Divergent Strategies for the π-Extension of Heteroaryl Halides Using Norbornadiene as an Acetylene Synthon

Article abstract of DOI:10.1021/acs.orglett.0c03732

Pd-catalyzed multicomponent coupling reactions of five-membered heteroaryl halides and norbornadiene (NBD) were developed. Either direct addition of (benzo)azoles or 2:1 annulation was achieved depending on the propensity of the intermediate complex to un

Full text of DOI:10.1021/acs.orglett.0c03732

pubs.acs.org/OrgLett
Letter
Divergent Strategies for the π‑Extension of Heteroaryl Halides Using
Norbornadiene as an Acetylene Synthon
Siyeon Jeong,§ Eunmin Kim,§ Minkyu Kim, Ye Ji Hwang, Birakishore Padhi, Jonghoon Choi, Yunho Lee,
and Jung Min Joo*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c03732
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Pd-catalyzed multicomponent coupling reactions of
five-membered heteroaryl halides and norbornadiene (NBD) were
developed. Either direct addition of (benzo)azoles or 2:1
annulation was achieved depending on the propensity of the
intermediate complex to undergo palladacycle formation, deter-
mined by the nature and substitution pattern of the heteroarene.
The obtained exo- and cis-diheteroaryl norbornenes underwent
epimerization and retro-Diels−Alder reactions to afford the
corresponding trans-isomers and π-extended heteroaromatic systems, respectively, demonstrating the versatility of NBD as an
acetylene synthon.
orbornadiene (NBD) is an important structural motif in
transition-metal-catalyzed reactions and polymerization
N
reactions.1,2 The rigid, strained alkene group readily undergoes
addition reactions to afford functionalized norbornene (NBE)
derivatives that can be polymerized by ring-opening metathesis
polymerization.3 In addition, NBE tailoring has emerged as an
important strategy to control efficiency and selectivity of the
Catellani reaction, in which NBE serves as a transient ortho-
directing mediator.4 In contrast, the incorporation of NBD
into the product offers additional synthetic opportunities. For
example, π-extended aromatic systems are accessible by retro-
Diels−Alder (rDA) reactions of NBD derivatives, which
function as acetylene synthons.5 This approach is facilitated
by Pd-catalyzed C−H functionalization, which allows the
straightforward decoration of NBD with one or more
heteroarenes.6 Importantly, the introduction of sites for
hydrogen bonding and metal coordination via this route
renders the products useful in various applications as
pharmaceuticals and ligands.1b,7 However, the strategic use of
NBD as a building block in C−H functionalization remains
underexplored in comparison with the remarkable progress of
Pd/NBE cooperative catalysis.8
Figure 1. Divergent Pd-catalyzed couplings of haloheteroarenes and
norbornadiene and subsequent retro-Diels−Alder reaction toward π-
extended heteroarenes: (A) 1:2 annulation; (B) three-component
coupling involving C−H functionalization; (C) 2:1 annulation.
fast, the Pd−NBD adduct underwent direct C−H hetero-
arylation (Figure 1B). This diheteroarylation approach is
complementary to diarylation of NBD with aryl halides and
aryl boron reagents.12 In contrast, the formation of the
palladacycle led to highly regioselective 2:1 annulation of
Recently, we developed 1:2 annulation reactions of five-
membered haloheteroarenes and NBD by controlling the
reactivity of the Pd−NBD adducts (Figure 1A).9 Whereas
divergent reaction pathways existed, common Pd−NBD
adducts favored 1:2 annulation over the Catellani reaction
when steric and coordinating effects of the heteroarenes
precluded the generation of the palladacycle intermediate.10
Herein, the dichotomy of the Pd-catalyzed reactions of five-
membered heteroarenes and NBD is applied to the synthesis of
diheteroaryl NBEs.11 When the formation of the palladacycle
was slow and C−H metalation of partner heteroarenes was
Received: November 9, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03732
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 1. Effect of the Position of the Iodide on the
Outcome of the Pd/NBE Reaction
Table 2. Pyrazole Scope of the Three-Component
a
a
Reaction
entry
R1
R2
yield (%)
1
2
3
4
5
6
7
8
9
Me
nBu
nHex
(Me)2CH
Ph
PhCH2
PhCH2CH2
(CH3)3SiCH2CH2OCH2
2-tetrahydropyranyl
H
H
H
H
H
H
H
H
H
Me
H
5a (72)
5c (64)
5d (65)
5e (60)
5f (68)
5g (74)
5h (57)
5i (69)
a
Reaction conditions: iodopyrazole (0.50 mmol), NBE (1.0 mmol),
benzoxazole (0.50 mmol), Pd(OAc)2 (0.025 mmol), DPEPhos
(0.0375 mmol), Cs2CO3 (1.0 mmol), 1,4-dioxane (0.50 M), 130
°C, 16 h, under Ar. Isolated yields.
