Ligand-promoted ruthenium-catalyzed: Meta C-H chlorination of arenes using N -chloro-2,10-camphorsultam

Article abstract of DOI:10.1039/c8cc03195a

A practical meta C-H chlorination protocol is established via a Ru(0)-catalyzed ortho-metalation strategy. The use of N-chloro-2,10-camphorsultam as a new chlorinating agent is crucial for the success of the current reaction and an N-heterocyclic carbene (NHC) ligand could significantly enhance the reactivity of the catalytic transformation. The mechanistic studies reveal that an unusual ortho C-H ruthenation relay process with ortho chlorination of the C-Ru bond is probably involved.

Full text of DOI:10.1039/c8cc03195a

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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Ligand-Promoted Ruthenium-Catalyzed Meta C-H Chlorination of
Arenes Using N-Chloro-2,10-camphorsultam†
Zhoulong Fan,ab Heng Lu,c Zhen Chengd and Ao Zhang*abc
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A practical meta C-H chlorination protocol is established via a substrate scope of anilines and phenols and b) installation and
Ru(0)-catalyzed ortho-metalation strategy. The use of N-chloro- removal of directing groups. As a consequence, establishment
2,10-camphorsultam as a new chlorinating agent is crucial for the of the practical and complementary meta C-H chlorination
success of the current reaction and the N-heterocyclic carbene method is still an impending demand.
(NHC) ligand could significantly enhance the reactivity of the
Recently, the emerging ortho-ruthenation strategy is an
catalytic transformation. The mechanistic studies reveal that an useful tool for meta functionalization.8,9 Pioneering works
unusual ortho C-H ruthenation relay ortho chlorination of C-Ru including meta sulfonation,10 alkylation,11 bromination,12
bond process is probably involved.
nitration13 and fluoromethylation14 have been accomplished.
To overcome the insufficiencies of previous meta C-H
chlorination as well as identify new meta C-H functionalization
Aryl chlorides constitute an ample source of chlorinated
pharmaceuticals that are used for the treatment of multiple
diseases, especially cardiovascular and central nervous
disorders.1 Meanwhile, they are also a class of versatile
precursors for diverse cross-coupling reactions.2 The
conventional methods for aromatic chlorination include
Sandmeyer reaction,3 electrophilic aromatic chlorination4 or
approach under Ru catalysis, herein, we report
a N-
heterocyclic carbene(NHC)-promoted Ru(0)-catalyzed meta-
selective C-H chlorination. This protocol contains several
notable features, including: a) ample scope of heterocyclic
substrates, b) the use of N-chloro-2,10-camphorsultam as a
new chlorinating agent, c) employing a NHC ligand to enhance
the reactivity, d) an ortho C-H ruthenation relay ortho
chlorination process is involved and e) the practical utility for
rapid synthesis and diversification of pharmaceutically useful
benzodiazepines and fluorescent probe molecules (Scheme
1b).
stoichiometric
ortho-metalation-chlorination
sequence.5
Despite these approaches have been frequently employed for
the preparation of aryl chlorides, they have significant
liabilities that limit their application involving tedious
operation, poor ortho-/para-selectivity and harsh reaction
conditions.
To overcome the limitations, transition metal-catalyzed ortho
C-H activation/chlorination have been realized.6 In stark
contrast, there have been few studies on meta C-H
chlorination. So far, only the Yu group recently revealed a
modified norbornene-mediated meta C-H chlorination
protocol, in which they used pyridone ligand to improve the
efficiency of Pd(II) catalysis (Scheme 1a).7 However, the
transformation suffered from two major drawbacks: a) limited
a.CAS Key Laboratory of Receptor Research and the State Key Laboratory of Drug
Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of
Sciences, Shanghai 201203, China. Email: aozhang@simm.ac.cn
Scheme 1 Different strategies enabled meta C-H chlorination
of arenes.
b.University of Chinese Academy of Sciences, Beijing 100049, China
c. School of Life Science and Technology, ShanghaiTech University, Shanghai, China
d.Molecular Imaging Program at Stanford, Department of Radiology, School of
Medicine, Stanford University, Stanford, California 94305-5484, USA
Electronic Supplementary Information (ESI) available: experimental procedures,
We commenced the study with substrate 1a and a variety of
chlorinating agents under Ru3(CO)12/PhI(TFA)2 catalytic
system.13b To our delight, the chlorinating agent [Cl]-1 gave the
meta chlorination product 2a in 15% yield. We subsequently
screened various factors including solvent, temperature and
characterization data and X-ray for 4bmono (CCDC 1587232), 6e (CCDC 1586057),
B
(CCDC 1586058) and 1H and 13C NMR spectra for all of the new compounds. See
DOI: 10.1039/x0xx00000x
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substrate concentration, however, the yield was only slightly the selective mono-chlorination product 2p in 79% yield. We
increased to 25% (see the Supporting Information). Notably, also found that reactions with substituted 2-phenylpyrimidines
the unusual PhBr is the best solvent for this transformation proceeded smoothly under the standard conditions (2q-s).
