Pd-Catalyzed Cyclization of Alkynyl Norbornene Derivatives for the Synthesis of Benzofused Heteroarenes

Article abstract of DOI:10.1002/adsc.202100763

Modular approaches, which allow a systematic variation of heteroaromatic cores and substituents, are crucial for the development of heteroaromatic drug candidates and organic functional materials. A new strategy involving the cyclization of heteroarenes tethered with alkynes through a norbornene bridge was developed. The precursors were readily prepared by a three-component coupling process of heteroaryl halides, norbornadiene, and terminal alkynes. The Pd catalytic system derived from Pd(OAc)₂ and 2-(pyrazol-1-yl)pyridine transformed a variety of five-membered heteroarenes to the corresponding benzofused products, including (di)benzothiophene, indazole, carbazole, indole, and benzofuran, with aryl and alkyl substituents at the C4(C7) position. During the cyclization process, the norbornene ring underwent a retro-Diels-Alder reaction, serving as an acetylene synthon. This approach was used to synthesize naphthalene derivatives from electron-rich arenes, demonstrating its versatility in the annulation of (hetero)aromatic rings. (Figure presented.).

Full text of DOI:10.1002/adsc.202100763

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doi.org/10.1002/adsc.202100763
Pd-Catalyzed Cyclization of Alkynyl Norbornene Derivatives for
the Synthesis of Benzofused Heteroarenes
Hayeon Kwak,a Eunsu Kang,a Jae Yeong Song,a Geunhee Kang,a and
Jung Min Jooa,*
a
Department of Chemistry and Chemistry Institute for Functional Materials, Pusan National University, Busan 46241, Republic
of Korea
E-mail: jmjoo@pusan.ac.kr
Manuscript received: June 19, 2021; Revised manuscript received: August 13, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100763
candidates against schizophrenia,[2] autoimmune
Abstract: Modular approaches, which allow a
systematic variation of heteroaromatic cores and
diseases,[3] cancers,[4] and pulmonary diseases.[5] There-
fore, strategies that are broadly applicable to the
substituents, are crucial for the development of
synthesis of a series of 5,6-fused bicycles, including
heteroaromatic drug candidates and organic func-
benzothiophene, benzofuran, indole, and indazole, are
tional materials. A new strategy involving the
highly desirable for examining the isostere effect of
cyclization of heteroarenes tethered with alkynes
heterocycles.[6] The installation of functional groups at
through a norbornene bridge was developed. The
the parent cores is one approach that affords function-
precursors were readily prepared by a three-compo-
alized 5,6-benzofused heteroarenes.[7] Recently, this
nent coupling process of heteroaryl halides, norbor-
approach has been greatly facilitated by transition
nadiene, and terminal alkynes. The Pd catalytic
metal-catalyzed CÀ H functionalization.[8] Although the
system derived from Pd(OAc)2 and 2-(pyrazol-1-yl)
pyridine transformed a variety of five-membered
heteroarenes to the corresponding benzofused prod-
ucts, including (di)benzothiophene, indazole,
CÀ H bonds of the five-membered rings have been
selectively transformed to CÀ C and C-heteroatom
bonds,[9] remote CÀ H functionalization reactions at the
aryl rings mostly rely on directing group-assisted
carbazole, indole, and benzofuran, with aryl and
approaches.[10] Alternatively, to produce C4(C7)-sub-
alkyl substituents at the C4(C7) position. During the
stituted benzofused heteroarenes, cyclization has been
cyclization process, the norbornene ring underwent
performed with alkyne-tethered heteroarenes using Au
a retro-Diels-Alder reaction, serving as an acetylene
and Ag catalysts (Figure 2A).[11] However, the cycliza-
synthon. This approach was used to synthesize
tion precursors are prepared by the addition of alkyne
naphthalene derivatives from electron-rich arenes,
group donors to carbonyl group-containing heteroar-
demonstrating its versatility in the annulation of
enes, which typically require additional steps during
(hetero)aromatic rings.
preparation.
To produce C4(C7)-substituted benzofused hetero-
arenes, we envisioned a strategy involving norborna-
diene (NBD). Recently, we demonstrated that the
incorporation of NBD as an acetylene synthon led to
the benzannulation of five-membered heteroarenes
Keywords: Palladium; Norbornene; Alkynes; Het-
erocycles; Cyclization; CÀ H functionalization
through a Pd-catalyzed cyclization followed by a retro-
The 5,6-fused bicyclic heteroaromatic ring system Diels-Alder reaction (Figure 2B, top).[12] In addition to
represents an indispensable subclass of heterocycles in the Pd-catalyzed 1:2 coupling reaction between hetero-
the development of biologically active compounds and aryl halides and NBD, a 2:1 coupling reaction was
organic functional materials.[1] The position and type developed to synthesize polycyclic heteroaromatic
of substituents are modulated to provide the desired systems (Figure 2B, middle).[13] Consequently, it was
biological and physicochemical properties, using the considered that C4(C7)-substituted benzofused hetero-
heterocyclic system as the core. In particular, bio- arenes could arise from alkynyl norbornene deriva-
logically active compounds with C4(C7)-substituted tives, through a simultaneous retro-Diels-Alder reac-
fused bicyclic rings (Figure 1) are important drug tion of the norbornene ring, which results in π-
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allowing the examination of various catalytic systems
for the cyclization (Table 1). To facilitate the intra-
molecular reaction, a large volume of solvents was
employed, which however could be reduced for other
substrates (vide infra). Au and Ag catalytic systems,
which are useful in the electrophilic cyclization of
alkynyl heteroarenes with a flexible linker, afforded a
trace amount of the cyclization product, 2a (see
Supporting Information).[11] Based on our previous
study on the development of new nitrogen bidentate
ligands that provide electrophilic Pd catalysts,[15] we
examined a series of nitrogen ligands with Pd(OAc)2.
