Synthesis, Isolation, and Characterization of Mono- and Bis-norbornene-Annulated Biarylamines through Pseudo-Catellani Intermediates

Article abstract of DOI:10.1021/acs.orglett.9b00119

A palladium-catalyzed C-H functionalization of an external ring of N-acyl 2-aminobiaryl with bicyclo[2.2.1]hept-2-ene (norbornene) via multiple C-H bond activations was developed. This study is the first report of the formation of bis-norbornene annulated biarylamines isomers (syn-3a′/anti-3a′ = 36:64) from multiple C-H bond functionalizations. Additionally, nondirected C-H bond functionalization at the C-4′ position with alkenes rendered complete C-H functionalization of five C-H bonds that formed a stable hexasubstituted benzene ring.

Full text of DOI:10.1021/acs.orglett.9b00119

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis, Isolation, and Characterization of Mono- and Bis-
norbornene-Annulated Biarylamines through Pseudo-Catellani
Intermediates
Pratheepkumar Annamalai,† Huan-Chang Hsiao,† Selvam Raju,† Yi-Hsuan Fu,‡ Pei-Ling Chen,‡
Jia-Cherng Horng,‡ Yi-Hung Liu,§ and Shih-Ching Chuang*,†
†Department of Applied Chemistry, National Chiao Tung University, Hsinchu 30010, Taiwan
‡Department of Chemistry, National Tsing Hua University, Hsinchu 30010, Taiwan
§Instrumentation Center, National Taiwan University, Taipei 10617, Taiwan
S
* Supporting Information
ABSTRACT: A palladium-catalyzed C−H functionalization
of an external ring of N-acyl 2-aminobiaryl with bicyclo[2.2.1]-
hept-2-ene (norbornene) via multiple C−H bond activations
was developed. This study is the first report of the formation of
bis-norbornene annulated biarylamines isomers (syn-3a′/anti-
3a′ = 36:64) from multiple C−H bond functionalizations.
Additionally, nondirected C−H bond functionalization at the C-4′ position with alkenes rendered complete C−H
functionalization of five C−H bonds that formed a stable hexasubstituted benzene ring.
Scheme 1. Previous Work and Our Findings
n recent years, C−H functionalization has become a
Ipopular research topic in organometallic chemistry and
catalysis.1 Site-selective activation and functionalization of inert
C−H bonds through regioselective and stereoselective
processes have been the foci of relevant studies.2 In 1997,
Catellani demonstrated palladium-catalyzed Heck-type ipso
and ortho aryl carbon functionalization in which norbornene
was used as a transient mediator.3 Subsequently, the Catellani
strategy was utilized to prepare arenes with diverse functional
moieties in both ipso and ortho positions.2f,4 The Catellani
reaction was also applied to prepare natural products and
medicinal molecules such as (+)-linoxepin,5 rhazinal,6
goniomitine, and aspidospermidine7 and various classes of
condensed heterocyclic compounds as well as polycyclic and
polyheterocyclic aromatic hydrocarbons.2a,f,8 Expanding the
scope of the Catellani reaction, Zhou et al. demonstrated
Heck−Catellani reactions involving aryl halide and norbornene
to produce strained norbornene-annulated arenes by using
palladium as a catalyst and PtBu3 as a ligand (Scheme 1a).9
Jiang et al. described C−H bond activation and oxidative
cyclization of acetanilide with norbornene to produce indolines
(Scheme 1b).10 Yu et al. reported site-selective ligand-enabled
direct meta C−H functionalization using norbornene as a
transient mediator, which provided a new pathway for site-
selective meta C−H functionalization with a wide variety of
functional groups such as aryls, amines, alkyls, and alkynes
(Scheme 1c).11 Protected and unprotected amino-containing
groups in aromatic and aliphatic substrates are potential
directing moieties and have been utilized in the synthesis of
various nitrogen-containing heterocycles ranging from bio-
active molecules to material science applications.2f,7,12 In
numerous studies, free amines or N-substituted amines have
been used as directing groups under various metal catalysts
such as Pd, Rh, Ru, Co, Cu, and Ir.13 In this context, our
research group demonstrated palladium-catalyzed C2′−H
activation of N-tosyl 2-aminobiaryls followed by the insertion
of [60]fullerene and CO to yield fullerobenzoazepines14 and
phenanthridinones, respectively.15 We also achieved the
aromatic homologation of N-acyl 2-aminobiaryls through
oxidative ortho/meta insertion of two diphenyl acetylenes.16
Received: January 10, 2019
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.9b00119
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Scheme 2. Substrate Scope of Various N-Acylbiarylaminesa
Recently, Yu et al. reported meta-selective C−H arylation of
nosyl-protected phenethylamines, benzylamines, and 2-aryla-
nilines.12b Additionally, Ling et al. demonstrated the
interannular meta-selective C−H arylations of biaryl-2-
trifluoroacetamides using Pd(II)/norbornene catalysis.17 It is
noteworthy that formation of norbornene-annulated arenes
was described as a pitfall in ligand-enabled direct meta C−H
functionalization.11b,c,18 Although mononorbornene annulation
through a C−H activation process has been described by
Yu,12b Takemoto,19 and Hong,20 respectively, their syntheses
provided poor yields and limited scopes and were not
applicable to double annulations in the biaryl system.
