C–H Arylation of N-Heteroarenes under Metal-Free Conditions and its Application towards the Synthesis of Pentabromo- and Pentachloropseudilins

Article abstract of DOI:10.1002/ejoc.201900353

Herein, we are reporting metal-free conditions for radical initiation and direct C–H arylation of N-heteroarenes. Starting from aniline, the corresponding arenediazonium salt generated in situ is reduced to an aryl radical in the presence of chloropromazine hydrochloride, a new reagent for this application. The optimized procedures are mild, operationally simple, and are working successfully with more diverse substrates in comparison to reported methods. The optimized method is also employed for the synthesis of marine natural products Pentabromo- and Pentachloropseudilins (PBP/PCP). In the present study, we also validated the potential of the Pentachloropseudilin (PCP), thus synthesized, for inhibition of Myosin1 function in mammalian cells and confirmed that PCP phenocopies Myosin1c depletion in cells.

Full text of DOI:10.1002/ejoc.201900353

A Journal of
Accepted Article
Title: C-H Arylation of N-heteroarenes under Metal-free conditions
and its Application towards the Synthesis of Pentabromo- and
Pentachloropseudilins
Authors: Mukesh Kumar, Shweta Sharma, Parijat Sil, Manoj
Kushwaha, Satyajit Mayor, Ram A Vishwakarma, and
Parvinder Pal Singh
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900353
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10.1002/ejoc.201900353
European Journal of Organic Chemistry
COMMUNICATION
C-H Arylation of N-heteroarenes under Metal-free conditions and
its Application towards the Synthesis of Pentabromo- and
Pentachloropseudilins
Mukesh Kumar,[a] Shweta Sharma,[a] Parijat Sil,[b] Manoj Kushwaha,[a] Satyajit Mayor,[b] Ram A.
Vishwakarma,[a] and Parvinder Pal Singh*[a]
Abstract: Here, we are reporting metal-free conditions for radical
initiation and direct C-H arylation of N-heteroarenes. Starting from
aniline, the corresponding arenediazonium salt generated in situ is
reduced to an aryl radical in the presence of chloropromazine
hydrochloride, a new reagent for this application. The optimized
procedures are mild, operationally simple, and also successfully
working with more diverse substrates in comparison to reported
methods. The optimized method is also employed for the synthesis
of marine natural products Pentabromo- and Pentachloropseudilins
(PBP/PCP). In the present study, we also validated the potential of
the Pentachloropseudilin (PCP), thus synthesized, for inhibition of
Myosin1 function in mammalian cells and confirmed that PCP
phenocopies Myosin1c depletion in cells.
diazonium salts to generate aryl radicals. However, most of these
method works well with an electron-withdrawing group containing
pyrroles such as N-Boc and N-tosyl pyrroles and pose problem with
electron-donating group containing pyrroles and NH-pyrroles which
gave unwanted azo-products instead of 2-arylated pyrroles18a except,
Gowrisankar and Seayed method.18b This method required high
temperature, which may pose a problem with sensitive substrates.
Considering the importance of 2-arylated pyrrole, a general and
effective method is highly required. The reported method suggested
that the reagents having the capability of complex formation and
single-electron transfer reaction could be highly useful for the
diverse scope. In the literature, phenothiazine derivatives are well
known for complex forming and single-electron transfer reaction
21,22,23a-c
and considering these properties and our interest in radical
chemistry,24 we hypothesized its use as a novel reagent for complex
formation and reduction of diazonium salt to generate phenyl
radicals.
Introduction
The substituted pyrrole particularly 2-arylated pyrrole ring represent
the most fascinating core because of its presence in many drugs,
clinical candidates and natural products. The notable examples of 2-
arylated pyrroles are atorvastatin (lipid-lowering agents),1
chlorfenapyr,2a-b
elopiprazole,3
lamellarins,4a-4b
prodigiosins,5
pentabromo,6,7,8/chloropseudilin,9 pyrrolomycin-E.10
2-Arylated
pyrroles also have shown interesting optical and electronic
properties.11a-d Considering the importance of this important core,
synthesis of 2-arylated pyrrole has become one of the most
important reaction in organic synthesis. The direct arylation of
pyrroles via C−H bond activation under transition metal and metal-
free conditions have been tried by employing diverse coupling
12,13a-c
partners such as aryl halides,
and aryl boronic acids.12,14 In
addition to this, Meerwein-type arylation15 using diazonium salts,16,17
and anilines18,19 have also been employed (Figure 1). In the recent
decade, this approach has attracted the major attraction because of
the recent development regarding the exploration of suitable
conditions for the in situ generation of diazonium salts.20 Moreover,
this approach work via aryl radical upon electron addition which has
been exploited from metals18 and photoredox16 conditions. Recently,
small molecules such as ascorbic acid,19a polyaniline17a,19b
hydrazine,17b gallic acid,17c and hydrogen peroxide19c capable of
single electron-transfer reactions were also used for the reduction of
Figure 1. Previous and present approaches
Result and Discussion
We started our investigation by using p-chloro aniline 1 and N-
Bocpyrrole 2 as coupling partners, DMSO as solvent, tert-butyl
nitrite as diazotizing agent and chlorpromazine hydrochloride
(CP salt) as a novel complex forming and reducing agent.
