Background and Originality Content
Palladium/norbornene (Pd/NBE) cooperative catalysis (namely, the
Catellani reaction)[1,2] is widely recognized as a
powerful strategy for expeditious synthesis of highly substituted
arenes. Recently, asymmetric Catellani
reaction[3-8] based on palladium/chiral norbornene
cooperative catalysis has also been realized in
desymmetrization,[5] kinetic
resolution[4-6] and axial chirality
construction.[7-8] However, current scope of this
chemistry is mainly limited to (hetero)aromatic substrates, and its
application to partially aromatic or non-aromatic scaffolds is rarely
reported,[9] because the vinylic C–H bonds are
generally more challenging to functionalize than (hetero)aryl C–H
bond.[10] Owing to the efforts of
Lautens,[9a] Yamamoto,[9b]Dong,[9c-d] and our
group,[9e-f] alkenyl Catellani reaction has
emerged as a new direction of this field (Figure 1A). For example, in
2018, the Yamamoto group uncovered a unique two-component alkenyl
Catellani annulation for the assembly of benzofused polycyclic products,
involving 4-iodo-2-quinolones and 4-iodo-coumarin as the substrates
(Figure 1B).[9b] Later on, the Dong group revealed
two elegant alkenyl Catellani reactions, utilizing alkenyl
(pseudo)halides[9c] and alkenes with a directing
group[9d] as the substrates, respectively.
Nevertheless, the asymmetric alkenyl-type Catellani reaction hasn’t been
realized for a long time. Until very recently, the Gong group reported
the first asymmetric case for enantioselective construction of
all-carbon brideged ring systems via Pd/NBE/chiral amino acid
cooperative catalysis (Figure 1C).[9g]
Recently, we[7a-b] and the Song
group[8a] independently reported de novo
construction of C–C axial chirality via palladium/chiral norbornene
cooperative catalysis. Later on, we extended this chemistry to
atroposelective construction of C–N axial
chirality.[7c] Inspired by these innovative
studies, we envisaged to develop the asymmetric alkenyl Catellani
reaction version for the construction of C–N axial chirality. As
illustrated in Figure 1D, 4-iodo-2-quinolone or 4-iodo-2-pyridone1 is employed as the substrate and 2,6-disubstituted aryl
bromide with a tethered amide group (2 ) is utilized as the
arylating reagent as well as terminating reagent. Firstly, 1undergoes sequential oxidative addition with Pd0,
chiral NBE* insertion and ortho -C–H activation to generate the
chiral vinyl-NBE* palladacycle species A , which then undergoes
oxidative addition by 2 . The resulting PdIVcomplex subsequently undergoes reductive elimination and β-carbon
elimination to form axially chiral Pd complex B , which
eventually leads to the final C–N axially chiral product 3via intermediate C . This step involves an intramolecular
amidation alongside the chirality transfer from C–C axis (Band C ) to C–N axis (3 ). This asymmetric alkenyl
Catellani reaction provides a promising strategy for constructing C–N
axial chirality in a partially aromatic heterocycle setting, which is
also a recognized challenging field due to the innate low
configurational stability of C–N atropisomers[11]as compared to the well-developed C–C
atropisomers.[12] Other potential features include
readily available substrates (both 1 and 2 ) and step
economy. Nevertheless, several challanges of this reaction are also
foreseeable. First, the asymmetric alkenyl Catellani reaction based on
palladium/chiral norbornene cooperative catalysis remains elusive since
very limited cases have been reported to date.[9]Second, the final C–N axial chirality is originated from the
preinstalled transient C–C axial chirality[6-8]through an intriguing but scarcely reported axial-to-axial chirality
transfer process.[7c,13] Lastly, the reaction
should be performed under mild conditions because of configurational
vulnerability of the obtained C–N
atropisomers.[11]
Results and Discussion
Our efforts commenced with a model reaction using readily available
1-benzyl-4-iodoquinolin-2(1H )-one (1a ) and
2-bromo-N-(2-(tert-butyl)phenyl)-3-methyl-benzamide (2a ) as the
substrates (Table 1). After extensive survey of the reaction parameters,
the optimal reaction conditions was identified to be:
Pd(OAc)2 (5 mol%) as the catalyst, the ethyl
(1S ,4R )-bicyclo[2.2.1]hept-2-ene-2-carboxylate
(N1 , 50 mol%) as the chiral
mediator,[5] K2CO3(2.5 equiv) as the base, heated THF (80 oC) as the
solvent, wherein the desired product 3a was afforded in a good
yield (83% NMR yield, 80% isolated yield) and excellent
enantioselectivity (93% e.e. ) (entry 1). In order to understand
the role of each component in this protocol, several control experiments
were subsequently conducted. In the absence of either Pd catalyst orN1 , no 3a was formed, indicating the
cirtical role they are taken (entries 2-3). The reaction efficiency
increased at a higher reaction temperature (90 oC),
however the enantioselectivity of the product was slightly declined
(entry 4). On the contrary, enantioselectivity maintained excellent at a
lower temperature (e.g., 70 oC), but the yield of3a dropped dramatically (entry 5). The reaction efficiency also
decreased while shortening the reaction time (to 36 h, entry 6) or
lowering the loading of N1 (to 25 mol%,
entry 7). The methyl ester chiral mediator N2behaved similar to N1 but with a slightly
diminished enantioselectivity. It is worthwhile mentioning that the
chiral mediator N1 could be recovered in 84%
yield without any erosion of the enantiopurity. Other details of the
reaction conditions optimization regarding the solvent and ligand
effects etc were listed in SI.