However, we perceived that bis-norbornene-annulated
biaryls through double C−H activations were previously
inaccessible.19,20 The target, a bis-norbornene-annulated
arene, can be separated to give chiral auxiliary molecules for
possible application in asymmetric catalysis.21 In our study of
palladium-catalyzed selective meta functionalization of N-acyl
2-aminobiaryls using activated olefins as a coupling partner and
norbornene as a transient mediator, we happened to isolate
bulk intermediate products from oxidative cyclization of
norbornene with N-acyl 2-aminobiaryls.
This indicated that formation of norbornene-annulated
arenes through reductive elimination was faster than
subsequent reaction with electrophiles toward meta function-
alization in the N-acyl 2-aminobiaryl system. Here, we report
the isolation and characterization of mono- and bis-
norbornene-annulated arenes from direct multiple C−H
activations of N-acyl 2-aminobiaryls. The major products,
syn-3a′/anti-3a′ = 36:64, were formed when two norbornenes
underwent insertion/reductive elimination, and minor prod-
ucts were formed with the mononorbornene functionalization
under palladium catalysis using Cu(OAc)2/O2 as oxidants at
120 °C for 24 h (Scheme 1d). The absolute configurations of
syn-3a′/anti-3a′ products were determined using single-crystal
X-ray diffraction and circular dichroism measurements after
separation of diastereomers and enantiomers. The substrate
scope of various bicyclic alkenes was also studied. Additionally,
nondirected C−H bond functionalization at the C-4′ position
with alkenes rendered complete C−H functionalization of five
C−H bonds that formed a stable hexasubstituted benzene ring
system.
We first evaluated condition optimization for preparation of
3a′ and 3a (see the Table S1). Scheme 2 summarizes the
reaction scope study of multiple C−H bond activation and
norbornene insertion followed by reductive elimination that
rendered formation of the major bis-norbornene annulated
compounds syn-3′/anti-3′ and the minor mononorbornene-
annulated compound 3. The bis-norbornene annulated
compounds contained syn-3′ and anti-3′. The anti-isomer
anti-3a′ exhibited a pair of chiral enantiomers, (R)-anti-3a′ and
(S)-anti-3a′, due to its chiral axis. These isomers were
practically separated using chiral high-performance liquid
chromatography (HPLC), and the isomers syn-3a′, (R)-anti-
3a′, and (S)-anti-3a′ were characterized using single-crystal X-
ray diffraction with CuKα as a source. To study the scope of
mononorbornene annulation, we used substrates with different
electron-donating groups (EDGs) and electron-withdrawing
groups (EWGs) in the C-3′ position of N-acyl 2-aminobiaryl-
amines. The reactivity of the studied substrates was highly
dependent on the electronic effect exerted by the substitutions
on the aryl moieties of N-acyl 2-aminobiaryls and the structural
moiety of bicyclic alkenes. Substrates containing EDGs on the
a
All reactions were conducted using 1 (0.30 mmol), 2a (0.9 mmol),
NaOAc (1.0 equiv), Pd(OAc)2 (10 mol %), and Cu(OAc)2 (1.0
equiv)/O2 (1 atm) in 2 mL DMF at 120 °C for 24 h. NaOPiv (1.0
equiv) was used instead of NaOAc.
b
bottom ring underwent smooth dual C−H bond activation and
coupling with a norbornene, resulting in moderate to good
yields (Scheme 2, 3b−h, 67−84%).