Initially, p-chloro aniline 1 (1 mmol), was treated with tert-butyl
nitrite in DMSO to generate diazonium salt, which then treated
with N-Bocpyrrole 2 (2.5 mmol) and CP salt was (1 mmol), the
desired coupled product 3a was formed in a yield of 53% (entry
1). In further experiments, a range of solvents such as DMF, d6-
DMSO, DCM, ACN and THF were screened (entries 2-6), only
DMF afforded the desired product but a comparatively lower
yield of 40% (entry 2). When the stoichiometry of p-chloro aniline
[a]
M. Kumar, S.Sharma, M. Kushwaha, Dr. R.A. Vishwakarma, Dr. P.
P. Singh.
Medicinal Chemistry Division, Academy of Scientific and Innovative
Research, CSIR-Indian Institute of Integrative Medicine, Canal
Road, Jammu-180001, India.
Email : ppsingh@iiim.ac.in
https://www.iiim.res.in/People/CV/cv_parvinder.php
[b]
P. Sil, Prof. S. Mayor
National Centre for Biological Sciences,
Tata Institute of Fundamental Research,
GKVK, Bellary Road, Bangalore- 560065,
Supporting information for this article is given via a link
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10.1002/ejoc.201900353
European Journal of Organic Chemistry
COMMUNICATION
was increased from 1 to 2.5 equivalents, surprisingly, significant
with N-methyl pyrrole, gave the coupled product with good yields
suppression was observed (entries 7 and 8). In the next reaction, (Scheme 1). N-Methyl pyrrole on reaction with 4-fluoro and 4-
decrease in the quantity of CP salt also drastically affected the
yield of the desired product (entry 9). Increase in the quantity of
CP salt along with degassing further increases the yield of
nitroanilines gave the corresponding desired products 3r and 3s
in a yield of 62 and 45%, respectively. Furthermore, optimized
conditions when tried for the coupling of 4-nitroaniline with NH-
desired product 3 upto 60% (entry 10). In the absence of CP salt, pyrrole, no 2-arylated product 3t was formed, instead 2-azo
no product formation was observed (entry 11). Further, other
salts such as DIPEA.HCl, ammonium chloride was also
evaluated but no product formation was observed (entries 12-
13). Furthermore, the reaction with chlorpromazine and other
bases did not produce the coupled product indicated that CP
salts played a major role (entries 15-18). After all the control
experiments, we found entry 10 as the best reaction conditions
and could be exploited for further derivatization.
product was observed. On the other hand, when 3-cyanoaniline
was employed, 2-aryl pyrrole 3v was observed in a yield of 25%
along with a 2-azo product. The position of substitution play an
important role to decide the fate of product and it seems the
presence of electron-withdrawing group at 3-position favors
dediazotization more frequently and could be the reason for
providing the coupled product (need more investigation, will be
studied in depth). This was further validated when 3,5-dichloro-
6-hydoxyaniline (having two electron-withdrawing groups at 3-
positions) was used, 2-arylated product 3w was formed in a
yield of 55% along with some quantity of 3-aryl product 3w’, no
azo product was formed.
Table 1. Optimization studies
Equipped with optimized conditions in hand, we further explored
the scope of C-2 arylation by investigating the reaction between
various anilines and pyrroles (Scheme 1). Electron-withdrawing
groups such as 4-bromo, 4-nitro, 4-fluoro, 4-acetyl, 4-iodo, 3-
cyano, 4-(trifluoromethyl) and 4-ethoxycarbonyl containing
anilines reacted smoothly with N-Bocpyrrole 2 and furnished the
coupled product 3b-3i in good to moderate yield (40-70%).
