[Cp*RhIII] in an Ionic Liquid as a Highly Efficient and Recyclable Catalytic Medium for Regio- and Diastereoselective Csp3–H Carbenoid Insertion

Article abstract of DOI:10.1002/ejoc.201901279

Reported herein is a bidentate-assisted Csp³–H bond insertion using Cp*Rh^III/IL as a highly efficient and recyclable catalytic medium, while showing good functional group tolerance. Notably, the application of ionic liquid not only lowered the temperature, but also enhanced the diastereoselectivity of this reaction. This work significantly expanded the scope of ionic liquids in Csp³–H functionalizations.

Full text of DOI:10.1002/ejoc.201901279

A Journal of
Accepted Article
Title: [Cp*RhIII] in an Ionic Liquid as a Highly Efficient and Recyclable
Catalytic Medium for Regio-and Diastereoselective Csp3-H
Carbenoid Insertion
Authors: Jianglian Li, Lin Zhou, Yaoling Wang, Qiang Ma, Yuan Lei,
Ruizhi Lai, Yi Luo, Li Hai, and Yong Wu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901279
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901279
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10.1002/ejoc.201901279
European Journal of Organic Chemistry
COMMUNICATION
[Cp*RhIII] in an Ionic Liquid as a Highly Efficient and Recyclable
Catalytic Medium for Regio-and Diastereoselective Csp3-H
Carbenoid Insertion
Jianglian Li, Lin Zhou, Yaoling Wang, Qiang Ma, Yuan Lei, Ruizhi Lai, Yi Luo, Li Hai* and Yong Wu*[a]
Abstract: Reported herein is a bidentate-assisted Csp3-H bond
insertion using Cp*Rh(III)/IL as a highly efficient and recyclable
catalytic medium, and this methodology showed good functional
group tolerance. Notably, the application of ionic liquid not only
lowered the temperature, but also enhanced the diastereoselectivity.
This work significantly expanded the scope of ionic liquids in Csp3-H
functionalizations
Cp*M(III)/ILs as recyclable catalytic media to enhance the
stereoselectivity of the more challenging Csp3-H bond
functionalization.
Introduction
In the past few decades, green chemistry, a relatively new
emerging field, has received general interests due to the
increased awareness of the environment issues worldwide.[1] In
order to achieve the goal of green chemistry, chemists have been
dedicated to optimizing the whole process of chemical reactions.
While modern chemistry is heavily relied on the use of low polar,
volatile and toxic organic solvents, which, unfortunately, accounts
for the largest proportion in most reaction systems. Discovering
alternative reaction mediums that are eco-friendly is one of the
major focal point of green chemistry.[2]
Ionic liquids (ILs) have been increasingly used as recyclable
solvents in both academic and industrial fields in recent years due
to many advantages, such as the low toxicity, nonflammable,
recyclable, excellent chemical and thermal stability, negligible
vapor pressure as well as the good solubility for organic and
inorganic compounds.[3] Rather intriguingly, the ability to recycle
the catalysts makes ILs ideal substitutes for many volatile organic
solvents in noble transition-metal catalyzed reactions, such as
Suzuki couplings,[4] Michael additions,[5] Olefin metathesis,[6] C-H
activations[7] and other reactions.[8] In addition, enhancing
stereoselectivity is another promising feature of using ionic liquids
as solvents, yet only a few types of reactions using chiral or non-
chiral ILs have been reported,[8b, 9] Therefore, the development of
more reaction types is still highly desirable. Most recently, our
group successfully demonstrated the directing groups (DGs)-
assisted C-H activations of using Cp*M(III)/ILs as recyclable
catalytic media (scheme 1a).[7a, 7b, 7e] As a continuous research of
our previous work, we envisage the possibility of using
Scheme 1. Related literature reports on Csp2-H/ Csp3-H functionalization
Transition-metal catalyzed heteroatom-adjacent Csp3-H
carbenoid insertions recently provide a new, atom-economic way
to construct C-C bonds,[10] while substrate-specific obstacles
prompt scientists to explore more effective approaches. In 2017,
Zeng’s group firstly reported
a bidentate-assisted Rh(III)-
catalyzed N-methylene Csp3-H bond insertion (scheme 1b).[11]
This strategy provides an effective approach to diverse β-amino
esters, but has a limited practicality because of the poor
diastereoselectivity and relatively high temperature. Herein, we
demonstrate a mild and green method for Csp3-H bond carbenoid
insertion with good diastereoselectivity by constructing a highly
efficient and recyclable catalytic medium using Cp*Rh(III)/IL
(scheme 1c).
