Well-Defined Palladium N-Heterocyclic Carbene Complexes: Direct C-H Bond Arylation of Heteroarenes

Article abstract of DOI:10.1021/acs.joc.0c02024

A series of palladium N-heterocyclic carbene (NHC) complexes of type trans-{(NHC)PdCl2L} (L = C5H5N, 3-ClC5H4N, and PPh3) (3-5) have been developed as efficient precatalysts for direct C-H bond arylation of various heteroarenes. In particular, an in situ generated new NHC ligand derived from {1,3-di-(2,6-diethylphenyl)acenaphtho[1,2-d] imidazolium} chloride (2) is used for the stabilization of the palladium metal center. Among the screened palladium precatalysts (3-5), the most active PEPPSI themed complex (3) was successfully employed toward direct C-H bond arylation of various heteroarenes and aryl bromides. A range of functional groups on aryl bromides as well as on heteroarenes sustained throughout the standard reaction conditions for easy access of various arylated heterocyclic compounds. Significantly, the utility of the protocol was demonstrated by the effective synthesis of a precursor of raloxifene, a selective estrogen receptor modulator.

Full text of DOI:10.1021/acs.joc.0c02024

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Article
Well-Defined Palladium N‑Heterocyclic Carbene Complexes: Direct
C−H Bond Arylation of Heteroarenes
Anuj Kumar, Manoj Kumar, and Akhilesh K. Verma*
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ABSTRACT: A series of palladium N-heterocyclic carbene
(NHC) complexes of type trans-{(NHC)PdCl2L} (L = C5H5N,
3-ClC5H4N, and PPh3) (3−5) have been developed as efficient
precatalysts for direct C−H bond arylation of various heteroarenes.
In particular, an in situ generated new NHC ligand derived from
{1,3-di-(2,6-diethylphenyl)acenaphtho[1,2-d] imidazolium} chlor-
ide (2) is used for the stabilization of the palladium metal center.
Among the screened palladium precatalysts (3−5), the most active
PEPPSI themed complex (3) was successfully employed toward direct C−H bond arylation of various heteroarenes and aryl
bromides. A range of functional groups on aryl bromides as well as on heteroarenes sustained throughout the standard reaction
conditions for easy access of various arylated heterocyclic compounds. Significantly, the utility of the protocol was demonstrated by
the effective synthesis of a precursor of raloxifene, a selective estrogen receptor modulator.
INTRODUCTION
■
Arylated heteroarenes are constructive units for several
important natural products, pharmaceuticals, and functional
materials.1−3 Primarily, thiophene-,4−6 indole-,7−9 and
furan10−12-derived motifs are present in a variety of drugs
and other bioactive organic molecules. The high utility of these
molecules always demands the development of new alternative
paths to access the arylated heterocycles and became an
exciting area in organic chemistry.13 Recently, the focus has
been shifted toward the development of convenient, efficient,
and time-dominant C−C bond formation methods.14−20 In
this order, direct C−H bond arylation emerged as an
alternative approach over the traditional cross-coupling
reactions as it does not require the preparation of organo-
metallic reagents, which avoid the formation of quantitative
metal waste (Figure 1).21−24
The last few decades were dedicated to ligand designing for
improving the catalytic efficiency of palladium complexes for
direct C−H bond arylation reaction.25−28 Notably, extensive
studies on bulky and electron-rich phosphine ligands have been
carried out over the past few years. In addition, various
phosphine-free nitrogen-based ligands, for example, 1,10-
phenanthroline,29,30 bipyridyl,31−33 bulky diamine,34,35 and
others,36 were used to increase the palladium catalytic
efficiency for this type of conversion. However, the efficacy
of the reported protocols was limited because of high catalytic
loading, very high reaction temperature (up to 150 °C), and
long reaction time.37−39 Therefore, there is a need to design an
efficient and structurally characterized catalytic system, which
can make these reactions more user-friendly.
Figure 1. Pd−NHC-catalyzed cross-coupling reactions.
catalysis.40−48 The great success of these classes of wonder
ligands lies in their easily tunable steric and electronic
properties, which play an essential role in catalysis.49−53 Pd−
NHC complexes were found to be extremely successful
precatalysts for C−C and C−N bond formation via cross-
Received: August 21, 2020
Parallelly, the development of N-heterocyclic carbene
(NHC) ligands achieved an extensive portfolio in chemical
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Scheme 1. Synthesis of Pd−NHC Complexes of Acenaphthoimidazoline-2-ylidene-Derived NHC Ligand
Figure 2. Molecular structures of complexes 3, 4, and 5 showing 50% probability ellipsoids; hydrogen atoms are omitted for clarity. Selected bond
lengths (Å) and angles (°) for 3: Pd1−C1 1.971(3), Pd1−N3 2.106(3), Pd1−Cl1 2.295(1), Pd1−Cl2 2.287(1), C1−Pd1−N3 179.4(3), Cl1−
Pd1−Cl2 178.0(5), and N1−C1−N2 105.5(2). 4: Pd1−C1 1.968(3), Pd1−N3 2.091(3), Pd1−Cl1 2.298(1), Pd1−Cl2 2.301(1), C1−Pd1−N3
175.3(3), Cl1−Pd1−Cl2 176.7(1), and N1−C1−N2 106.1(3). 5: Pd1−C1 2.036(2), Pd1−P1 2.317(1), Pd1−Cl00 2.279(1), Pd1−Cl02 2.296(1),
C1−Pd1−P1 175.3(3), Cl00−Pd1−Cl02 179.6(3), N1−C1−N2 105.8(2).
coupling reactions.54−58 In particular, pyridine-enhanced
precatalyst preparation, stabilization, and initiation (PEP-
PSI)-themed and mixed NHC-/phosphine-derived Pd−NHC
RESULTS AND DISCUSSION
■
The imidazolium NHC ligand precursor (2) has been prepared
from N,N′-(acenaphthylene-1,2-diylidene)bis(2,6-diethylani-
line) using a modified literature procedure.74 Ganter et al.
complexes have emerged as highly active precatalysts in terms
1
of their low catalyst loading and broad applications.55,56,59
described that the heteronuclear J(C−H) coupling constant
in azolium salts could provide an estimate on the σ-donor
property of the corresponding NHCs.75 Recently, Szostak and
co-workers also extended this method for various commonly
used azolium salts and ranked the σ-donor efficiency of the
respective NHCs.76 A larger coupling constant would indicate
a lower σ-donor strength of the parent NHCs because of the
63−66
Seminal reports by Shao et al.,60−62 Ozdemir et al.,
and
̈
others67,68 represent the high catalytic efficiency of
[PdX2(NHC)(imidazole)], [PdX2[(NHC)2], and trans-
[PdX2(NHC)(pyridine)] type palladium complexes in C−H
bond arylation of various heteroarenes. Recently, we explored
the C−H bond amination of arenes69−71 and are further
interested to explore the scope of NHCs in direct C−H bond
arylation of heteroarenes.10,72,73 In the present study, we chose
to explore the potential of Pd−NHC complexes in more
challenging and competitively less studied direct C−H bond
arylating C−C bond formation reactions. In this article, we
have reported a series of Pd−NHC complexes (3−5) based on
a bis(imino)acenaphthene-derived new NHC ligand. The
scope of various heteroarenes is explored with the most
efficient catalyst 3 and 4-bromobenzonitrile as an arylating
substrate.
1
increased s-orbital character of the C−H bond. The J(C−H)
coupling constant for salt 2 (227.28 Hz) was obtained from
13C satellites of the acidic C2−H proton observed in 1H NMR
spectra. This value was found to be larger than that of IPr·HCl
(223.70 Hz) and IMes·HCl (225.20 Hz).76 It indicates toward
less σ-donor ability of novel carbene ligand as compared to the
famous IPr and IMes NHC ligands. Two PEPPSI-themed
palladium complexes (3) and (4) were obtained by the
reaction of imidazolium ligand precursor (2) in the presence of
PdCl2, K2CO3 as a base and pyridine or 3-chloropyridine as a
solvent, respectively (Scheme 1). Finally, the mixed NHC/
phosphine Pd−NHC complex (5) was synthesized by
replacing the labile pyridine ligand of the complex (3) with
B
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a
Table 1. Optimization of Reaction Conditions
b
s. no.
Cat. (mol %)
time (h)
temp (°C)
solvent
base
conv.
71
NR
NR
1
2
3
4
5
6
7
8
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
1.0
1.0
2.5
1.0
18
18
18
18
18
18
18
18
24
3
18
2
2
2
2
130
130
130
130
130
130
130
130
130
130
90
130
130
130
130
130
130
130
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMF
NaOAc
AgOAc
NH4OAc
KtBuO
Cs2CO3
K3PO4
Na2CO3
K2CO3
K2CO3
KOAc
K2CO3
KOAc
KOAc
KOAc
KOAc
d
NP
NP
NP
51
d
d
100
100
100
29
9
10
11
12
13
14
15
16
17
18
c
100/89
NR
71
1.0
1.0
1.0
1.0
1.0
DMSO
toluene
DME
29
NR
13
2
2
2
KOAc
KOAc
KOAc
dioxane
5
a
Reaction conditions: 2-methyl thiophene 6a (0.6 mmol, 2 equiv), 4-bromobenzonitrile 7a (0.3 mmol, 1 equiv), base (0.9 mmol, 3 equiv), and
b
c
d
Pd−NHC 5 (x mol %) heated at t °C in a screw cap sealed tube under nitrogen atmosphere. Conversion by GC. Isolated yield. Undefined
product observed.
a
Table 2. Screening of Pd−NHC Complexes
b
c
s. no.
Pd−NHC
(3)
(4)
(5)
(5)
catalyst (mol %)
time (h)
conversion /yield
1
2
3
4
5
6
7
8
1
1
1
1
0.5
0.5
0.5
0.5
1
1
1
2
2
2
2
2
100/92
100/91
84/-
100/89
100/90
74/60
61/-
(3)
(4)
Pd-PEPPSI-IPr
d
Pd(OAc)2
60/-
a
Reaction conditions: 2-methyl thiophene 6a (0.6 mmol, 2 equiv), 4-bromobenzonitrile 7a (0.3 mmol, 1 equiv), KOAc (0.9 mmol, 3 equiv), and
Pd−NHC (0.003 mmol, 1 mol % or 0.0015, 0.5 mol % mmol) heated at 130 °C in a screw cap sealed tube under nitrogen atmosphere.
b
c
d
Conversion by GC. Yield isolated yield, DMAc = N,N-dimethylacetamide. Reaction conditions (6a = 1.2 mmol, 7a = 0.6 mmol, and KOAc =
1.8 mmol).
