Catalytic Enantioselective Methylene C(sp3)?H Amidation of 8-Alkylquinolines Using a Cp*RhIII/Chiral Carboxylic Acid System

Article abstract of DOI:10.1002/anie.201911268

Catalytic enantioselective directed methylene C(sp³)?H amidation reactions of 8-alkylquinolines using a Cp*Rh^III/chiral carboxylic acid (CCA) hybrid catalytic system are described. A binaphthyl-based chiral carboxylic acid efficiently differentiates between the enantiotopic methylene C?H bonds, which leads to the formation of C?N bonds with good enantioselectivity.

Full text of DOI:10.1002/anie.201911268

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Accepted Article
Title: Catalytic Enantioselective Methylene C(sp3)–H Amidation of 8-
Alkylquinolines Using Cp*RhIII/Chiral Carboxylic Acid System
Authors: Seiya Fukagawa, Masahiro Kojima, Tatsuhiko Yoshino, and
Shigeki Matsunaga
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201911268
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10.1002/anie.201911268
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COMMUNICATION
Catalytic Enantioselective Methylene C(sp3)–H Amidation of 8-
Alkylquinolines Using Cp*RhIII/Chiral Carboxylic Acid System
Seiya Fukagawa, Masahiro Kojima, Tatsuhiko Yoshino,* and Shigeki Matsunaga*
Abstract: The catalytic enantioselective directed methylene C(sp3)–
H amidation reactions of 8-alkylquinolines using a Cp*RhIII/chiral
carboxylic acid (CCA) hybrid catalytic system is described. A
binaphthyl-based chiral carboxylic acid efficiently differentiates
between the enantiotopic methylene C–H bonds, which leads to the
formation of C–N bonds in good enantioselectivity.
Transition-metal-catalyzed C–H functionalization[1] is an
attractive approach to develop atom-[2] and step-economical[3]
synthetic routes for organic molecules. Among various metal
catalysts employed in directing group-assisted C–H
functionalization reactions, group
9
metals wtih
a
cyclopentadienyl-type ligand, i.e., CpxMIII (M = Co, Rh, or Ir),
exhibit high reactivity, broad substrate generality, and
robustness, realizing a wide range of synthetically valuable
transformations[4]. In particular, when one wishes to functionalize
enantiotopic C–H bonds of prochiral substrates to generate
chiral products, stereocontrol at the C–H bond cleavage step, i.e.
an enantioselective C–H activation, is crucial. Cramer and co-
workers, followed by Li and co-workers, have achieved such
enantioselective C–H activation/functionalization reactions by
using well-designed chiral CpxMIII catalysts[5–9] (Scheme 1a),
where a chiral carboxylic acid was sometimes employed as a
[7c,d,f,g]
secondary chiral source.
Although this strategy is
successful for the enantioselective functionalization of C(sp2)–H
bonds, functionalization of less reactive enantiotopic C(sp3)–H
bonds has not yet been achieved. On the other hand, our group
has recently reported enantioselective C–H functionalization
reactions catalyzed by readily available achiral CpxMIII catalysts
that were combined with external chiral sources.[10–12] Notably,
our hybrid approach using an achiral CpxCoIII catalyst and a
chiral amino acid derivative has been successfully applied to
enantioselective C(sp3)–H functionalization reactions via the
differentiation of two enantiotopic methyl groups[10c,d] (Scheme
1b). However, enantioselective functionalization reactions of
methylene C(sp3)–H bonds, which are more challenging but also
more attractive from a synthetic point of view, were unsuccessful
using this previously reported catalytic system.
Herein, we report directed enantioselective methylene C(sp3)–
H functionalization reactions using a Cp*RhIII/chiral carboxylic
acid (CCA) hybrid catalytic system (Scheme 1c), in which a
binaphthyl-based CCA assists the enantioselective cleavage of
methylene C(sp3)–H bonds to construct a C–N bond at the
stereocenter. Although such directing-group-asssited catalytic
Scheme 1. Enantioselective C–H functionalization reactions with stereocontrol
at the C–H cleavage step using CpXMIII catalysts (M = Co, Rh, Ir).