This result is likely attributable to the enhanced reactivity of
the bottom ring toward C−H bond activation and reductive
annulation promoted by the EDGs. Substrates containing an
EWG exhibited relatively poor reactivity toward C−H bond
activation or coupling with norbornene, and they had
moderate yields (3i−k, 48−58%). The sterically bulky 1-
naphthyl group exhibited coupling, but it enabled formation of
diastereomers syn-3l/anti-3l and syn-3m/anti-3m isomers in a
50:50 ratio (78−88% yields). Additionally, the substrate with
the 3′-position bearing EWG such as the Cl, Br, and I (1n−p)
moiety underwent oxidative annulation to produce the double-
norbornene annulated product 3a′ (35−52%) and mono-
norbornene-annulation products 3a and 3n,o (15−28%). In
the case of iodo-substitution, only trace mononorbornene-
annulated product was observed. Substrates with a C-4 Me or
C-4′ Me group also had high yields through quadruple bond
C−H activation products and corresponding mononorbornene
annulation products (3q′,r′ and 3q,r, 76−77%), with
diastereometric ratios of 32:68 and 48:52, respectively.
Furthermore, substrates without meta protection on the
bottom aryl moiety and with EWGs, such as 4-F and 4-Cl
groups, on their top rings provided moderate yields through
quadruple bond C−H activation and corresponding mono-
annulation products (3s′,t′ and 3s,t, 62−78%), with
diastereometric ratios of 34:66 and 33:67, respectively.
We also studied the norbornene annulation toward the
bicyclic alkenes 2b−f (Scheme 3). In the case with
norbornadiene 2b, the yield was low at 16% (85% based on
converted reactants) (Scheme 3, 3u); this was likely due to its
B
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a
alkenylation to give 6e′ with a yield of 50% (syn-6e′/anti-6e′
= 40:60). The reactants, 3t′ and 3s′, also underwent
alkenylation to provide 6f′ and 6g′ with yields of 76 and
60%, respectively.
Scheme 3. Substrate Scope of Various Bicyclic Alkenes
Figure 1 represents the Oak Ridge Thermal Ellipsoid Plot
solid-state structures of pure syn-3a′, (R)-anti-3a′, and (S)-
a
All reactions were conducted using 1 (0.10 mmol), 2a (0.3 mmol),
NaOPiv (1.0 equiv), Pd(OAc)2 (10 mol %), and Cu(OAc)2 (1.0
b
equiv)/O2 (1 atm) in 2 mL DMF at 120 °C for 36 h. 1a (0.3 mmol),
2a (0.9 mmol), Pd(OAc)2 (10 mol %), and AgOAc (3.0 equiv) under
N2 at 120 °C for 24 h.
coordinative effect on palladium.19 By contrast, electron-
deficient bicyclic alkenes (2c,d) with EDG- and EWG-
substituted N-acyl biarylamine underwent annulation with
moderate yields (3v−y, 47−68%). Reactions with N-Boc-7-
azabenzonorbornadiene (2e) produced 3z with a yield of 51%;
however, the reaction with 7-oxabenzonorbornene did not give
the desired product. Interestingly, reactions with cyclo-
pentadiene dimer 2f provided moderate yields of inseparable
isomers (3za, 76:24), and their regiochemistry could not be
exactly determined. Other biaryl systems, namely 2-phenyl-
azoles and 2-phenylpyridine, were also tested, but only 2-
phenylazole provided norbornene-annulated product 3zab
with a yield of 24% under the optimized conditions.
Figure 1. Solid-state structure of (a) syn-3a′, (b) (R)-anti-3a′, and (c)
(S)-anti-3a′.
anti-3a′ isomers drawn with 50% probability, with hydrogens
omitted for clarity. These isomers were practically separated
through HPLC on a CHIRALPAK IG column with hexanes/2-
propanol (v/v 70/30) as eluents. These single crystals in the
form of thin white needles can be prepared from their hexane
solutions through slow evaporation at room temperature.
Isomers syn-3a′, (R)-anti-3a′, and (S)-anti-3a′ crystallized in
space groups P212121 (orthorhombic), P21 (monoclinic), and
P21 (monoclinic), respectively. The isomer syn-3a′ was achiral
due to the plane of symmetry, and the isomers (R)-anti-3a′
and (S)-anti-3a′ were a mutual pair of enantiomers. For isomer
syn-3a′, the NHAc moiety rested on a less hindered side that is
on a different face compared to that of the [2.2.1]
bicyclooctane ring.
