Sterically enriched bulky 1,3-bis(: N, N ′-aralkyl)benzimidazolium based Pd-PEPPSI complexes for Buchwald-Hartwig amination reactions

Article abstract of DOI:10.1039/d0nj01294g

Pd-PEPPSI (palladium-pyridine enhanced pre-catalyst preparation stabilization and initiation) complexes are now emerging as well-defined catalysts for C-C and C-N bond formation. In connection with this, we prepared a family of six air and moisture stable

Full text of DOI:10.1039/d0nj01294g

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Sterically Enriched Bulky 1,3-Bis(N,N'-Aralkyl)Benzimidazolium
based Pd-PEPPSI Complexes for Buchwald-Hartwig Amination
Reactions
Received 00th March 2020,
Accepted 00th March 2020
Motakatla Venkata Krishna Reddy, Gokanapalli Anusha and Peddiahgari Vasu Govardhana Reddy*
DOI: 10.1039/x0xx00000x
Pd-PEPPSI (palladium-pyridine enhanced pre-catalyst preparation stabilization and initiation) complexes are now emerging
as well defined catalysts for C-C and C-N bond formations. In this connection, we prepared a family of six air and moisture
stable, simple to bulky benzyl substituents bearing benzimidazolium core Pd-PEPPSI complexes, C1-C6. Structure of C6 is
confirmed from X-ray diffraction (XRD) studies and the steric pressure of N-heterocyclic carbene is determined by vBur
%
calculation. Notably, these NHC-Pd-Py frameworks execute good 훔-donating and π-extended electronic property of
benzimidazolium NHCs which is an essential requirement for catalysis. The prepared complexes are proved to accomplish
an outstanding and overwhelming reactivity than the other previously reported catalysts for the Buchwald-Hartwig cross-
coupling reactions between 3-chloropyridine and various aryl/heteroaryl amines under mild reaction conditions. On the
other hand, there is no need of external additives or ligands for the complete conversion of lead parent molecules to
products. More remarkably, C6 executed significant catalytic activity compared to other complexes, C1-C5 for C-N bond
formations. Further, the substrate scope is extended to other heteroaryl chlorides such as N-(5-chloro-4-methylpyridin-2-
yl)acetamide, 2,4,6-trichloro-1,3,5-triazine, 3-chlorothiophene and 3-chloroquinoline.
the synthesis of some of the catalysts is expensive11 and a few
catalysts are known to be less tolerant to air. Hence, to protect
the Pd (0) species, they should be typically run under an inert
Introduction
Transition metal mediated catalysis has emerged as widely used
strategy offering a valuable tool for the synthesis of several
biologically active drugs, agricultural chemicals, natural
products and other building blocks.1 This technique has been
widely disseminating a variety of organic processes such as
hydroamination, silylation, cyclo addition, double cyclization
etc.2 Although, different metal complexes3-5 have been utilized
to carry-out these reactions, the efficacy of palladium
conjugates remained unbeaten since many years. Among
various organic transformations, cross-coupling reactions like
Buchwald−Hartwig and Suzuki−Miyaura couplings with
palladium complexes are extensively studied by great number
of research teams for C(sp2)-N and C(sp2)-C(sp2) bond
formations due to their generality and wide functional groups
tolerance in organic synthesis.6-7 In this perspective, several
ligands8 and Pd catalysts9 were built for a range of catalysis
reactions, but their usage is sometimes restricted due to the
variability and less compatibility to the substrates. For instance,
till today, direct amination on heteroaryl halides with
conventional catalysts remains a practical challenge10 despite of
the formation of insoluble co-ordinate complexes. Moreover,
atmosphere.
Consequence to this anticipation, metal-N-heterocyclic carbene
(NHC) complexes have come into existence. These are the gifted
substitutes to phosphines, emerging as bench top class of
transition-metal complexes with strong σ-donating and weak
accepting ligands. Their electronic and steric tunability by
N,N'-substituents adds flush catalytic activity. Ofele12 and
Wanzlick13 identified the existence of NHCs in the year 1968.
After a long period, Arduengo14 isolated the first stable bis
adamantyl NHC. Since then, many researchers across the globe
have been continuously focusing on the synthesis of diverse
NHCs15 and M-NHC complexes16 for distinct conversions. With a
major effort, Nolan put forth the use of (η3-allyl)Pd(NHC)-X
complexes as efficient pre-catalysts for cross-coupling
reactions,17 while extended to phosphine ligands as external
additives by Colacot.18 Although, several Pd-NHC complexes19
were synthesized and applied to catalysis reactions, they are
however set with few short comings like multi-step catalyst
synthesis,20 requirement of high catalyst load etc., Hence,
Organ and team introduced a new class of air stable and
environmentally benign Pd-PEPPSI pre-catalysts.21
Infact, a pile of reports are available on (N,N'-diaryl)imidazolium
Pd-PEPPSI complexes,22 but they display limited substrate scope
by virtue of their stability to certain reaction conditions.
Nevertheless, it is apparent that the synthesis of these
complexes requires skillful workup besides low reaction yields.