b
5j (51)
5k (46)
2a (64)
10
11
Me
Me
c
a
Table 1. Three-Component Reactions of 4-Halopyrazoles
a
Reaction conditions: pyrazole (0.50 mmol), NBD (1.0 mmol),
benzoxazole (0.50 mmol), Pd(OAc)2 (0.025 mmol), DPEPhos
(0.0375 mmol), TBAI (0.25 mmol), Cs2CO3 (1.0 mmol), 1,4-
b
dioxane (0.50 M), 130 °C, 16 h, under Ar. Isolated yields. Isolated
yield of the corresponding (NH)-free pyrazole after deprotection.
c
With NBE instead of NBD.
reactions to afford cis- and trans-diheteroaryl ethylenes and
polycyclic heteroaromatic systems.
In the studied systems, palladacycle formation depends on
the type of heteroarene and position of the halide
substituent.14 Our investigations started with iodopyrazoles,
NBE, and benzoxazole (Scheme 1). 4-Iodopyrazole 1a
afforded the corresponding three-component coupling product
2a via Pd−NBD adduct I (Scheme 1A). As cyclization of this
intermediate was hampered by the steric effect of the pyrazole
N-substituent, reaction with benzoxazole occurred instead.15 In
contrast, the 5-iodo counterpart furnished the 2:1 annulation
product 3a without detectable formation of other annulation
isomers or 4a (Scheme 1B). The selectivity toward trans-
isomer 3a is attributed to C(sp2)−C(sp2) reductive
elimination of the Pd(IV) intermediate II, which was formed
by oxidative addition of the corresponding palladacycle (see
Figure S1 for details).16
Based on the observed reactivity, optimization studies of the
three-component coupling reaction were conducted with 4-
halopyrazoles (Table 1). A combination of bromide 1a′ and
TBAI outperformed the iodide 1a or the bromide 1a′ alone
(entries 1−4).17 Ligand screening revealed that DPEPhos was
optimal (entries 5−7). Regarding the base, LiOtBu was
comparable to Cs2CO3, whereas K2CO3 was incompetent
(entries 8 and 9). High exo- and cis-selectivities were achieved
except when both TBAI and CuI were added (entries 10 and
11). However, the addition of CuI was useful to facilitate the
reaction with (benzo)thiazoles and benzimidazoles, which are
less prone to C−H functionalization than benzoxazole (vide
infra). The structures of isomers 5a and 5b were supported by
X-ray crystallography. The intriguing isomerization of 5a to 5b
was favored by the use of DMA as the solvent (entry 12).
Based on this finding, the epimerization and selective
deuterium incorporation at the junction of the functionalized
NBEs were developed (vide infra).
a
Reaction conditions: 4-halo-1-methyl-1H-pyrazole (0.50 mmol),
NBD (1.0 mmol), benzoxazole (0.50 mmol), Pd(OAc)2 (0.025
mmol), ligand (0.0375 mmol), base (1.0 mmol), 1,4-dioxane (0.50
M), 130 °C, 16 h, under Ar. Yields determined by H NMR with an
internal standard. ORTEP diagrams of 5a and 5b with anisotropic
displacement parameters at 50% probability. With 0.075 mmol
ligand instead. With CuI (0.25 mmol). With DMA instead of 1,4-
dioxane.
1
b
c
d
heteroarenes and NBD (Figure 1C), which contrasts with
similar transformations of six-membered haloarenes.13 Fur-
thermore, the resulting functionalized NBEs underwent rDA
B
https://dx.doi.org/10.1021/acs.orglett.0c03732
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 2. Substrate Scope of the Three-Component
Reaction
Table 3. Substrate Scope of the 2:1 Annulation Reaction:
Haloheteroarenes
a
a
a
Reaction conditions: heteroarene (0.50 mmol), NBD (1.0 mmol),
1,3-azole (0.50 mmol), Pd(OAc)2 (0.025 mmol), DPEPhos (0.0375
mmol), TBAI (0.25 mmol), Cs2CO3 (1.0 mmol), 1,4-dioxane (0.50
b
M), 130 °C, 16 h, under Ar. Isolated yields. With CuI (0.25 mmol).
c
With P(2-furyl)3 (0.075 mmol) instead of DPEPhos.
a
Reaction conditions: heteroarene (1.0 mmol), NBE or NBD (1.0
The optimized method was applied to various substituted
pyrazoles (Table 2). Alkyl, phenyl, and benzyl groups at the
nitrogen atom were all tolerated (R1, entries 1−7).
