Enantioselective C(sp3)–H Amidation of Thioamides Catalyzed by a CobaltIII/Chiral Carboxylic Acid Hybrid System

Article abstract of DOI:10.1002/anie.201812215

Recent advances in Cp^xM^III catalysis (M=Co, Rh, Ir) have enabled a variety of enantioselective C(sp²)?H functionalization reactions, but enantioselective C(sp³)?H functionalization is still largely unexplored. We describe an asymmetric C(sp³)?H amidation of thioamides using an achiral Co^III/chiral carboxylic acid hybrid catalytic system, which provides easy and straightforward access to chiral β-amino thiocarbonyl and β-amino carbonyl building blocks with a quaternary carbon stereocenter.

Full text of DOI:10.1002/anie.201812215

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Cobalt(III)/Chiral Carboxylic Acid-Catalyzed Enantioselective
C(sp3)-H Amidation of Thioamides
Authors: Seiya Fukagawa, Yoshimi Kato, Ryo Tanaka, Masahiro
Kojima, Tatsuhiko Yoshino, and Shigeki Matsunaga
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812215
Angew. Chem. 10.1002/ange.201812215
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Angewandte Chemie International Edition
10.1002/anie.201812215
COMMUNICATION
Cobalt(III)/Chiral Carboxylic Acid-Catalyzed Enantioselective
3
C(sp )-H Amidation of Thioamides
Seiya Fukagawa, Yoshimi Kato, Ryo Tanaka, Masahiro Kojima, Tatsuhiko Yoshino,* and Shigeki
Matsunaga*
x
Abstract: Recent advances in Cp M(III) catalyses (M = Co, Rh, Ir)
2
have enabled a variety of enantioselective C(sp )-H functionalization
3
reactions, but enantioselective C(sp )-H functionalization is still
3
largely unexplored. Here we describe an asymmetric C(sp )-H
amidation of thioamides using an achiral Co(III)/chiral carboxylic acid
hybrid catalytic system, providing easy and straightforward access to
chiral -amino thiocarbonyl and -amino carbonyl building blocks with
a quaternary carbon stereocenter.
Transition metal-catalyzed C-H functionalization[1] is attracting
increasing attention in organic synthesis due to the potential to
enable atom-[2] and step-economical[3] synthesis of functional
molecules. Trivalent group 9 metals with a cyclopentadienyl-type
(
Cpx) ligand exhibit remarkable catalytic performance and
generality for directing group-assisted C-H
activation/functionalization reactions. Although catalytic control
[
4]
[
5]
x
of enantioselectivity under the Cp M(III) (M = Co, Rh, Ir)
catalyses was a longstanding problem due to the lack of vacant
coordination sites for an external chiral ligand, well-designed
chiral Cpx ligands have been developed as
solution.[
a
powerful
5a,b,6-12]
[6]
After the pioneering works by Cramer’s group,
several types of chiral Cpx ligands and their metal complexes
were synthesized and used for enantioselective C-H
functionalization reactions (Scheme 1a).[7-11] We recently
x
demonstrated that an achiral Cp Rh(III) catalyst hybridized with
an external chiral source realizes enantioselective C-H
functionalization reactions (Scheme 1b).[13] These previous
studies on group
9
metals, however, only focused on
2
enantioselective C(sp )-H functionalization reactions, and more
3
challenging C(sp )-H functionalization reactions remain
unexplored.[10c,14] Furthermore, Cp Co(III) catalysts were less
investigated for enantioselective reactions despite their ready
availability and unique properties.[4d-f,h,I,15] During the preparation
of this manuscript, Ackermann and co-workers reported an
x
x
Scheme 1. Cp M(III)-catalyzed enantioselective C-H functionalization reactions
(M = Co, Rh, Ir).
enantioselective alkylation of indoles with olefins using
a
Cp*Co(III)/chiral carboxylic acid system, in which enantioselective
[
16]
protonation is a key step for the stereocontrol (Scheme 1c).
under the assistance of carbonyl-based directing groups,
providing a straightforward route to -amino carbonyl compounds.