Anilines containing electron-donating groups such as 4-methyl,
2-methoxy and 4-(trifluoromethoxy) aniline also reacted
smoothly and afforded the desired products 3j-3l in a moderate
to good yields (35-53%). Sensitive substrates which pose a
problem under metal-catalyzed conditions such as 4-
ethynylaniline when tried under optimized conditions gave the
corresponding coupled product in a yield of 53%. Several
disubstituted anilines such as 3-bromo-4-methylaniline, 3-chloro-
4-fluoroaniline and 3-chloro-2-iodoanline also coupled with N-
Bocpyrrole and afforded the corresponding products 3n, 3o and
3p in a yield of 35, 46 and 40%, respectively. Furthermore, the
optimized reaction condition was also applied to substituted
pyrroles to further expand the scope of the present protocol. 2-
Acetyl-N-Bocpyrrole underwent reaction with p-nitroaniline and
gave the coupled products 3q in a yield of 60%. Unlike a most
reported method, the present optimized conditions when tried
Scheme 1. Substrate scope of Boc-Pyrrole.
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To increase the diversity, other heteroarenes such as thiophene
and furan were also tried, and the results are provided in
Scheme 2. Thiophene reacted well with both electron-
withdrawing and electron-donating groups containing anilines
supporting information (SI)) involves the construction of pyrrole
nucleus by using multi-step synthetic strategies starting from
aliphatic intermediates already containing the aromatic
substituent and none of them have used the direct method of
and afforded the desired products (4a-4e) with a yield of 55-65%. synthesizing 2-arylated pyrrole. This might be because of
On the other hand, 2-methylfuran when reacted with p-
nitroaniline and 4-ethoxycarbonyl anilines, coupling happened
and afforded the desired products 4f and 4g in a yield of 45%
and 35 %, respectively.
functionalities such as the hydroxyl group present on the
arylated nucleus and offered difficulties during synthesis by
direct methods. As the present method has good functional
group compatibility with an electron-donating group (2-methoxy)
containing anilines, therefore, its corresponding coupled product
3k is further explored for the synthesis of pentabromopseudilin
7a (Scheme 3). To synthesized pentabromopseudilin 7a, the
coupled product 3k was first treated with potassium carbonate
for the deprotection of Boc group and then heated with pyridine
hydrochloride for demethylation to get key intermediate 2-(2-
hydroxyphenyl)pyrrole 6. The intermediate 6 was then treated
with brominating agent (pyridinium tribromide) which furnished
the final product i.e PBP in a yield of 25%.
Scheme 3. Synthesis of Pentabromopseudilin (PBP).
Scheme 2. Substrate scopes with other heteroarenes.
In order to get the pentachloropseudilin (PCP, 7b, the
intermediate 2-(2-hydroxypheyl)pyrrole
6 was treated with
As mentioned above in the introductory paragraph, 2-arylated
pyrrole present in many pharmacologically active molecules and
various chlorinating agents such as boron trichloride and N-
chorosuccinimide but none gave the desired product,
pentachloropseudilin in our hand. In most of the attempts, a
mixture of di-and tri-chloro products was observed based on LC-
MS analysis. These results suggested that the presence of
chloro-groups makes the system deficient and suppressed the
formation of required pentachloro product 7b. Later, we changed
the strategy, where 2-arylated product 3w was taken as
substrate and when treated with N-chlorosuccinimide,
successfully yielded PCP 7b in a yield of 46% (Scheme 4).
among
those,
marine
natural
products
namely
pentabromopseudilin (PBP) and pentachloropseudilin (PCP)
represent an important class, which were first isolated from
Pseudomonas bromoutilis in 19666,7 and later from
Chromobacteria, Alteromonas luteoviolaceus, and other
Pseudoalteromonas sp.9 They have attracted the potential
because of their role as allosteric inhibitors of Myosin ATPase25
and Non-mevalonate pathways of Isoprenoid (IspD).26 Apart
from these, pseudilins are also known for potential anti-bacterial
and anti-fungal activities.27 Myosin 1 is an ancient family of motor
proteins. Most Myosin 1 motors are a single headed molecular
motor that travels on actin tracks, and its functions are poorly
understood.28 Although it is reported to be involved in multiple
cellular functions, 29 there are few tools to address its precise
role. The discovery of the potential of inhibiting Myosin family
proteins via the pseudilin family of molecules has opened up
new ways of exploring the role of this important motor class. The
availability of new and facile synthetic strategies for pseudilin is
an important step towards finding small molecule chemical
inhibitors for this family. The strategy of allosteric inhibition that
is reported here should provide a potential flexibility of deriving
specific inhibitors of this family of molecules.
Scheme 4. Synthesis of pentachloropseudiline (PCP).