Furthermore, both (CH3)3SiCH2CH2OCH2- and 2-tetrahy-
dropyranyl-protected pyrazoles afforded the corresponding
three-component coupling products (entries 8 and 9). In
addition, 1,3-dimethylpyrazole furnished the desired product,
albeit in a moderate yield (entry 10). The reaction of
bromopyrazole 1a′ with NBE was more efficient than that of
the corresponding iodide 1a, producing 2a in 64% yield
(Scheme 1A vs Table 2, entry 11).
Next, the scope of the transformation was explored by
varying heteroarene components and bridged bicyclic alkenes
(Scheme 2). Benzoxazoles featuring different substituents on
the benzene core underwent a three-component coupling
reaction (6a−6d). Furthermore, substituted oxazoles were
coupled with 1a′ and NBD in the presence of CuI (6e and 6f).
The reactions of (benzo)thiazole and benzimidazole deriva-
tives also required CuI to facilitate C−H bond functionaliza-
tion (7a−7d and 8). In addition to bromopyrazoles,
bromothiophene derivatives were installed on the NBD ring
(9a−9c). However, their ambivalent character led to moderate
mmol), Pd(OAc)2 (0.050 mmol), DPEPhos (0.075 mmol), Cs2CO3
(1.5 mmol), PivOH (0.15 mmol), 1,4-dioxane (1.0 M), 130 °C, 16 h,
b
c
under Ar. Isolated yield. With TBAI (0.50 mmol). Regioisomers
d
were formed (16c/16a = 2.6:1). Regioisomers were formed (16d/
16b = 6:1).
yields owing to the formation of both Pd−NBD adducts and
palladacycles, and yields were not significantly improved by
switching ligands.9,14a Interestingly, the reaction of an indole
led to the corresponding trans-isomer 10 in high selectivity,
indicating that the steric demand of this substrate promoted
epimerization. Furthermore, substituted NBEs were amenable
to the three-component reaction, providing 2b and 2c in good
yields.
As an alternative to the synthesis of diheteroaryl ethylenes
by three-component reactions, the 2:1 annulation of
haloheteroarenes and bridged bicyclic alkenes toward fused
polycyclic heteroarenes was developed (Table 3). In these
examples with NBD, rDA reactions spontaneously occurred,
directly generating π-extended heteroarenes. The addition of
pivalic acid increased the yields of these annulation reactions
(see Table S2 for optimization studies). Iodoheteroarenes in
C
https://dx.doi.org/10.1021/acs.orglett.0c03732
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Table 4. Transformations of the Diheteroaryl NBE Products
a
b
Reaction conditions: 5a, 7a, or 9b (0.3 mmol), Cs2CO3 (0.15 mmol), DMA (0.50 M), 130 °C, 16 h. Reaction conditions: 5a, 7a, or 9b (0.2
c
mmol), Ph2O (0.10 M), 200 °C, 7 h. Reaction conditions: 5a, 7a, or 9b (0.3 mmol), Cs2CO3 (0.075 mmol), DMSO-d6 (0.50 M), 130 °C, 16 h.
d
The amounts of D incorporation are illustrated in brackets. Reaction conditions: 17c, 18c, or 19d (0.2 mmol), Ph2O (0.10 M), 200 °C, 7 h.
Isolated yields.
which the halide is adjacent to a substituted nitrogen atom
afforded the corresponding trans-annulation products (Table 3,
entries 1 and 2). The oxidative addition followed by C(sp2)−
C(sp2) reductive elimination illustrated in Scheme 1B accounts
for the formation of the trans-annulation products. Similar to
1b, the use of 11, NBD, and benzoxazole in the three-
component reaction only furnished 12b in 30% yield (not
shown), illustrating the influence of the halide position.
Analogously, the reactions of 3-bromothiophene were trans-
selective, providing exclusively 14a and 14b as annulation
products (entry 3). Importantly, TBAI had a significant effect
on the selectivity toward cis-annulated products, leading to the
formation of 14c and 14d, respectively (entry 4, cis/trans >
20:1). Presumably, the added halide salts provided halide-
bridged binuclear palladium complexes that favored the
C(sp2)−C(sp3) reductive elimination to the usual C(sp2)−
C(sp2) one (see Figure S1).18,19 Furthermore, a methyl
substituent on the thiophene core was tolerated in the trans-
annulation, whereas it considerably affected the cis-annulation
(entries 5 and 6). This result further supports the involvement
of halide salts in the selectivity-determining step, which was
sensitive to steric effects.
