Chiral 2-Aryl Ferrocene Carboxylic Acids for the Catalytic Asymmetric C(sp3)-H Activation of Thioamides

Article abstract of DOI:10.1021/acs.organomet.9b00407

Enantioselective C-H functionalization reactions using trivalent group 9 metals (Co, Rh, Ir) have been investigated mainly on the basis of the development of well-designed chiral cyclopentadienyl (Cp) ligands. Although it has recently been demonstrated th

Full text of DOI:10.1021/acs.organomet.9b00407

Communication
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Cite This: Organometallics XXXX, XXX, XXX−XXX
Chiral 2‑Aryl Ferrocene Carboxylic Acids for the Catalytic
Asymmetric C(sp3)−H Activation of Thioamides
Daichi Sekine, Kazuki Ikeda, Seiya Fukagawa, Masahiro Kojima, Tatsuhiko Yoshino,*
and Shigeki Matsunaga*
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
S
* Supporting Information
ABSTRACT: Enantioselective C−H functionalization reactions using
trivalent group 9 metals (Co, Rh, Ir) have been investigated mainly on
the basis of the development of well-designed chiral cyclopentadienyl (Cp)
ligands. Although it has recently been demonstrated that chiral carboxylic
acids combined with achiral Cp-type ligands can enable highly
enantioselective C−H functionalization reactions, the structural diversity
of the applied chiral acids remains limited. Here, we report that chiral 2-
aryl ferrocene carboxylic acids, which are easily obtained from
diastereoselective ortho lithiation and Suzuki−Miyaura coupling, can
serve as external chiral sources for the Cp*CoIII-catalyzed enantioselective
C(sp3)−H amidation of α-aryl thioamides using dioxazolones.
ince the seminal work on Cp*RhIII catalysis by Satoh,
catalyzed asymmetric C−H functionalizations.17,18 Further
development of appropriate chiral carboxylic acids is highly
demanded for expanding the scope of Cp*MIII-catalyzed
enantioselective C−H functionalization reactions.
S
Miura, and co-workers in 2007,1 trivalent group 9 metal
(Co, Rh, Ir) complexes with a pentamethylcyclopentadienyl
(Cp*) or other Cp-type (Cpx) ligand have been used for a
wide variety of catalytic C−H functionalization reactions in
organic synthesis.2,3 Such Cp*MIII catalysts are characterized
by their particularly high reactivity, functional group
compatibility, and robustness. More recently, the development
of catalytic asymmetric C−H functionalization reactions4 using
these catalysts has attracted considerable attention, as
controlling stereochemistry is crucial for the synthesis of
complex molecules.5−16 Cramer and co-workers,5,6 as well as
other groups,7 have demonstrated that well-designed chiral Cpx
ligands and their metal complexes provide a powerful and
versatile platform for asymmetric C−H functionalization
reactions. Engineered protein-conjugated chiral CpxRh cata-
lysts also provide efficient chiral environments, as reported by
Ward, Rovis, and co-workers.8 Our group has focused on the
combination of achiral CpxMIII complexes and chiral
disulfonates9 or chiral carboxylic acids10 as an alternative
approach to enantioselective C−H functionalization reactions.
Chiral carboxylic acids participate in the C−H activation step
as the external chiral source in a carboxylate-assisted concerted
metalation−deprotonation mechanism, leading to the selective
cleavage of enantiotopic C−H bonds (Figure 1a).11−13 The
groups of Ackermann14 and Shi15 have also reported the use of
chiral carboxylic acids in enantioselective C−H functionaliza-
tion reactions.16 Although these approaches using chiral
carboxylic acids are attractive in terms of the accessibility of
the chiral catalytic components, the diversity of the applied
chiral carboxylic acids therein is still limited in comparison to
chiral Cp ligands5−7,12 and bidentate ligands used in PdII-
Unsymmetrically 1,2-disubstituted ferrocenes, which exhibit
planar chirality, have been extensively explored in asymmetric
catalysis.19,20 On the basis of their unique but readily accessible
chirality, a variety of chiral ligands and organocatalysts have
been developed over the past few decades (Figure 1b). We
anticipated that chiral carboxylic acids with a planar chiral
ferrocene backbone could serve as external chiral sources for
CpxMIII-catalyzed enantioselective C−H functionalization
reactions, which would significantly expand catalyst diversity.
Herein, we report the synthesis of chiral 2-aryl ferrocene
carboxylic acids and their application to the enantioselective
C(sp3)−H amidation of α-aryl thioamides using a Cp*CoIII
catalyst (Figure 1c).10b,21−23 This synthetic route provides easy
access to various derivatives, which is often necessary for
optimization studies in asymmetric catalysis.