Department of Chemistry, Yogi Vemana University, Kadapa-516005, Andhra
Pradesh, India. Tel.: +91-8562-225410; fax: +91-8562-225419; e-mail:
pvgr@yogivemanauniversity.ac.in.
Electronic Supplementary Information (ESI) available: General experimental section,
characteristic data, copies of NMR (1H
DOI: 10.1039/x0xx00000x
&
13C) and Crystal XRD data See
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Furthermore, application of these complexes has not been respective heteroaryl chlorides and aryl/heteroaryl amines in
firmly established.
Benzimidazole nucleus is considered to be far stable than the benzimidazolium Pd-PEPPSI complexes (Scheme 1).
simple imidazole nucleus due to the extended aromaticity and
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the presence of electron rich stDeOriIc:a1l0ly.1039e/nDc0uNmJ0b1e29r4eGd
hence, the current decade is witnessed with the synthesis and
exploration of few massive, symmetrical and unsymmetrical
benzimidazole core Pd-NHC complexes. Additionally, the steric
bulk of these complexes enables the stabilization of low valent
active intermediates and favors easy reductive elimination step,
thereby increases the catalytic activity for several cross-
coupling reactions. From the literature survey, it is identified
that Baker and group introduced bulky o-xylyl linked
Previous work
G
N
G
N
Cl
(a)
R1
HN
Pd
Cat (0.2 - 4.0 mo%)
R1
Cl
Cl
N
H2N
10
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Cl
Cat: Pd-PEPPSI-iPr
Y. Zhang et al. Eur. J. Org. Chem., 2015, 2042–2050
R2
R
Ph
Ph
1 N
Cl
Cat (1.0 mol%)
R2
N
N
R
1 N
H
(b)
R
Pd
Cl
Cl
Ph
alkoxybenzimidazolin-2-ylidine-Pd-NHC
complexes
for
N
Ph
Mizoroki-Heck and Suzuki-Miyaura reactions.23 Later, Akkoc
and Gok reported benzimidazole based Pd-PEPPSI complexes
for arylations on thiazole, furan and thiophene compounds by
C-C bond formation reactions.24 Recently, Boubakri et al.
synthesized few Pd-PEPPSI complexes for Suzuki-Miyaura
coupling and evaluated their biological properties.25 Lately,
benzimidazolyl Pd-NHC complexes were exercised for
sustainable chemistry on aryl bromides by Zhu and his co-
workers.26
X
82
X. -B. Lan et al. J. Org. Chem., 2017, , 2914-2925
Cat: Pd-PEPPSI
R
R
Si
N
X
(c)
Cat (0.2-1.0 mol%)
N
N
Dipp
R
R
Dipp
N
H
Pd
Cl Cl
38
T. Mizusaki et al. Organometallics, 2019, , 1872-1876
Cat: Silylated Pd-NHC
R2 R1
Current work
R3
R3
R3
R3
H
Cl
N
Cat
N
N
Het
Alk/Ar/Het
Alk/Ar/Het-NH2
Het
R3
R3
(0.5 mol%)
Much before from the original discovery, many of the teams are
endlessly focusing on the synthesis and applications of assorted
Pd-NHC complexes precisely for C-C bond formations, while
only a few are directing on C-N bond formations. For instance,
Zhang22a reported the Buchwald-Hartwig amination reaction
Pd
Cl Cl
N
Cl
Cat: Pd-PEPPSI (C1-C6)
with imidazolyl Pd-PEPPSI-IPr(NMe ) catalyst in 2015. Later, Lan
2 2
et al. employed flexible and bulky bis(imino)acenaphthene
(BIAN) Pd-PEPPSI complex for amination reaction in open air.27
Recently, Mizusaki and group19c put forth the silyl supportive
Pd-NHCs for these type of reactions (Scheme 1).
Most of the heteroaryl chlorides are less reactive or reluctant to
cross-couplings due to their electron deficit property. Hence,
several teams are continuously putting their efforts towards
synthesizing abnormal metal complexes and activating them for
derivatization of heterocyclic amines.
Scheme 1 Representative examples of previous and present
works.
NH
F3C
N
Results and discussion
CF3
Cl
H
N
N
N
N
N
F
N
Since 2016, we gained a rich experience in the development of
new protocols for C-C and C-N bond formation reactions on
heterocyclic compounds30 using Pd-PEPPSI catalysts.
Cl
N
N
Cl
O
HN
N
H2N
N
N
O
UDD, EPL-BSO967
Anti Cancer Drug
Crizotinib
Anti Cancer Drug
Imatanib
Anti Parasitic
Cl
N
R3
R3
N
N
N
N
N
Cl
R2
R1
PdCl2, K2CO3
80 oC, 10-12 h
N
R2
R1
N
N
N
Cl
PdN
Cl
N
H
H
Cl
N
N
Altretamine
Anti Cancer Drug
Atrazine
Insecticidal
R3
R3
Fig. 1 Few pyridine and triazine based drugs.
Cl
Cl
Cl
Cl
Cl
N
N
Cl
Pd
Cl
N
N
N
PdN
Cl
N
Pd
N
N
F
Pyridine and triazine scaffolds represent important classes of
heteroaromatic compounds in spite of their potential biological
activities.28,29 Some of the biologically active compounds are
presented in figure 1.