With the optimal reaction conditions in hand, we then investigated the
scope of iodoheterocycles, with 2a as the reaction partner
(Table 2). First, the reactivity of various substituted
4-iodo-2-quinolones were explored (Table 2A). Gratifyingly, whether it
is electron-donating or -withdrawing groups on the 4-iodo-2-quinolones,
all could be reacted smoothly and afforded the desired products
(3a -3m ) in from good to excellent yields (76%-93%)
and high enantioselectivities (88%-94% e.e.s ). Notably, the
tricyclic 4-iodo-2-quinolone was also a suitable substrate to deliver
the complex polycyclic product 3o in 76% yield and 90%e.e. . Importantly, the reaction showed good chemoselectivity, and
a wide range of functional groups were tolerated, including alkyl
(3b , 3i and 3n ), trifluoromethyl
(3c ), ester (3d and 3j ), methoxy (3eand 3k ), and halogen atoms (3f-h and 3l-m ),
providing handles for further manipulations. In addition,
4-iodo-coumarin was also a suitable substrate to afford the desired
product 3p in 91% yield, however the enantioselectivity was
declined to 76% e.e. . Moreover, the scope of iodoheterocycles
can be extended to monocyclic 4-iodo-2-pyridones under slightly modified
reaction conditions compared to standard conditions of Table 2A (see
Table S5 of Supporting Information for details), which included the use
of tri-2-furanylphosphine (TFP, 10 mol%) as the ligand and an increase
of the reaction temperature to 90 °C. A series of substituted
4-iodo-2-pyridones were suitable substrates (Table 2B). For example,
4-iodo-5-methyl-2-pyridones with different 1-N substitution, eg,N -methyl (1q ), N -Bn (benzyl) (1r ),N -PMB (p- methoxybenzyl) (1s ), andN -mesityl (2,4,5-trimethylbenzyl) (1t ), reacted well
with 2a to provide the desired products 3q –twith 73–89% yields and excellent enantioselectivities. Beside the
methyl group, the C5 substituent of 4-iodo-2-pyridones could be switched
to various functional groups, such as fluoro (3u ), chloro
(3v ) and substituted methylene groups
(3w –z ). Interestingly, 3-methyl-4-iodo-2-pyridone
(3aa ) showed a much higher reactivity than the aforementioned
substrates, and its reaction with 2a took place at 60 °C to
afford the desired product 3aa in 87% yield and 93%e.e. . Addtionally, 1,3-dibenzyl-6-iodo-uracil was a substrate
with good reactivity to deliver the product 3ab in 84% yield,
albeit with a poor enantioselectivity (21% e.e. ). Importanly,
the absolute C–N axial configuration of product 3a was
unambiguously determined to be (R ) by X-ray crystallographic
analysis,[14] and those of other products were
assigned by analogy.
Next, the scope of arylbromides 2 were investigated. The
reaction of naphthyl bromide with 1a and 1q delivered
the desired product 3aʹ and 3bʹ respectively with
excellent yields and enantioselectivities. Then, we focused on examing
aryl bromides 2 with different aniline moieties. We found
modifications at the para position of the aniline moiety of2 were well tolerated, including the introuction of a bromo
(3cʹ ), alkene (3dʹ ), alkyne (3eʹ ) group
aldehyde (3fʹ ) or benzyl alcohol (3gʹ ). The
corresponding products were obtained with excellent enantioselectivities
(93–98% e.e. s). In addition, modifications at the orthoposition of the aniline moiety were also investigated. Switching one
methyl of the ortho tert -butyl group to OTBS
(tert -butyldimethylsilyloxy) (3hʹ –iʹ ) or
TBS-protected hydroxymethyl (3jʹ ) group produced the
corresponding axially chiral
benzo[c ][1,6]naphthyridinediones with excellent
enantiocontrol (94–95% e.e. s). Notably, the free hydroxyl group
of arylbromide was tolerated, and the corresponding product
(3kʹ ) was obtained in 77% yield, albeit with a slightly
dropped enantioselectivity (87% e.e. ). 3kʹ was facilely
transformed into aldehyde 3lʹ and ester 3mʹ without
any erosion of the enatioselectivity.[15] Overall,
these results indicated that sterically bulky aniline moieties were
required to ensure high fidelity of the axial-to-axial chirality
transfer process. In addition, we performed both racemization
experiments and DFT calculations to probe the thermal stability of the
obtainded stereogenic C–N axis. For example, the rotation barrier of3a is experimentally measured as 31.9 kcal/mol
(ΔG≠ exp), which is well
consistent with the DFT computational value
(ΔG≠ calc = 32.0 kcal/mol) (see
SI for details), indicating excellent thermal stability.