C–H activation with the differentiation of methylene C(sp3)–H
bonds have been intensively studied using palladium and other
metal catalysts over the past years, most studies have focused
on C–C or C–B bond formation reactions[13–19]
, leaving
enantioselective C–N bond formation reactions barely
explored.[16a–c,20,21]
Our investigation on the enantioselective methylene C–H
amidation of 8-ethylquinoline 1a using dioxazolone 2a to afford
3aa started with attempting to identify an appropriate CCA under
the Cp*RhIII catalysis (Table 1).[22] The combination of
[Cp*RhCl2]2 and AgSbF6 was selected as the precursor for an
active cationic [Cp*RhIII] catalyst. Initially, we tested H2-BHTL 4,
which is the best CCA for the enantioselective C(sp3)–H
amidation of thioamides using a CoIII catalyst (entry 1).[10c] The
desired reaction proceeded in excellent yield, albeit with low
enantioselectivity. Thus, we were motivated to evaluate other
types of CCAs. Gratifyingly, binaphthyl-based CCA 5a exhibited
a promising level of selectivity (entry 2, 68:32 er), which
prompted us to fine-tune the binaphthyl structure. We found that
a Ph group at the ortho position relative to the carboxylic acid
group had a positive effect on the enantioselectivity (5b; entry 3),
and therefore continued to examine other substituents. While a
4-OMe-C6H4 group at the same position was not effective (5c;
[a]
S. Fukagawa, Dr. M. Kojima, Dr. T. Yoshino, Prof. Dr. S. Matsunaga
Faculty of Pharmaceutical Sciences
Hokkaido University
Kita-ku, Sapporo 060-0812, Japan
E-mail: tyoshino@pharm.hokudai.ac.jp;
smatsuna@pharm.hokudai.ac.jp
Supporting information for this article is given via a link at the end of
the document.
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COMMUNICATION
Table 1. Screening of chiral carboxylic acids and optimization of the reaction
conditions[a]
Entry
CCA
Temp.
Solvent
Additive
Yield[b]
Er[c]
1
2
3
4
80 °C
80 °C
80 °C
DCM
DCM
DCM
none
none
none
94%
90%
73%
57/43
68/32
71/28
5a
5b
4
5c
5d
5e
5f
5f
5f
5f
5f
5f
5f
5f
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
30 °C
30 °C
4 °C
DCM
DCM
DCM
DCM
PhCF3
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
none
83%
68%
78%
75%
66%
69%
53%
93%
93%
0%
69/31
78/22
81/19
85/15
86/14
87/13
90/10
91/9
92/8
–
Scheme 2. Synthetic route of 5f. Reagents and conditions: a) TsCl, Et3N,
DMAP, DCM, then Tf2O, 91%; b) Pd(OAc)2, dppp, iPr2NEt, CO, MeOH,
DMSO, 80%; c) 2-naphthaleneboronic acid, Ni(cod)2, PCy3, K3PO4, THF; d)
5
none
6
none
KOH, EtOH/H2O, 80% over
2
steps; e) 5-bromo-1,3-di-tert-butyl-2-
7
none
methoxybenzene, [RuCl2(p-cymene)]2, PEt3•HBF4, K2CO3, NMP, 89%.
8
none
corresponding chiral carboxylate, drastically improved the
reactivity without decreasing the selectivity (entry 11). The
reaction proceeded even at 4 °C, and the product (3aa) was
obtained in 93% yield with 92:8 er under the optimized
conditions (entry 12). Under the identical conditions,
Cp*CoI2(CO) or [Cp*IrCl2]2 instead of the rhodium catalyst did
not afford the desired product (entries 13 and 14).
