The C-H Activation/Bidirecting Group Strategy for Selective Direct Synthesis of Diverse 1,1′-Biisoquinolines

Article abstract of DOI:10.1021/acs.orglett.0c01260

Multidentate ligands are highly important but difficult to access. Herein we disclose an atom- and step-economic synthesis of highly substituted 1,1′-biisoquinolines by a C-H activation/bididirecting group strategy. Through rational design of a bididirecting group to "N-OH + N-OAc", selective unsymmetrical diannulation with two different alkynes in a one-pot reaction has been achieved for the first time to access unsymmetrical biisoquinolines. Moreover, the resultant biisoquinolines show tunable photoluminescence and serve as aggregation-induced emission (AIE) systems.

Full text of DOI:10.1021/acs.orglett.0c01260

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Letter
The C−H Activation/Bidirecting Group Strategy for Selective Direct
Synthesis of Diverse 1,1′-Biisoquinolines
Shiqing Li,* Hongxu Lv, Rongrong Xie, Yu Yu, Xiuqing Ye, and Xiangfei Kong*
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ABSTRACT: Multidentate ligands are highly important but difficult to
access. Herein we disclose an atom- and step-economic synthesis of
highly substituted 1,1′-biisoquinolines by a C−H activation/bididirect-
ing group strategy. Through rational design of a bididirecting group to
“N−OH + N−OAc”, selective unsymmetrical diannulation with two
different alkynes in a one-pot reaction has been achieved for the first
time to access unsymmetrical biisoquinolines. Moreover, the resultant
biisoquinolines show tunable photoluminescence and serve as aggregation-induced emission (AIE) systems.
xially chiral biaryl compounds, such as the well-known
BINAP, BINOL, and their diverse derivatives, have
and give H2O as the byproduct. For example, the synthesis of
isoquinolines through DGox-mediated annulation of aromatic
oximes,7 imines,8 hydrazone,9 azines,10 and azides11 with
alkynes using Rh, Ru, or Co as the catalyst has been well-
developed. Glorius12a and Qi12b reported the RhIII-catalyzed
C−H activation/1,3-diyne strategy to access 3,3′-biisoquino-
lines and 3,4′-biisoquinolines, respectively (Scheme 1a). More
recently, Volla and co-workers reported the RuII-catalyzed C−
H activation/1,3-diyne strategy to form 4,4′-biisoquinolines
(Scheme 1b).13 However, the synthesis of 1,1′-biisoquinoline
derivatives through transition-metal-catalyzed C−H activation
has not been reported, and to the best of our knowledge,
selective unsymmetrical diannulation with two different
alkynes in one pot has not been described to date.14 In this
context, we envisaged that a bidirecting group (BIDG), that is,
two DGs connected with a single bond, such as a dioxime,
would react with an alkyne to generate a 1-oximido
isoquinoline, which would then annulate with another alkyne
to afford the 1,1′-biisoquinoline (Scheme 1c).
A
received considerable attention because they can be used as
privileged ligands in asymmetric catalysis (Figure 1).1 Their
Figure 1. Axially chiral biaryl ligands.
analogues, 1,1′-biisoquinolines, showed privileged coordina-
tion with metal species, and their complexes have attractive
photophysical properties.2 Chiral 1,1′-biisoquinoline N,N′-
dioxides have shown superior catalytic capacity in asymmetric
propargylation reactions.3 Unexpectedly, we found that the
structural diversity of 1,1′-biisoquinoline (N,N′-dioxides) is
only limited to a few symmetrical ones with −H or −Ph at the
3- and 3′-positions.2−4 One of the possible reasons for the rare
diversity of 1,1′-biisoquinoline derivatives is a tedious synthetic
procedure. Another reason may be the high cost of direct
functionalization of very expensive 1,1′-biisoquinoline. In
addition, transition-metal-catalyzed direct C−H functionaliza-
tion of multidentate ligands poses a great challenge because
coordination of the substrate with the metal species may
inhibit the catalysis.5 Thus, the development of an efficient
method to synthesize 1,1′-biisoquinolines is urgently needed.