For the synthesis of the chiral ferrocene carboxylic acids, we
initially subjected ferrocene oxazoline 1 to diastereoselective
ortho lithiation (Scheme S1 in the Supporting Information)
under previously reported conditions.24 After quenching with
1,1,2,2-tetrabromoethane, bromide 2 was obtained as an
almost single diastereomer. Partial hydrolysis of the oxazoline
moiety, acetylation of the resulting primary amine,25 and
Special Issue: Asymmetric Synthesis Enabled by Organometallic
Complexes
Received: June 18, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.9b00407
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
Figure 1. (a) Our previous work on enantioselective C(sp3)−H amidation of α-alkyl thioamides. (b) Representative examples of chiral 1,2-
disubstituted ferrocenes used in asymmetric catalysis. (c) Chiral ferrocene carboxylic acids for Cp*CoIII-catalyzed enantioselective C(sp3)−H
amidation of α-aryl thioamides (this work).
methanolysis of the ester intermediate led to the common
precursor 3 in 76% yield over three steps. Chiral HPLC
analysis of 3 indicated that an essentially pure enantiomer was
obtained (99:1 er). Subsequently, we investigated cross-
coupling reactions to synthesize various derivatives from 3.
Suzuki−Miyaura coupling reactions under Buchwald’s con-
ditions using SPhos26 as a ligand proceeded smoothly to afford
2-aryl ferrocene carboxylic acids 4 (28−85% yield) after
hydrolysis of the ester.
Table 1. Screening of Chiral Carboxylic Acids 4 and
Optimization
a
With several chiral carboxylic acids in hand (4a−d), we
investigated the cobalt-catalyzed enantioselective C(sp3)−H
amidation reaction of α-aryl thioamide 5a using dioxazolone
6a (Table 1). In our previous studies (Figure 1a), only α-alkyl
and α-benzyl thioamides were examined as substrates.10b
Considering the synthetic importance of this transformation
to give chiral β-amino carbonyl building blocks, we decided to
explore expanding the substrate scope using the newly
synthesized chiral acids 4. Our optimization studies started
with screening the chiral acids 4 using [Cp*Co(CH3CN)3]-
(SbF6)2 (Table 1, entries 1−4). While 4a−c exhibited similar
reactivities (57−62% yield) and selectivities (65:35−67:33 er),
the most sterically hindered derivative (4d; Ar = 3,5-di-tert-
butylphenyl) led to higher conversion with higher enantiose-
lectivity (84:16 er; entry 4). Since the reactivity was greatly
enhanced by 4d, lower reaction temperatures were then
examined in order to improve the selectivity (entries 5−7).
Although the reaction barely proceeded at 15 °C (entry 5), the
addition of molecular sieves 13X (MS13X) significantly
accelerated the reaction and provided a high yield with
increased selectivity (entry 6). To our surprise, the reaction
proceeded even at 4 °C, affording the product in 90% yield
with 87:13 er after 72 h (entry 7).
b
c
entry acid
additive
temp (°C) time (h) yield (%)
er
1
2
3
4
5
6
7
4a
4b
4c
4d
4d
4d
4d
none
none
none
none
none
MS13X
MS13X
30
30
30
30
15
15
4
24
24
24
24
24
24
72
59
57
62
90
5
66:34
65:35
67:33
84:16
85:15
86:14
87:13
90
90
a
Reactions were carried out using 5a (0.050 mmol), 6a (0.06 mmol),
[Cp*Co(CH3CN)3](SbF6)2 (0.0025 mmol, 5 mol %), acid (0.005
mmol, 10 mol %), and additive (10 mg) in DCE (0.5 mL) unless
b
otherwise noted. Determined by 1H NMR analysis of the crude
mixture using 1,1,2,2-tetrachloroethane as the internal standard.