PPh3 at room temperature. All the three palladium complexes
(3−5) were structurally characterized by X-ray diffraction
studies (Figure 2 and Table S2). As expected, Pd−NHC
complexes (3−5) having a square-planar geometry around the
central palladium atom and two chloride ligands occupied the
remaining positions (Scheme 1).
The catalytic efficiency of Pd−NHC complexes (3−5) was
examined in the catalytic C−H arylation of 2−methyl
thiophene (6a). Significantly, all the three Pd−NHC
complexes (3−5) were found to be active precatalysts for
the C−H arylation reaction of 2-methyl thiophene (6a) and 4-
bromobenzonitrile (7a) at 130 °C under standard reaction
conditions. The mixed NHC/phosphine complex (5) has been
chosen for optimization studies and the reaction progress was
analyzed by gas chromatography−mass spectrometry (GC-
GCMS).
The reaction of 2−methyl thiophene (6a) and 4-
bromobenzonitrile (7a) yielded 71% conversion of 7a by
using 3.0 equiv of NaOAc as a base and 2.5 mol % catalyst 5 at
130 °C temperature in 18 h (Table 1, entry 1). No conversion
was observed while using AgOAc or NH4OAc (Table 1, entries
2 and 3), and the undefined product was formed by using
KtBuO, Cs2CO3, and K3PO4 as a base under similar reaction
conditions (Table 1, entries 4−6). In the presence of Na2CO3,
the catalyst was found to be moderately active with 51%
conversion (Table 1, entry 7). The complete conversion of 4-
bromobenzonitrile (7a) was achieved by using K2CO3 as a
base in the presence of 2.5 mol % precatalyst (5) in 18 h
(Table 1, entry 8). However, on reducing the catalyst loading
C
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from 2.5 mol % to 1 mol %, the reaction time was increased up
to 24 h for achieving the complete conversion (Table 1, entry
9). Last, KOAc was found to be the most suitable base for the
catalytic C−H arylation reaction of 6a and 7a at 130 °C
temperature (Table 1, entries 10 and 11). The precatalyst 5
was efficient enough to complete the reaction within 2 h in the
presence of KOAc and afforded the isolated product in 89%
yield (Table 1, entry 12). There was no reaction in the absence
of a catalyst (Table 1, entry 13), and solvents other than
DMAc were not suitable for the given transformations (Table
1, entries 14−18).
After having the optimized reaction condition in hand, we
have performed the screening of synthesized Pd−NHC
complexes for this reaction. PEPPSI-themed catalysts 3 and
4 were found to be more active under standard reaction
conditions and yielded the complete conversion of 7a in 1 h
while loading 1 mol % catalyst (Table 2, entries 1−2). Catalyst
5 was found to be comparatively less efficient, which yielded
only 84% conversion in 1 h and takes 2 h for completing the
reaction (Table 2, entries 3−4). The most active catalyst (3)
completes the reaction within 2 h, using 0.5 mol % catalyst
loading (Table 2, entry 5). However, under this catalyst
loading, catalyst 4 was unable to complete the reaction (Table
2, entry 6). Pd-PEPPSI-IPr was much less efficient than
catalyst 3 under the identical reaction conditions and yielded
61% product conversion (Table 2, entry 7). Probably, the
introduction of bulky acenaphthyl backbone in 3−5 would
facilitate the stabilization of catalytically active Pd(0) species as
compared to less-hindered Pd-PEPPSI-IPr, which has hydro-
gen atoms on the backbone.67,77 Pd(OAc)2 was also found
catalytically less efficient under the given reaction conditions
and afforded only 60% product as calculated by GC-GCMS
(Table 2, entry 8). The superior activity of two PEPPSI-
themed Pd−NHC complexes 3 and 4 makes us interested in
comparing the reaction kinetics under low catalyst loading
conditions (Figures 3 and 4).
Figure 4. Reaction progress of 2-methyl thiophene and para (8aa)-,
meta (8ab)-, and ortho (8ac)-substituted bromobenzonitrile by 0.1%
catalyst loading of PEPPSI-themed complex (3).
electronic and steric influences of the CN group in the
arylating substrate 7 was observed by conducting the reaction
of 2-methyl thiophene (6a) with differently −CN-substituted
bromobenzene as 4-bromobenzonitrile (7a), 3-bromobenzoni-
trile (7b), and 2-bromobenzonitrile (7c) with 0.1 mol %
loading of the most active catalyst 3 under the standard
reaction conditions (Figure 4). The electron-withdrawing CN
group increases the reactivity of ortho- and para-substituted
bromobenzene because of the −R effect. However, 2-
bromobenzonitrile (7c) was found marginally slower reactive
and can be explained by the steric fact. 3-Bromobenzonitrile
(7b) was found to be least reactive and unable to give
complete conversion even after 8 h under 0.1% catalyst
loading.
As shown in Figure 3, catalyst 3 was found to be the most
active precatalyst, which can give a 100% conversion with 0.5%
catalyst loading in 2 h. The reaction time increases up to 4 h,
with 0.1 mol % catalyst loading, while catalyst 4 was found
comparatively less efficient under these observations. The
In the view of time-efficient reaction conditions, the
substrate scope of various aryl bromides was explored with
0.5 mol % catalyst loading and using 2-methyl thiophene (6a)
as a heteroarene under standard reaction conditions. Activated
aryl bromides, containing −CN and −CHO groups at ortho
and para positions 7a, 7c, and 7g, were more active and
provide respective products in good yields (Scheme 2, 8aa,
8ac, and 8ag) within 2−3 h. −OMe and −NHCOCH3 groups
at para position, that is, 7e and 7h, decreased the reactivity of
aryl bromides and the reaction time increased up to 6−12 h.
The products (8ae and 8ah) were obtained in 81 and 60%
yields, respectively, while using 1 mol % catalyst. −OMe at
meta position 7d was comparatively active and produced 78%
yield in 4 h (8ad). Bromobenzene 7f and para phenyl
bromobenzene 7i afforded the respective products (8ai and
8af) in 69 and 77% yields, respectively, in 6 h. We did not get
product using chlorobenzene as the arylating reagent under
reaction conditions, while iodobenzene yielded only 52% yield
of product 8af, and GC-GCMS indicated the formation of
homocoupled biphenyl as a side product. 6-Bromo-1-methyl-
1H-indazole 7j and 7-bromo-4-chloroquinoline 7k reacted
slowly and afforded the desired products (8aj and 8ak) in 12 h.
Finally, 5-bromo-1-methyl-1H-indole 7l was also found to be
suitable and afforded 29% yield of product in 12 h by using 1
mol % of most active catalyst 3.
Figure 3. Comparison of the reaction progress of 2-methyl thiophene
6a and 4-bromobenzonitrile 7a by 0.1 and 0.5% catalyst loading of
PEPPSI-themed complexes (3) and (4).
The substrate scope for heteroarenes was elaborated with 4-
bromobenzonitrile (7a) as an arylating precursor under
D
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a
Scheme 2. Scope of Haloarenes for C−H Arylation Reaction of 2−Methyl Thiophene
a
Reaction conditions: 2-methyl thiophene 6a (1.0 mmol, 2 equiv), aryl bromides (aryl halide for entry 8af) (0.5 mmol, 1 equiv), KOAc (3 mmol, 3
equiv), and Pd−NHC (0.0025, 0.5 mol % mmol) heated at 130 °C in a screw cap sealed tube under nitrogen atmosphere, d0.005 mmol, 1 mol %
Pd−NHC, yield = isolated yield, and GC conversion.
e
a
Scheme 3. Scope of Heteroarenes for C−H Arylation Reaction
a
Reaction conditions: heteroarene (1.0 mmol, 2 equiv), aryl bromide 7a (0.5 mmol, 1 equiv), KOAc (3 mmol, 3 equiv), and Pd−NHC (0.0025
mmol, 0.5 mol % mmol) heated at 130 °C in a screw cap sealed tube under nitrogen atmosphere, d0.005 mmol, 1 mol % Pd−NHC, yield = isolated
yield, GC conversion. DMAc = N,N-dimethylacetamide, and reaction time not optimized.
e
optimized reaction conditions. Significantly, various thio-
phene-, pyrrole-, indole-, and furan-derived heteroarenes are
suitable under standard reaction conditions and afforded the
corresponding products in moderate to good yield (Scheme 3).
E
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In particular, thiophene-derived heteroarenes such as 2-acetyl
thiophene 6b, benzo[b]thiophene 6c, 3-bromobenzo[b]-
thiophene 6d, 6-methoxybenzo[b]thiophene 6e, 4-
methoxybenzo[b]thiophene 6f, and even more satirically
hindered 3-(3,4,5-trimethoxyphenyl)benzo[b]thiophene 6g
efficiently react to afford the respective products (9ba−9ga)
in good yields (72−85%).
arylating agent, and the strategy is applicable for various
heteroarenes. In particular, 2-methylthiophene 6a and 1-
methylpyrrole 6p reacted with 1,3- and 1,4-dibromobenzene
7m and 7n to afford desired products in good yield by using 1
mol % of catalyst 3 and under optimized reaction conditions
(Scheme 5).
Additionally, we have extended our synthetic methodology
for catalytic double C−H arylation of unsubstituted furan 6t
and 1-methylpyrrole 6p. Significantly, C−H-activated arylation
observed selectively at C2 and C5 positions (Scheme 6). 4-
Bromobenzonitrile (7a) reacted with respective heteroarenes
to provide corresponding bis-arylated products 12 a−b in
moderate yield (55−79%). Notably, we obtained dominant or
exclusively α-arylated products during arylation of a library of
heteroarenes, which indicate that the catalytic cycle followed
the concerted metalation−deprotonation mechanism.27,78
The competitive experiment studies may provide a deep
understanding of heteroarene reactivity. The results are
summarized in Scheme 7. 2-Methyl thiophene 6a was found
to be more reactive toward the C−H arylation reaction with 4-
bromobenzonitrile 7a as compared to the 2-acetyl thiophene
6b (Scheme 7a) and 1,3-dimethylindole 6i (Scheme 7b). 1,3-
Dimethylindole 6i has shown far better reactivity as compared
to 3-methylindole 6h (Scheme 7c). 1,3-Dimethylindole 6i and
1,2-dimethylindole 6m reacted similarly, and an equal amount
of C3- and C2-activated product was observed by GC (Scheme
7d).