because of its excellent solubility. Considering ligand effect on Regrettably, the bicycloheterocyles such as 2-phenylquinoline
ruthenium-catalyzed C-H activation,14a we next investigated a gave incomplete conversion with lower yield (2t, 34%).
number of commonly used ligands. The significant
improvement was observed in the presence of NHC ligands
(entries
1-9,
Table
1).
1,3-Bis(2,4,6-
trimethylphenyl)imidazolium chloride (IMes.HCl) was found as
the optimal ligand to afford 2a in 58% total yield (entry 2).
Along with employing higher amount of ligand and prolonging
the reaction time, the best result was obtained in 82% isolated
yield and the ratio of mono-/di-chlorination products is 8:1.
Therefore, entry 11 is chosen as the standard condition.
Table 1 Optimization of the reaction conditionsa
Entry
Ligand
Total yield
(mono+di)(%)b
Scheme 2 Meta C-H chlorination of 2-arylheterocycle scaffolds.
a Ratio of isolated mono- vs di-chlorination products. b Yield
based on recovered starting material.
1
2
3
4
5
6
7
8
9
IPr•HCl
IMes•HCl
SIMes•HCl
IMes
47
58
54
46
41
43
52
49
37
We then examined the transformation of a wide range of
purine bases under slightly modified meta C-H chlorination
conditions (Scheme 3). Though the electronic property of the
para or meta substituents has little influence on the reactivity,
the selectivity of mono- or di-chlorination products was
markedly relevant (4a-j). Notably, the substrate bearing 4-
methoxyl substituent almost only afforded di-chlorination
IiPr•HBF4
ItBu•HBF4
L1
L2
L3
IMes•HCl
IMes•HCl
10c
11c,e
67d
86(82)d,f
a Reaction conditions: 1a (0.1 mmol), [Cl]-1 (1.75 equiv), Ru3(CO)12 (7.5
product 4e
.
This approach was also applicable to
mol%), ligand (20 mol%), PhI(TFA)2 (1.3 equiv), PhBr (1 mL), air, 95 oC, 24
h. Yields were determined by 1H NMR analysis using CH2Br2 as an
internal standard. Unless otherwise stated, mono/di > 20:1. c Using 40
mol% ligand. d mono/di = 8:1. e For 48 h. f Isolated yield.
naphthylpurine affording the corresponding product 4l in
moderate yield. In the cases of N-benzyl, -butyl, -methyl and -
cyclopentyl purines, the desired products 4m-p were obtained
in moderate yields. More appealingly, the key synthetic
intermediate for a p-38 kinase inhibitor15 was also suitable for
the protocol and the chlorinated product 4q was obtained in
63% yield, which may provide a fast-track en route to various
antineoplastic drugs.
b
With the optimized reaction conditions in hand, we probed
the versatility of the meta C-H chlorination of 2-
arylheterocycle scaffolds (Scheme 2). It was found that both
the electron-rich and -deficient substituents on phenyl or
pyridyl rings were widely tolerated and the desired products
were obtained in moderate to excellent yields (2b-o). However,
the lower selectivity of mono-/di-chlorination was received for
the substrates bearing electron-rich substituents on the para
position of phenyl rings. Unexpectedly, the preferable
chlorination on the less steric meta position was observed in
the cases of ortho-substituted arylpyridines as the substrates
Next, we turned our attention to benzodiazepine scaffolds
that generally have sedative activities (Scheme 4).16 The
compatibility of substituents on the aromatic ring was
investigated first (6a-h). Interestingly, only meta-selective
mono-chlorination products were generated, among which the
structure of 6e was confirmed by the X-ray diffraction. The
frontline antidepressant drug diazepam13b,17 was subjected to
the catalytic system as well and the desired product 6h was
obtained in 54% yield. Besides, diverse N-substituted
benzodiazepines also participated in the reaction albeit with
lower yields (6i-k). All these compounds built in a new library
(
2i-l). Due to the Ru-C bond owns the ortho/para-directing
effect, we supposed that less ortho steric hinderance of
complex and the smaller chlorine may cause the ortho
chlorination of C-Ru bond. Besides, 2-(naphthalen-2-yl)pyridine
was subjected to the meta chlorination reaction and afforded
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of chlorinated benzodiazepines that may help identifying new yield, starting from borylation product 12 through Suzuki-
sedative-hypnotics drugs.
