Calcd. for C18H22N4O3Pd: C, 48.17; H, 4.94; N,
extracted with toluene (10 mL x 2) and the solution was 12.48. Found: C, 47.84; H, 4.73; N, 11.99.30
concentrated under vacuum. Et2O (6.0 mL) was added to
precipitate the product, which was then dried under high Synthesis of (Et2NNN8-Q)PdCl (3a). To a Schlenk flask equipped
vacuum to obtain a yellow solid. Yield: 0.16 g, 58%. M. p. = 160 with magnetic stir bar was introduced ligand 1a (0.30 g, 1.166
1
oC. H NMR (500 MHz, CDCl3): δ 8.67 (d, J = 7.8 Hz, 1H, Ar–H), mmol) and PdCl2 (0.207 g, 1.167 mmol). To the reaction
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mixture, freshly distilled THF (20 mL) and Et3N (0.2 mL, 1.434 Synthesis of 2-(p-tolyl)benzo[d]thiazole (7aa). To a flame-
mmol) was added, and the reaction mixture was heated to dried Schlenk tube containing magnetic stir bar were added
reflux for 3 h. The reaction mixture was cooled to ambient the catalyst 3a (0.0015 mmol, 0.5 mol%, 240 μL of 0.0063 M
temperature and the volatiles were evaporated under vacuum. stock solution in toluene) and CuI (0.003 mmol, 1.0 mol%, 60
The crude compound was extracted with toluene (10 mL x 2), μL of 0.0525 M stock solution in CH3CN). The Schlenk tube with
concentrated under vacuum and Et2O (6 mL) was added to catalysts mixture was evacuated under vacuum and refilled
obtain crystalline compound of 3a. Yield: 0.30 g, 65%. M. p. = with argon. Subsequently, 4-iodotoluene (6a; 0.098 g, 0.45
165 oC. 1H NMR (500 MHz, CDCl3): δ 8.93 (d, J = 4.3 Hz, 1H, Ar– mmol), benzothiazole (5a; 0.041 g, 0.30 mmol), K2CO3 (0.062 g,
H), 8.71 (d, J = 7.9 Hz, 1H, Ar–H), 8.28 (d, J = 8.2 Hz, 1H, Ar–H), 0.45 mmol) and DMSO (1.0 mL) were added under argon. The
7.52 (vt, J = 7.9 Hz, 1H, Ar–H), 7.42 (dd, J = 8.5, 5.2 Hz, 1H, Ar– resultant reaction mixture was degassed, refilled with argon
o
H), 7.37 (d, J = 8.2 Hz, 1H, Ar–H), 3.73 (s, 2H, CH2), 3.42-3.35 and was stirred at 130 C in a pre-heated oil bath for 24 h. At
(m, 2H, CH2), 2.64-2.57 (m, 2H, CH2), 1.82 (t, J = 7.0 Hz, 6H, ambient temperature, H2O (10 mL) was added and the
CH3). 13C NMR (125 MHz, CDCl3): δ 175.8 (CO), 150.4 (CH), reaction mixture was extracted with EtOAc (20 mL x 3). The
147.1 (Cq), 145.2 (Cq), 139.2 (CH), 130.1 (Cq), 129.6 (CH), 121.4 combined organic layers were dried over Na2SO4 and the
(CH), 120.7 (CH), 120.5 (CH), 66.4 (CH2), 58.8 (2C, CH2), 13.5 volatiles were evaporated in vacuo. The resultant residue was
(CH3). HRMS (ESI): m/z calcd. for C15H18ClN3OPd – Cl+ [M – Cl]+ purified by column chromatography on silica gel (petroleum
362.0479, found 362.0474. Anal. Calcd for C15H18ClN3OPd: C, ether/EtOAc: 50/1→30/1) to yield 7aa (0.058 g, 86%) as an off-
45.24; H, 4.56; N, 10.55. Found: C, 45.21; H, 4.37; N, 10.39.