Pd(OAc)2 alone afforded a low yield, and the addition
of 3- and 4-cyano pyridines (3CP and 4CP, respec-
tively) did not significantly improve the yield. In
contrast to the low reactivity of 4,5-diazafluorenone
(DAF) and 2,2’-bipyridine (BPY), 2-(pyrazol-1-yl)
pyridine (L1) generated a high yield.[16] The L2 and L3
ligands, which are more electron-deficient than L1,
afforded lower yields than that of L1. In addition,
conformationally rigid tricyclic ligands, L4–L6, were
inferior to their conformationally flexible counterparts,
L1–L3.
Figure 1. Biologically active compounds with C4(C7)-substi-
tuted benzofused heteroarenes.
The scope of alkynes was investigated (Table 2),
using L1 as the optimal ligand. Aryl groups substituted
with alkyl, methoxy, chloro, and trifluoromethyl
groups afforded 7-aryl benzothiophenes in good yields
(2b–2j). Notably, the position of the substituents on
the aryl ring did not affect the cyclization, as
demonstrated in the reactions of o-, m-, and p-
chloroarene derivatives as well as anisole-containing
ones (2d–2i). Furthermore, this cyclization approach
Figure 2. Strategies for preparing substituted 5,6-benzofused
heteroarenes.
Table 1. Ligand effect on the Pd-catalyzed cyclization of the
alkynyl norbornene, 1a.[a]
conjugated structures (Figure 2B, bottom). This ap-
proach provides increased accessibility to the cycliza-
tion precursors prepared by Pd-catalyzed three-compo-
nent reactions, using readily available heteroaryl
halides, NBD, and terminal alkynes in one step
(Scheme 1).[14] In the key cyclization process, the
alkyne substituent was transferred to the C4(C7)
substituent, while a variety of five-membered hetero-
arenes were incorporated into the 5,6-fused bicyclic
system.
A slightly modified three-component coupling[14]
procedure readily afforded the alkynyl norbornene, 1a,
[a] Reaction
conditions:
1a
(0.40 mmol),
Pd(OAc)2
(0.010 mmol), ligand (0.010 mmol), AcOH (16 mL), DMSO
°
(1.6 mL), 80 C, and 16 h. Isolated yields.
Scheme 1. Preparation of cyclization precursors.
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Table 2. Scope of alkynes.[a]
cyclization reactions, were successfully converted to
the corresponding indazoles (entries 9 and 10). The
low yield of 4j, compared to that of the regioisomer
4i, is attributed to the electronic effect observed in the
cyclization of thiophenes, which was not overcome by
increasing the amounts of the catalyst and ligand. This
is because the pyrazole C4 position is more nucleo-
philic than the C5 position. Indole, pyrrole, and furan
derivatives underwent cyclization reactions to afford
the corresponding carbazole 4k, indole 4l, and
benzofuran 4m, respectively (entries 11–13). For the
model substrate 1a that is susceptible to intermolecular
reactions, a large volume of solvents was required
(Table S1). However, reducing the amount of solvents
did not generate a significant impact on yields with
substrates that are less likely to undergo dimerization
than monosubstituted thiophene 1a, as demonstrated in
the reactions of benzothiophene 3g and disubstituted
pyrrole 3l.
The cyclization reaction was used to synthesize
naphthalene derivatives using aryl norbornene com-
pounds (Table 4). Similar to heteroarenes, electron-rich
arenes with available nucleophilic sites were amenable
to the synthesis of functionalized naphthalenes. For
example, alkynyl dimethoxybenzene, 5a, afforded an
excellent yield of 6a (entry 1). However, when two
nucleophilic sites were present, regioisomers were
formed, and the less hindered regioisomers, such as 6b
and 6c, were preferred (entries 2 and 3). The xylyl and
tolyl norbornenes, 5d and 5e, produced inferior
results, presumably because they are less electron-rich
[a] Reaction conditions: alkynyl thiophene (0.40 mmol),
Pd(OAc)2 (0.010 mmol), L1 (0.010 mmol), AcOH
°
(16 mL), DMSO (1.6 mL), 80 C, and 16 h. Isolated
yields.