9
none
10
11
12[d]
13[d,e]
14[d,f]
none
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
4 °C
4 °C
0%
–
With the optimized reaction conditions in hand, we investigated
the substrate scope with respect to the 8- ethylquinolines 1
(Scheme 3). 8-Ethylquinolines with an electron-donating
methoxy group at the C4- or C6-positions (1b and 1d) furnished
the desired products (3ba and 3da) in good to high yield and
good selectivity. Electron-deficient 8-ethylquinolines (1c, 1e–1i)
reacted even at –10 °C, providing the corresponding products
(3ca, 3ea–3ia) in 46–99% yield with 91:9–94:6 er.[25] Carbonyl
groups and halogen substituents were not affected under the
applied reaction conditions. Next, we examined the scope of
dioxazolones 2 using 4-chloro-8-ethylquinoline 1e. Dioxazolones
bearing a substituent at different positions on the phenyl ring
were tolerated and afforded the products (3eb–3ed) in 64–98%
yield and 92:8–93:7 er. The C–H amidation proceeded smoothly,
even when using a sterically hindered dioxazolone (3eb).
Heteroaromatic and aliphatic dioxazolones also afforded the
corresponding products (3ee–3eh) in 78–97% yield and 93:7–
94:6 er.
To further expand the substrate scope of this reaction, we also
investigated amidation reactions of other 8-alkylquinolines
(Scheme 4). Although the presence of a larger alkyl group at the
reactive site decreased the reactivity, reasonable conversion
was achieved by increasing the amount of Ag2CO3 and
prolonging the reaction time. Under such modified reaction
conditions, 8-propylquinoline 1j and 8-pentylquinoline 1k
afforded the amidated products (3jb and 3kb) in 70–72% yield
and 93:7 er.
[a] Reaction conditions (unless otherwise stated): 1a (0.05 mmol), 2a (0.06
mmol), [Cp*RhCl2]2 (0.002 mmol), and CCA 4 or 5 (0.004 mmol), AgSbF6
(0.008 mmol), and additive (0.002 mmol) in the indicated solvent (0.075 M).
[b] Determined by 1H NMR analysis of the crude mixture using dibenzyl
ether as the internal standard. [c] Determined by chiral HPLC analysis. [d]
0.2 M, 18 h. [e] Cp*CoI2(CO) (8 mol %) was used instead of [Cp*RhCl2]2. [f]
[Cp*IrCl2]2 (4 mol %) was used instead of [Cp*RhCl2]2.
entry 4), a sterically more demanding aryl group enhanced the
enantiomeric ratio to 78:22 (5d; entry 5). Finally, we discovered
that a 3,5-di-tert-butyl-4-methoxy-phenyl (DTBM) group afforded
the best results (5e; entry 6). In addition, changing the Ph group
at the 2’-position to a 2-naphthyl group improved the selectivity
(5f; entry 7). As shown in Scheme 2, binaphthyl-based CCA 5f
can be synthesized from BINOL 6 in five steps via a Ni-
catalyzed Suzuki-Miyaura cross-coupling[23] and carboxylic acid-
directed Ru-catalyzed C–H arylation,[24] indicating that further
derivatization in order to expand the scope of application would
be facile. Subsequently, we optimized the reaction conditions
using 5f. A screening of other halogenated solvents revealed
that PhCl was the most suitable solvent in terms of
enantioselectivity (entries 7–9). Lowering the reaction
temperature to 30 °C improved the enantioselectivity further,
albeit under concomitant decrease of the reactivity (entry 10).
The addition of a catalytic amount of Ag2CO3, which is expected
to deprotonate CCA 5f to facilitate the formation of the
We conducted H/D exchange experiments in order to confirm
whether a C–H activation step is reversible or not (Scheme 5).