In recent decades, transition-metal-catalyzed C−H bond
functionalization has developed as a promising strategy for
organic synthesis.6 However, in oxidative C−H functionaliza-
tion, stoichiometric oxidants such as peroxides or metal
oxidants are generally required. Oximes are employed as
oxidizing directing groups (DGox) without external oxidants
In the frame of our interest in the synthesis and application
of polyaryl N-heterocyclic compounds,15 in this work we
examined the possibility of RhIII-catalyzed dual C−H
activation/annulation of dioxime derivatives with alkynes to
yield polyaryl 1,1′-biisoquinolines. Through rational design of
the BIDGs and reaction conditions, we overcame the
challenges of inhibition through coordination, the steric
hindrance effect, and selectivity to assemble symmetrical and
Received: April 10, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01260
© XXXX American Chemical Society
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A

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a
Scheme 1. Synthesis of Biisoquinolines via C−H Activation
Scheme 2. Scope of Dioximes
unsymmetrical 1,1′-biisoquinolines with high efficiency and
good selectivity.
Initially, benzil dioxime (1a) (BIDG = N−OH/N−OH)
and diphenylacetylene (2a) were selected as the model
substrates, and [RhCp*Cl2]2 (2.5 mol %) was used as a
catalyst. As shown in Table S1, a catalytic amount of NaOAc
proved innocent in the diannulation, and the monoannulated
compound 7 was generated (Table S1, entries 1−3). The
target biisoquinoline 3a was isolated in a good yield of 80%
after chromatography on silica gel when 2 equiv of NaOAc was
used (entry 4). Diannulated 3a was not formed, and only
monoannulated 7 was generated in 20% yield, when the
loading of [Cp*RhCl2]2 was reduced to 1 mol % (entry 5).
The reaction ceased in the absence of [Cp*RhCl2]2 or when
other catalysts (e.g., Ru and Ir) were used instead (entry 6).
Pleasingly, when TsOH·H2O was employed as the additive, 3a
was obtained in an excellent yield of 93% (entry 8). More
interestingly, 3a precipitated from the reaction solvent and
could be gained in a high yield of 87% just by filtration (entry
9).16 When O,O-diacetyl dioxime (1a-diOAc) was used
instead of 1a, 3a was obtained in 96% yield after filtration
(for details, see Table S2).
With the optimal conditions in hand, the scope of dioximes
was first investigated (Scheme 2). Various symmetrical
dioximes possessing either an electron-donating or electron-
withdrawing functionality (1b−e) could diannulate with 2a
smoothly to deliver the desired 1,1′-biisoquinolines in
moderate to high yields (3b−e). It is noted that although
three regioisomers might be generated from meta-substituted
dioxime in diannulation, here only one type of regioisomer
(3f), annulated at sterically less hindered sites, was generated
in 76% yield. o-Methyl dioxime was not compatible with this
diannulation, which might be due to strong steric hindrance
between the two methyl groups. To our delight, unsymmetrical
dioximes could smoothly react with 2a to give the target
unsymmetrical biisoquinolines 3h−j in good to excellent
yields. To the best of our knowledge, this is the first example of
the synthesis of unsymmetrical 1,1′-biisoquinolines. Notably,
a
Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), [RhCp*Cl2]2
(2.5 mol %), TsOH·H2O (25 mol %), and NaOAc (2 equiv) in
MeOH (2 mL) at 110 °C for 12 h under a N2 atmosphere. Isolated
b
yields after filtration are shown. 1a-diOAc was used instead of 1a.
c
At 120 °C.
all of the products could be obtained simply by filtration
without further processing.