Cl
C1
C2
C3
With this perception, our present study aimed at the synthesis
of different series of pyridine and triazine mimics from the
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iPr
iPr
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Cl
Fig. 2 ORTEP diagram drawn with 50% eDllOipIs: o10id.10p3r9o/Db0aNbJil0it1y29f4oGr
non-H atoms of the crystal structure of C6 determined at 296 K
(CCDC Deposit No.: 1982273).
Cl
Cl
iPr
Cl
Cl
Pd
Cl
Cl
Pd
Cl
N
N
N
N
N
N
N
Pd N
Cl
N
iPr
iPr
iPr
C4
C5
Crystal showed the monoclinic geometry with space group
P21/n around the metal center. The complex has single bond
character between Pd (1) and Ccarbene(46) with bond length
1.939 Å while the bond distance between Pd(1) and N(1) (of
pyridine) is 2.144 Å. In this complex, NHC ligand and 3-
chloropyridine are oriented trans to each other with a bond
angle of 177.45° for C(46)-Pd(1)-N(1). The 2,4,6-triisopropyl-
benzyl groups on N2 and N3 are much more tilted, probably due
to the skewed geometry of the NHC backbone with bond angles
118.9° and 119.4° for C(46)-N(3)-C(14) and C(46)-N(2)-C(30)
respectively (Figure 2).
C6
10
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iPr
Cl
iPr
iPr
Cl
Pd
Cl
N
N
N
iPr
Pd-PEPPSITM-iPr
Commercially Available
Scheme 2 Preparation of various Pd-PEPPSI complexes C1-C6
Reagents and conditions: benzimidazolium chlorides (1.0 Besides the crystal refinement, %VBur was also calculated for C6
mmol), PdCl2 (1.0 mmol), K2CO3 (4.0 mmol), 3-chloropyridine (4 complex using web application SambVca31 by setting the bond
mL), 80 oC, 10-12 h.
radius scaled by 1.17, sphere radius R = 5 Å and Pd–Ccarbene
distance d = 2.00 Å. The obtained percentage buried volume
To further continue our efforts on NHCs, we here-in constructed was 44.8% which is greater than the computed values for IPr-
an array of six different N,N'-symmetrically substituted PdCl2-3-chloropyridine and SIPr-PdCl2-3-chloropyridine (34.3
benzimidazolium chloride salts from the low cost, readily and 39.3 respectively)32 and this revealed its greater steric
available, o-phenylenediamines following a simple reaction environment. The steric map for graphical representation of C6
pathway.27e These salts were then allowed to react with PdCl2 is presented in figure 3.
o
and 3-chloropyridine in the presence of K2CO3 at 80 C for 10-
12 h to afford the highly active Pd-PEPPSI complexes C1-C6
(Scheme 2). All the prepared candidates were well
characterized by IR and NMR (1H & 13C) spectroscopies.
Structure of one of the bulky and highly reactive complex, C6
has been analyzed by single crystal X-ray diffraction
spectroscopy.
X-ray crystallography study
To establish the geometry, suitable crystals of Pd-PEPPSI C6
were grown by slow diffusion of ethanol in saturated
dichloromethane solution. A good quality pale yellow colour
single crystal of size 0.200 x 0.150 x 0.150 mm3 was selected for
single-crystal diffraction analysis under a polarizing microscope.
Data was collected on the 'Bruker axs kappa apex2 CCD
diffractometer' generated from fine-focus sealed tube
diffraction radiation source under graphite monochromator.
Theta range employed for data collection is 2.149 to 25.000° at
296(2)K.
Fig. 3 Steric map of catalyst C6.
As an element of study, to judge the catalytic activity of various
synthesized Pd-PEPPSI complexes, we have chosen Buchwald-
Hartwig amination reaction. For this, we initiated C-N bond
formation reaction between 3-chloropyridine and aniline in the
presence of Pd-PEPPSI catalyst C1 (0.5 mol% load), KOtBu and in
toluene at room temperature for about 8 h, but obtained no
desired product (Table 1, entry 1). Temperature was then raised
gradually to 50 oC and 90 oC and noticed product formation with
increase in the percentage yield (Table 1, entries 2 and 3). With
this scope, reactivity by different complexes C2-C6 was checked
and found that bulkiness due to 2,4,6-methyl/triisopropylbenzyl
groups on 1,3 positions (of NHC) and the direct methyl groups
on benzimidazole core could together influence the reactivity
and hence amplified result was gained with C6 (Table 1, entries
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4-8). For the purpose of comparison, the catalytic activity was catalysis. So, bases like K2CO3, Cs2CO3, NaOtBu, KOtBu, K3PO4,
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also monitored with Pd-PEPPSI-iPr and observed the lowering in NEt3 and pyridine were tested and received superior yield with
DOI: 10.1039/D0NJ01294G
yield (Table 1, entry 13). This states the impact of bulky yet KOtBu (Table 2, entries 7-13 and Table 1, entry 9).
flexible nature of 2,4,6-triisopropyl benzyl groups which is less
noticed in Pd-PEPPSI-iPr.