The developed Pd-catalyzed reactions of heteroarenes and
NBD allowed access to heteroarene-functionalized NBEs and
π-extended heteroaromatic systems (Table 4). By exploiting
the C−H bond acidity of azoles, the isolated cis-adducts 5a, 7a,
and 9b were successfully converted to the corresponding trans-
products 5b, 18a, and 19a, respectively. In addition,
elimination of cyclopentadiene by the rDA reaction occurred
upon heating at 200 °C. It was notable that the Z-
stereochemistry was retained for benzoxazole derivatives 17a
and 19b, whereas benzothiazole derivative 7a exclusively
afforded the E-isomer 18b. The carbon atoms at the junction
were deuterated by performing the isomerization in deuterated
DMSO (17c, 18c, and 19d).20 The selective deuterium
incorporation at this stage allows the subsequent preparation
of selectively deuterated 1,2-diheteroaryl alkenes (17d, 18d,
and 19e).
In conclusion, we have developed Pd-catalyzed reactions of
five-membered heteroaryl halides and NBD in which the latter
D
https://dx.doi.org/10.1021/acs.orglett.0c03732
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
serves as a building block and an acetylene synthon. The type
of heteroarene and position of the halide substituent affected
the reactivity of the Pd−NBD adduct intermediate. Pd−NBD
adducts with sterically demanding substituents underwent
direct coupling with the C−H bond of (benzo)azoles to afford
cis-diheteroaryl NBEs. Subsequently, epimerization of the
benzoazole-substituted carbon atom, optionally with concom-
itant deuteration, produced trans-diheteroaryl NBEs, which
were converted to diheteroaryl ethylenes. Alternatively, less
sterically hindered Pd−NBD adducts underwent palladacycle
formation. In this manner, 2:1 annulation of heteroaryl halides
and NBD furnished fused polycyclic heteroaromatic systems.
The selectivity resulting from the intrinsic reactivity of the
heteroarene-containing Pd complexes will be useful in the
development of new Pd-catalyzed reactions using NBD and
NBE as mediators and building blocks. In addition, practical
applications of the obtained heteroarene-functionalized NBEs
will be reported in due course.
Yunho Lee − Department of Chemistry, Seoul National
University, Seoul 08826, Republic of Korea; orcid.org/
0000-0002-9113-9491
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03732
Author Contributions
§S.J. and E.K. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Research
Foundation of Korea (NRF-2019R1A2C1007852 and NRF-
2019R1A4A1028007).
REFERENCES
■
(1) For reviews, see: (a) Lautens, M.; Klute, W.; Tam, W. Transition
Metal-Mediated Cycloaddition Reactions. Chem. Rev. 1996, 96, 49−
92. (b) Defieber, C.; Grutzmacher, H.; Carreira, E. M. Chiral Olefins
̈
ASSOCIATED CONTENT
■
sı
* Supporting Information
as Steering Ligands in Asymmetric Catalysis. Angew. Chem., Int. Ed.
2008, 47, 4482−4502. (c) Teo, Y. C.; Lai, H. W. H.; Xia, Y. Synthesis
of Ladder Polymers: Developments, Challenges, and Opportunities.
Chem. - Eur. J. 2017, 23, 14101−14112.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03732.
Experimental procedures, compound characterization
data, and NMR spectra (PDF)
(2) For recent examples of Pd-catalyzed addition to NBD, see:
(a) Liu, S.; Jin, Z.; Teo, Y. C.; Xia, Y. Efficient Synthesis of Rigid
Ladder Polymers via Palladium Catalyzed Annulation. J. Am. Chem.
Soc. 2014, 136, 17434−17437. (b) Yang, K.; Song, Q. Palladium-
Catalyzed Arylboration of Bicyclic Alkenes. J. Org. Chem. 2016, 81,
1000−1005. (c) Lai, H. W. H.; Teo, Y. C.; Xia, Y. Functionalized
Rigid Ladder Polymers from Catalytic Arene-Norbornene Annulation
Polymerization. ACS Macro Lett. 2017, 6, 1357−1361. (d) Lai, H. W.