Last, we demonstrated the application of catalyst 3 in the
synthesis of 6-methoxy-2-(4-methoxyphenyl)benzo[b]-
thiophene (13), which is a key intermediate for the total
synthesis of bioactive raloxifene79 and known as a selective
estrogen receptor modulator (Scheme 8). 6-Methoxybenzo-
[b]thiophene 6e reacted with 1-bromo-4-methoxybenzene 7e
with 1 mol % of catalyst to afford 67% of the desired
compound (13) under standard reaction conditions. Similarly,
the practical utility of the method as a synthetic tool is
highlighted by the gram-scale synthesis of compound 8aa in
good (85%) yield. A comparison of precatalyst 3 has been
made with some literature-reported precatalysts which are
utilized for C−H arylation reaction of heteroarenes (Support-
ing Information Table S1). However, a fair comparison is not
possible because of using different reaction conditions,
arylating substrates, and temperature in various reports.
Nevertheless, it resulted that precatalyst 3 afforded the arylated
heteroarenes in a time-efficient way, without the requirement
of any external additive, and with a decent catalyst loading.
After the successful implementation of our Pd−NHC
catalyst on thiophene-derived heteroarenes, we became
interested in another important class of heterocycles, that is,
indoles, which are also important building blocks of various
important biologically active organic molecules. Many
substituted indoles, for example, 3-methylindole 6h, 1,3-
dimethylindole 6i, 1-methylindole 6j, 5-bromo-1-methylindole
7l, 5-chloro-1-methylindole 6l, and 2-(3-methyl-1H-indol-1-
yl)benzonitrile 6n have been examined toward the C−H
arylation reaction catalyzed by Pd−NHC complex 3. 1,3-
Dimethylindole 6i yielded 88% product (9ia) under optimized
reaction conditions while 3-methylindole 6h afforded 62%
product (9ha) yield even after 1 mol % of catalyst loading. 1-
Methylindole 6j yielded two products corresponding to C2−H
and C3−H activation and found more selective for C2−H
activation, as products were obtained in 60:40 ratio,
respectively (9′ja & 9″ja). It is noteworthy that 5-bromo-1-
methylindole 7l and 5-chloro-1-methylindole 6l afforded
predominantly C2−H-activated products (9ka and 9la) in
69% and 71% yield, respectively. However, a less amount of
C3−H-activated product can be identified by GC-GCMS. 2-
(3-methyl-1H-indol-1-yl)benzonitrile 6n yielded the corre-
sponding products in 65% (9na) and 1-acetylindole 6o
remained unreacted in the standard reaction condition (9oa).
We have also extended the application of our Pd−NHC
catalyst toward C−H activation of pyrroles. 1-Methylpyrrole
6p and 2-(1H-pyrrol-1-yl) aniline 6n were reacted well with 4-
bromobenzonitrile (7a) to afford the corresponding arylated
product (9pa and 9qa) in good yields. 2-Acetyl furan yielded
the respective C−H arylated product (9ra) in moderate yield.
Quite interestingly, benzo[b]furan reacted to afford the
predominantly double C−H-activated product 9sa in 79%
yield. 3-Bromobenzo[b]thiophene also behaved as a hetero-
arylating agent and afforded a self hetero-arylated product,
namely, 3-bromo-2,3′-bibenzo[b]thiophene (10) in 52% yield
(Scheme 4).
Scheme 4. Self-Heteroarylation by C−H Activation of 3-
Bromobenzo[b]thiophene
CONCLUSIONS
■
The new structurally characterized Pd−NHC complexes (3−
5) are active precatalysts for the C−H arylation of 2-methyl
thiophene by using 4-bromobenzonitrile under optimized
reaction conditions. PEPPSI-themed Pd−NHC complex (3)
and (4) were found to be a better precatalyst than mixed
Furthermore, the bis(hetero)benzene 11(a−d) type organic
framework was constructed using dibromo benzene as an
Scheme 5. Synthesis of Bis(hetero)benzene-Type Framework by Using Dibromo Benzene
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Scheme 6. C2 and C5 Activation of Heteroarenes
Scheme 7. Competitive Experiment Studies
Scheme 8. Synthesis of Intermediate Compound (13) by Direct C−H Arylation Reaction
resonance of the solvent. Data are reported as follows: chemical
shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, and dd = doublet of doublet), coupling constants in Hertz,
and integration. The Pd-PEPPSI-IPr complex was prepared by the
literature-reported procedure.80 High-resolution mass spectra were
recorded on a q-TOF electrospray mass spectrometer. X-ray
diffraction data for compounds 3, 4, and 5 were collected on an
Oxford Diffraction XCALIBUR diffractometer using graphite-
monochromatic Mo Kα radiation (λ = 0.71073 Å). Crystal data
collection and refinement parameters are summarized in Table S2.
The structures were solved by direct methods using SHELXS-97and
refined with SHELXL-2014 using Olex2. The non-hydrogen atoms
were refined anisotropically, whereas the hydrogen atoms were fixed
at the calculated positions with isotropic thermal parameters. TLC
analysis was performed on commercially prepared 60 F254 silica gel
plates and visualized by either UV irradiation or by staining with I2.
All purchased chemicals were used as received. Aromatic carbon
signals were assigned as (Ar−C) in the 13C{1H}NMR spectrum of
respective compounds. The preheated oil bath has been used as a
heating source for the reactions performed at higher than room
temperature.
NHC/phosphine complex (5), which again shows the
superiority of these classes of NHC-derived, easily prepared,
and demanding precatalysts. The aryl bromides were found to
be a better choice of the arylating agent as compared to aryl
iodides and aryl chlorides. The substrate scope of aryl bromide
and heteroarenes elaborated with the most active precatalyst
complex (3), which concluded that the reaction conditions
sustain with various substituents on both the reactants.
Competitive experimental studies suggest that the reactivity
of heteroarenes follows the order thiophene > N-methylated
indole > 1H indole in standard reaction conditions. Catalyst
(3) was used to obtain an organic intermediate (13), which is a
building block for a selective estrogen receptor modulator
known as raloxifene. This is projecting its potential in the
application for synthesis of natural products and other
biologically active molecules, where the C−C bond formation
reaction can be achieved in reduced steps and less metal waste
manner by the C−H arylation reaction. Overall, the study
keeps the NHC promise to behave as an efficient ligand in the
world of chemical catalysis.
Synthesis of N,N′-(Acenaphthylene-1,2-diylidene)bis(2,6-diethy-
laniline) (1). Acenaphthenequinone (6.00 g, 33.0 mmol), 2,6-
diethylaniline (10.3 g, 69.2 mmol), and ZnCl2 (4.50 g, 33.0 mmol)
were suspended in glacial acetic acid (ca. 100 mL). The mixture was
refluxed for 2 h and then cooled to room temperature, during which a
red-colored precipitate was observed. The precipitate was filtered and
washed with water, followed by diethyl ether. The precipitate was
dried under vacuum and further suspended in dichloromethane (ca.
EXPERIMENTAL SECTION
■
1
General Information and Method. H NMR (400 MHz) and
13C{1H}NMR (100 MHz) spectra were recorded in CDCl3 and
(CD3)2SO. Chemical shifts for protons and carbons are reported in
ppm from tetramethylsilane and are referenced to the carbon
G
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300 mL). A solution of potassium oxalate (12.1 g, 66.0 mmol) in 30
mL of H2O was added to the suspension and stirred vigorously for 45
min. A white precipitate of zinc oxalate was observed in the aqueous
phase during this period. The organic layer was separated, washed
with water (ca. 3 × 40 mL), and dried over anhydrous sodium sulfate.
Finely, the organic layer was filtered and vacuum-dried to afford the
7.53 (m, 1H, C5H4Cl), 7.43 (d, 4H, 3JHH = 8 Hz, C10H13), 7.41−7.37
3
(m 2H, C12H6), 7.09−7.05 (m, 1H, C5H4Cl), 6.96 (d, 2H, JHH = 8
Hz, C12H6), 3.08−2.98 (m, 4H, CH2CH3 of C10H13), 2.84−2.73 (m,
3
4H, CH2CH3 of C10H13), 1.15 (t, 12H, JHH = 8 Hz, CH2CH3 of
C10H13), 13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ 158.8 (Pd−
NCN), 151.5, 142.1, 139.5, 137.4, 135.3, 130.1, 128.0, 127.6, 126.3,
123.9, 121.0 (Ar−C), 24.8 (CH2CH3), 14.2. Anal. Calcd for
C38H36Cl3N3Pd: C, 61.06; H, 4.85; N, 5.62. Found: C, 60.59; H,
4.58; N, 5.76%.