Asymmetric variants of these reactions provide attractive
methods for synthesizing related chiral building blocks, but they
are scarcely studied.[20] Here we report an achiral Cp Co(III)/chiral
Group 9 Cp*M(III),[17] Pd,[18] and other catalysts were used for
directed intermolecular -C(sp )-H amination/amidation reactions
[19]
3
x
3
carboxylic acid hybrid system-catalyzed C(sp )-H amidation of
[
a]
S. Fukagawa, Y. Kato, R. Tanaka, 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
thioamides (Scheme 1d). Good enantioselectivity was achieved
using a readily available ligand and carboxylic acid under mild
conditions via enantioselective carboxylate-assisted concerted
metalation-deprotonation (CMD).[
13b,21,22]
Dixon, Seayad, and co-workers reported Cp*Co(III)-catalyzed
3
[17c]
C(sp )-H amidation of thioamides.
Their quantum chemical
calculations suggested that the C-H bond cleavage step would
proceed via an external carboxylate-assisted CMD mechanism.
Supporting information for this article is given via a link at the end of
the document.
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Angewandte Chemie International Edition
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COMMUNICATION
Table 1. Screening of Chiral Carboxylic Acids and Optimization of Reaction
Conditions
Table 2. Substrate Scope of Enantioselective Amidation of Thioamides[a]
[
a]
1
2
Yield[b] Er[c]
Entry R (1)
R (2)
3
Entry
Co cat.
CCA
Solvent
Additive
Yield[b]
Er[c]
1
2
3
Ph (1a)
pCl-C
pBr-C
Ph (2a)
Ph (2a)
Ph (2a)
3aa
3ba
3ca
82%
81%
91%
92/8
91/9
91/9
1
2
3
4a
4a
4a
5a
5b
5c
DCE
DCE
DCE
none
none
none
67%
47%
66%
68/32
60/40
75/25
6
H
4
(1b)
(1c)
6 4
H
4
5
6
7
8
9
3
pCF -C
6
H
4
(1d)
(1e)
Ph (2a)
Ph (2a)
3da
3ea
3fa
89%
88%
81%
73%
87%
93%
50%
76%
86%
63%
90%
65%
96%
99%
55%
73%
92/8
92/8
91/9
93/7
94/6
92/8
90/10
91/9
93/7
94/6
92/8
91/9
92/8
92/8
92/8
92/8
4
5
6
7
8
9
4a
4a
4a
4b
4c
4b
4b
4b
4b
5d
5e
5f
5f
5f
5f
5f
5f
5f
DCE
DCE
DCE
DCE
DCE
DCE
PhCl
oDCB
oDCB
none
60%
77%
93%
30%
38%
68%
20%
81%
82%[f]
85/15
78/22
87/13
90/10
84/16
90/10
89/11
92/8
pMeO-C
6
H
4
none
3,5-(CF
3
)
2
-C
6
H
3
(1f) Ph (2a)
none
2,6-Me
2
-C
6
H
3
(1g)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
3ga
3ha
3ia
none
1-naphthyl (1h)
2-naphthyl (1i)
iPr (1j)
none
MS13X[d]
MS13X[d]
MS13X[d]
MS13X[d]
1 [
0
d]
3ja
1
1
1
0
11
12
13
14
15
16
17
18
19
cyclohexyl (1k)
Ph (1a)
3ka
3ab
3hc
3ad
3ae
3af
1
pCl-C
pBr-C
pMeO-C
6
H
4
(2b)
(2c)
2[e]
92/8
1-naphthyl (1h)
Ph (1a)
6
H
4
6
H
4
(2d)
Ph (1a)
oMe-C
6 4
H
(2e)
Ph (1a)
2-furyl (2f)
Ph (1a)
2-thienyl (2g)
Me (2h)
3ag
3ah
3ai
Ph (1a)
Ph (1a)
tBu (2i)
[
(
a] 1 (0.20 mmol), 2 (0.24 mmol), 4b (0.01 mmol), 5f (0.02 mmol), and MS13X
40 mg) in oDCB (0.2 M) at 40 °C for 24 h unless otherwise noted. [b] Isolated
yield. [c] Determined by chiral HPLC analysis. [d] 48 h.