Then the scope of alkynes was tested with 1a and 1a-diOAc
under conditions A and B, respectively (Scheme 3). Both 1a
and 1a-diOAc could react with various alkynes smoothly to
deliver the corresponding 1,1′-biisoquinolines 4b−m in
moderate to excellent yields, and the structure of 4g was
determined by single-crystal X-ray diffraction. Hex-3-yne
reacted with 1a to afford tetraalkyl-substituted molecule 4n
in 77% yield. Upon treatment of alkyl aryl alkynes with 1a, two
types of regioisomers were generated (4o and 4p).
With the success of symmetrical diannulation with the same
alkyne, we turned our attention to one-pot sequential
diannulation with two different alkynes, which needed two
separate steps in previous reports.14 1a was treated with 1
equiv of alkyne 2a under the conditions of [RhCp*Cl2]2 (2.5
mol %) and NaOAc (1 equiv) for 5 h (step 1), and then alkyne
2f, additional NaOAc (1 equiv), and TsOH·H2O (25 mol %)
were added and allowed to react for a further 10 h (step 2).
However, all the three isomers, cross-annulated 5af and
homoannulated 3a and 4f, were generated with poor selectivity
(Scheme 4, eq 1). Also, poor selectivity was observed in the
one-pot, two step reaction of 1a-diOAc, 2a, and 2f (Scheme 4,
eq 2). Finally, we synthesized benzil O-acetyl dioxime (1a-
OH/OAc), a “mixed BIDG” containing one N−OH and one
N−OAc. 1a-OH/OAc was treated with 2a under the
conditions of [RhCp*Cl2]2 (2.5 mol %) and NaOAc (0.3
B
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Scheme 3. Scope of Alkynes
Scheme 4. Selectivity of Unsymmetrical Diannulation
Scheme 5. One-Pot Unsymmetrical Diannulation with Two
a
Different Alkynes
a
Condition A: 1 (0.2 mmol), 2 (0.4 mmol), [RhCp*Cl2]2 (2.5 mol
%), TsOH·H2O (25 mol %), and NaOAc (2 equiv) in MeOH (2 mL)
b
at 110 °C for 12 h. Condition B: 1a-diOAc (0.2 mmol), 2 (0.4
mmol), [RhCp*Cl2]2 (2.5 mol %), and NaOAc (0.6 equiv) in MeOH
c
a
(2 mL) at 100 °C for 10 h. Yield after chromatography on silica gel.
Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), [RhCp*Cl2]2
d
e
Yield after filtration. Only the main regioisomer is shown.
(2.5 mol %), and NaOAc (0.3 equiv) in MeOH (1 mL) at 100 °C for
1 h, then addition of another alkyne (0.1 mmol), NaOAc (2 equiv),
and TsOH·H2O (25 mol %) and further reaction at 100 °C for 10 h.
Isolated yields after chromatography are shown.
equiv) for 1 h (step 1), followed by addition of alkyne 2f and a
further 10 h of reaction (step 2). To our delight, cross-
annulated 5af was exclusively generated in a good yield of 75%
with excellent selectivity (Scheme 4, eq 3).
With the selective conditions in hand, we chose various
alkynes to annulate with 1a-OH/OAc, leading to the title
unsymmetrical 1,1′-biisoquinolines 5ac−ig in good yields with
high selectivities (Scheme 5). For example, using 2a for the
first annulation and substituted alkynes for the second one
afforded biisoquinolines 5ac−ai in 53−82% yield with good
selectivities. The sequential diannulation of p-Cl (2i) and p-
OMe (2g) substituted alkynes with 1a-OH/OAc afforded
multifunctionalized unsymmetrical biisoquinoline 5ig in 55%
yield.
obtained in high yield after oxidation of 3a (Scheme 6, eq
5), which may applied to asymmetric catalysis after chiral
resolution. It is noted that both the 1,1′-biisoquinoline and its
N,N′-dioxide could be synthesized in a quicker and more
efficient way than before.