Next, to find the exact time of conversion, the reaction was formation
Table 2. Effect of role of solvents and bases on C-N bond
Yielda (%)
repeated with C6 and recognized best yield formation in just 3
h (Table 1, entry 9). Finally, to reduce the effort in large scale
catalyst manufacturing, effective catalyst loading was aspired.
For this study, reaction was started with 0.05 mol% of C6 and
obtained 23% of yield. Later, the loading was increased to 0.1
and 0.5 mol% and received 59 and 91% yields respectively
(Table 1, entries 11 and 9). An additional increase to 0.8 mol%
did not offer any increase in product yield (Table 1, entry 12).
Therefore, the optimum catalyst load for carrying out the
reaction was set to 0.5 mol%.
Entry
Solvent (mL)
Dimethylsulfoxide
1,4-dioxane
Base
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
K2CO3
Cs2CO3
1
2
3
4
5
6
7
8
9
55
67
61
N.P
57
52
49
51
73
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Dimethoxyethane
Water
Toluene:Water (1:1)
Dioxane:Water (1:1)
THF:Water (1:1)
Toluene
Toluene
10
11
12
13
Toluene
Toluene
Toluene
Toluene
NaOtBu
K3PO4
NEt3
69
58
38
45
Table 1. Screening of Pd-PEPPSI complexes C1 to C6 for the
preparation of N-phenylpyridine-3-amine
Pyridine
NH2
H
N
Cl
Catalyst (mol %)
Reaction conditions: 3-chloropyridine (1.0 mmol), aniline (1.0
mmol), base (3.0 mmol), solvent (3 mL), 90 oC, 3 h.
KOtBu, Toluene
Temp (oC)
+
N
4
N
5
6
Rate of reaction with catalysts C1-C6 towards C-N bond formation
on 3-chloropyridine
Temp (oC)
Entry
Catalyst
(mol%)
C1 (0.5)
Time (h)
Yielda (%)
To widen the studies, an auxiliary evaluation of rate of reaction
with C1-C6 was endeavored. With the optimum reaction
condition in hand, 3-chloropyridine was coupled with aniline in
the presence of series of complexes C1-C6 (0.5 mol%) at 90 oC.
In all the cases, reaction was observed to start in 30 min of time
followed by a steep raise in activity between 2 to 3 h, reaches a
maximium yield and therafter remained constant (Fig.4).
1
2
3
25
50
90
90
90
90
90
90
90
90
90
90
90
8
8
8
8
8
8
8
8
3
3
3
3
3
N.P
34
58
67
76
63
85
91
91
23
59
91
86
C1 (0.5)
C1 (0.5)
C2 (0.5)
C3 (0.5)
4
5
6
C4 (0.5)
C5 (0.5)
C6 (0.5)
C6 (0.5)
7
8
9
10
11
12
13
C6(0.05)
C6 (0.1)
C6 (0.8)
Pd-
PEPPSITM-
iPr (0.5)
Reaction conditions: 3-chloropyridine (1.0 mmol), aniline (1.0
mmol), KOtBu (3.0 mmol), toluene (3 mL).
Subsequently, to make the condition more specific, the role of
solvents was also examined. Several teams are interested in the
development of green methodologies using solvents/solvent
systems like dimethyl sulfoxide, water, toluene:water etc.
Hence investigations were repeated with organic solvents
alone/water/mixture of organic solvents and water (1:1), but
unfortunately obtained ambiguous results (Table 2, entries 1-7).
Hence toluene is optimized as the best solvent for this reaction
(Table 1, entry 9). Apart from all the above parameters, the
selection of base is also very much imortant in the area of
Fig. 4 Rate of Reaction.
From the above all practices, the best optimum reaction
condition for the coupling of different amines with 3-
chloropyridine is catalyst: C6, base: potassium tert-butoxide,
solvent: toluene and temperature: 90 oC. With this tool in hand,
we then explored the substrate scope and obtained good to
excellent yields of products as shown in Table 3.
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Table 3. Identification of catalyst activity for coupling of 3-chloropyridine with primary amines
H
N
Cl
C6
R
R-NH2
5a-l
KOtBu, Toluene
90 oC
N
4
N
6a-l
H
N
H
N
H
N
H
N
N
N
N
N
OCF3
CF3
6c
, 92 %
3h 10min
6b
, 98 %
3 h
6a
3 h
, 91%
6d
, 83%
3h 20min
H
N
H
N
Cl
H
H
N
N
Cl
N
Br
N
N
CF3
N
N
6f
, 88%
6g
, 79%
3h 25min
6h
, 83%
3h 25min
6e
, 89%
3h 15min
3h 15min
H
N
Cl
H
N
H
H
N
N
N
N
N
N
Cl
N
Br
N
I
N
6j
, 85%
3h 20min
6l
, 82%
3h 25min
6i
, 87%
3h 15min
6k
3h 30min
, 81%
Reaction conditions: 3-chloropyridine (1.0 mmol), 1o amine (1.0 mmol), C6 (0.5 mol%), KOtBu (3.0 mmol), toluene (3 mL), 90 oC.