H.; Liu, S.; Xia, Y. Norbornyl Benzocyclobutene Ladder Polymers:
Conformation and Microporosity. J. Polym. Sci., Part A: Polym. Chem.
2017, 55, 3075−3081. (e) Abdulhamid, M. A.; Lai, H. W. H.; Wang,
Y.; Jin, Z.; Teo, Y. C.; Ma, X.; Pinnau, I.; Xia, Y. Microporous
Polyimides from Ladder Diamines Synthesized by Facile Catalytic
Arene−Norbornene Annulation as High-Performance Membranes for
Gas Separation. Chem. Mater. 2019, 31, 1767−1774. (f) Annamalai,
P.; Hsiao, H.-C.; Raju, S.; Fu, Y.-H.; Chen, P.-L.; Horng, J.-C.; Liu, Y.-
H.; Chuang, S.-C. Synthesis, Isolation, and Characterization of Mono-
and Bis-norbornene-Annulated Biarylamines through Pseudo-Catella-
ni Intermediates. Org. Lett. 2019, 21, 1182−1186. (g) Ma, X.; Lai, H.
W. H.; Wang, Y.; Alhazmi, A.; Xia, Y.; Pinnau, I. Facile Synthesis and
Study of Microporous Catalytic Arene-Norbornene Annulation−
Accession Codes
CCDC 1969896 and 2041199 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.
AUTHOR INFORMATION
■
Corresponding Author
Jung Min Joo − Department of Chemistry and Chemistry
Institute for Functional Materials, Pusan National University,
Busan 46241, Republic of Korea; orcid.org/0000-0003-
1645-3322; Email: jmjoo@pusan.ac.kr
Authors
̈
Troger’s Base Ladder Polymers for Membrane Air Separation. ACS
Macro Lett. 2020, 9, 680−685.
Siyeon Jeong − Department of Chemistry and Chemistry
Institute for Functional Materials, Pusan National University,
Busan 46241, Republic of Korea
Eunmin Kim − Department of Chemistry and Chemistry
Institute for Functional Materials, Pusan National University,
Busan 46241, Republic of Korea
Minkyu Kim − Department of Chemistry and Chemistry
Institute for Functional Materials, Pusan National University,
Busan 46241, Republic of Korea
Ye Ji Hwang − Department of Chemistry and Chemistry
Institute for Functional Materials, Pusan National University,
Busan 46241, Republic of Korea
Birakishore Padhi − Department of Chemistry and Chemistry
Institute for Functional Materials, Pusan National University,
Busan 46241, Republic of Korea; orcid.org/0000-0002-
9649-5866
Jonghoon Choi − Department of Chemistry, Seoul National
University, Seoul 08826, Republic of Korea
(3) Bermeshev, M. V.; Chapala, P. P. Addition Polymerization of
Functionalized Norbornenes as a Powerful Tool for Assembling
Molecular Moieties of New Polymers with Versatile Properties. Prog.
Polym. Sci. 2018, 84, 1−46.
(4) (a) Catellani, M.; Motti, E.; Della Ca’, N. Catalytic Sequential
Reactions Involving Palladacycle-Directed Aryl Coupling Steps. Acc.
Chem. Res. 2008, 41, 1512−1522. (b) Martins, A.; Mariampillai, B.;
Lautens, M. Synthesis in the Key of Catellani: Norbornene-Mediated
ortho C−H Functionalization. Top. Curr. Chem. 2009, 292, 1−33.
(c) Ye, J.; Lautens, M. Palladium-Catalysed Norbornene-Mediated
C−H Functionalization of Arenes. Nat. Chem. 2015, 7, 863−870.
(d) Della Ca’, N.; Fontana, M.; Motti, E.; Catellani, M. Pd/
Norbornene: A Winning Combination for Selective Aromatic
Functionalization via C−H Bond Activation. Acc. Chem. Res. 2016,
49, 1389−1400. (e) Cheng, H.-G.; Chen, S.; Chen, R.; Zhou, Q.
Palladium(II)-Initiated Catellani-Type Reactions. Angew. Chem., Int.
Ed. 2019, 58, 5832−5844. (f) Wang, J.; Dong, G. Palladium/
Norbornene Cooperative Catalysis. Chem. Rev. 2019, 119, 7478−
7528. (g) Li, R.; Dong, G. Structurally Modified Norbornenes: A Key
E
https://dx.doi.org/10.1021/acs.orglett.0c03732
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Factor to Modulate Reaction Selectivity in the Palladium/
Norbornene Cooperative Catalysis. J. Am. Chem. Soc. 2020, 142,
17859−17875.