Miyaura cross-coupling following by reduction and cyclization
(Fig. 1b).20 The UV-Vis-NIR absorption spectrum of 13 in DMSO
exhibited an absorption peak at 555 nm, whereas the
fluorescence emission spectrum disclosed an emission peak
centered at 654 nm (see the Supporting Information).
Fig. 1 a) Reductive transformation of pyridine. b) Diversified
conversion and synthetic application of meta chlorinated
benzodiazepines.
a
Scheme 3 Substrate scope with 6-arylpurines. Ratio of
isolated mono- vs di-chlorination products. b Yield based on
recovered starting material.
To get more insights on the details of reaction mechanism,
we firstly captured the active dinuclear ruthenium complex
the structure was inferred by X-ray analysis of its stable
derivative which was cordinated with MeCN. The
successfully catalytic reaction and the significant ortho H/D
exchange of [D5]-1a using species instead of Ru3(CO)12 imply
that species may be involved in the catalytic cycle.
A,
B
A
A
Subsequently, the use of radical scavengers was found to
obviously suppress the meta chlorination, indicating that a
single electron transfer (SET) process might be involved. Then,
more than 50% ortho hydrogen atom was deuterated when 1a
was treated with or without [Cl]-1 under the standard
condition in the presence of 5 equivalent of D2O, supporting
that the initial ortho C-H ruthenation is reversible.
Furthermore, the parallel kinetic isotope effect was measured
and the value of kH/kD was 1.0, which reveals that the meta
C−H cleavage doesn’t occur at the rate-determining step.
Eventually, the LC-MS study of the reaction mixture confirmed
the formation of Mes ligand, release of [N]-H and the
formation of ruthenacycle intermediate II (see the Supporting
Information).
Scheme 4 Meta chlorination of benzodiazepines. a Yields based
on recovered starting material.
To further demonstrate the synthetic application of this
methodology, we then proceeded the reduction of 2-(3-
chlorophenyl)pyridine (2a) via a B(C6F5)3-catalyzed cascade
process,18 leading to cyclopentylamine
7 in 82% yield, which
Taking into account these results and the reported literature
precedents,13b,21 we proposed the reaction mechanism as
can be used for further transformations (Fig. 1a). Meanwhile,
palladium-catalyzed arylation,19a alkynylation,7 amination,19b
alkenylation19c and borylation19d of chloro-benzodiazepine 6a
with corresponding coupling partners were conducted under
modified literature conditions yielding corresponding products
8-12 in high yields. The use of Cs2CO3 or K2CO3 as the base was
found to be crucial for the success of these conversions (Fig.
depicted in Scheme 5. Coordination of species
ligand gives the active catalyst , which then initiates the ortho
C-H bond activation of 1a to afford the intermediate II
A with the
I
.
Subsequently, ortho SET chlorination of C-Ru bond occurs in
the presence of chlorinating agent, which is different from the
reported meta functionalization under ruthenium catalysis.10-14
1b). Moreover,
a shortcut synthesis of benzodiazepine-
The reductive deprotonation of III leads to the intermediate IV
.
containing fluorescent probe 13 was developed in 41% overall
The ligand exchange of species IV with TFA delivers the desired
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Scheme 5 Proposed mechanism.
In conclusion, we have developed a commercially available
NHC ligand-accelerated meta C-H chlorination of arenes under
ruthenium catalysis. In this protocol, the use of N-chloro-2,10-
camphorsultam as a chlorinating agent is demonstrated for the
first time. Further, the reaction is suitable for ample scope of
heterocyclic substrates including arylpyridines, arylpyrimidines,
purines and benzodiazepines. The mechanism studies disclose
that the catalytic meta chlorination involves an ortho C-H
ruthenation relay ortho chlorination of C-Ru bond. Synthetic
application of this method is showcased through the late-stage
diversified conversion of druglike benzodiazepines and the
synthesis of potential fluorescent probes.
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This work was supported by grants from Chinese NSF
(81430080, 81773565). Supporting from the National Program
on Key Basic Research Project of China (2015CB910603), the
International Cooperative Program (GJHZ1622) and Key
Program of the Frontier Science (QYZDJ-SSW-SMC002) of the
Chinese Academy of Sciences, the Shanghai Commission of
Science and Technology (16XD1404600) are also highly
appreciated.
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Conflicts of interest
There are no conflicts to declare.
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