[
a] Reactions were run using 1a (0.05 mmol), 2a (0.06 mmol), 4 (0.0025
mmol), and 5 (0.005 mmol) in the indicated solvent (0.1 M) unless otherwise
1
noted. [b] Determined by H NMR analysis of the crude mixture using 1,1,2,2-
tetrachloroethane as an internal standard. [c] Determined by chiral HPLC
analysis. [d] 200 mg/mmol 1a. [e] 0.20 mmol scale, 0.2 M. [f] Isolated yield.
Based on their results, we started our investigation with an
amidation of thioamide 1a using dioxazolone 2b to afford 3aa,
anticipating that enantioselective CMD is possible by a chiral
carboxylic acid (Table 1).[23] In this study, amino acid derivatives
were selected due to their accessibility, and we found that tert-
leucine derivatives (5a–5d)[24] were suitable for this reaction
Scheme 2. Scope and limitations of enantioselective amidation of thioamides.
The reaction conditions are same as those in Table 2.
enantioselectivity, although the reactivity significantly decreased
(
entry 7). Sterically less hindered 4c decreased both the reactivity
(
entries 1–4). Initial screening using Cp*Co(III) catalyst 4a
and selectivity (entry 8). After optimization studies using 4b, we
found that adding MS13X improved the reactivity without
decreasing the selectivity (entry 9). Finally, screening of other
halogenated solvents identified ortho-dichlorobenzene (oDCB) as
the most suitable solvent (entries 10–12), and product 3aa was
obtained in 82% isolated yield with 92/8 er (entry 12).
revealed that (S)-BHTL 5d[24b] was an efficient co-catalyst in terms
of enantioselectivity (entry 4, 85/15 er). L-Valine derivative 5e
exhibited higher reactivity, but lower selectivity (entry 5). We
2
further synthesized (S)-H -BHTL 5f, which resulted in slightly
improved selectivity and was selected as the optimal carboxylic
x
acid (entry 6). We next examined the steric effects of Cp Co
catalysts 4. Sterically more hindered catalyst 4b afforded higher
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Angewandte Chemie International Edition
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COMMUNICATION
Scheme 3. Gram-scale reaction and transformation of product. See Supporting
Information for the detailed reaction conditions.
3
The scope and limitations of the enantioselective C(sp )-H
amidation of thioamides 1 using dioxazolones 2 are summarized
in Table 2 and Scheme 2. We first investigated the scope of
thioamides 1. Thioamides bearing a various substituent at the -
position afforded the corresponding products in good yield and
enantioselectivity (entries 1–11, 90/10–94/6 er). Functional
groups on the aromatic moiety did not affect the reactivity or
selectivity (entries 2–7). Bulkier -substituents tended to confer
slightly better enantioselectivity (entries 7 and 8). While non-cyclic
thioamide 1i also resulted in good enantioselectivity (Scheme 2a),
isobutyric acid-derived thioamide 1j exhibited very low reactivity
and selectivity (Scheme 2b).[25] Next, the scope of dioxazolones 2
was examined using thioamides 1a and 1h. Both electron-
withdrawing and electron-donating groups on 2 were well
tolerated to afford 63%–90% yields and 91/9–94/6 er (entries 12–
Scheme 4. Reversibility of C-H activation step and enantio-determining step of
C-H amidation.