(8) For Pd-catalyzed C−H annulation reaction using NBD as an
acetylene synthon, see: (a) Hulcoop, D. G.; Lautens, M. Palladium-
Catalyzed Annulation of Aryl Heterocycles with Strained Alkenes.
Org. Lett. 2007, 9, 1761−1764. (b) Guimond, N.; Gorelsky, S. I.;
Fagnou, K. Rhodium(III)-Catalyzed Heterocycle Synthesis Using an
Internal Oxidant: Improved Reactivity and Mechanistic Studies. J. Am.
Chem. Soc. 2011, 133, 6449−6457.
(9) Padhi, B.; Kang, G.; Kim, E.; Ha, J.; Kim, H. T.; Lim, J.; Joo, J.
M. Pd-Catalyzed C−H Annulation of Five-Membered Heteroaryl
Halides with Norbornene Derivatives. ACS Catal. 2020, 10, 1792−
1798.
(10) For recent examples of Catellani reactions involving C−H
functionalization of five-membered heteroarenes, see: (a) Wang, P.;
Farmer, M. E.; Huo, X.; Jain, P.; Shen, P.-X.; Ishoey, M.; Bradner, J.
E.; Wisniewski, S. R.; Eastgate, M. D.; Yu, J.-Q. Ligand-Promoted
Meta-C−H Arylation of Anilines, Phenols, and Heterocycles. J. Am.
Chem. Soc. 2016, 138, 9269−9276. (b) Shi, H.; Wang, P.; Suzuki, S.;
Farmer, M. E.; Yu, J.-Q. Ligand Promoted meta-C−H Chlorination of
Anilines and Phenols. J. Am. Chem. Soc. 2016, 138, 14876−14879.
(c) Wang, P.; Farmer, M. E.; Yu, J.-Q. Ligand-Promoted meta-C−H
Functionalization of Benzylamines. Angew. Chem., Int. Ed. 2017, 56,
5125−5129. (d) Li, R.; Zhou, Y.; Xu, X.; Dong, G. Direct Vicinal
Difunctionalization of Thiophenes Enabled by the Palladium/
Norbornene Cooperative Catalysis. J. Am. Chem. Soc. 2019, 141,
18958−18963.
(11) Three-component coupling products from NBE, aryl halides,
and (6-nitro)benzoxazoles were formed as minor products. (a) Lei,
C.; Jin, X.; Zhou, J. Palladium-Catalyzed Heteroarylation and
Concomitant ortho-Alkylation of Aryl Iodides. Angew. Chem., Int.
Ed. 2015, 54, 13397−13400. (b) Zhang, P.; Pan, S.; Chen, W.; Liu,
M.; Wu, H. Palladium-Catalyzed Sequential Heteroarylation/
Acylation Reactions of Iodobenzenes: Synthesis of Functionalized
Benzo[d]oxazoles. J. Org. Chem. 2018, 83, 3354−3360.
(12) (a) Catellani, M.; Chiusoli, G. P.; Concari, S. A new palladium
catalyzed synthesis of cis,exo-2,3-diarylsubstituted bicyclo[2.2.1]-
heptanes or bicyclo [2.2.1] hept-2-enes. Tetrahedron 1989, 45,
5263−5268. (b) Shaulis, K. M.; Hoskin, B. L.; Townsend, J. R.;
Goodson, F. E.; Incarvito, C. D.; Rheingold, A. L. Tandem Suzuki
Coupling−Norbornadiene Insertion Reactions. A Convenient Route
to 5,6-Diarylnorbornene Compounds. J. Org. Chem. 2002, 67, 5860−
5863. (c) Zhao, X.; Bai, J.; Zeng, F.; Xing, Y.; Zhu, R.; Huang, J.
Direct Double Arylation of Bridged Alkenes and Efficient Bis-C−H
Alkylation of Benzamides. ChemistrySelect 2018, 3, 8040−8044.
(13) (a) Catellani, M.; Chiusoli, G. P. Palladium-catalyzed synthesis
of 1,2,3,4,4a,12b-hexahydro-1,4-methanotriphenylenes. J. Organomet.
Chem. 1985, 286, c13−c16. (b) Albrecht, K.; Reiser, O.; Weber, M.;
Knieriem, B.; Meijere, A. d. Palladium-Catalyzed Domino Coupling
Reactions of Aryl Halides with Norbornene and Norbornene
Derivatives − A Simple Route to Polycyclic Aromatic Compounds.
Tetrahedron 1994, 50, 383−401.