The typical dihedral angles φC31C36C37C54,
φC54C53C52C56, and φC38C39C40C55 were 57.8(5)°,
58.8(4)°, and −58.0(4)°, respectively. For chiral (R)-anti-
3a′, the typical dihedral angles φC8C7C6C11,
φC5C20C21C22, and φC11C12C13C24 were 69.0(3)°,
−58.8(2)°, and −56.2(2)°, respectively. The typical bond
angles around the annulated norbornene moiety
∠C12C11C18 and ∠C11C12C17 were 93.7(2)° and
86.0(1)°, respectively. For chiral (S)-anti-3a′, the typical
dihedral angles φC8C7C6C5, φC5C4C3C22, and
φC11C18C17C19 were −151.7(2)°, −57.9(2)°, and
−59.0(2)°, respectively.
The versatility of the developed strategy was systematically
examined in various control experiments (Scheme 5). The
stepwise oxidative coupling of 3a with norbornene was
confirmed to produce 3a′ with a yield of 66% (Scheme 5a).
Compound 3a underwent intramolecular oxidative C−N
coupling to produce carbazole with a yield of 70% (Scheme
5b). Aromatic homologation of 3a with diphenylacetylene
produced isomer syn-5ab and anti-5ab (1:1) with a yield of
86% (Scheme 5c). Compound 3ab underwent oxidative
coupling with norbornene to give a moderate yield of syn-
5ab and anti-5ab (1:1) (Scheme 5d). Oxidative coupling of 3a
The plausible catalytic cycle, kinetic isotopic effect study
(KIE), circular dichroism (CD) of (R)-anti-3a′ and (S)-anti-
1
3a′, and H NMR plots of all isomers were studied (see
descriptions in Schemes S1 and S2 and Figures S1 and S2).
Scheme 4 summarizes the reaction scope study of nondirected
Scheme 4. Nondirected C−H Bond Functionalization
C−H bond activation and oxidative insertion of various
activated olefins followed by reductive elimination to form syn-
6a′/anti-6a′. We examined the reaction scope with substituted
olefins (4a−d). The reaction of 3a′ (a mixture of syn-3a′ and
anti-3a′) with acrylate 4a produced C-4′-activated product 6a′
with a yield of 64% (syn-6a′/anti-6a′ = 37:63). Similarly,
reactions with phenyl vinyl sulfone 4b produced 6b′ with a
yield of 54% (syn-6b′/anti-6b′ = 26:74). The reaction with
diethylvinyl phosphonate 4c also provided the selective
product 6c′ (syn-6c′/anti-6c′ = 40:60), but the yield was
40%. Substrate acrylonitrile 4d was also tolerated in this
alkenylation and produced 6d′ (syn-6d′/anti-6d′ = 28:72)
with a yield of 45%. The reactant 3r′ also underwent
C
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Notes
Scheme 5. Functionalization of 3a with Versatile Reactivity
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Ministry of Science and Technology of Taiwan
for supporting this research financially (MOST104-2113-M-
009-014-MY3 and MOST105-2628-M-009-002-MY3).
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inseparable syn-5ac and anti-5ac (1:1) with a yield of 56%
(Scheme 5e). Similarly, oxidative coupling of 3a with methyl
acrylates followed by Michael addition produced dihydrophe-
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(Scheme 5f).
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formation of bis-norbornene-annulated biarylamines isomers
through dual and quadruple oxidative cyclization of norbor-
nene with N-acyl 2-aminobiaryls via ortho and meta C−H bond
activation/insertion/reductive elimination sequences. The
versatility and synthetic utility of stepwise C−H bond
activation with different reactive functional substrates were
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position provided a penta C−H activation product with the
complete functionalization of aromatic systems. This finding
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00119.
■
S
1
Detailed experimental procedures, spectral data, and H
13
and spectra for compounds (PDF)
Accession Codes
CCDC 1848316−1848318, 1848323−1848324, 1849514, and
1858119 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
*E-mail: jscchuang@faculty.nctu.edu.tw.
ORCID
Jia-Cherng Horng: 0000-0002-9936-5338
Shih-Ching Chuang: 0000-0002-6926-9812
D
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