Chiral Carboxylic Acid Enabled Achiral Rhodium(III)-Catalyzed Enantioselective C?H Functionalization

Article abstract of DOI:10.1002/anie.201807610

Reported is an achiral Cp^xRh^III/chiral carboxylic acid catalyzed asymmetric C?H alkylation of diarylmethanamines with a diazomalonate, followed by cyclization and decarboxylation to afford 1,4-dihydroisoquinolin-3(2H)-one. Secondary

Full text of DOI:10.1002/anie.201807610

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Accepted Article
Title: Chiral Carboxylic Acid-Enabled Achiral Rhodium(III)-Catalyzed
Enantioselective C−H Functionalization
Authors: Luqing Lin, Seiya Fukagawa, Daichi Sekine, Eiki Tomita,
Tatsuhiko Yoshino, and Shigeki Matsunaga
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201807610
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10.1002/anie.201807610
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Chiral Carboxylic Acid-Enabled Achiral Rhodium(III)-Catalyzed
Enantioselective C−H Functionalization
Luqing Lin,* Seiya Fukagawa, Daichi Sekine, Eiki Tomita, Tatsuhiko Yoshino,* and Shigeki
Matsunaga*
Abstract: We report an achiral CpxRh(III)/chiral carboxylic acid-
catalyzed asymmetric C–H alkylation of diarylmethanamines with a
diazomalonate followed by cyclization and decarboxylation to afford
1,4-dihydroisoquinolin-3(2H)-one. Secondary alkylamines as well as
non-protected primary alkylamines underwent the transformation with
high enantioselectivities (up to 98.5/1.5 er) by using a newly
developed chiral carboxylic acid as the sole chiral source to achieve
enantioselective C–H cleavage via a CMD mechanism.
Transition metal-catalyzed direct C–H functionalization has been
investigated as an atom-[1] and step-economical[2] strategy in
organic synthesis over the last few decades.[3-5] Group 9 CpxM(III)
(Cp = cyclopentadienyl, M = Co, Rh, Ir) complexes are prominent
catalysts in this field due to their high reactivity and functional
group compatibility.[4] Enantioselective C–H functionalization has
recently attracted much attention for the synthesis of complex
molecules including chiral stereocenters.[5] In this context,
Cramer’s group reported that Rh(III)[6] and Ir(III)[7] complexes
bearing precisely designed chiral Cpx ligands enabled catalytic
asymmetric C–H functionalization reactions.[8] You’s group[9] and
Antonchick and Waldmann’s group[10] also developed different
types of chiral Cpx ligands. These designed Cpx ligands greatly
facilitated the development of enantioselective C–H
functionalization reactions (Scheme 1a).[11] However, the
derivatization of chiral CpxM(III) catalysts for optimizing the
desired reaction can potentially be problematic, although some
easily accessible chiral Cpx ligands[10,12] and CpxRh complexes[13]
were recently developed. Therefore, new approaches to achieve
enantioselective C–H functionalization using more easily
available achiral CpxM(III) complexes in combination with external
chiral sources are highly demanded.[14]
Our group recently developed a Cp*Rh(III)/chiral disulfonate-
catalyzed enantioselective conjugate addition of aromatic C–H
bonds to enones, in which the chiral disulfonate enabled
stereocontrol during the insertion step after C–H bond cleavage
Scheme 1. Different Approaches for Enantioselective C–H Functionalization
Using CpxM(III) Catalysts.
(Scheme 1b).[15] On the other hand, stereocontrol at the C-H bond
cleavage step still requires chiral Cpx ligands.[6g,h,7b] In most cases,
C–H activation under CpxM(III) catalysis is proposed to proceed
via a carboxylate-assisted concerted metalation-deprotonation
carboxylic acid (CCA) hybrid system should be able to achieve
(CMD) mechanism.[4,16] Accordingly, an achiral CpxM(III)/chiral
asymmetric C–H activation. Although CCAs were investigated in
Ir(III)-catalyzed C-H amidation reactions of phosphine oxides by
Chang’s group[17] and Cramer’s group,[7b] a chiral Cpx ligand was
[a]
Dr. L. Lin, S. Fukagawa, D. Sekine, E. Tomita, Dr. T. Yoshino, Prof.