To gain more insight into the mechanism of this reaction, a
H/D exchange experiment was first conducted in the absence
of 2a. Deuterium incorporation of 15% was observed at the
ortho position of 1a. Notably, 1a-diOAc was hydrolyzed into
1a with 46% deuterium incorporation (Scheme 7, eq 6).
Moreover, an identical kinetic isotope effect (KIE) of kH/kD ≈
1.0 was observed for both the competitive and parallel
deuterium experiments using substrates 1a and/or [D10]-1a
with 2a under the standard reaction conditions (Scheme 7, eq
7). These results indicated that cleavage of the C−H bond may
not be involved in the rate-determining step. Furthermore, the
reaction of monoannulated compound 7 with 1 equiv of 2a
Aiming to evaluate the practicality of this catalytic process, a
gram-scale experiment was conducted with 1a (0.48 g) and 2a
(0.71 g), which gave the target product 3a (1.06 g) in an
excellent yield of 95% after filtration (Scheme 6, eq 4).
Additionally, biisoquinoline N,N′-dioxide 3a-dioxide was
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intensity was observed when fw was increased to 95% (Figure
2A). Interestingly, the THF solution of 4h (containing four
Scheme 6. Gram-scale Synthesis and Oxidation of 3a
Scheme 7. Mechanistic Studies
Figure 2. PL spectra of (A) 3a, (B) 4h, and (C) 5ah (10 μM) in THF
and THF/water mixtures with different water fractions (fw). (D)
Fluorescence responses (I/I0) to different compounds (I0 for fw = 0%
and I for fw = 90%).
−NMe2 groups) emitted strong green fluorescence under UV
irradiation, and the fluorescence steeply declined when the fw
was increased (Figure 2B), demonstrating the aggregation-
caused quenching (ACQ) nature. Compound 5ah (containing
two −NMe2 groups) showed intense fluorescence emission in
solution as well as in the aggregates (I/I0 ≈ 1) (Figure 2C).
Most of the products are AIE-active, except 4h and 5ah, with
over 5-fold enhancement of the PL intensity for fw = 90%
versus 0% (Figure 2D; for details, see the Supporting
Information).
In conclusion, we have successfully developed an atom- and
step-economical method for the synthesis of highly substituted
1,1′-biisoquinoline compounds from dioxime derivatives and
internal alkynes, overcoming the challenges of inhibition
through coordination, the steric hindrance effect, and
selectivity (chemo-, regio-, mono-, di-, symmetrical, and
unsymmetrical selectivity). This protocol features the following
properties: (a) easily available/prepared and cheap substrates;
(b) broad scope and high yields of up to 96% as well as in
gram-scale synthesis; (c) workup with filtration; (d) greatly
streamlined steps; (e) high atom economy of up to 96% and
environmental friendliness; (f) selective one-pot unsymmetrical
diannulation with two different alkynes; (g) tunable
fluorescence between AIE and ACQ, making the compounds
potentially useful as fluorophores in OLEDs and bioimaging
tools. Further applications of these compounds for organo-
catalysis and luminescence are currently in progress.
delivered 3a in 98% yield, which indicated that 7 could
probably be the intermediate in the diannualtion (Scheme 7,
eq 8).
On the basis of the above investigation and related
references,7−14 a plausible mechanistic pathway is proposed
(Scheme S1). First, cyclorhodium intermediate A is formed
from 1a and the rhodium catalyst through oxime-assisted
reversible C−H activation. Then alkyne insertion produces
cationic species B, which is consequently transformed to
monoannulated compound 7. A similar catalytic process (1a →
7) happens to 7, releasing the diannulated product 3a.
Besides the synthesis and mechanistic study, we were also
interested in the material properties of these novel polyaryl
biisoquinolines. As we know, propeller-like organic frameworks
with polyaryl substituents are promising candidates for
aggregation-induced emission (AIE)-active molecules, which
are widely applied in optoelectronics, bioimaging, nanoscience,
etc.17 Intrigued by the multiaryl structures of these
compounds, the AIE characteristics in THF/water were tested.