white solid. The 1H and 13C NMR data as well as HRMS of
compound 7aa and other arylated benzothiazoles were in
Synthesis of (PipNNN8-Q)PdCl (3c). Procedure similar to the accordance with those reported in the literature.16
synthesis of 3a was followed, using 1c (0.05 g, 0.176 mmol),
PdCl2 (0.032 g, 0.18 mmol), Et3N (0.032 mL, 0.229 mmol) and
Procedure for catalyst recycling experiment
THF (10 mL). The compound 3c was obtained as a yellow
o
1
To a flame dried Schlenk tube equipped with magnetic stir bar
was introduced the catalyst 3a (0.001 g, 0.0025 mmol), CuI
(0.001g, 0.005 mmol), K2CO3 (0.104 g, 0.750 mmol), 4-
crystalline solid. Yield: 0.045 g, 60%. M. p. = 210 C (dec). H
NMR (500 MHz, CDCl3): δ 8.96 (d, J = 4.3 Hz, 1H, Ar–H), 8.64 (d,
J = 7.6 Hz, 1H, Ar–H), 8.23 (d, J = 7.9 Hz, 1H, Ar–H), 7.49 (vt, J =
7.9 Hz, 1H, Ar–H), 7.39 (dd, J = 8.2, 5.2 Hz, 1H, Ar–H), 7.34 (d, J
= 7.9 Hz, 1H, Ar–H), 4.13 (vt, J = 11.6 Hz, 2H, CH2), 4.00 (s, 2H,
CH2), 3.35 (d, J = 11.9 Hz, 2H, CH2), 2.64 (br s, 2H, CH2), 2.43 (br
s, 2H, CH2), 2.30 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): δ
174.2 (CO), 150.8 (CH), 147.0 (Cq), 144.8 (Cq), 139.2 (CH), 130.0
(Cq), 129.5 (CH), 121.5 (CH), 120.7 (CH), 120.7 (CH), 59.3 (3C,
CH2), 49.4 (2C, CH2), 46.1 (CH3). HRMS (ESI): m/z calcd. for
C16H19ClN4OPd – Cl+ [M – Cl]+ 389.0588, found 389.0582. Anal.
Calcd for C16H19ClN4OPd: C, 45.19; H, 4.50; N, 13.18. Found: C,
44.87; H, 4.94; N, 12.84.30
iodotoluene (6a; 0.164 g, 0.750 mmol), and benzothiazole (5a
;
0.071 g, 0.524 mmol). To this reaction mixture, DMSO (2.0 mL)
o
was added and the reaction vessel was heated at 130 C in a
preheated oil bath for 24 h. At ambient temperature, the
reaction vessel was transferred to glove box and para-xylene
(0.030 mL, 0.243 mmol, internal standard) was added into it.
The solution was shaken well and an aliquot of the sample was
withdrawn and subjected to the GC analysis. The yield of the
arylated product 7aa was determined to be 98% by the GC
analysis w.r.t. the internal standard para-xylene. The product
7aa and other volatiles were distilled out under high vacuum
(5 × 10-5 bar) at 140 oC. The GC analysis of the remaining
residue confirms the absence of both the starting compounds
as well as product 7aa in the reaction vessel. The reaction
vessel was further charged with fresh K2CO3 (0.104 g, 0.750
mmol), 6a (0.164 g, 0.750 mmol) and 5a (0.070 g, 0.516 mmol),
and DMSO (2.0 mL) inside the glove box (cat. 3a and CuI were
not added). The resultant reaction mixture was then stirred at
Synthesis of (Et2NNN8-Q)PdI (4a). The mixture of 3a (0.017 g,
0.043 mmol) and KI (0.011 g, 0.066 mmol) in CH2Cl2 (5.0
mL)/MeOH (5.0 mL) was stirred at room temperature for 14 h.
Then the volatiles were evaporated under vacuum and the
compound was extracted with Et2O (5 mL x 3). Upon
evaporation of the solvent, the compound 4a was obtained as
a brown solid. Yield: 0.020 g, 95%. M. p. = 176-178 oC (dec.). 1H
NMR (500 MHz, CDCl3): δ 9.56 (d, J = 4.2 Hz, 1H, Ar–H), 8.78 (d,
J = 8.0 Hz, 1H, Ar–H), 8.25 (d, J = 8.0 Hz, 1H, Ar–H), 7.52 (vt, J =
7.8 Hz, 1H, Ar–H), 7.38 (d, J = 8.0 Hz, 1H, Ar–H), 7.33 (dd, J =
8.2, 5.2 Hz, 1H, Ar–H), 3.74 (s, 2H, CH2), 3.64-3.57 (m, 2H, CH2),
2.73-2.67 (m, 2H, CH2), 1.84 (t, J = 7.1 Hz, 6H, CH3). 13C NMR
(125 MHz, CDCl3): δ 176.9 (CO), 156.4 (CH), 146.9 (Cq), 145.6
(Cq), 138.9 (CH), 130.4 (Cq), 129.6 (CH), 122.2 (CH), 120.8 (CH),
120.7 (CH), 67.1 (CH2), 61.9 (2C, CH2), 14.3 (CH3). MALDI-TOF:
m/z calcd for C15H18IN3OPd + H+ [M + H]+ 489.9608, found
489.8192 and C15H18IN3OPd – I+ [M – I]+ 362.0485, found
361.9155. Anal. Calcd for C15H18IN3OPd: C, 36.79; H, 3.71; N,
8.58. Found: C, 37.39; H, 4.21; N, 7.73.30
o
130 C in a preheated oil bath for the second cycle. Following
the steps mentioned above, the yield of the arylated product
7aa was determined to be 99% by GC analysis for the second
cycle. This recycling experiment was continued for further
three cycles and the yields of the product 7aa were analyzed
to be 98%, 96% and 93% for the third, fourth and fifth cycles,
respectively. At the end of 5th cycle, the product was isolated
by column chromatography, wherein the yield of coupled
product 7aa was 87%.