Dr. S. Matsunaga
Faculty of Pharmaceutical Sciences
Hokkaido University
Kita-ku, Sapporo 060-0812, Japan
still essential to obtain high selectivity.[7b] In Pd catalysis, mono-
N-protected amino acids (MPAAs) and related ligands, mainly
developed by Yu’s group, are effective for asymmetric C–H
activation.[18-20] However, they would not be suitable for CpxM(III)
catalyses because these ligands require at least four coordination
sites, i.e., two for ligands, a directing group, and a C–H bond to
E-mail: Lin.Luqing@pharm.hokudai.ac.jp;
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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10.1002/anie.201807610
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COMMUNICATION
be cleaved,[19] while CpxM(III) complexes have only three vacant
coordination sites.[21]
Table 1. Screening of Chiral Carboxylic Acids and Optimization of Reaction
Conditions[a]
Here we report achiral CpxRh(III)/chiral binaphthyl
monocarboxylic acid hybrid catalysts for enantioselective C–H
alkylation of diarylmethanamines with diazomalonate followed by
cyclization and decarboxylation (Scheme 1c).[22] Both secondary
and non-protected primary alkylamines functioned as a directing
group in our catalytic system. Directed C–H alkylation reactions
with diazo compounds are well investigated using Cp*M(III)
catalysts,[23] but Pd-catalyzed conditions have not been
reported,[24] and thus the development of CCAs specifically
optimized for CpxRh(III) is crucial to achieve this transformation.
We began our investigation by screening several types of CCAs
using secondary diarylmethanamine 1a as a model substrate
(Table 1).[25] The reaction conditions selected were based on
those previously reported for benzylamine derivatives,[22] but
Ag2CO3 and CCAs were directly used instead of silver
carboxylates for easy reaction setup. Two commercially available
MPAAs (4a, 4b) were selected for the initial trials (entries 1, 2).
The desired product 3a was obtained in moderate yield after
Krapcho decarboxylation, but the enantioselectivity was low in
both cases. We next focused on CCAs based on a binaphthyl
backbone. As the simple binaphthyl monocarboxylic acid 5a[26]
exhibited almost no enantioselectivity (entry 3), we considered
that increasing the steric hindrance around the carboxylic acid
moiety would improve the enantioselectivity. CCA 5b, with a
phenyl group at the 2’-position, resulted in 37/63 er (entry 4),
partially supporting our assumption. Therefore, we next screened
binaphthyl carboxylic acids with a diaryl phosphine oxide group,
which is bulky and easy to modify, at the 2’-position (6).[27] As
expected, the addition of 6a delivered 3a in good yield with
moderate enantioselectivity (entry 5, 75.5/24.5 er). The aryl
groups on the phosphine oxide (6b, 6c) had only minor effects on
the selectivity (entries 6, 7). To further increase the steric
hindrance, a 3,5-di-tert-butyl-4-methoxy-phenyl (DTBM) group
was introduced at the ortho-position of the carboxylic acid by
directed C–H arylation (6d, 6e).[28] The use of 6d dramatically
improved the selectivity to 94.5/5.5 er with a modest yield (entry
8). Changing the 3,5-bis(trifluoromethyl)phenyl groups of 6d to
3,4,5-trifluorophenyl groups (6e, entry 9) increased both the yield
and selectivity. With the optimized CCA 6e, we briefly examined
the effects of Cpx ligands (entries 10–12). While a slightly less
hindered CpMe4 ligand afforded almost the same selectivity and
reactivity (entry 10), sterically more hindered ligands exhibited
lower reactivity and enantioselectivity (entries 11, 12). We also
investigated other silver sources, but only very low yields were
observed when using AgOTf or AgSbF6 (entries 13, 14). Thus,
the reaction conditions in entry 9 were identified to be optimal. We
performed several control experiments to elucidate the
importance of each component of the catalytic system (entry 15–
18). The desired reaction did not proceed without [Cp*RhCl2]2 or
6e (entry 15, 16). The use of ester 6f instead of carboxylic acid 6e
afforded no desired product (entry 17), indicating that the
carboxylic acid moiety is essential. On the other hand, the product
was obtained when Ag2CO3 was omitted, albeit in lower yield
(entry 18).
Entry
[CpxRhCl2]2
CCA
[Ag]
Yield[b]
Er
1
2
[Cp*RhCl2]2
[Cp*RhCl2]2
4a
4b
Ag2CO3
Ag2CO3
63%
61%
43.5/56.5
54/46
3
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[CpMe4RhCl2]2
[Cp*tBuRhCl2]2
[CpEtRhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
–
5a
5b
6a
6b
6c
6d
6e
6e
6e
6e
6e
6e
6e
–
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
AgOTf
43%
20%
67%
56%
82%
54%
84%[c]
80%[c]
34%
51%
19%
15%
0%
49.5/50.5
37/63
75.5/24.5
70.5/29.5
71/29
94.5/5.5
96/4
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
96/4
91/9
93.5/6.5
95/5
AgSbF6
Ag2CO3
Ag2CO3
Ag2CO3
–
95/5
–
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
0%
–
6f
0%
–
6e
63%
96/4
[a] See Supporting Information for the general conditions. [b] Determined by
1H NMR analysis of the crude mixture. [c] Isolated yields
para-position were efficiently converted to the corresponding
products 3a–3h with high enantioselectivities (91.5/8.5–96/4
er). The sterically less hindered C–H bond was selectively
We next investigated the substrate scope of the secondary
diarylmethanamines 1 (Scheme 2). Substrates 1a–1h bearing an
electron-withdrawing group or electron-donating group at the
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10.1002/anie.201807610
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Scheme 3. Primary Non-Protected Amines as Substrates. See Supporting
Information for the general conditions. [a] [CpMe4RhCl2]2 was used instead of
[Cp*RhCl2]2. [b] AgOTf (12 mol %) was used instead of Ag2CO3.