The study was generalized from the coupling of 3- of these complexes, 3-chloropyridine was allowed to react with
chloropyridine with simple aniline and extended to substituted 4-bromoaniline, 2-amino-5-bromopyridine and 5-
aromatic and heteroaromatic amines. Amines bearing electron iodopyrmidin-2-amine and gained surprising results in all these
donating groups like -CH3 coupled very efficiently compared to cases. Particularly 4-bromoaniline gave a little higher yield than
those bearing withdrawing groups like -CF3 (Table 3, entries 6b the other two amines (Table 3, entries 6f, 6j and 6l). This clearly
and 6d, 6e). In the other case, effect due to electron evidences the tolerability and good compatibility of the catalyst
withdrawing groups at different positions was tested and even for different halo surrogates of amines. The results also
observed a negligible variation in yields. In this respect, amines explain that the hetero aromatic amines could efficiently
with -CF3 group at meta-position afforded lower yield than that couple with 3-chloropyridine under satisfactory yields (Table 3,
at para-position (Table 3, entries 6d and 6e). Similarly, when we entries 6j-l).
monitored the effect of chlorines at different positions of From the literature reports, most of the catalysts shown to
aniline, 2-chloroaninine was observed to couple with lower execute good activity towards coupling of primary amines with
yield compared to 3- and 4-chloroanilines (Table 3, entries 6g- aryl/heteroaryl halides than do with secondary amines. Hence,
i).
in a quest to find out the substrate scope of the catalyst,
Limited protocols are available on the coupling of aromatic coupling of 3-chloropyridine with secondary amines was
halides with amines bearing bromo/iodo substituents.33 routed. For this, initially morpholine was allowed to couple with
Despite, with our objective to bring out the rationale on working 3-chloropyridine and achieved promising yield (Table 4,
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Table 4. Investigation on catalyst activity for coupling of 3-chloropyridine with secondary amines
6
7
8
9
R
N
Cl
C6
R
R-NHR
5aa-ae
KOtBu, Toluene
90 oC
N
4
N
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6aa-ae
O
N
N
N
N
N
N
N
N
N
N
N
N
6ab
3h 05min
, 93%
6ac
6aa
3h
, 91%
3h
, 90%
6ae
, 84%
3h 10min
6ad
, 87%
3h
Reaction conditions: 3-chloropyridine (1.0 mmol), 2o amine (1.0 mmol), C6 (0.5 mol%), KOtBu (3.0 mmol), toluene (3 mL), 90 oC.
entry 6aa). With this inception, we then proceeded to react with Although, 2,4,6-trichlorotriazine can effectively couple with
1-methylbenzylamine,
1-benzylpiperazine,
1- different nucleophilic partners under mild base conditon, they
benzhydrylpiperazine & 1,1,2,2-tetrahydroquinoline (Table 4, are sometimes reported with long reaction time,34 and at high
entries 6ab - 6ae) and acquired un-anticipated results. The temperatures.35,36
above results gives us a crystal inference of more or less same
reactivity effect of C6 for both 1o and 2o amines.
NH
N
N
Table 5. Survey on effect of catalyst for coupling of N-(5-chloro-
4-methylpyridin-2-yl)acetamide with 1o aromatic amines
NH2
N
N
N
H
H
6ca
, 92%
3h 20min
Cl
N
N
H
H2N
N
O
Cl
N
Cl
O
i
ii
4c
N
N
N
N
Cl
O
H
F3CO
O
N
6ba
, 83%
iii
B(OH)2
HN
3h 30min
N
H
N
N
N
NH2
H
6cb
, 83%
H
N
H2N
F3CO
3h 20min (In final step)
O
N
N
OCF3
OCF3
Scheme 3. Rational design for the synthesis of 2,4,6-
trisubstituted triazines with C6.
Reaction conditions: For 6ca: 2,4,6-trichlotriazine (1.0 mmol), 4-
methyl aniline (3.0 mmol), C6 (1.0 mol%), KOtBu (5.0 mmol),
toluene (3 mL), 90 oC.
H
6bb, 79%
3h 30min
Reaction conditions: N-(5-chloro-4-methylpyridin-2-yl)acetami-
de (1.0 mmol), amine (1.0 mmol), C6 (0.5 mol%), KOtBu (3.0
mmol), toluene (3 mL), 90 oC.
For 6cb: Step i: 2,4,6-trichlotriazine (1.0 mmol), morpholine (1.0
mmol), C6 (0.5 mol%), K2CO3 (3.0 mmol), toluene (3 mL), 90 oC,
1h 20min. Yield (91%). Step ii: 4-(4,6-dichloro-1,3,5-triazin-2-
yl)morpholine (1.0 mmol), phenylboronic acid (1.0 mmol), C6
(0.5 mol%), K2CO3 (2.0 mmol), toluene (3 mL), 90 oC, 2h 30min.
Yield (94%). Step iii: 4-(4-chloro-6-phenyl-1,3,5-triazin-2-
yl)morpholine (1.0 mmol), 4-trifluoromethyl aniline (1.0 mmol),
To further explore the scope of the catalyst, N-(5-chloro-4-
methylpyridin-2-yl)acetamide was coupled with electron rich p-
toluidine and electron deficient p-trifluoromethoxy aniline, and
attained better result with the former than the latter owing to
its electronic property (Table 5, 6ba and 6bb).
