2. Copper-Catalyzed Intramolecular Borylative Coupling with Imines
2.1. Copper-Catalyzed Intramolecular Borylative Cyclization with Alkenes and Imines
The copper-catalyzed enantioselective borylative cyclization of aldimine derivative of styrenes was disclosed by You and co-workers in 2018, affording 2,3-disubstituted indolines
[20]. Following this report, Xiong groups simultaneously developed a similar enantioselective intramolecular borylative coupling of aldimine of 2-aminostyrene derivatives
1 to access boron-containing indolines
[21]. A broad range of styrene derivatives were reacted smoothly. A general mechanism for borylative reactions was shown in Scheme 1C. Initially, the active species (
L1Cu-Bpin) is generated after reaction with B
2pin
2, ligand and base. Then, the active species (
L1Cu-Bpin) react with styrene to furnish an organocopper intermediate
1a, which equilibrium to
1a’ followed by intramolecular cyclization gives boron-containing 2,3-disubstituted indolines. The active catalyst
L1Cu-Bpin is regenerated in presence of base and B
2pin
2. An enantioselective coupling reaction was reported by both groups using (
S,
S)-Ph-BPE as a chiral ligand. A variety of aryl substituted imines were well tolerated and gave high enantioselectivities (Scheme 1B). This methodology offers a simple way to potentially lead regio-, diastereo-, and enantioselective chiral 2,3-disubstituted indolines with the versatile boron functional group. At nearly the same time, Shen, Xu, and co-workers unveiled another borylative diastereoselective coupling of aldimine of 2-aminostyrene derivatives using dppf
L2 as a ligand (Scheme 2)
[22]. The ligand dppf was found to be the best for diastereoselective reaction. Borylative indoles were used for further application to access indoline-derived scaffolds. Interestingly,
cis-tetrahydroindenoindole was synthesized through a palladium-catalyzed intramolecular Suzuki coupling of 2-bromoaryl part of
cis-2,3 disubstituted indolines.
Scheme 1. Copper-catalyzed intramolecular borylative cyclization for the synthesis of 2,3-disubstituted indolines.
Scheme 2. Copper-catalyzed intramolecular borylative cyclization for the synthesis of 2,3-disubstituted indolines.
2.2. Copper-Catalyzed Intramolecular Borylative Cyclization with 1,3-Dienes and Imines
Following previous works on copper-catalyzed intramolecular cyclization alkenes, the Yun group reported a graceful intramolecular copper-catalyzed borylative coupling of 1-dienylarenes
4 with tethered imines in 2018 (Scheme 3A)
[23]. A range of aryl and heterocyclic aldimines as well as various ketimines were well tolerated, providing rapid access to 2,3-disubstituted
cis-1-benzo[
b]azepines with high diastereoselectivity. Interestingly, a mixture of (
E/
Z)-dienyl arenes, instead of pure dienyl arene could be used to obtain high diastereoselectivity. Following the racemic reaction, asymmetric reactions were developed using the N-heterocyclic carbene (NHC) ligand (
L3). Chiral NHC ligands are well known for copper-catalyzed borylative coupling (Scheme 3C). However, a conceivable drawback with this method is that lower enantioselectivity (41% ee) was achieved after using pure (
E)-dienyl arene bearing aldimine ((
E)-4). The suggested mechanism proposed by the authors involves the initial formation of the active
LCuBpin species by reaction with B
2pin
2, base and copper salt. Then, the active species undergoes 1,4-borylcupration with the mixture of (
E/Z)-1,3-dienes to furnish (
Z)-σ-allylcopper intermediate
4a (Scheme 4). The allylcopper
4a attacks the imine intramolecularly, generating an intermediate
4b via a favored 6-membered ring transition state
TS-A with a large group (R
3) in the less hindered equatorial position.
Scheme 3. Copper-catalyzed intramolecular borylative cyclization for the synthesis of 2,3-disubstituted cis-1-benzo[b]azepines.
Scheme 4. A. Proposed catalytic cycle.
2.3. Copper-Catalyzed Intramolecular Borylative Cyclization with Conjugated Alkenes and Imines
An enantioselective copper-catalyzed conjugate intramolecular borylation/cyclization of electron-deficient alkenes with aldimines was developed by Lautens and co-workers using bis (pinacolato)diboronreagent (Bi
2pin
2) as boron sources to produce enantioenriched tetrahydroquinoline scaffolds (Scheme 5A)
[24]. Initially, the active species (
L4Cu-Bpin) generate in situ after transmetallation of
L4Cu-O
tBu with B
2pin
2 followed by 1,4-addition into the alkene to produce organocopper intermediate
5a. The organocopper species then cyclizes with imine to afford borylated tetrahydroquinoline, followed by routine oxidation with NaBO
3•4H
2O furnish alcohol-containing products. The authors screened several bisphospine ligands. Josiphos proved to be the best ligand in terms of enantio- and diastereoselectivity. This method worked well with a wide range of electron-deficient alkenes and delivered excellent enantioselectivities. Substrates bearing various aryl imines were well tolerated with representative procedures for the preparation of enantioenrich tetrahydroquinoline scaffolds. The established method was further applied to composing a variety of valuable building blocks.
Scheme 5. Copper-catalyzed intramolecular borylation cyclization for the synthesis of tetrahydroquinoline.
2.4. Copper-Catalyzed Intramolecular Borylative Cyclization with Alkenes and Amidines
In 2021, Procter and co-workers demonstrated a copper-catalyzed borylative intramolecular coupling of quinazolinone bearing alkenes to prepare boron-containing heterocycles (Scheme 6A)
[25]. By far, this was the introductory report on enantioselective borylative coupling of aliphatic alkenes as well as substituted styrenes with amidines to obtain boron-bearing quinazoline scaffolds. This method proceeds very smoothly with high enantiocontrol and diastereocontrol. Interestingly, ligand
L6 was found to be finest when unsubstituted alkene (R
1 H) was used for the coupling reaction. The use of the ligand
L5 for intramolecular borylative coupling with aryl-substituted alkenes (R
1 aryl) provided excellent diastereo- and enantioselectivities. Various substitutions on the aryl ring of the amidine component were well tolerated, delivered pyrroloquinazolines featuring quaternary stereocenters with high enantio- and diastereocontrol. Various aryl-substituted alkenes were successfully used in the borylative cyclization and formation of two adjacent stereocentres to yield pyrroloquinazolinones with very good to excellent enantio- and diastereocontrol. This method demonstrates the use of amidine derivatives for the borylative coupling in following transformations to access more riveting complex structures.
Scheme 6. Copper-catalyzed borylative cyclization for the synthesis of quinazolinones.
According to the proposed mechanism by the authors, an active LCu-Bpin intermediate is formed initially by reacting with B2pin2, base, and copper salt. Then, the active species (LCu-Bpin) undergo enantioselective borocupration across the double bond of the alkene to generate intermediate 6a (Scheme 7). The authors proposed stereochemical models for forming the most favorable enantiomers. Then, the LCu-Bpin intermediate interacts with alkenes in which the phenyl group of the substrate is oriented toward the ligand’s less hindered position, resulting in a major enantiomer A. The intermediate 6b is then formed by diastereoselective cyclization of the amidine carbon-nitrogen double bond via TS-1b. Finally, the active catalyst (LCu-Bpin) is regenerated in the presence of base, alcohol, and B2pin2.
Scheme 7. Proposed mechanism and model for the origin of stereocontrol. (L* = chiral ligand).