In conclusion, we developed an achiral CpxRh(III)/CCA-
catalyzed
enantioselective
C–H
functionalization
of
diarylmethanamines, including non-protected primary amines, to
afford potentially bioactive 1,4-dihydroisoquinolin-3(2H)-ones[32]
(see Supporting Information for a proposed catalytic cycle).
Enantioselective C–H bond cleavage via a CMD mechanism was
achieved using a newly developed binaphthyl-based chiral mono-
carboxylic acid as the sole chiral source. The developed CCAs
will be useful for further development of reactions involving
enantioselective C–H activation and protonation under CpxM(III)
and other transition metal catalyses. Furthermore, their synergic
effects with chiral CpxM(III) catalysts will be promising for
achieving highly enantioselective transformations.
Scheme 2. Substrate Scope of Secondary Diarylmethanamines. See
Supporting Information for the general conditions. [a] [Cp*RhCl2]2 (1 mol %),
Ag2CO3 (2.4 mol %), 6e (4.8 mol %) were used. [b] [CpMe4RhCl2]2 was used
instead of [Cp*RhCl2]2. [c] AgOTf (12 mol %) was used instead of Ag2CO3.
functionalized to furnish 3i and 3j in 98.5/1.5 er and 95.5/4.5 er,
respectively, while a meta-fluorine-substituted substrate 1k
reacted selectively at the more acidic C–H bond ortho to the
fluorine, providing 3k in 66% yield and 90.5/9.5 er. A substrate
with two enantiotopic naphthyl groups 1l and a tricyclic amine 1m
Acknowledgements
also
afforded
the
products
(3l,
3m)
with
good
This work was supported in part by JSPS KAKENHI Grant Num-
ber JP15H05802 in Precisely Designed Catalysts with
Customized Scaffolding, JSPS KAKENHI Grant Number
JP18H04637 in Hybrid Catalysis, JSPS KAKENHI Grant Number
JP17H03049, JP17K15417, and JP16F16409, JST ACT-C Grant
Number JPMJCR12Z6, and The Asahi Glass Foundation and
Naito Foundation (S.M.).
enantioselectivities.[29] For several substrates, the use of
[CpMe4RhCl2]2 instead of [Cp*RhCl2]2 and AgOTf instead of
Ag2CO3 was slightly beneficial to obtain higher enantioselectivity.
Even when the catalyst loading was decreased to 1 mol % of
[Cp*RhCl2]2 and 4.8 mol % of 6e using 1a as a substrate, the
enantioselectivity was maintained (96/4 er) with moderate yield.
Our CpxRh(III)/CCA catalytic system was successfully applied
not only to secondary amines 1, but also to primary amines 7
(Scheme 3). Non-protected primary alkyl amines are common
and synthetically attractive functional groups, but their use as
directing groups in C–H functionalization is challenging, probably
due to their strong coordinating ability leading to catalyst
deactivation.[30] To our delight, non-protected primary amines 7
exhibited good reactivity and enantioselectivity under the optimal
conditions. Substrates bearing various substituents afforded
product 8a–8g in 55%–79% yields with 90/10–97/3
enantioselectivities.[31] A substrate with a methyl group at the -
position of the nitrogen was also applicable to give product 8h in
90% yield and 90/10 er.
Keywords: C-H activation • asymmetric catalysis • rhodium •
amine • chiral carboxylic acid
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10.1002/anie.201807610
Angewandte Chemie International Edition
COMMUNICATION
[31] For determination of the absolute configuration of 8a, see Supporting
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Information.
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10.1002/anie.201807610
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Enantioselective
activation/functionalization
achieved using an achiral CpxRh(III)
C–H
was
Luqing Lin,* Seiya Fukagawa, Daichi
Sekine, Eiki Tomita, Tatsuhiko Yoshino,*
and Shigeki Matsunaga*
catalyst with
a
newly developed
Page No. – Page No.
binaphthyl monocarboxylic acid as the
sole chiral source. Both secondary and
primary diarylmethanamines reacted
Chiral Carboxylic Acid-Enabled
Achiral Rhodium(III)-Catalyzed
Enantioselective C−H
with
CpxRh(III)/chiral carboxylic acid hybrid
catalysis to give 1,4-
a
diazomalonate under the
Functionalization
dihydroisoquinolin-3(2H)-ones in high
enantioselectivity.
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