Next, to identify the substrate scope of the catlyst for other
nitrogen heterocycles, we selected highly versatile and
biologically active 2,4,6-trichlorotriazine for cross-coupling
reactions.
C6 (0.5 mol%), KOtBu (3.0 mmol), toluene (3 mL), 90 C, 3h
o
20min. Yield (83%).
Conversely, M. S. Muller and team displayed coupling of
morpholine to 2,4,6-trichlorotriazine in the presence of
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triethylamine followed by 2-substituted benzimidazole coupling SingaCycleTM-A1 and all the products (6da-dd) were matched
View Article Online
DOI: 10.1039/D0NJ01294G
in the presence of Pd(OAc)2 and xantphos.36 Similarly, palladium with the earlier literature report.(30c)
complexes catalyzed C-C bond formations for active 2,4,6-
triazines synthesis was presented by various teams.30e,37 Hence,
to ascertain the efficiency of the synthesized Pd-PEPPSI
Experimental
complexes, we also conducted few more experiments. First
2,4,6-trichloro traiazine was reacted with toluidine via
I. General Experimental Section
o-Phenylenediamines,
benzyl
halides
(aralkylhalide),
Buchwald coupling and obtained 92% of trisubstituted product
with just 1 mol % of C6. With this enthusiastic report, we then
proceded to examine the captivity of catalyst for Suzuki-
Miyaura reaction. In this consequence, 4-(4,6-dichloro-1,3,5-
triazin-2-yl)morpholine (step-i product of 6cb) was coupled with
phenylboronic acid in the presence of Pd-PEPPSI C6 and K2CO3
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triethylorthoformate, 3-chloropyridine, 2,4,6-trichloro-1,3,5-
triazine, aromatic amines, phenylboronic acid, Pd-PEPPSITM-iPr
and SingaCycleTM-A1 were purchased from Sigma Aldrich and
TCI companies, palladium chloride was procured from Alfa
Aesar company, N-(5-chloro-4-methylpyridin-2-yl)acetamide
was received from Avra Synthesis, solvents were acquired from
Merck company and were used without any further
purification. Bases were collected from Sigma Aldrich and Acros
companies. Benzimidazolium salts were prepared from our
recent work.30e All the reactions were carried out in non-inert
atmosphere. Progress of the reactions was monitored from TLC
analysis using Merck silica gel 60 F254 plates and visualized under
UV lamp.
o
in toluene at 90 C and acquired 4-(4-chloro-6-phenyl-1,3,5-
triazin-2-yl)morpholine in best yield. During the conversion of
2,4,6-trichlorotriazine to 4-(4-chloro-6-phenyl-1,3,5-triazin-2-
yl)morpholine, sequential Buchwald-Hartwig (morpholine
substitution), Suzuki-Miyaura (phenyl substitution) and
Buchwald-Hartwig
couplings
(p-trifluoromethoxyphenyl
substitution) were performed to achieve products in 91, 94%
and 83% respectively (Scheme 3).
The NMR spectra were recorded on Bruker Top spin 400 MHz
instrument at ambient temperature using TMS as an internal
standard and CDCl3 or DMSO-d6 as solvents with a decoupled
nucleus. Chemical shifts (δ) are reported in ppm. Multiplicities
in the 1H-NMR spectra are described as: s = singlet, d = doublet,
t = triplet, q = quartet, dd = doublet of doublet, td = triplet of
doublet, qd = quartet of doublet, m = multiplet; Coupling
constants are reported in Hz. High Resolution Mass Spectra
were recorded on microTOF-Q II-Bruker compass mass
spectrometer operating at 70 eV.
Table 6. Assessment of substrate scope of C6 for different
heteroaryl chlorides
H
C6
N
Het-NH2
Het-Cl
Het
Het
KOtBu, Toluene
6da-dd
HN
HN
N
S
N
Melting points of the synthesized compounds are uncorrected.
Infrared spectra for all the compounds recorded on Bruker
Alpha-Eco ATR-FTIR (Attenuated total reflection-Fourier
transform infrared) interferometer with single reflection
sampling module equipped with KBr crystal. X-ray diffraction
data for single crystal of Pd-PEPPSI C6 was obtained using the
ω-2θ scan mode on a Bruker kappa apex2 CCD diffractometer
with graphite monochromator under Mo Kα radiation 2.149 to
25.000° at 296(2)K. Global refinement of all positions from the
reflections used for recording cell parameters. The crystal
structure was solved by direct methods and refined by full-
matrix least-squares on F2. Structure solution and refinement
were performed by using the SHELXL-97 package. All the non-
hydrogen atoms were refined anisotropically. Hydrogen atoms
were introduced in calculated positions with the displacement
factors of the host carbon atoms.