Therefore, enantioselective C-H activation is a key step for the
enantioselective C-H amidation.[
27]
In summary, we demonstrated that the combination of achiral
Co(III) complex 4b and chiral carboxylic acid 5f promoted
3
asymmetric C(sp )-H amidation reactions of thioamides 1 using
dioxazolones 2. Good enantioselectivity was achieved with a wide
3
range of substrates via enantioselective C(sp )-H activation,
giving useful chiral building blocks with a quaternary carbon
stereocenter. Further applications of similar hybrid catalytic
systems are ongoing in our laboratory.
1
5). Even a sterically hindered dioxazolone worked
efficiently as the amidation reagent (entry 15). In addition to
aromatic dioxazolones, heteroaromatic and
dioxazolones afforded similarly good enantioselectivity (entries
aliphatic Acknowledgements
1
6–19).
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 JP17K15417, and The Asahi Glass Foundation
and Naito Foundation (S.M.). We acknowledge Mr. Takuro Suzuki
in our group for X-ray crystallographic analysis.
A gram-scale reaction using 1a and 2a was successfully carried
out to afford 3aa in 92% yield with 93/7 er (Scheme 3). It is worth
noting that our optimized reaction conditions are feasible for
scale-up because only readily available catalysts are required.
Product 3aa was readily converted to amide 6 and amine 7 by
2
CO
3
2 4
and NiCl /NaBH ,
respectively.[17c]
treatment with Ag
Furthermore, methylation and subsequent reduction of 3aa
provided chiral -amino aldehyde 8 in 73% yield,[26] demonstrating
the utility of the enantioselective amidation products.
To confirm that the enantioselectivity is determined by
enantioselective C-H bond cleavage, we checked the reversibility
of the C-H activation step (Scheme 4). If this step is reversible,
we cannot rule out the possibility that a chiral acid participates in
the following steps and achieves the enantioselectivity. The
Keywords: C-H activation • asymmetric catalysis • cobalt •
thioamide • chiral carboxylic acid
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3 2
reaction of 1a and 2a using an excess amount of CH CO D
instead of a chiral acid proceeded to afford 3aa, but deuterium
incorporation was not observed in product 3aa or recovered 1a
(
Scheme 4a). We also confirmed that H/D exchange barely
proceeded even in the absence of 2a (Scheme 4b). These results
unambiguously indicate that the C-H activation step is irreversible.
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This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
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COMMUNICATION
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[
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3
2018, 57, 4048-4052.
[25] We also examined a methylene C(sp )-H amidation reaction of the
[
10] Antonchick and Waldmann’s chiral Cpx ligands: a) Z.-J. Jia, C. Merten,
following substrate, but no reaction proceeded under the current reaction
conditions.
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3
an enantioselective reaction through formal C(sp )-H functionalization is
reported: H. Li, R. Gontla, J. Flegel, C. Merten, S. Ziegler, A. P.
[27] The absolute configuration of 3aa was determined after conversion into
a known -amino acid. The same absolute configuration was suggested
for 3ae by the X-ray crystallographic analysis (CCDC number: 1880679).
See Supporting Information for details.
Antonchick,
H.
0.1002/ange.201811041; Angew. Chem. Int. Ed. 2018, DOI:
0.1002/anie.201811041.
Waldmann,
Angew.
Chem.
2018,
DOI:
1
1
.
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Angewandte Chemie International Edition
10.1002/anie.201812215
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
3
Thioamide-directed
amidation using
C(sp )-H
Seiya Fukagawa, Yoshimi Kato, Ryo
Tanaka, Masahiro Kojima, Tatsuhiko
Yoshino,* and Shigeki Matsunaga**
dioxazolones
proceeded in good enantioselectivity.
Hybridization of a readily available
cobalt catalyst and a chiral amino acid
derivative opened up a straightforward
route to chiral -amino carbonyl
building blocks. Irreversible and
Page No. – Page No.
Cobalt(III)/Chiral Carboxylic Acid-
3
Catalyzed Enantioselective C(sp )-H
Amidation of Thioamides
3
enantioselective cleavage of a C(sp )-
H
bond was achieved via chiral
carboxylate-assisted
concerted
metalation-deprotonation.
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