1
product as an orange solid (12.4 g, 85%). H NMR (CDCl3, 400
MHz, 25 °C): δ 7.88 (d, 2H, 3JHH = 8 Hz, C12H6), 7.37 (t, 2H, 3JHH
=
8 Hz, C10H13), 7.22−7.15 (m, 6H, C12H6 & C10H13), 6.68 (d, 2H,
3JHH = 8 Hz, C12H6), 2.81−2.54 (m, 4H, CH2CH3 of C10H13), 2.50−
Synthesis of [{1,3-Bis(2,6-diethylaniline)acenaphthylenyl-4,5-
imidazolium-2-ylidene}PdCl2-(PPh3)] (5). A mixture of palladium
complex (3) (0.100 g, 0.140 mmol) and PPh3 (0.036 g, 0.140 mmol)
was stirred in CH2Cl2 (ca. 20 mL) at room temperature for 3 h. The
solvent was removed under vacuum to afford the crude product as a
yellow solid. The crude product was recrystallized from CH3CN to
afford the product as a yellow solid (0.112 g, 89%). Single crystals
were obtained by slow evaporation of concentrated acetonitrile
3
2.42 (m, 4H, CH2CH3 of C10H13), 1.11 (t, 12H, JHH = 8 Hz,
CH2CH3 of C10H13), 13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ
160.7 (CN), 148.5, 140.6, 131.0, 130.7, 129.6, 128.8, 128.1, 126.4,
123.9, 122.9 (Ar−C), 24.7 (CH2CH3), 13.9 (CH2CH3). HRMS (ESI-
TOF) m/z: [M + H]+ calcd for [C32H33N2], 445.2662; found,
445.2599. (Unable to get satisfactory CHN results after multiple
attempts.)
solutions. 1H NMR (CDCl3, 400 MHz, 25 °C): δ 7.73 (d, 2H, JHH
=
Synthesis of 1,3-Bis(2,6-diethylaniline)acenaphthylenyl-4,5-imi-
dazolium Chloride (2). N,N′-(Acenaphthylene-1,2-diylidene)bis(2,6-
diethylaniline) (1) (0.800 g, 1.80 mmol) and chloromethyl ethyl ether
(ca. 5 mL) were added to a thick-walled sealed tube and then the
reaction mixture was allowed to stir overnight at 90 °C. A brown-
colored suspension was separated from a clear red solution during this
period. The reaction mixture was cooled to ambient temperature and
diethyl ether (ca. 20 mL) was added into it. After that, the resulting
yellow precipitate was filtered off, washed with diethyl ether (ca. 60
mL), and dried under vacuum to afford a yellow solid (0.731 g, 82%).
1H NMR (CDCl3, 400 MHz, 25 °C): δ 11.9 (s, 1H, NCHN), 8.01 (d,
8 Hz, C12H6), 7.61 (t, 2H, 3JHH = 8 Hz, C10H13), 7.42 (d, 4H, 3JHH = 8
Hz, C10H13), 7.41−7.20 (m 17H, C12H6 & C18H15P), 6.99 (d, 2H,
3JHH = 8 Hz, C12H6), 3.03−2.92 (m, 4H, CH2CH3 of C10H13), 2.88−
3
2.79 (m, 4H, CH2CH3 of C10H13), 1.09 (t, 12H, JHH = 8 Hz,
CH2CH3 of C10H13), 13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ
176.5 (Pd−NCN), 142.1, 139.0, 138.9, 135.5, 135.0, 134.9, 130.7,
130.2, 129.7, 129.6, 129.6, 127.8, 127.7, 127.6, 126.1, 126.0, 120.9
(Ar−C), 24.7 (CH2CH3), 14.0 (CH2CH3). Anal. Calcd for
C51H47Cl2N2PPd: C, 68.35; H, 5.29; N, 3.13. Found: C, 67.87; H,
5.22; N, 3.20%.
2H, 3JHH = 8 Hz, C12H6), 7.63−7.56 (m, 4H, C12H6 & C10H13), 7.42
General Procedure for Reaction Optimization, Catalyst
Screening, and Kinetic Studies. 2-methyl thiophene 6a (0.6
mmol, 2 equiv), bromobenzonitrile 7a (or 7b or 7c) (0.3 mmol, 1
equiv), base (0.9 mmol, 3 equiv), and Pd−NHC (x mol %) were
transferred to a screw cap sealed tube under nitrogen atmosphere.
The solvent (ca. 2 mL) was added and the sealed tube was heated at
130 °C for the respective time. The reaction mixture was cooled to
ambient temperature and an aliquot was taken out with the help of a
micropipette under the nitrogen atmosphere. The aliquot was diluted
with ethyl acetate and analyzed by GC-GCMS.
General Procedure for Schemes 2 and 3. Heteroarene (1.0
mmol, 2 equiv), aryl halide (0.5 mmol, 1 equiv), base (3 mmol, 3
equiv), and Pd−NHC (3) (0.5−1.0 mol %) were transferred to the
screw cap sealed tube under nitrogen atmosphere. DMAc (ca. 3 mL)
was added via a syringe, and the sealed tube was heated at 130 °C for
the respective time. The reaction mixture was cooled to ambient
temperature, diluted with ethyl acetate (ca. 60 mL), and then washed
with water (ca. 3 × 15 mL). The organic layer was separated, dried
over Na2SO4, and finally vacuum-dried to afford the crude product.
The crude product was purified by column chromatography using
hexane/EtOAc.
General Procedure for Scheme 5. Heteroarene (1.5 mmol, 3
equiv), dibromobenzene (0.5 mmol, 1 equiv), base (4.0 mmol, 4
equiv), and Pd−NHC (3) (1.0 mol %) were transferred to the screw
cap sealed tube under nitrogen atmosphere. DMAc (ca. 3 mL) was
added via a syringe and the sealed tube was at 130 °C for 12 h.
General Procedure for Scheme 6. Heteroarene (0.5 mmol, 1
equiv), dibromobenzene (1.25 mmol, 2.5 equiv), base (3.0 mmol, 3
equiv), and Pd−NHC (3) (1.0 mol %) were transferred to the screw
cap sealed tube under nitrogen atmosphere. DMAc (ca. 3 mL) was
added via a syringe and the sealed tube was heated at 130 °C for 12 h.
General Procedure for Competitive Experiment Studies.
Heteroarenes (0.6 mmol each), 4-bromobenzonitrile 7a (0.3 mmol, 1
equiv), base (1.2 mmol, 4 equiv), and Pd−NHC (x mol %) were
transferred to the screw cap sealed tube under nitrogen atmosphere.
DMAc (ca. 2 mL) was added and the sealed tube was heated at 130
°C for the respective time. The reaction mixture was cooled to
ambient temperature and an aliquot was taken out with the help of a
micropipette under nitrogen atmosphere. The aliquot was diluted
with ethyl acetate and analyzed by GC-GCMS.
3
3
(d, 4H, JHH = 8 Hz, C10H13), 7.24 (d, 2H, JHH = 8 Hz, C12H6),
3
2.74−2.57 (m, 8H, CH2CH3 of C10H13), 1.19 (t, 12H, JHH = 8 Hz,
CH2CH3 of C10H13), 13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ
141.8 (NCHN), 140.1, 137.1, 131.8, 130.9, 130.5, 130.4, 129.9, 128.2,
127.7, 123.1, 123.0 (Ar−C), 24.5 (CH2CH3), 14.5 (CH2CH3).
HRMS (ESI-TOF): 457.2632 [M − Cl]+ calcd for [C33H33N2],
457.2638; found, 457.2632. Anal. Calcd for C33H33ClN2·2H2O: C,
74.91; H, 7.05; N, 5.29. Found: C, 75.28; H, 6.32; N, 5.90%.
Synthesis of [{1,3-Bis(2,6-diethylaniline)acenaphthylenyl-4,5-
imidazolium-2-ylidene}PdCl2-(pyridine)] (3). A mixture of NHC·
HCl (2) (0.200 g, 0.406 mmol), PdCl2 (0.072 g, 0.406 mmol), and
K2CO3 (0.224 g, 1.62 mmol) was refluxed in pyridine (ca. 5 mL) for
16 h. Then, the reaction mixture was cooled to room temperature,
diluted with ethyl acetate (ca. 150 mL), and then washed with an
aqueous CuSO4 solution (ca. 3 × 70 mL) and water (ca. 70 mL). The
organic layer was separated, dried over Na2SO4, and finally vacuum-
dried to afford the product as a yellow solid (0.215 g, 74%). Single
crystals were obtained by slow evaporation of concentrated
acetonitrile solutions. 1H NMR (CDCl3, 400 MHz, 25 °C): δ
8.52−8.49 (m, 2H, C5H5), 7.75 (d, 2H, JHH = 8 Hz, C12H6), 7.58 (t,
3
2H, JHH = 8 Hz, C10H13), 7.57−7.53 (m, 1H, C5H5), 7.42 (d, 4H,
3JHH = 8 Hz, C10H13), 7.41−7.37 (m 2H, C12H6), 7.10 (d, 2H, 3JHH
=
3
7 Hz, C5H5), 6.96 (d, 2H, JHH = 8 Hz, C12H6), 3.09−2.99 (m, 4H,
CH2CH3 of C10H13), 2.85−2.75 (m, 4H, CH2CH3 of C10H13), 1.15 (t,
12H, 3JHH = 8 Hz, CH2CH3 of C10H13), 13C{1H} NMR (CDCl3, 100
MHz, 25 °C): δ 158.8 (Pd−NCN), 151.5, 142.0, 139.2, 137.4, 135.1,
130.1, 128.0, 127.6, 126.3, 125.8, 123.9, 121.0 (Ar−C), 24.8
(CH2CH3), 14.2 (CH2CH3). Anal. Calcd for C38H37Cl2N3Pd: C,
64.01; H, 5.23; N, 5.89. Found: C, 63.84; H, 5.06; N, 6.15%.
Synthesis of [{1,3-Bis(2,6-diethylaniline)acenaphthylenyl-4,5-
imidazolium-2-ylidene}PdCl2-(3-chloropyridine)] (4). A mixture of
NHC·HCl (2) (0.300 g, 0.610 mmol), PdCl2 (0.108 g, 0.610 mmol),
and K2CO3 (0.338 g, 2.45 mmol) was stirred at 90 °C in 3-
chloropyridine (ca. 3 mL) for 24 h. After that, 3-chloropyridine was
removed by vacuum distillation to afford a crude product as a brown
solid. The crude product was purified by column chromatography
using petroleum ether/EtOAc (90:10 v/v) to afford a yellow solid
(0.257 g, 56%). Single crystals were obtained by slow evaporation of
1
concentrated acetonitrile solutions. H NMR (CDCl3, 400 MHz, 25
°C): δ 8.57 (s, 1H, C5H4Cl), 8.47 (d, 1H, JHH = 5 Hz, C5H4Cl), 7.75
4-(5-Methylthiophen-2-yl)benzonitrile (8aa). The crude product
was purified by column chromatography (hexane/EtOAc = 98/02) to
(d, 2H, JHH = 8 Hz, C12H6), 7.58 (t, 2H, 3JHH = 8 Hz, C10H13), 7.57−
H
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1
afford 8aa as a white solid (90 mg, 90%), H NMR (CDCl3, 400
N-(4-(5-Methylthiophen-2yl)phenyl)acetamide (8ah). The crude
product was purified by column chromatography (hexane/EtOAc =
85/15) to afford 8ah as a white solid (69 mg, 60%), 1H NMR
(CDCl3, 400 MHz, 25 °C): δ 7.86 (br, 1H, NHCOCH3), 7.41−7.35
3
MHz, 25 °C): δ 7.61 (br, 4H, C6H4), 7.22 (d, 1H, JHH = 4 Hz,
3
C5H5S), 6.77 (d, 1H, JHH = 4 Hz, C5H5S), 2.53 (s, 3H, CH3 of
C5H5S), 13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ 142.2, 139.6,
138.9, 132.6, 126.8, 125.5, 125.1 (Ar−C), 118.9 (CN), 109.9 (Ar−
C), 15.5 (CH3). HRMS (ESI-TOF): [M + H]+ calcd for [C12H10NS],
200.0528; found, 200.0516.