S
S
6da
6db
C6
Yield with Pd-PEPPSI- :
a59%
C6
Yield with Pd-PEPPSI-
:
a69%
SingaCycleTM-A1: b43%
SingaCycleTM-A1: b48%
H
N
H
N
N
N
S
N
N
6dc
C6
6dd
a71%
C6
:
Yield with Pd-PEPPSI-
:
a81% Yield with Pd-PEPPSI-
SingaCycleTM-A1: b68%
SingaCycleTM-A1: b52%
Reaction conditions: heteroarylchlorides (1.0 mmol),
heteroarylamine (1.0 mmol), C6 (0.5 mol%), KOtBu (3.0 mmol),
toluene (3 mL), 90 oC, 3 h. aIsolated Yield. bReported Yield.
The aforementioned results prompted us to further explore the
synthetic utility of the complexes. Hence, we tried the
application of Pd-PEPPSI C6 for coupling of different
heteroaromatic chlorides such as 3-chlorothiophene and 3-
chloroquinoline which we were moderately successful with
SingaCycleTM-A1 in our previous report.30c These compounds
were effectively coupled with 5-phenylpyridin-2-amine and 5-
(thiophen-3-yl)pyridin-2-amine with comparatively good yields
of products in the presence of Pd-PEPPSI C6 than with
II. Common route for the synthesis of Benzimidazolium Pd-PEPPSI-
Complexes (C1-C6)
a. Synthesis of Bis N,N-diaralkyl benzene-1,2-diamines
o-phenylenediamine (1.0 mmol) was taken into a clean 50 mL
RBF and charged with dry acetonitrile solvent (10 mL). To that
solution, triethylamine (3.0 mmol) and aralkylhalide (2.0 mmol)
were added at 0 oC and allowed to stir for 30 min at 25 oC and 3
h at reflux condition. The reaction mixture was then cooled to
room temperature (25 oC), monitored the progress of reaction
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by TLC, distilled off the solvent, added 5 mL of water and For 6f, 6j and 6l: Initially 3-chloropyridine (1.0 mmol) was added
extracted with CH2Cl2 twice (2x10 mL). The combined organics to a round bottomed flask charged with Pd-PEPPSI C6 (0.5
View Article Online
DOI: 10.1039/D0NJ01294G
was dried over anhydrous Na2SO4 and the CH2Cl2 solvent was mol%) in toluene (3 mL) at room temperature and stirred for 10-
removed under high vacuum to obtain the crude mass which 15 min. To that, were added corresponding aryl/heteroaryl
o
was then purified through column chromatography using 100- amines (1.0 mmol) and KOtBu (3.0 mmol) and stirred at 90 C
200 silica mesh to obtain the pure colourless solids.
b. Typical method for the construction of symmetrical bis N,N-
diaralkyl benzimidazolium chlorides
for 3-4 h without inert atmosphere condition. The progress of
the reaction was monitored through TLC and the reaction
mixture was cooled and worked up with water and ethyl
acetate. The combined organics was dried over anh. Na2SO4,
removed the solvent under vacuum and chromatographed with
100-200 mesh silica gel using hexane-ethyl acetate as eluent
and acquired pure products.
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In a 25 mL round bottomed flask containing symmetrical N,N'-
diaralkylbenzene-1,2-diamine (1.0 mmol) and triethyl
orthoformate (1.0 mmol) was added conc. HCl (1.0 mmol) at 0
oC and the resulting mixture was refluxed for 3 h. After the
completion of reaction (examined over TLC), the mixture was
cooled to room temperature and evaporated the solvent under
the reduced pressure to yield the crude mass. This was
triturated with n-hexane/diethyl ether (2*5 mL) and dried
under high vacuum to afford colourless salts.
IV. Suzuki coupling for the synthesis of 4-(4-chloro-6-phenyl-1,3,5-
triazin-2-yl)morpholine (Step ii for 6cb synthesis)
Int 1, 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (1.0 mmol),
phenylboronic acid (1.01 mmol) and K2CO3 (2.0 eq) were taken
into a 25 mL round bottomed flask containing toluene (3 mL)
and the reaction mixture was allowed to stir for 5 minutes at
room temperature. Later, C6 (0.5 mol%) was included and
continued stirring for further 5 minutes at the same
temperature. The reaction mixture was then transferred to a
pre-heated oil bath at 90 ˚C and stirred for another 2 h. After
the completion of reaction as monitored by TLC, the reaction
mixture was brought to room temperature and filtered through
Whatman filter paper followed by hexane washings. To the
filtrate was added 5 mL of saturated sodium bicarbonate
solution and extracted with ethyl acetate twice to remove the
un reacted boronic acid. The combined organics was dried over
anhydrous sodium sulphate and evaporated under vacuum. The
obtained crude mass was purified by flash column
chromatography over silica gel using hexane-ethyl acetate as
the eluent to get the pure product, int 2 (yield: 94%).
c. Versatile procedure for the synthesis of Pd-PEPPSI complexes
C1-C6
A 25mL round bottomed flask containing magnetic stir bar was
charged with 3-4 mL of 3-chloropyridine, N,N'-symmetrically
disubstituted benzimidazolium chlorides (1.0 mmol) and
palladium chloride (1.0 mmol). To that, was added K2CO3 (3.0
o
mmol) and allowed to stir for 10-12 h at 80 C in non-inert
atmosphere during which the reaction mixture converts initially
to yellow followed by deep color change to orange-red mass.