Typically, 3a showed faint photoluminescence (PL) peaking at
422 nm when dissolved in THF. Increasing the water fraction
(fw) to 70% allowed a significant emission signal to be
detected, and an approximately 16-fold enhancement of
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01260.
Experimental procedures and characterization of related
compounds (PDF)
D
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Accession Codes
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emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
■
(3) (a) Malkov, A. V.; Westwater, M.-M.; Gutnov, A.; Ramírez-
Shiqing Li − Guangxi Key Laboratory of Electrochemical and
Magneto-Chemical Function Materia, College of Chemistry and
Bioengineering, Guilin University of Technology, Guilin 541004,
China; orcid.org/0000-0001-9883-4553; Email: lisq@
glut.edu.cn
Xiangfei Kong − Guangxi Key Laboratory of Electrochemical
and Magneto-Chemical Function Materia, College of Chemistry
and Bioengineering, Guilin University of Technology, Guilin
541004, China; Email: xiangfei.kong@glut.edu.cn
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Authors
Hongxu Lv − Guangxi Key Laboratory of Electrochemical and
Magneto-Chemical Function Materia, College of Chemistry and
Bioengineering, Guilin University of Technology, Guilin
541004, China
Rongrong Xie − Guangxi Key Laboratory of Electrochemical
and Magneto-Chemical Function Materia, College of Chemistry
and Bioengineering, Guilin University of Technology, Guilin
541004, China
(5) Kwak, J.; Ohk, Y.; Jung, Y.; Chang, S. Rollover cyclometalation
pathway in rhodium catalysis: Dramatic NHC effects in the C−H
bond functionalization. J. Am. Chem. Soc. 2012, 134, 17778−17788.
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W.; Liu, Z.; Zhang, Y. Transition metal-catalyzed C−H bond
functionalizations by the use of diverse directing groups. Org. Chem.
Front. 2015, 2, 1107−1295. (b) Huang, H.; Ji, X.; Wu, W.; Jiang, H.
Transition metal-catalyzed C−H functionalization of N-oxyenamine
internal oxidants. Chem. Soc. Rev. 2015, 44, 1155−1171. (c) Jamison,
C. R.; Overman, L. E. Fragment coupling with tertiary radicals
generated by visible-light photocatalysis. Acc. Chem. Res. 2016, 49,
1578−1586. (d) Kacprzak, K.; Skiera, I.; Piasecka, M.; Paryzek, Z.
Alkaloids and isoprenoids modification by copper(I)-catalyzed
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allylation with alkynes and allenes. Acc. Chem. Res. 2016, 49, 1524−
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the rapid construction and late-stage diversification of functional
molecules. Nat. Chem. 2013, 5, 369−375. (g) Yang, Y.; Lan, J.; You, J.
Oxidative C−H/C−H coupling reactions between two (hetero)-
arenes. Chem. Rev. 2017, 117, 8787−8863. (h) Zheng, L.; Hua, R. C−
H activation and alkyne annulation via automatic or intrinsic directing
groups: Towards high step economy. Chem. Rec. 2018, 18, 556−569.
(i) Song, G.; Li, X. Substrate activation strategies in rhodium(III)-
catalyzed selective functionalization of arenes. Acc. Chem. Res. 2015,
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Yu Yu − Guangxi Key Laboratory of Electrochemical and
Magneto-Chemical Function Materia, College of Chemistry and
Bioengineering, Guilin University of Technology, Guilin
541004, China
Xiuqing Ye − Guangxi Key Laboratory of Electrochemical and
Magneto-Chemical Function Materia, College of Chemistry and
Bioengineering, Guilin University of Technology, Guilin
541004, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01260
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by grants from Guangxi Natural
Science Foundation (2018GXNSFAA294037), Guangxi Sci-
ence & Technology Base and Talent Special (AD19245095),
and Key Laboratory of Electrochemical and Magneto-
Chemical Function Materia.
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