(14) (a) Mitsudo, K.; Thansandote, P.; Wilhelm, T.; Mariampillai,
B.; Lautens, M. Selectively Substituted Thiophenes and Indoles by a
Tandem Palladium-Catalyzed Multicomponent Reaction. Org. Lett.
2006, 8, 3939−3942. (b) Jang, J. H.; Ahn, S.; Park, S. E.; Kim, S.;
Byon, H. R.; Joo, J. M. Synthesis of Redox-Active Phenanthrene-
Fused Heteroarenes by Palladium-Catalyzed C−H Annulation. Org.
Lett. 2020, 22, 1280−1285.
(15) For the meta constraint in the Catellani reaction, see: Wang, J.;
Zhou, Y.; Xu, X.; Liu, P.; Dong, G. Entry to 1,2,3,4-Tetrasubstituted
Arenes through Addressing the “Meta Constraint” in the Palladium/
Norbornene Catalysis. J. Am. Chem. Soc. 2020, 142, 3050−3059.
(16) (a) Maestri, G.; Motti, E.; Della Ca’, N.; Malacria, M.; Derat,
E.; Catellani, M. Of the Ortho Effect in Palladium/Norbornene-
Catalyzed Reactions: A Theoretical Investigation. J. Am. Chem. Soc.
2011, 133, 8574−8585. (b) Malacria, M.; Maestri, G. Palladium/
Norbornene Catalytic System: Chelation as a Tool To Control
Regioselectivity of Pd(IV) Reductive Elimination. J. Org. Chem. 2013,
78, 1323−1328.
(5) For annulation by three-component coupling reactions with
NBD and retro-Diels−Alder reactions, see: (a) Fan, L.; Liu, J.; Bai, L.;
Wang, Y.; Luan, X. Rapid Assembly of Diversely Functionalized
Spiroindenes by a Three-Component Palladium-Catalyzed C−H
Amination/Phenol Dearomatization Domino Reaction. Angew. Chem.,
Int. Ed. 2017, 56, 14257−14261. (b) Fu, W. C.; Wang, Z.; Chan, W.
T. K.; Lin, Z.; Kwong, F. Y. Regioselective Synthesis of Polycyclic and
Heptagon-embedded Aromatic Compounds through a Versatile π-
Extension of Aryl Halides. Angew. Chem., Int. Ed. 2017, 56, 7166−
7170. (c) Cheng, M.; Yan, J.; Hu, F.; Chen, H.; Hu, Y. Palladium-
Catalyzed Cascade Reactions of 3-Iodochromones with Aryl Iodides
and Norbornadiene Leading to Annulated Xanthones. Chem. Sci.
2013, 4, 526−530. (d) Della Ca’, N.; Maestri, G.; Malacria, M.; Derat,
E.; Catellani, M. Palladium-Catalyzed Reaction of Aryl Iodides with
ortho-Bromoanilines and Norbornene/Norbornadiene: Unexpected
Formation of Dibenzoazepine Derivatives. Angew. Chem., Int. Ed.
2011, 50, 12257−12261.
(6) For reviews about C−H functionalization of heteroarenes, see:
(a) Ackermann, L.; Vicente, R.; Kapdi, A. R. Transition-Metal-
Catalyzed Direct Arylation of (Hetero)Arenes by C−H Bond
Cleavage. Angew. Chem., Int. Ed. 2009, 48, 9792−9826. (b) Cho, S.
H.; Kim, J. Y.; Kwak, J.; Chang, S. Recent Advances in The Transition
Metal-Catalyzed Twofold Oxidative C−H Bond Activation Strategy
for C−C and C−N Bond Formation. Chem. Soc. Rev. 2011, 40, 5068−
5083. (c) Wencel-Delord, J.; Glorius, F. C−H Bond Activation
Enables the Rapid Construction and Late-Stage Diversification of
Functional Molecules. Nat. Chem. 2013, 5, 369−375. (d) Segawa, Y.;
Maekawa, T.; Itami, K. Synthesis of Extended π-Systems through C−
H Activation. Angew. Chem., Int. Ed. 2015, 54, 66−81. (e) Liu, C.;
Yuan, J.; Gao, M.; Tang, S.; Li, W.; Shi, R.; Lei, A. Oxidative Coupling
between Two Hydrocarbons: An Update of Recent C−H
Functionalizations. Chem. Rev. 2015, 115, 12138−12204. (f) Bheeter,
C. B.; Chen, L.; Soule, J.-F.; Doucet, H. Regioselectivity in Palladium-
Catalysed Direct Arylation of 5-Membered Ring Heteroaromatics.