3
(m, 4H, 3JHH C6H4), 6.94 (d, 1H, JHH = 4 Hz, C5H5S), 6.61 (d, 1H,
3JHH = 4 Hz, C5H5S), 2.40 (s, 3H, CH3 of C5H5S), 2.07 (s, 3H,
NHCOCH3),13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ 168.7
(COCH3), 141.3, 139.1, 136.8, 131.8, 130.8, 126.1, 125.8, 122.4,
120.3 (Ar−C), 24.4 (CH3)., 15.4 (CH3). HRMS (ESI-TOF): [M +
H]+ calcd for [C13H13NOS], 232.0791; found, 232.0778.
3-(5-Methylthiophen-2-yl)benzonitrile (8ab). The crude product
was purified by column chromatography (hexane/EtOAc = 98/02) to
1
afford 8ab as a white solid (88 mg, 88%), H NMR (CDCl3, 400
MHz, 25 °C): δ 7.77 (s, 1H, C6H4), 7.77 (d, 1H, 3JHH = 8 Hz, C6H4),
2-([1,1′-Biphenyl]-4-yl)-5-methylthiophene (8ai). The crude
product was purified by column chromatography (hexane/EtOAc =
95/05) to afford 8ai as a white solid (96 mg, 77%), 1H NMR (CDCl3,
400 MHz, 25 °C): δ 7.72−7.66 (m, 6H, C6H4 & C6H5), 7.53 (t, 1H,
3
3
7.47 (d, 1H, JHH = 8 Hz, C6H4), 7.41 (t, 1H, JHH = 8 Hz, C6H4),
7.13 (d, 1H, 3JHH = 4 Hz, C5H5S), 6.73 (d, 1H, 3JHH = 4 Hz, C5H5S),
2.50 (s, 3H, CH3 of C5H5S), 13C{1H} NMR (CDCl3, 100 MHz, 25
°C): δ 141.2, 139.0, 135.8, 130.0, 1129.5, 129.4, 128.5, 126.5, 124.3
(Ar−C), 118.6 (CN), 112.9 (Ar−C), 15.4 (CH3). HRMS (ESI-
TOF): [M + H]+ calcd for [C12H10NS], 200.0528; found, 200.0516.
2-(5-Methylthiophen-2-yl)benzonitrile (8ac). The crude product
was purified by column chromatography (hexane/EtOAc = 98/02) to
3
3JHH = 8 Hz, C6H5), 7.43 (t, 1H, JHH = 8 Hz, C6H5), 7.23 (d, 1H,
3JHH = 4 Hz, C5H5S), 6.84−6.82 (m, 1H, C5H5S), 2.60 (s, 3H, CH3 of
C5H5S), 13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ 141.5, 140.5,
139.7, 139.6, 133.7, 128.8, 127.4, 127.3, 126.8, 126.3, 125.8, 122.9
(Ar−C), 15.5 (CH3). HRMS (ESI-TOF): [M + H]+ calcd for
[C17H15S], 251.0889; found, 251.0913.
1
afford 8ac as a white solid (89 mg, 89%), H NMR (CDCl3, 400
MHz, 25 °C): δ 7.62 (d, 1H, 3JHH = 8 Hz,C6H4), 7.50 (s, 1H, C6H4),
1-Methyl-6-(5-methylthiophen-2-yl)-1H-indazole (8aj). The
3
crude product was purified by column chromatography (hexane/
7.49−7.48 (m, 1H, C6H4), 7.39 (d, 1H, JHH = 4 Hz, C5H5S), 7.28−
1
3
EtOAc = 90/10) to afford 8aj as a white solid (92 mg, 81%), H
7.24 (m, 1H, C6H4), 6.75 (d, 1H, JHH = 4 Hz, C5H5S), 2.47 (s, 3H,
CH3 of C5H5S), 13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ 142.1,
137.5, 136.8, 134.1, 132.7, 129.0, 127.4, 126.9, 126.4 (Ar−C), 118.9
(CN), 109.1 (Ar−C), 15.2 (CH3). HRMS (ESI-TOF): [M + H]+
calcd for [C12H10NS], 200.0528; found, 200.0516.
NMR (CDCl3, 400 MHz, 25 °C): 7.94 (s, 1H, C8H7N2), 7.67 (d, 1H,
3
3JHH = 8 Hz, C8H7N2), 7.50 (s, 1H, C8H7N2), 7.38 (d, 1H, JHH = 8
Hz, C8H7N2), 7.19 (d, 1H, 3JHH = 3 Hz, C5H5S), 6.76 (d, 1H, 3JHH
=
3 Hz, C5H5S), 4.08 (s, 1H, CH3 of C8H7N2), 2.53 (s, 3H, CH3 of
C5H5S), 13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ 142.3, 140.6,
140.1, 133.2, 132.9, 126.5, 123.8, 123.3, 121.5, 119.6, 105.2 (Ar−C),
35.7 (CH3), 15.7 (CH3). HRMS (ESI-TOF): [M + H]+ calcd for
[C13H13N2S], 229.0794; found, 229.0805.
2-(3-Methoxyphenyl)-5-methylthiophene (8ad). The crude prod-
uct was purified by column chromatography (hexane/EtOAc = 98/
02) to afford 8ad as a white solid (79 mg, 78%), H NMR (CDCl3,
1
3
400 MHz, 25 °C): δ 7.33 (t, 1H, JHH = 8 Hz, C6H4), 7.22 (d, 1H,
3JHH = 8 Hz, C6H4), 7.18 (d, 1H, JHH = 4 Hz, C5H5S), 7.17 (s, 1H,
3
4-Chloro-7-(5-methylthiophen-2-yl)quinoline (8ak). The crude
product was purified by column chromatography (hexane/EtOAc =
90/10) to afford 8ak as a white solid (92 mg, 71%), 1H NMR
(CDCl3, 400 MHz, 25 °C): 8.71 (br, 1H,, C9H5ClN), 8.21 (s, 1H,
C6H4), 6.87 (dd, 1H, 3JHH = 8 Hz, 1H, 4JHH = 1 Hz, C6H4), 6.79−6.78
(m, 1H, C5H5S), 3.88 (s, 3H, OCH3), 2.56 (s, 3H, CH3 of C5H5S),
13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ 159.8, 141.7, 139.5,
135.9, 129.7, 126.1, 123.0, 118.0, 112.3, 111.0 (Ar−C), 55.0 (OCH3),
15.3 (CH3). HRMS (ESI-TOF): [M + H]+ calcd for [C12H13OS],
206.0682; found, 206.0665.
C9H5ClN), 8.12 (d, 1H, 3JHH = 8 Hz,, C9H5ClN), 7.79 (d, 1H, 3JHH
=
8 Hz,, C9H5ClN), 7.37 (d, 1H, 3JHH = 6 Hz,, C9H5ClN), 7.29 (d, 1H,
3JHH = 4 Hz, C5H5S), 6.76 (d, 1H, 3JHH = 4 Hz, C5H5S), 2.51 (s, 3H,
CH3 of C5H5S), 13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ 150.3,
149.4, 142.4, 141.5, 140.3, 136.6, 126.6, 125.5, 125.3, 124.7, 124.5,
124.4, 120.6 (Ar−C), 15.5 (CH3). HRMS (ESI-TOF): [M + H]+
calcd for [C14H11ClNS], 260.0295; found, 260.0310.
2-(4-Methoxyphenyl)-5-methylthiophene (8ae). The crude prod-
uct was purified by column chromatography (hexane/EtOAc = 98/
02) to afford 8ae as a white solid (82 mg, 81%), H NMR (CDCl3,
1
3
400 MHz, 25 °C): δ 7.48 (d, 2H, JHH = 8 Hz, C6H4), 6.98 (d, 1H,
4-(5-Acetylthiophen-2-yl)benzonitrile (9ba). The crude product
3JHH = 4 Hz, C5H5S), 6.89 (d, 1H, 3JHH = 8 Hz, C6H4), 6.70−6.79 (m,
1H, C5H5S), 3.82 (s, 3H, OCH3), 2.50 (s, 3H, CH3 of C5H5S),
13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ 158.8, 141.9, 138.4,
127.6, 126.7, 126.0, 1218, 114.2 (Ar−C), 55.3 (OCH3), 15.4 (CH3).
HRMS (ESI-TOF): [M + H]+ calcd for [C12H13OS], 206.0682;
found, 206.0665.
was purified by column chromatography (hexane/EtOAc = 95/05) to
1
afford 9ba as a white solid (93 mg, 82%), H NMR (CDCl3, 400
MHz, 25 °C): 7.72−7.70 (m, 2H, C6H4), 7.67−7.65 (m, 3H, C6H4 &
3
C6H5OS), 7.39 (d, 1H, JHH = 4 Hz, C6H5OS), 2.56 (s, 3H, CH3 of
C6H5OS). 13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ 190.4
(COCH3), 149.5, 144.9, 137.4, 133.3; 132.8, 127.8, 126.5, 125.7,
118.3, 112.1 (Ar−C), 26.6 (CH3). HRMS (ESI-TOF): [M + H]+
calcd for [C13H10NOS], 228.0478; found, 228.0492.