afforded 7-alkyl benzothiophenes (2k–2n), which are than arenes with methoxy and dimethylamino groups
often difficult to prepare by the conventional cross- (entries 4 and 5).
coupling reactions of 7-halobenzothiophenes. In addi-
The effect of the rigid, nonconjugated structure
tion, cyclization reactions of norbornane derivatives enabled by the norbornene bridge was investigated,
were performed to produce nonplanar heterocycles, 2o using a bridged bicyclic ring-free structure. Heating
and 2p, without retro-Diels-Alder reactions because of the cyclization precursor, 3i, afforded the correspond-
the absence of the olefin in the bridged bicyclic rings. ing (Z)-enyne, 7, by a retro-Diels-Alder reaction
Next, the scope of heteroarenes was investigated by (Scheme 2). In contrast to the norbornene precursors, 7
varying their substituents and types (Table 3). The did not produce the desired cyclization product,
methyl substituent of the thiophene ring was tolerated illustrating the advantage of the norbornene bridge that
in the cyclization reactions (entries 1 and 2). When puts the heterocycle and the alkyne close together
thiophene was attached to the norbornene unit prox- compared to the π-conjugated planar system of 7
imal to the sulfur atom, the obtained yields were low (Figure S2).
(entries 3 and 4). These results indicate that the
Based on previous studies, a plausible reaction
nucleophilic site of heteroarenes is favored during mechanism is proposed (Figure 3).[18] The coordination
cyclization because the α-carbon atom proximal to the of substrate 1a to Pd catalyst I activates the alkyne π-
sulfur atom in thiophene is a more electron-rich system, facilitating the electrophilic cyclization of
position than the β-carbon atom. However, the pres-
ence of an electron-withdrawing group on the
thiophene ring created a marginal impact (entries 5 and
6). Product 4e generated crystals that are suitable for
X-ray analysis, confirming its structure.[17] Besides
thiophene, both regioisomers of benzothiophene deriv-
atives were transformed to cyclization products, 4g
and 4h (entries 7 and 8). Furthermore, pyrazole
derivatives, which have not been used in electrophilic
Scheme 2. Retro-Diels-Alder reaction followed by cyclization.
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Table 3. Scope of heteroarenes.[a]
[a] Reaction conditions: alkynyl heteroarene (0.40 mmol), Pd(OAc)2 (0.010 mmol), L1 (0.010 mmol), AcOH (16 mL), DMSO
°
(1.6 mL), 80 C, and 16 h. Isolated yields.
[b] AcOH (4.0 mL) and DMSO (0.40 mL).[c] Pd(OAc)2 (0.020 mmol), L1 (0.020 mmol), and 100 C. ORTEP diagram of 4e with
°
anisotropic displacement parameters at 50% probability.
Diels-Alder reaction of IV produces product 2a.
Alternatively, electrophilic concerted metalation-depro-
tonation (eCMD) of the heteroaromatic ring using the
Pd(II) complex, I, first occurs to produce V;[19]
a
subsequent migratory insertion in the alkyne and
protonation may generate the product. In both cases,
the use of the pyrazolopyridine ligand could be
beneficial to generate a vacant coordination site by
facile dissociation of the weakly coordinating pyrazole
part, yet flexibly provide the stabilization effect as a
bidentate ligand. However, the formation of a consid-
erable amount of more sterically hindered isomers, 6b’
and 6c’, in the cyclization of 5b and 5c, respectively
(Table 4, entries 2 and 3), is in favor of the former
mechanism because the metalation is prohibited by the
Figure 3. Proposed mechanism.
complex II through a concerted mechanism for the steric hindrance from adjacent substituents.[15]
In conclusion, we developed Pd-catalyzed cycliza-
cleavage of the CÀ H bond, the formation of the CÀ C
bond, and the palladation at the alkyne, which is tion reactions of alkynyl (hetero)arenes for the syn-
supported by a preliminary DFT calculation (Fig- thesis of benzofused (hetero)cyclic compounds. The
ure S3). The protodepalladation of III affords IV while norbornene bridge spacing between the (hetero)aryl
regenerating the Pd(II) complex, I. A subsequent retro- ring and alkynyl group facilitates the cyclization
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Table 4. Scope of arenes.[a]
Acknowledgements
This research was supported by the National Research
Foundation of Korea (NRF-2019R1A2C1007852 and NRF-
2019R1A4A1028007).
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°
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Experimental Section
Representative procedure for cyclization. Pd(OAc)2 (2.2 mg,
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(30 mL), and concentrated under reduced pressure to evaporate
the AcOH. The residue was purified by flash column
chromatography to obtain the desired product.
°
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Pd-Catalyzed Cyclization of Alkynyl Norbornene Derivatives
for the Synthesis of Benzofused Heteroarenes
Adv. Synth. Catal. 2021, 363, 1–7
H. Kwak, E. Kang, J. Y. Song, G. Kang, J. M. Joo*