Finally, we focused on illustrating the synthetic utility of the C–N
atropisomers in Tables 2-3 (Scheme 1). For instance, N -Bn
deprotection of 3a proceeded smoothly under the catalytic
hydrogenation conditions (with 10 mol% Pd(OH)2 as the
catalyst)[16] to deliver 4 in 90% yield,
which could be readily transformed into a OTf-substituted chiral
quinoline derivative 5 through an aromatization promoted by
Tf2O and pyridine.[17]Furthermore, 5 underwent an intramolecular cyclization to
generate a chiral polycyclic compoud 6 through a
C(sp3)–H activation[18]promoted by Pd(PPh3)4 catalyst and
K2CO3 with good efficieny.
Interestingly, if the loading of Pd(OH)2 was increased
to 30 mol%, together with prolonged reaction time (18 h), one aromatic
ring of 3a could be partially hydrogenated during the
debenzylation process, and the polycyclic product 7 with a
newly generated chiral center was obtained as the sole product,
indicating the excellent diastereoselectivity (dr >
20:1) of the hydrogenation step which was dictated by the remote C–N
axial chirality through an axial-to-central diastereoinduction
process.[13c-d]. Then, chiral quinoline derivative8 was generated in excellent yield following the same
aromatization protocol. Similarly, complex chiral pyridine derivatives10 and 13 with an OTf substitution were efficiently
assembled from product 3r through catalytic hydrogenation and
aromatization. Moreover, 10 was transfermed to
3,4,5-tri-substituted chiral pyridine derivative 13 under a
mild Pd-catalyzed reduction conditions.[19]Additionally, catalytic hydrogenation of the N -Me product3q was performed (with Pd/C as the catalyst) to deliever the
dearomatization product 14 with excellent diastereoselectivity
(dr > 20:1). The absolute configurations of14 are unambiguously determined to be (R , aR ) by
X-ray crystallographic analysis.[14] It is worth
mentioning that all these transformations proceeded without any erosion
of the enantiopurity.
Conclusions
In summary, we have developed an asymmetric two-component alkenyl
Catellani reaction for the construction of C–N axial chirality, which
is based on a palladium/chiral norbornene cooperative catalysis and an
axial-to-axial chirality transfer process. Various partially aromatic
iodinated 2-pyridones, quinolones and coumarin substrates react with
2,6-disubstituted aryl bromides with a tethered amide group, to afford a
wide variety of polycyclic C–N atropisomers with excellent
enantioselectivities. The obtained C–N axial chirality is originated
from the preformed transient C–C axial chirality with high fidelity.
The synthetic utility of this chemistry is demonstrated by facile
preparation of complex quinoline- and pyridine-based C–N atropisomers
through a N-deprotection and aromatization sequence, and a remote
axial-to-central diastereoinduction process dictated by C–N axial
chirality is observed with excellent diastereocontrol.
Experimental
General procedure for the synthesis of enantioenriched
compounds 3a-p and 3a’ :
Unless otherwise noted, in an argon-filled glove box, an oven-dried 4.0
mL vial equipped with a magnetic stir bar was charged with
Pd(OAc)2 (0.005 mmol, 5.0 mol%),N1 (99% e.e. , 0.05 mmol, 0.5 equiv),
K2CO3 (0.25 mmol, 2.5 equiv),
iodoheterocycles 1a -p (0.1 mmol, 1.0 equiv), aryl
bromide 2 (0.1 mmol, 1.0 equiv), and dry THF (0.5 mL). The vial
was sealed with a cap and stirred at r.t. for about 5 min, and then the
reaction mixture was heated at 80 oC for 48 h. After
the reaction vessel was cooled to r.t., the mixture was filtered, and
concentrated in vacuo . The residue was directly purified by
column chromatography on silica gel or pre-TLC to yield the desired
chiral products 3a -p and 3a’ .
General procedure for the synthesis of enantioenriched compounds
3q-ab and 3b’-3m’ :
Unless otherwise noted, in an argon-filled glove box, an oven-dried 4.0
mL vial equipped with a magnetic stir bar was charged with
Pd(OAc)2 (0.005 mmol, 5.0 mol%), TFP (0.01 mmol, 10
mol%), N1 (99% e.e. , 0.05 mmol, 0.5 equiv),
K2CO3 (0.25 mmol, 2.5 equiv),
iodoheterocycles 1q -ab (0.1 mmol, 1.0 equiv), aryl
bromide 2 (0.1 mmol, 1.0 equiv), and dry THF (0.5 mL). The vial
was sealed with a cap and stirred at r.t. for about 5 min, and then the
reaction mixture was heated at 90 oC for 48 h. After
the reaction vessel was cooled to r.t., the mixture was filtered and
concentrated in vacuo. The residue was directly purified by column
chromatography on silica gel or pre-TLC to yield the desired chiral
products 3q -ab and 3b’-3m’ .
Supporting Information
The supporting information for this article is available on the WWW
under https://doi.org/10.1002/cjoc.2023xxxxx.
Acknowledgement
We are grateful to the start-up funding from Wuhan University for
financial support. We thank Prof. Wen-Bo Liu for sharing the
instruments.
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