After the completion of reaction, the mixture was cooled to
room temperature and filtered through a pad of celite by
washing with small amount of ethyl acetate (15 mL). To the
filtrate was added 10 mL of water, extracted with ethyl acetate
twice (2x5 mL) and the combined organics was evaporated
under reduced pressure to obtain the crude mass. This was
purified by gravity column using silica mesh with hexane:ethyl
acetate eluent to obtain pure Pd-PEPPSI complexes C1 to C6 as
yellow solids (Yields: 63-85%). All the complexes were
characterized by 1H and 13C NMR and IR spectroscopies.
Compound C6 was also characterized by crystal XRD.
Conclusions
In summary, we report a more convenient approach for the
preparation of
a
new class of N,N'-symmetrical
III. Typical procedure for the preparation of N-alkyl/aryl/heteroar-
ylpyridine/triazine amines (6a-l, 6aa-6ae, 6ba-bb, 6ca-cb, 6da-dd)
benzimidazolium clock Pd-PEPPSI complexes. From the
reactivities of different catalysts C1-C6 towards Buchwald-
In a dry 10 mL round bottomed flask charged with toluene (3 Hartwig cross-coupling on heterocyclic halides, it can be
mL), pyridine/triazine/thiophene/quinoline chlorides (1.0 concluded that the bulky N,N'-triisopropylbenzyl substituents
mmol), alkyl/aryl/heteroaryl 1o or 2o amines (1.0 mmol (3.0 on benzimidazolium NHC ligands in as-synthesized Pd-PEPPSI
mmol for 6ca)), C6 (0.5 mol% (1 mol% for 6ca)) and KOtBu (3.0 complexes effectively influence the C-N bond formations.
mmol (5.0 mmol for 6ca)) were added at room temperature and Moreover, all these catalysts are new and worthy to replicate
then stirred at 90 oC for 3-4 h in the absence of any inert gases. the catalytic conversion in short reaction time at low loading
After the complete progress of reaction (monitored through (0.5 mol%) under non-inert atmosphere with excellent yields.
TLC), the mixture was cooled to room temperature, added 3 mL Thus, the benzimidazolium Pd-PEPPSI complexes opens new
of water, extracted with ethyl acetate twice (2x5 mL), dried the route of dynamic catalytic system that could be paramount
combined organic over anh. Na2SO4 and distilled-off the solvent importance in constructing several new and vulnerable
under vacuum to get the crude material. This obtained mass biologically active lagoons.
was then purified through gravity column with silica gel (100-
200 mesh) using hexane-ethyl acetate as eluent to obtain the
pure products. 6a-l, 6aa-ae, 6ba-bb, 6ca-cb, 6da-dd (yields: up
Conflicts of interest
to 98%). The identity and purity of the compounds were
confirmed from NMR and HRMS spectroscopic analyses.
There are no conflicts to declare.
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(a) J. -M. Makdissi, J. K. Vandavasi, S. G. Newman, Org. Lett.,
Acknowledgements
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2018, 20, 4094; (b) P. Weber, A. BiaDfoOrIa: ,10A.1.03D9o/Dp0pNiuJ,01H2.94-GJ.
Bongard, H. Kelm, L. Gooben, Org. Process Res. Dev., 2019, 23,
1462-1470.
Council of Scientific and Industrial Research (CSIR), Pusa, New
Delhi, India is highly acknowledged for the financial assistance
(No. 02/(0248)/15/EMR-II) to this work. M. V. K. Reddy thanks
Council of Scientific and Industrial Research (CSIR), Pusa, New
Delhi, India for sanctioning SRF fellowship (Ack. No:
121252/2K17/1). Department of Science and Technology, New
Delhi, India is recognized for financial support to G. Anusha with
10 Q, Deng, Y. Zhang, H. Zhu, T. Tu, Chem. Asian J., 2017, 12,
2364-2368.
11 S. You, R. Xiao, H. Liu, M. Cai, New J. Chem., 2017, 41, 13682-
13870.
12 K. Ofele, J. Organomet. Chem., 1968, 12, 42-43.
13 H. W. Wanzlick, H. J. Schonherr, Angew. Chem. Int. Ed., 1968,
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14 A. J. Arduengo III, R. L. Harlow, M. Kline, J. Am. Chem. Soc.,
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Simler, P. Braunstein, Chem. Rev., 2019, 119, 3730-3961; (d)
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DST-INSPIRE-JRF
fellowship
(No.
DST/INSPIRE
Fellowship/[IF160138].
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Graphical Abstract
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Sterically Enriched Bulky 1,3-Bis(N,N'-Aralkyl)Benzimidazolium based Pd-PEPPSI
Complexes for Buchwald-Hartwig Amination Reactions
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Motakatla Venkata Krishna Reddy, Gokanapalli Anusha and Peddiahgari Vasu Govardhana Reddy*
A simple and efficient synthesis of a series of unexisting Pd-PEPPSI complexes is summarized. These complexes are
exploited for their high catalytic activity towards Buchwald-Hartwig amination reactions without any external ligand or
additive. A great influence is perhaps noticed with the increase in steric bulk of the catalysts.