2-Methyl-5-phenylthiophene (8af). The crude product was
purified by column chromatography (hexane/EtOAc = 98/02) to
afford 8af as a white solid (66 mg, 69%), 1H NMR (CDCl3, 400 MHz,
25 °C): δ 7.58 (d, 2H, 3JHH = 8 Hz, C6H5), 7.37 (t, 2H, 3JHH = 8 Hz,
C6H5), 7.26 (t, 1H, JHH = 8 Hz, C6H5), 7.13 (d, 1H, JHH = 4 Hz,
C5H5S), 6.75−6.73 (m, 1H, C5H5S), 2.53 (s, 3H, CH3 of C5H5S),
13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ 142.1, 139.6, 138.9,
132.6, 126.8, 125.5, 125.1, 118.9, 109.9 (Ar−C), 15.5 (CH3). HRMS
(ESI-TOF): [M + H]+ calcd for [C11H11S], 175.0576; found,
175.0564.
4-(5-Methylthiophen-2-yl)benzaldehyde (8ag). The crude prod-
uct was purified by column chromatography (hexane/EtOAc = 95/
05) to afford 8ag as a white solid (86 mg, 85%), H NMR (CDCl3,
400 MHz, 25 °C): δ 9.97 (s, 1H, CHO), 7.84 (d, 2H, JHH = 8 Hz,
C6H4), 7.68 (d, 2H, JHH = 8 Hz, C6H4), 7.26 (d, 1H, JHH = 4 Hz,
4-(Benzo[b]thiophen-2-yl)benzonitrile (9ca). The crude product
was purified by column chromatography (hexane/EtOAc = 95/05) to
3
3
1
afford 9ca as a white solid (99 mg, 85%), H NMR (CDCl3, 400
MHz, 25 °C): 7.83 (d, 1H, 3JHH = 8 Hz, C8H5S), 7.80 (d, 1H, 3JHH
=
8 Hz, C8H5S), 7.76 (d, 2H, 3JHH = 8 Hz, C6H4), 7.60 (d, 2H, 3JHH = 8
Hz, C6H4), 7.63 (s, 1H, C8H5S), 7.40−7.34 (m, 2H, C8H5S). 13C{1H}
NMR (CDCl3, 100 MHz, 25 °C): δ 141.6, 140.2, 139.9, 138.5, 132.7,
126.7, 125.3, 124.9, 124.1, 122.3, 121.7 (Ar−C), 118.6 (CN), 111.3
(Ar−C). HRMS (ESI-TOF): [M + H]+ calcd for [C15H10NS],
236.0528; found, 236.0518.
1
4-(3-Bromobenzo[b]thiophen-2-yl)benzonitrile (9da). The crude
product was purified by column chromatography (hexane/EtOAc =
95/05) to afford 9da as a white solid (117 mg, 75%), 1H NMR
(CDCl3, 400 MHz, 25 °C): 7.89 (d, 2H, 3JHH = 8 Hz, C6H4), 7.83 (d,
2H, 3JHH = 8 Hz, C8H4SBr), 7.40 (d, 2H, 3JHH = 8 Hz, C6H4), 7.83 (d,
3
3
3
3
C5H5S), 6.78 (d, 1H, JHH = 4 Hz, C5H5S), 2.53 (s, 3H, CH3 of
C5H5S), 13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ 191.5 (CHO),
142.1, 140.4, 140.2, 134.7, 130.4, 126.9, 126.7, 125.4, 125.2 (Ar−C),
15.6 (CH3). HRMS (ESI-TOF): [M + H]+ calcd for [C12H11OS],
203.0525; found, 203.0514.
3
2H, JHH = 8 Hz, C6H4), 7.57−7.43 (m, 2H, C8H4SBr). 13C{1H}
NMR (CDCl3, 100 MHz, 25 °C): δ 138.9, 137.7, 137.6, 135.6, 132.3,
130.1, 126.2, 125.6, 124.0, 122.3 (Ar−C), 118.5 (CN), 112.2, 106.6
I
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Article
3
(Ar−C). HRMS (ESI-TOF): [M + H]+ calcd for [C15H9BrNS],
313.9634; found, 313.9654.
4H, C6H4), 7.38 (d, 1H, JHH = 8 Hz, C8H4NBr), 7.31 (s, 1H,
3
C8H4NBr), 7.24 (d, 1H, JHH = 8 Hz, C8H4NBr), 3.84 (s, 3H, CH3).
13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ 139.8, 136.3, 132.6,
128.7, 127.1, 125.4, 122.1 (Ar−C), 119.2 (CN), 114.5, 114.2,
111.4, 108.8 (Ar−C), 33.2 (CH3). HRMS (ESI-TOF): [M + H]+
calcd for [C16H12BrN2], 311.0178; found, 311.0182.
4-(6-Methoxybenzo[b]thiophen-2-yl)benzonitrile (9ea). The
crude product was purified by column chromatography (hexane/
1
EtOAc = 90/10) to afford 9ea as a white solid (95 mg, 72%), H
NMR (CDCl3, 400 MHz, 25 °C): 7.66−7.57 (m, 5H, C6H4
&
C8H4S), 7.48 (s, 1H, C8H4S), 7.28 (s, 1H, C8H4S), 6.98−6.95 (m,
1H, C8H4S), 3.84 (s, 3H, OCH3). 13C{1H} NMR (CDCl3, 100 MHz,
25 °C): δ 158.1, 141.5, 138.8, 134.2, 132.5, 126.1, 124.8, 121.3 (Ar−
C), 118.7 (CN), 115.1, 110.6, 104.6 (Ar−C), 55.5 (OCH3).
HRMS (ESI-TOF): [M + H]+ calcd for [C16H12NOS], 266.0634;
found, 266.0628.
4-(5-Chloro-1-methyl-1H-indol-2-yl)benzonitrile (9la). The crude
product was purified by column chromatography (hexane/EtOAc =
90/10) to afford 9la as a white solid (94 mg, 71%), 1H NMR (CDCl3,
400 MHz, 25 °C): 7.82 (s, 1H, C8H4NCl), 7.74 (d, 1H, 3JHH = 8 Hz,
C8H4NCl), 7.66 (s, 4H, C6H4), 7.32 (s, 1H, C8H4NCl), 7.24 (d, 1H,
3JHH = 8 Hz, C8H4NCl), 3.82 (s, 3H, CH3). 13C{1H} NMR (CDCl3,
100 MHz, 25 °C): δ 143.4, 139.8, 135.9, 132.8, 128.9, 126.9, 126.6,
122.8(Ar−C), 119.0 (CN), 114.5, 110.9, 108.7 (Ar−C), 33.2
(CH3). HRMS (ESI-TOF): [M + H]+ calcd for [C16H12ClN2],
267.0684; found, 267.0674.
4-(4-Methoxybenzo[b]thiophen-2-yl)benzonitrile (9fa). The
crude product was purified by column chromatography (hexane/
1
EtOAc = 90/10) to afford 9fa as a white solid (100 mg, 76%), H
NMR (CDCl3, 400 MHz, 25 °C): 7.48 (s, 1H, C8H4S), 7.68 (d, 2H,
3
3JHH = 8 Hz, C6H4), 7.58 (d, 2H, JHH = 8 Hz, C6H4), 7.36 (d, 1H,
4-(1,2-Dimethyl-1H-indol-3-yl)benzonitrile (9ma). The crude
product was purified by column chromatography (hexane/EtOAc =
3JHH = 8 Hz, C8H4S), 7.26 (t, 1H, 3JHH = 8 Hz, C8H4S), 6.71 (d, 1H,
3JHH = 8 Hz, C8H4S), 3.93 (s, 3H, OCH3). 13C{1H} NMR (CDCl3,
1
90/10) to afford 9ma as a white solid (106 mg, 87%), H NMR
(CDCl3, 400 MHz, 25 °C): 7.71 (d, 2H, 3JHH = 8 Hz, C6H4), 7.63 (d,
1H, 3JHH = 8 Hz, C8H4N), 7.57 (d, 2H, 3JHH = 8 Hz, C6H4), 7.34 (d,
1H, 3JHH = 8 Hz, C8H4N), 7.23 (t, 1H, 3JHH = 8 Hz, C8H4N), 7.15 (t,
100 MHz, 25 °C): δ 155.2, 141.3, 139.8, 138.6, 132.5, 131.1, 126.5,
118.7, 118.5, 114.6, 110.8, 104.4 (Ar−C), 55.4 (OCH3). HRMS (ESI-
TOF): [M + H]+ calcd for [C16H12NOS], 266.0634; found, 266.0628.
4-(3-(3,4,5-Trimethoxyphenyl)benzo[b]thiophen-2-yl)-
benzonitrile (9ga). The crude product was purified by column
chromatography (hexane/EtOAc = 85/15) to afford 9ga as a white
3
1H, JHH = 8 Hz, C8H4N), 3.75 (s, 3H, CH3), 2.50 (s, 3H, CH3).
13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ 141.2, 136.9, 134.6,
132.4, 129.9, 126.4, 121.8, 120.5, 119.5 (Ar−C), 118.3 (CN),
112.7, 109.2, 108.8 (Ar−C), 29.9 (CH3), 11.3 (CH3). HRMS (ESI-
TOF): [M + H]+ calcd for [C17H15N2], 247.1230; found, 247.1228.
2-(2-(4-Cyanophenyl)-3-methyl-1H-indol-1yl)benzonitrile (9na).
The crude product was purified by column chromatography (hexane/
1
solid (166 mg, 83%), H NMR (CDCl3, 400 MHz, 25 °C): 7.86 (d,
1H, 3JHH = 8 Hz, C8H4S), 7.68 (d, 1H, 3JHH = 8 Hz, C8H4S), 7.52 (d,
2H, 3JHH = 8 Hz, C6H4), 7.42 (d, 2H, 3JHH = 8 Hz, C6H4), 7.40−7.37
(m, 2H, C8H4S), 6.51 (s, 2H, C6H2), 3.92 (s, 3H, OCH3), 3.73 (s,
6H, OCH3). 13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ 153.5,
140.3, 138.7, 137.6, 136.5, 135.0, 131.9, 129.9, 129.6, 127.6, 125.3,
124.8, 123.6, 122.0 (Ar−C), 118.4 (CN), 110.8, 107.0 (Ar−C),
60.8 (OCH3), 55.9 (OCH3). HRMS (ESI-TOF): [M + H]+ calcd for
[C24H20NO3S], 402.1158; found, 402.1166.