[a]
J. Li, L. Zhou, Dr. Y. Wang, Q. Ma, Y. Lei, R. Lai, Y. Luo, Dr. L. Hai,
Prof. Dr. Y. Wu*
Results and Discussion
Key Laboratory of Drug-Targeting and Drug Delivery System of the
Education Ministry and Department of Medicinal Chemistry, Sichuan
Engineering Laboratory for Plant-Sourced Drug and Sichuan
Research Center for Drug Precision Industrial Technology, West
China School of Pharmacy
Sichuan University
No. 17 Southern Renmin Road, Chengdu, Sichuan 610041,
People’s Republic of China.
At the start of our investigation, N-butyl-pyridine-2-carboxylic
acid amide (1a) was treated with [Cp*RhCl2]2 (5 mol%), AgOAc
(20 mol%) and α-diazo-β-ketoester (2a) in 1-butyl-3-
methylimidazolium bis(trifluoromethanesulfonyl) ([BMIM]NTf2) at
100 °C for 24 h, and the desired product (3a) was obtained in 88%
yield (Table 1 entry 1). Encouraged by this result, we had
investigated other 1-butyl-3-methyl- imidazolium salts and found
E-mail: wyong@scu.edu.cn
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10.1002/ejoc.201901279
European Journal of Organic Chemistry
COMMUNICATION
that [BMIM]BF4 gave the best result (Table 1, entries 2-6). The
following screening of the catalysts and silver salts didn’t increase
the yield (see table S1). From our previous works,[7a, 7b, 7e] ionic
liquids could reduce the reaction temperature, the effect of
lowering temperatures on the reaction was evaluated.
Delightingly, the yield and the d.r. value increased when the
temperature was lowered to 60 °C compared with the original
literature (entries 7-9). Whether reducing or increasing the loading
of α-diazo-β-ketoester 2a, catalysts and silver salts, the yields
would decrease more or less (entries 10-14). Accordingly, the
reaction condition was optimized to the following: 1a (0.15 mmol),
2a (0.225 mmol), [Cp*RhCl2]2 (5 mol%) and AgOAc (20 mol%) in
0.5 mL [BMIM]BF4 at 60 °C for 24 h under Ar.
Besides, the yields and d.r. values were better than those in
organic solvents (3e-3m). Therefore, we were also interested in
the replacement of phenyl with naphthalene, and it failed to afford
a good diastereoselectivity (3n). However, phenylethylamine-
based amides could tolerate this reaction system smoothly (3o).
To further evaluate the scope of this process, we then
investigated some substrates with alkenyl groups. Unfortunately,
most of them were not tolerated for this transformation well and
gave low yields, except cyclopentene substrate (3p-3s). In
addition, the naphthenic and shorter straight-chain alkylamine-
based amides were amenable to the reaction with good to
excellent d.r. values (3t, 3u). Because of the widespread
applications
of
organofluorine
compounds
in
drug
.
development,[12] the fluoroalkylamine-based amides were studied
Table 1. Optimization of the reaction conditions.[a]
and proved to be compatible substrates (3v-3x).
Entry
1
Temp (°C)
100
100
100
100
100
100
80
ILs
Yield (%)[b]
d.r. [c]
5:1
[BMIM]NTf2
[BMIM]BF4
[BMIM]PF6
[BMIM]OAc
[BMIM]SbF6
[BDMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
88
93
54
trace
73
81
92
91
58
76
88
70
78
82
2
8:1
3
3:1
4
-
5
4:1
6
6:1
7
10:1
15:1
20:1
10:1
12:1
10:1
13:1
12:1
8
60
9
40
10[d]
11[e]
12[f]
13[g]
14[h]
60
60
60
60
Scheme 2. Substrate scope. Reaction conditions: 1a (0.15 mmol), 2a (0.225
mmol), [Cp*RhCl2]2 (5 mol%) and AgOAc (20 mol%) in 0.5 mL [BMIM]BF4 at
60 °C for 24 h under Ar; isolated yield by chromatography on silica gel.; d.r.
values were determined by 1H NMR spectroscopy.
60
[a] Reaction conditions: 1a (0.15 mmol), 2a (0.225 mmol), [Cp*RhCl2]2 (5
mol%) and AgOAc (20 mol%) in 0.5 mL solvent at specific temperature for
24 h under Ar. [b] Isolated yield by chromatography on silica gel. [c] d.r.
values were determined by 1H NMR spectroscopy. [d] [Cp*RhCl2]2 3 mol%.