Determined by chiral HPLC analysis. Cp* = 1,2,3,4,5-pentam-
c
ethylcyclopentadienyl.
the enantioselectivity (7aa−ca), although the reactivity was
somewhat deteriorated when a pCl-phenyl-substituted sub-
strate was used (7ca). 6-Methoxy-2-naphthyl-substituted
thioamide 5d also provided the corresponding product (7da)
The optimized reaction conditions using 4d as the chiral
source were then applied to other α-aryl thioamides 5 (Scheme
1). The electronic properties of the α-aryl group did not affect
B
DOI: 10.1021/acs.organomet.9b00407
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
Scheme 1. Substrate Scope of the Enantioselective C(sp3)−
a
H Amidation of α-Aryl Thioamides 5 with Dioxazolone 6
Figure 2. Stereochemical models for plausible transition states of the
C−H activation to rationalize the observed enantioselectivity using
chiral carboxylic acid 4d.
with concave and convex faces. The ferrocene moiety of 4d
would be aligned on the convex face to avoid steric repulsion
with the thioamide. On the basis of this assumption, four
different transition states (TSs) for the C−H activation are
possible. In TS-(S)-1 and TS-(R)-1, the α-aryl group of the
thioamide is located on the concave face, which would render
these two TSs unfavorable. TS-(S)-2 might be less favored
than TS-(R)-2 due to the steric repulsion between the 3,5-di-
tert-butyl-phenyl group of 4d and the N-benzyl groups of the
thioamide. Overall, TS-(R)-2 is the most plausible transition
state for the C−H activation, which selectively provides R
products.28
In summary, we have synthesized several chiral 2-aryl
ferrocene carboxylic acids 4, one of which exhibited good
reactivity and enantioselectivity in cobalt-catalyzed C(sp3)−H
amidation reactions of α-aryl thioamides. These carboxylic
acids can be easily synthesized and modified by changing the
aryl substituent, which is introduced via a cross-coupling
reaction in a late step of the synthesis. Investigations on
catalytic enantioselective C−H functionalization using these
carboxylic acids in combination with Cp*CoIII or Cp*RhIII
catalysts are currently in progress in our group.
a
Reactions were carried out using 5 (0.20 mmol), 6 (0.24 mmol),
[Cp*Co(CH3CN)3](SbF6)2 (0.01 mmol, 5 mol %), 4d (0.02 mmol,
10 mol %), and MS13X (40 mg) in DCE (2 mL). 1.0 mmol scale.
b
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.9b00407.
■
in 96% yield with 87:13 er. Changing the substituents at the
thioamide moiety to iBu groups had negligible influence on the
reactivity and selectivity (7ea). We examined a range of
dioxazolones 6 using thioamide 5a. Aromatic, heteroaromatic,
and aliphatic dioxazolones all provided the targeted products in
good yield and enantioselectivity (7ab−af). Steric hindrance
around the dioxazolone functionality did not affect the
reactions (7ac,af). Finally, the reaction using 5a and 6a was
carried out in 1.0 mmol scale, providing 7aa in 92% yield with
85:15 er.
S
Experimental procedures, characterization data of the
synthesized compounds, and copies of their NMR
spectra (PDF)
Cartesian coordinates of the calculated structures (XYZ)
Accession Codes
In order to rationalize the observed enantioselectivity using
4d, we propose the qualitative stereochemical models shown in
Figure 2.27 Due to the piano-stool structure of Cp*CoIIIL3
complexes, the CoL3 fragment constitutes a conical scaffold
CCDC 1935636 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
C
DOI: 10.1021/acs.organomet.9b00407
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
Rh(III) Catalysis for C−H Functionalization. Acc. Chem. Res. 2018,
51, 170−180. (h) Yoshino, T.; Matsunaga, S. Cp*CoIII-Catalyzed C−
H Functionalization and Asymmetric Reactions Using External Chiral
Sources. Synlett 2019, 30, 1384−1400.
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
*E-mail for T.Y.: tyoshino@pharm.hokudai.ac.jp.
*E-mail for S.M.: smatsuna@pharm.hokudai.ac.jp.
■
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ORCID
Masahiro Kojima: 0000-0002-4619-2621
Tatsuhiko Yoshino: 0000-0001-9441-9272
Shigeki Matsunaga: 0000-0003-4136-3548
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by JSPS KAKENHI Grant
Number JP15H05802 in Precisely Designed Catalysts with
Customized Scaffolding, JP18H04637 in Hybrid Catalysis,
JP17K15417, JP19K16306. S.M. is grateful for support from
the Asahi Glass Foundation and the Naito Foundation.
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Organometallics
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(27) Although the external CMD mechanism in which two
carboxylates are involved was proposed in a previous report on the
basis of quantum chemical calculations,22a our own preliminary
computational studies on the racemic model systems indicate that an
internal CMD mechanism is more likely. See the Supporting
Information for the details.
(28) The absolute configuration of the products was determined to
be R by the X-ray analysis of 7ba (see the Supporting Information).
F
DOI: 10.1021/acs.organomet.9b00407
Organometallics XXXX, XXX, XXX−XXX