1
EtOAc = 90/10) to afford 9na as a white solid (108 mg, 65%), H
NMR (CDCl3, 400 MHz, 25 °C): 7.69−7.64 (m, 3H, C6H4), 7.56 (d,
2H, 3JHH = 8 Hz, C6H4), 7.46−7.43 (m, 1H, C8H4N), 7.37−7.33 (m,
3H, C8H4N & C6H4), 7.27−7.25 (m, 2H, C8H4N & C6H4), 7.11−
7.09 (m, 2H, C8H4N), 2.43 (s, 3H, CH3). 13C{1H} NMR (CDCl3,
100 MHz, 25 °C): δ 141.1, 138.2, 136.0, 135.0, 134.0, 133.8, 131.8,
130.8, 129.9, 129.3, 128.2, 124.0, 121.2, 119.7 (Ar−C), 118.6 (C
N), 115.9, 114.2, 112.7, 110.8, 110.1 (Ar−C). HRMS (ESI-TOF):
[M + H]+ calcd for [C23H16N3], 334.1339; found, 334.1324.
4-(1,3-Dimethyl-1H-indol-2-yl)benzonitrile (9ia). The crude
product was purified by column chromatography (hexane/EtOAc =
95/05) to afford 9ia as a white solid (108 mg, 88%), 1H NMR
(CDCl3, 400 MHz, 25 °C): 7.80 (d, 2H, 3JHH = 8 Hz, C6H4), 7.66 (d,
1H, 3JHH = 8 Hz, C8H4N), 7.54 (d, 2H, 3JHH = 8 Hz, C6H4), 7.39 (d,
1H, 3JHH = 8 Hz, C8H4N), 7.34 (t, 1H, 3JHH = 8 Hz, C8H4N), 7.22 (t,
4-(1-Methyl-1H-pyrrol-2-yl)benzonitrile (9pa). The crude product
was purified by column chromatography (hexane/EtOAc = 98/02) to
3
1H, JHH = 8 Hz, C8H4N), 3.66 (s, 3H, CH3), 2.35 (s, 3H, CH3).
1
afford 9pa as a white solid (61 mg, 67%), H NMR (CDCl3, 400
13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ 137.7, 136.8, 135.4,
132.0, 130.9, 128.2, 122.7, 119.5, 119.1 (Ar−C), 118.7 (CN),
111.1, 110.3, 109.4 (Ar−C), 31.1 (CH3), 9.35 (CH3). HRMS (ESI-
TOF): [M + H]+ calcd for [C17H15N2], 247.1230; found, 247.1219.
4-(1-Methyl-1H-indol-2-yl)benzonitrile (9′ja). The crude product
was purified by column chromatography (hexane/EtOAc = 95/05) to
MHz, 25 °C): 7.65 (d, 2H, 3JHH = 8 Hz, C6H4), 7.50 (d, 2H, 3JHH = 8
3
Hz, C6H4), 6.79−6.78 (m, 1H, C4H3N), 6.35 (dd, 1H, JHH = 4 Hz,
3
4
4JHH = 2 Hz, C4H3N), 6.23 (dd, 1H, JHH = 4 Hz, JHH = 2 Hz,
C4H3N), 3.71 (s, 3H, CH3). 13C{1H} NMR (CDCl3, 100 MHz, 25
°C): δ 137.8, 132.9, 134.4, 128.4, 126.0 (Ar−C), 119.2 (CN),
110.9, 109.7, 108.7 (Ar−C), 35.6 (CH3). HRMS (ESI-TOF): [M +
H]+ calcd for [C12H11N2], 183.0917; found, 183.0917.
1
afford 9′ja as a white solid (60 mg, 60%), H NMR (CDCl3, 400
MHz, 25 °C): 7.78 (d, 2H, 3JHH = 8 Hz, C6H4), 7.68 (d, 1H, 3JHH = 8
Hz, C8H5N), 7.66 (d, 2H, 3JHH = 8 Hz, C6H4), 7.42 (d, 1H, 3JHH = 8
Hz, C8H5N), 7.33 (t, 1H, 3JHH = 8 Hz, C8H5N), 7.22 (t, 1H, 3JHH = 8
Hz, C8H5N), 6.69 (s, 1H, C8H5N), 3.81 (s, 3H, CH3). 13C{1H} NMR
(CDCl3, 100 MHz, 25 °C): δ 139.5, 139.2, 137.5, 132.5, 129.7,127.9,
122.9, 121.1, 120.6 (Ar−C), 118.9 (CN), 111.4, 110.0, 103.7 (Ar−
C), 31.7 (CH3). HRMS (ESI-TOF): [M + H]+ calcd for [C17H15N2],
247.1230; found, 247.1219.
4-(1-(2-Aminophenyl)-1H-pyrrol-2-yl)benzonitrile (9qa). The
crude product was purified by column chromatography (hexane/
1
EtOAc = 85/15) to afford 9qa as a white solid (88 mg, 68%), H
3
NMR (CDCl3, 400 MHz, 25 °C): 7.42 (d, 2H, JHH = 8 Hz, C6H4),
3
3
7.25 (d, 2H, JHH = 8 Hz, C6H4), 7.19 (t, 1H, JHH = 8 Hz, C6H4),
7.03 (d, 1H, 3JHH = 8 Hz, C6H4), 6.88−6.84 (m, 1H, C4H3N), 6.77−
6.72 (m, 2H, C6H4), 6.63 (dd, 1H, 3JHH = 4 Hz, 4JHH = 2 Hz, C4H3N),
6.42 (dd, 1H, 3JHH = 4 Hz, 4JHH = 2 Hz, C4H3N), 3.62 (br, 2H, NH2).
13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ 143.1, 137.1, 133.0,
132.2, 131.9, 129.8, 128.6, 128.1, 127.1, 126.9, 126.4, 125.9, 119.3,
119.0 (Ar−C), 118.7 (CN), 116.2, 111.7, 110.5, 109.2 (Ar−C).
HRMS (ESI-TOF): [M + H]+ calcd for [C17H14N3], 260.1182;
found, 260.1169.
4-(1-Methyl-1H-indol-3-yl)benzonitrile (9″ja). The crude product
was purified by column chromatography (hexane/EtOAc = 90/10) to
1
afford 9″ja as a white solid (41 mg, 40%), H NMR (CDCl3, 400
MHz, 25 °C): 7.96 (d, 1H, 3JHH = 6 Hz, C8H5N), 7.73 (d, 4H, 3JHH
=
8 Hz, C6H4), 7.44−7.29 (m, 4H, C8H5N), 3.89 (s, 3H, CH3).
13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ 140.8, 137.8, 133.0,
132.7, 128.1, 128.0, 127.2, 125.7, 122.7, 120.9, 119.7 (Ar−C), 119.7
(CN), 115.0, 110.1, 108.5 (Ar−C), 33.3 (CH3). HRMS (ESI-
TOF): [M + H]+ calcd for [C16H13N2], 233.1073; found, 233.1052.
4-(5-Bromo-1-methyl-1H-indol-2-yl)benzonitrile (9ka). The
crude product was purified by column chromatography (hexane/
4-(5-Acetylfuran-2-yl)benzonitrile (9ra). The crude product was
purified by column chromatography (hexane/EtOAc = 95/05) to
1
afford 9ra as a white solid (59 mg, 56%), H NMR (CDCl3, 400
MHz, 25 °C): 7.84 (d, 2H, 3JHH = 8 Hz, C6H4), 7.67 (d, 2H, 3JHH = 8
Hz, C6H4), 7.24 (br, 1H, C6H5O2), 6.90 (br, 1H, C6H5O2), 2.50 (s,
3H, CH3 of C6H5O2). 13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ
190.4 (COCH3), 149.5, 144.9, 137.4, 133.4, 132.8, 127.8, 126.5, 125.7
1
EtOAc = 90/10) to afford 9ka as a white solid (107 mg, 69%), H
NMR (CDCl3, 400 MHz, 25 °C): 8.00 (s, 1H, C8H4NBr), 7.68 (s,
J
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Article
(Ar−C), 118.3 (CN) 112.1 (Ar−C), 26.6 (CH3). HRMS (ESI-
TOF): [M + H]+ calcd for [C13H10NO2], 212.0706; found, 212.0701.
4,4′-(Benzofuran-2,3-diyl)dibenzonitrile (9sa). The crude product
was purified by column chromatography (hexane/EtOAc = 90/10) to
7.59 (d, 4H, 3JHH = 8 Hz, C6H4), 6.42 (br, 2H, C5H5N), 3.68 (s, 6H,
CH3 of C5H5N). 13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ 137.3,
137.1, 132.6, 128.8 (Ar−C), 119.0 (CN), 111.5, 110.5 (Ar−C),
35.1 (CH3). HRMS (ESI-TOF): [M + H]+ calcd for [C19H14N3],
284.1182; found, 284.1162.
1
afford 9sa as a white solid (63 mg, 79%), H NMR (CDCl3, 400
MHz, 25 °C): 7.79−7.78 (m, 2H, C8H4O), 7.70−7.68 (m, 2H,
C8H4O & C6H4), 7.61−7.57 (m, 5H, C8H4O & C6H4), 7.46−7.40 (m,
1H, C8H4O & C6H4), 7.29−7.24 (m, 1H, C8H4O), 13C{1H} NMR
(CDCl3, 100 MHz, 25 °C): δ 141.6, 140.2, 139.9, 138.5, 132.7, 126.7,
125.3, 124.9, 124.1, 122.3, 121.7 (Ar−C), 118.6 (CN), 111.3 (Ar−
C). HRMS (ESI-TOF): [M + H]+ calcd for [C22H13N2O], 321.1022;
found, 321.1034.