Catal. Sci. Technol. 2016, 6, 2005−2049. (g) Zhu, R.-Y.; Farmer, M.
E.; Chen, Y.-Q.; Yu, J.-Q. A Simple and Versatile Amide Directing
Group for C−H Functionalizations. Angew. Chem., Int. Ed. 2016, 55,
10578−10599. (h) Yang, Y.; Lan, J.; You, J. Oxidative C−H/C−H
Coupling Reactions between Two (Hetero)Arenes. Chem. Rev. 2017,
117, 8787−8863. (i) Choy, P. Y.; Wong, S. M.; Kapdi, A.; Kwong, F.
Y. Recent developments in palladium-catalysed non-directed coupling
of (hetero)arene C−H bonds with C−Z (Z = B, Si, Sn, S, N, C, H)
bonds in bi(hetero)aryl synthesis. Org. Chem. Front. 2018, 5, 288−
321. (j) Kang, E.; Kim, H. T.; Joo, J. M. Transition-metal-catalyzed
C−H functionalization of pyrazoles. Org. Biomol. Chem. 2020, 18,
6192−6210.
(7) For a representative review, see: (a) Stockdale, T. P.; Williams,
C. M. Pharmaceuticals that contain polycyclic hydrocarbon scaffolds.
Chem. Soc. Rev. 2015, 44, 7737−7763. For recent examples, see:
(b) Ruffoni, A.; Ferri, N.; Bernini, S. K.; Ricci, C.; Corsini, A.;
Maffucci, I.; Clerici, F.; Contini, A. 2-Amino-3-(phenylsulfanyl)-
norbornane-2-carboxylate: An Appealing Scaffold for the Design of
Rac1−Tiam1 Protein−Protein Interaction Inhibitors. J. Med. Chem.
2014, 57, 2953−2962. (c) Manetti, D.; Garifulina, A.; Bartolucci, G.;
Bazzicalupi, C.; Bellucci, C.; Chiaramonte, N.; Dei, S.; Di Cesare
Mannelli, L.; Ghelardini, C.; Gratteri, P.; Spirova, E.; Shelukhina, I.;
Teodori, E.; Varani, K.; Tsetlin, V.; Romanelli, M. N. New Rigid
Nicotine Analogues, Carrying a Norbornane Moiety, Are Potent
Agonists of α7 and α3* Nicotinic Receptors. J. Med. Chem. 2019, 62,
1887−1901. (d) Hansen, B. B.; Jepsen, T. H.; Larsen, M.; Sindet, R.;
Vifian, T.; Burhardt, M. N.; Larsen, J.; Seitzberg, J. G.; Carnerup, M.
́
A.; Jerre, A.; Mølck, C.; Lovato, P.; Rai, S.; Nasipireddy, V. R.; Ritzen,
A. Fragment-Based Discovery of Pyrazolopyridones as JAK1
Inhibitors with Excellent Subtype Selectivity. J. Med. Chem. 2020,
63, 7008−7032.
F
https://dx.doi.org/10.1021/acs.orglett.0c03732
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(17) For the halide effect in the Catellani reaction, see: Dong, Z.; Lu,
G.; Wang, J.; Liu, P.; Dong, G. Modular ipso/ortho Difunctionaliza-
tion of Aryl Bromides via Palladium/Norbornene Cooperative
Catalysis. J. Am. Chem. Soc. 2018, 140, 8551−8562.
(18) Dupont, J.; Consorti, C. S.; Spencer, J. The Potential of
Palladacycles: More Than Just Precatalysts. Chem. Rev. 2005, 105,
2527−2572.
́
(19) Larraufie, M.-H.; Maestri, G.; Beaume, A.; Derat, E.; Ollivier,
̂
C.; Fensterbank, L.; Courillon, C.; Lacote, E.; Catellani, M.; Malacria,
M. Exception to the ortho Effect in Palladium/Norbornene Catalysis.
Angew. Chem., Int. Ed. 2011, 50, 12253−12256.
(20) Wang, D.; Chen, S.; Wang, J.; Astruc, D.; Chen, B. Base-
Catalyzed Hydrogen−Deuterium Exchange and Dehalogenation
Reactions of 1,2,3-Triazole Derivatives. Tetrahedron 2016, 72,
6375−6379.
G
https://dx.doi.org/10.1021/acs.orglett.0c03732
Org. Lett. XXXX, XXX, XXX−XXX