When we performed the C–H amidation reaction of 1a using 2a
in the presence of a catalytic amount of CCA 5f and an excess
amount of CH3CO2D, only a very small amount of deuterium was
incorporated into the product (3aa) and recovered 1a
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COMMUNICATION
Scheme 5. H/D exchange experiments to check the reversibility of the C–H
activation step.
chiral carboxylic acid (5f), which provides modular and concise
design capability and may find new applications in the future.
Acknowledgements
This work was supported in part by JSPS KAKENHI Grant
Number JP15H05802 in Precisely Designed Catalysts with
Customized Scaffolding, JSPS KAKENHI Grant Number
JP18H04637 in Hybrid Catalysis, JSPS KAKENHI Grant
Number JP17H03049 and JP19K16306.
Keywords: C-H activation • asymmetric catalysis • rhodium •
quinoline • chiral carboxylic acid
Scheme 3. Substrate scope. Yields of the isolated products were given. For
detailed reaction conditions: see the Supporting Information. [a] –10 °C. [b] –
20 °C.
[1]
J.-Q. Yu, Z.-J. Shi, C–H Activation, Topics in Current Chemistry, Vol.
292, Springer, Berlin, 2010.
[2]
[3]
[4]
B. M. Trost, Science 1991, 254, 1471-1477.
P. A. Wender, B. L. Miller, Nature 2009, 460, 197-201.
Selected reviews on Cp*M(III)-catalyzed C–H functionalization: a) T.
Satoh, M. Miura, Chem. Eur. J. 2010, 16, 11212-11222; b) N. Kuhl, N.
Schröder, F. Glorius, Adv. Synth. Catal. 2014, 356, 1443-1460; c) G.
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Asian J. 2018, 13, 1089-1102.
[5]
Recent reviews on enantioselective C–H functionalization reactions: a)
C. G. Newton, S.-G. Wang, C. C. Oliveira, N. Cramer, Chem. Rev.
2017, 117, 8908-8976; b) T. G. Saint-Denis, R.-Y. Zhu, G. Chen, Q.-F.
Wu, J.-Q. Yu, Science 2018, 359, eaao4798; c) J. Loup, U. Dhawa, F.
Pesciaioli, J. Wencel-Delord, L. Ackermann, Angew. Chem. 2019,
https://doi.org/10.1002/ange.201904214; Angew. Chem. Int. Ed. 2019,
https://doi.org/10.1002/anie.201904214.
Scheme 4. Enantioselective C–H amidation of other 8-alkylquinolines. For
detailed reaction conditions: see the Supporting Information.
(Scheme 5a). Furthermore, deuterium incorporation was not
observed in the absence of 2a (Scheme 5b). These results
suggest that the C–H activation step is almost irreversible and
thus determines the enantioselectivity. CCA 5f would be
involved in a carboxylate-assisted C–H activation process.[26]
In summary, we have demonstrated that a Cp*RhIII/CCA
catalytic system enables the enantioselective cleavage of
methylene C(sp3)–H bonds. Enantioselective amidation
reactions of 8-alkylquinolines using dioxazolones 2 proceeded in
good yield and enantioselectivity by using a binaphthyl-based
[6]
[7]
Reviews on enantioselective C–H functionalization reactions with chiral
CpxMIII: a) B. Ye, N. Cramer, Acc. Chem. Res. 2015, 48, 1308-1318; b)
C. G. Newton, D. Kossler, N. Cramer, J. Am. Chem. Soc. 2016, 138,
3935-3941.
Enantioselective C–H activation/functionalization reactions using chiral
CpxMIII catalysts: a) Y. Sun, N. Cramer, Angew. Chem. 2017, 129, 370-
373; Angew. Chem. Int. Ed. 2017, 56, 364-367; b); Y. Sun, N. Cramer,
Chem. Sci. 2018, 9, 2981-2985; c) Y.-S. Jang, M. Dieckmann, N.
Cramer, Angew. Chem. 2017, 129, 15284-15288; Angew. Chem. Int.
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