3-Bromo-2,3′-Bibenzo[b]thiophene (10). The crude product was
purified by column chromatography (hexane/EtOAc = 95/05) to
afford 10 as a white solid (90 mg, 52%), 1H NMR (CDCl3, 400 MHz,
25 °C): 7.91−7.88 (m, 3H, C8H4SBr & C8H5S), 7.82−7.77 (m, 1H,
C8H4SBr or C8H5S), 7.72 (s, 1H, C8H5S), 7.47−7.46 (m, 1H,
C8H4SBr or C8H5S), 7.42−7.37 (m, 3H, C8H4SBr & C8H5S),
13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ 139.8, 138.5, 138.1,
137.7, 132.0, 128.5, 128.1, 125.6, 125.4, 125.3, 124.8, 124.5, 123.6,
123.5, 122.7, 122.2, 107.5 (Ar−C). HRMS (ESI-TOF): [M + H]+
calcd for [C16H10BrS2], 344.9402; found, 344.9396.
6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (13). The
crude product was purified by column chromatography (hexane/
EtOAc = 90/10) to afford 13 as a white solid (90 mg, 67%), 1H NMR
(CDCl3, 400 MHz, 25 °C): 7.53 (d, 1H, 3JHH = 8 Hz C8H4S), 7.51 (d,
3
2H, JHH = 8 Hz, C6H4), 7.24 (s, 1H, C8H4S), 7.21 (s, 1H, C8H4S),
3
3
6.88 (d, 1H, JHH = 8 Hz C8H4S), 7.85 (d, 2H, JHH = 8 Hz, C6H4),
3.79 (s, 3H, OCH3), 3.76 (s, 3H, OCH3). 13C{1H} NMR (CDCl3,
100 MHz, 25 °C): δ 158.4, 156.2, 140.5, 139.6, 133.9, 126.4, 126.2,
122.9, 116.7, 113.3, 103.9 (Ar−C), 54.6 (OCH3), 54.3 (OCH3).
HRMS (ESI-TOF): [M + H]+ calcd for [C16H15O2S], 271.0787;
found, 271.0791.
Gram-Scale Synthesis of 4-(5-Methylthiophen-2-yl)benzonitrile
(8aa). 1-Methyl thiophene 6a (1.08 g, 11.1 mmol), 4-bromobenzoni-
trile 7a (1.00 g, 5.55 mmol), KOAc (1.63 g, 16.6 mmol), and Pd−
NHC (3) (0.020 g, 0.028 mmol, 0.5 mol %) were transferred to the
Schlenk tube under nitrogen atmosphere and DMAc (ca. 20 mL) was
added via a syringe. The Schlenk tube was closed using a glass stopper
and a steel clamp, and the reaction mixture was heated at 130 °C for
the 2 h. After this, the volatiles were removed under vacuum at 80 °C,
and then the reaction mixture was cooled to ambient temperature.
The residue was diluted with ethyl acetate (ca. 150 mL) and then
washed with water (ca. 3 × 50 mL). The organic layer was separated,
dried over Na2SO4, and finally vacuum-dried to afford the crude
product. The crude product was purified by column chromatography
using petroleum ether/EtOAc to afford a white solid (0.941 g, 85%).
1,3-Bis(5-methylthiophen-2-yl)benzene (11a). The crude product
was purified by column chromatography (hexane/EtOAc = 98/02) to
1
afford 11a as a white solid (110 mg, 82%), H NMR (CDCl3, 400
MHz, 25 °C): δ 7.82 (s, 1H, C6H4), 7.50 (d, 2H, 3JHH = 8 Hz, C6H4),
3
3
7.41 (t, 1H, JHH = 8 Hz, C6H4), 7.23 (d, 1H, JHH = 1 Hz, C5H5S),
3
7.82 (d, 1H, JHH = 1 Hz, C5H5S), 2.60 (s, 6H, CH3 of C5H5S),
13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ 141.6, 139.6, 135.2,
129.2, 126.2, 124.1, 123.2, 123.1, 122.5 (Ar−C), 15.4 (CH3). HRMS
(ESI-TOF): [M + H]+ calcd for [C16H15S2], 271.0610; found,
271.0591.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02024.
■
1,3-Bis(1-methyl-1H-pyrrol-2-yl)benzene (11b). The crude prod-
uct was purified by column chromatography (hexane/EtOAc = 98/
02) to afford 11b as a white solid (100 mg, 85%), 1H NMR (CDCl3,
400 MHz, 25 °C): δ 7.48−7.42 (m, 2H, C6H4), 7.36 (d, 2H, 3JHH = 8
sı
3
Comparison table, NMR spectra, elemental analysis data
(2−5), selected crystallographic data table (3−5), and
selected GC-GCMS data (PDF)
Crystallographic data of 4 (CIF)
Crystallographic data of 3 (CIF)
Hz, C6H4), 7.41 (t, 1H, JHH = 8 Hz, C6H4), 6.75 (br, 2H, C5H6N),
6.28 (d, 2H, 3JHH = 4 Hz, C5H6N), 6.24 (d, 2H, 3JHH = 4 Hz, C5H6N),
3.72 (s, 6H, CH3 of C5H6N). 13C{1H} NMR (CDCl3, 100 MHz, 25
°C): δ 134.3, 133.4, 128.6, 128.3, 126.9, 127.7, 108.8, 107.8 (Ar−C),
35.1 (CH3). HRMS (ESI-TOF): [M + H]+ calcd for [C16H17N2],
237.1386; found, 237.1392.
Crystallographic data of 5 (CIF)
1,4-Bis(5-methylthiophen-2-yl)benzene (11c). The crude product
was purified by column chromatography (hexane/EtOAc = 98/02) to
Accession Codes
1
afford 11c as a white solid (111 mg, 82%), H NMR (CDCl3, 400
CCDC 1887442, 1887443, and 1887444 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
3
MHz, 25 °C): δ 7.51 (s, 4H, C6H4), 7.10 (d, 2H, JHH = 1 Hz,
3
C5H5S), 6.72 (d, 2H, JHH = 1 Hz, C5H5S), 2.50 (s, 6H, CH3 of
C5H5S), 13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ 141.6, 139.5,
133.3, 126.3, 125.7, 122.8, 122.7 (Ar−C), 29.7 (CH3). HRMS (ESI-
TOF): [M + H]+ calcd for [C16H15S2], 271.0610; found, 271.0591.
1,4-Bis(1-methyl-1H-pyrrol-2-yl)benzene (11d). The crude prod-
uct was purified by column chromatography (hexane/EtOAc = 95/
05) to afford 11d as a white solid (101 mg, 86%), 1H NMR (CDCl3,
400 MHz, 25 °C): δ 7.46 (s, 4H, C6H4), 6.77 (br, 2H, C5H6N), 6.30−
6.29 (m, 2H, C5H6N), 6.26−6.25 (m, 2H, C5H6N), 3.75 (s, 6H, CH3
of C5H6N). 13C{1H} NMR (CDCl3, 100 MHz, 25 °C): δ 134.4,
131.8, 128.6, 124.0, 108.9, 108.0 (Ar−C), 35.3 (CH3). HRMS (ESI-
TOF): [M + H]+ calcd for [C16H17N2], 237.1386; found, 237.1392.
4,4′-(Furan-2,5-diyl)dibenzonitrile (12a). The crude product was
purified by column chromatography (hexane/EtOAc = 90/10) to
AUTHOR INFORMATION
Corresponding Author
■
Akhilesh K. Verma − Synthetic Organic Chemistry Research
Laboratory, Department of Chemistry, University of Delhi,
Delhi 110007, India; orcid.org/0000-0001-7626-5003;
Email: averma@acbr.du.ac.in
1
afford 12a as a white solid (74 mg, 55%), H NMR (CDCl3, 400
MHz, 25 °C): δ 7.83 (d, 4H, 3JHH = 8 Hz, C6H4), 7.70 (d, 4H, 3JHH
=
Authors
8 Hz, C6H4), 6.95 (br, 2H, C4H2O). 13C{1H} NMR (CDCl3, 100
MHz, 25 °C): δ 153.0, 134.0, 132.9, 124.3 (Ar−C), 118.9 (CN),
111.1, 110.8 (Ar−C). HRMS (ESI-TOF): [M + H]+ calcd for
[C18H11N2O], 271.0866; found, 271.0863.
Anuj Kumar − Synthetic Organic Chemistry Research
Laboratory, Department of Chemistry, University of Delhi,
Delhi 110007, India
Manoj Kumar − Synthetic Organic Chemistry Research
Laboratory, Department of Chemistry, University of Delhi,
Delhi 110007, India
4,4′-(1-Methyl-1H-pyrrole-2,5 diyl)dibenzonitrile (12b). The
crude product was purified by column chromatography (hexane/
1
EtOAc = 90/10) to afford 12b as a white solid (112 mg, 79%), H
NMR (CDCl3, 400 MHz, 25 °C): δ 7.74 (d, 4H, 3JHH = 8 Hz, C6H4),
Complete contact information is available at:
K
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J. Org. Chem. XXXX, XXX, XXX−XXX

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pubs.acs.org/joc
Article
(15) Choi, J.; Fu, G. C. Transition metal-catalyzed alkyl-alkyl bond
formation: Another dimension in cross-coupling chemistry. Science
2017, 356, No. eaaf7230.
https://pubs.acs.org/10.1021/acs.joc.0c02024
Notes
(16) Schmidt, N. G.; Eger, E.; Kroutil, W. Building Bridges:
Biocatalytic C-C-Bond Formation toward Multifunctional Products.
ACS Catal. 2016, 6, 4286−4311.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(17) Yang, H.; Yang, X.; Tang, W. Transition-metal catalyzed
asymmetric carbon−carbon cross-coupling with chiral ligands.
Tetrahedron 2016, 72, 6143−6174.
The research work was supported by SERB (EEQ/2018/
000317) and PDF/2016/002263 from Science & Engineering
Research Board, Department of Science & Technology (SERB-
DST), Government of India. M.K. thanks CSIR, New Delhi,
for the research fellowship.
(18) Henrion, M.; Ritleng, V.; Chetcuti, M. J. Nickel N-Heterocyclic
Carbene-Catalyzed C−C Bond Formation: Reactions and Mecha-
nistic Aspects. ACS Catal. 2015, 5, 1283−1302.
(19) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E.
Enantioselective and Enantiospecific Transition-Metal-Catalyzed
Cross-Coupling Reactions of Organometallic Reagents To Construct
C-C Bonds. Chem. Rev. 2015, 115, 9587−9652.
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