Procedure for NMR tube experiment
Representative procedure for arylation of benzothiazoles
10 | New J. Chem.
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A mixture of 3a (0.015 g, 0.038 mmol), CuI (0.014 g, 0.075 This work was financially supported by SERB, New Delhi, India
mmol), K2CO3 (0.026 g, 0.188 mmol), benzothiazole (0.026 g, (SR/S1/IC-42/2012). We are thankful to the Alexander von
0.192 mmol) and 4-iodotoluene (0.041 g, 0.188 mmol) was Humboldt Foundation, Germany for an equipment grant.
taken in a J. Young NMR tube, and DMSO-d6 (0.5 mL) was H.P.P. and V.S. thank CSIR - New Delhi for research fellowships.
added into it. The J. Young NMR tube with the reaction We are grateful to Dr. P. R. Rajmohanan for NMR facility, Dr.
mixture was heated in a pre-heated oil-bath at 130 oC. At (Mrs) Shanthakumari for HRMS analyses and Dr. S. P. Borikar
regular intervals, the J. Young NMR tube was taken out from for GC-MS analyses.
1
the oil bath and reaction progress was monitored by H NMR
analysis. The major palladium species observed were (Et2NNN8-
Q)PdCl (3a) and (Et2NNN8-Q)PdI (4a) in 65% and 35% (12 h), 69%
and 28% (24 h), and 68% and 28% (48 h), respectively. The
yields (%) were calculated w.r.t the external standard
mesitylene (in toluene-d8) in a sealed capillary.
Notes and references
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Procedure for additive (Hg, PPh3, PVPy) experiments
Additive experiments were performed following the procedure
similar to the representative procedure for arylation of
benzothiazoles, additionally employing Hg (0.09 g, 0.45 mmol;
0.45 g, 2.24 mmol) or PPh3 (0.0012 g, 0.0045 mmol) or PVPy
(0.024 g, 0.225 mmol). After stirring the reaction mixtures at
130 oC for 24 h, the reactions were quenched with H2O (5.0
mL) at ambient temperature, and EtOAc (5 mL) and para-
xylene (0.030 mL, 0.243 mmol; internal standard) were added.
An aliquot of the reaction mixture was subjected to GC
analysis. The GC yield of the coupled product 7aa obtained
was 72% (0.45 mmol Hg), 63% (2.24 mmol Hg), 98% (0.0045
mmol PPh3) and 78% (0.225 mmol PVPy).
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Procedure for kinetic experiment
To a flame dried Schlenk tube was introduced catalyst 3a
(0.0012 g, 0.003 mmol), CuI (0.0011 g, 0.006 mmol), K2CO3
(0.124 g, 0.9 mmol), benzothiazole 5a (0.081 g, 0.6 mmol) and
4-iodootoluene (0.196 g, 0.9 mmol) or [4-iodoanisole (0.211 g,
0.9 mmol); iodobenzene (0.0184 g, 0.9 mmol); 4-chloro-
iodobenzene (0.215 g, 0.9 mmol); methy-4-iodobenzoate
(0.236 g, 0.9 mmol)] and required amount of DMSO to make
total volume 2.0 mL. To the reaction mixture, mesitylene
(0.030 mL, 0.2156 mmol) was added as an internal standard.
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oil bath. At regular intervals, the reaction vessel was cooled to
ambient temperature and an aliquot of sample was withdrawn
under argon and subjected to GC analysis. The concentration
of the product 7aa obtained in each sample was determined
with respect to the internal standard mesitylene. The data was
collected till 60 min. The final data was obtained by averaging
the results of two independent experiments. The initial rate
for the coupling reactions are shown in Figure 6. The Hammett
plot was drawn from the correlation between the initial rates
and Hammett substituent constants, i.e log (kR/kH) vs. σp, and
obtained a slope of -0.85344, i.e. Hammett reaction constant
(ρ)<0 (Figure 7).
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Acknowledgements
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Abstract: Well-defined (quinolinyl)amido-pincer palladium
complexes are developed and employed for the catalytic C–H
bond arylation of benzothiazoles with aryl iodides, which can
be recycled and reused for several rounds.
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