[e] [Cp*RhCl2]2 10 mol%. [f] AgOAc 10 mol%. [g] AgOAc 40 mol%. [h] 2a 2.0
To further verify the recovery and applicability of this catalyst
system, the recycling of the [Cp*RhIII]/[BMIM]BF4 system was
investigated under the optimized condition with 1a and 2a as
substrates. After completion, the crude product was simply
separated by extraction. The organic layer was directly subjected
to purification, and the ionic liquid layer was further subjected to
vacuum to remove the remaining diethyl ether before it was
reused in subsequent reactions (without adding fresh Rh catalyst).
After they were reused five times, there was no notable loss of
catalytic activity (Figure 1).
eq. Cp*
=
pentamethylcyclopentadieny; [BMIM]
=
1-butyl-3-
methylimidazolium; [MTMG] = N, N, N’, N’, N -pentamethyl-quinone.
With the optimized conditions in hand, we set out to explore the
feasibility and generality of this approach (Scheme 2). A range of
diazo compounds was first investigated and most of them gave
moderate to excellent yields but poor diastereoselectivities (3a-
3d). To our delight, when we studied N-benzyl-substituted
substrates, electron-withdrawing and electron-donating groups at
different positions on phenyl rings had little effect on the reaction.
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10.1002/ejoc.201901279
European Journal of Organic Chemistry
COMMUNICATION
chromatography with petroleum/ethyl acetate as the eluent to afford the
desired product.
100
90
80
70
60
50
40
30
20
10
0
91
88
87
86
85
Acknowledgements
We thank Prof. Yong Wu for helpful discussions and preliminary
experiments. This work was supported by the National Natural
Science Foundation of China (grant number 81573286, 81373259
and 81773577).
Conflict of interest
1
2
3
4
5
Cycle
The authors declare no conflict of interest.
Figure 1. Recycling study results.
Keywords: Csp3-H Carbenoid Insertion • diastereoselectivity •
Ionic Liquids • Recyclable catalyst system
Structurally, ionic liquids are similar to N-heterocyclic carbenes
(NHCs), which are outstanding nucleophilic catalysts in organic
synthesis and electron-rich ligands in transition-metal-catalyzed
transformations.[13] Among these reactions, free carbene is
necessary because it can form complexes with metals, so we
studied a 2-substituted ionic liquid and found that this procedure
was still tolerated (Table 1, entry 6). This result indicated that ionic
liquid we used may just act as solvent or PTC in this system. On
the basis of the above results (Table 1, Entries 1-6) and previous
reports, [9e, 9f] it seems that anions in ionic liquid play a crucial role
as solvent in the stereoselectivity even though the effect was not
very clear.
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In summary, we have developed a recyclabe strategy of
bidentate-assisted Csp3-H carbenoid insertion using Cp*Rh(III)/IL
catalytic medium with advantages of lower temperature and better
diastereoselectivity. This procedure tolerates various kinds of
amine-based substrates and provides an effective approach to
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Experimental Section
[8]
[9]
General procedure for the synthesis of 3a: To a test tube with a
magnetic stir bar were added picolinamide 1a (0.15 mmol), α-diazo-β-
ketoester 2a (0.225 mmol, 1.5 eq.), [Cp*RhCl2]2 (5 mol %), AgOAc (20
mol %) and [BMIM]BF4 (0.5 mL ) under Ar atmosphere. The reaction
mixture was stirred at 60 °C for 24 h. Afterward, the mixture was extracted
with diethyl ether (5 × 1mL). The organic solvents were removed under
reduced pressure and the residue was purified by silica gel column
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COMMUNICATION
Csp3-H Carbenoid Insertion, Ionic
Liquids
Jianglian Li, Lin Zhou, Yaoling Wang,
Qiang Ma, Yuan Lei, Ruizhi Lai, Yi Luo,
Li Hai* and Yong Wu*
Page No.1 – Page No.5
[Cp*RhIII] in an Ionic Liquid as a Highly Efficient and Recyclable Catalytic Medium
for Regio-and Diastereoselective Csp3-H Carbenoid Insertion
[Cp*RhIII] in an Ionic Liquid as a Highly
Efficient and Recyclable Catalytic
Medium
for
Regio-and
Diastereoselective Csp3-H Carbenoid
Insertion
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