Considering their importance, many groups have attempted
their synthesis and till date, four synthetic routes have been
developed for the synthesis of pentabromopseudilin (PBP),30a-
b,25,30c however, on the other hand there is only route towards the
synthesis of pentachloropseudilin (PCP).25 All the literature
reported methods (detail provided in Figures S1 and S2 of
To gain insight into the reaction mechanism, a series of control
experiments were performed (eq. 1-4, Scheme 5). When the
reaction was performed in the presence of free radical
scavengers such as TEMPO, the formation of the product, 3a,
was significantly suppressed (eq. 1), confirming the involvement
of a radical pathway. In another attempt, the preformed
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10.1002/ejoc.201900353
European Journal of Organic Chemistry
COMMUNICATION
diazonium
salt
such
as
4-bromobenzenediazonium
CP.HCl, no product formation was observed (eq. 4). During the
optimization study, when the reaction was conducted in the
tetrafluoroborate 1a was tried under optimized conditions, the
corresponding coupled product was formed in a yield of 60% (eq. presence of chlorpromazine (entry 15, Table 1), no desired
2). On the other hand, when the same reaction was conducted
in the absence of CP salt (eq. 3), no product formation was
observed confirming that CP salt plays an important role in the
present reaction. The reaction in the presence of CP salt
product was formed suggested that CP.HCl might be balancing
the tert-butoxide ion and then allowing the diazonium salt to
interact with chlorpromazine.
On the basis of the above observation and literature
precedents16,17,18,19 a tentative mechanism is proposed as shown
in Figure 2. First, aniline reacts with tert-butyl nitrite to yield the
diazonium salt18,19 which undergo an exchange of anion with
CP.HCl and generate the intermediate I2, because of complex
forming properties of CP. The intermediate I2 undergo single-
electron transfer reaction lead to the formation of phenyl radical
I3 which was subsequently intercepted by the pyrrole (2) to
generate the resonance stabilized allyl radical I4. The radical
intermediate I4 is further oxidized by cation radical followed by
the loss of a proton to furnish the expected coupled products 3.
Here, we have also investigated the effect of the PCP on several
reported phenotypes in mammalian cells. We studied the effect
of PCP 7b on the distribution of GFP-tagged GPI anchored
proteins (GFP GPI), stably expressed in Chinese hamster ovary
(CHO) cells (Figure 3). Myosin 1c depletion has been shown to
affect the trafficking of GPI-anchored proteins in earlier
studies.31 Treatment of cell with PCP 7b for 3.5 h, reduces levels
of GPI-anchored protein at the plasma membrane as observed
by total internal reflection microscopy (TIRF-M) (Figure 3A and
B). Using confocal microscopy, we also observed perinuclear
accumulation of GFP GPI (Figure 3C) which has also been
reported upon depletion of Myosin 1c in cells.31 Finally, we
examined the effect of PCP 7b upon cell spreading on
fibronectin (Figure 3D and E). We observed that the cells spread
to a lesser extent when treated with the drug compared to
vehicle-treated cells. This is in agreement with earlier reports on
the effect of Myosin1c depletion on spreading of cells.31
Altogether, our results suggest that the treatment with PCP 7b
phenocopies Myosin1c depletion in cells, providing a strong
biological validation of the activity of this compound.
Scheme 5. Control experiments.
suggested that chloride ion may also play some role in
dediazotization step. In order to ruled out this, when the reaction
was conducted in the presence of HCl instead of
Conclusion
We have developed a general method for the arylation of N-
heteroarenes under metal-free and mild reaction conditions. In
this methodology, CP.HCl has been successfully employed as a
radical initiator for the direct C-H arylation of (hetero)arenes. The
reaction is mild, operationally simple, and constitutes a good
approach for arylation. Remarkably, the present methodology
was also utilized for the synthesis of highly important marine
based natural products namely pentabromopseudilin and
pentachloropseudilin. Pentachloropseudilin (PCP) has been
shown to phenocopy the effect of Myosin1c depletion with
respect to the accumulation of lysosomal vesicles in HeLa
cells,32 and several other trafficking defects. PCP treatment
appears to phenocopy these effects, remarkably faithfully,
providing strong justification for the use of PCP as a Myosin 1
inhibitor in cellular studies. The lack of effects on the function of
other Myosins32 indicates that this compound may be used as a
specific probe for Myosin 1 function in cells. This study indicates
the huge potential application of CP or its derivatives as a
radical initiator and opening a new opportunity for its further use
as a catalyst in other radical processes.
Figure 2. Plausible mechanism.
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10.1002/ejoc.201900353
European Journal of Organic Chemistry
COMMUNICATION
buffer saline (HBS) containing 2mg/ml glucose for acute perturbation.
For cell spreading experiments, cells were pre-incubated with the drug
and plated on fibronectin coated surface.
Microscopy
Cells were imaged on TIRF using a 100X oil objective, 1.49NA, using an
inverted Nikon Ti Eclipse microscope and Cascade 512 cameras. For a
perinuclear vesicle identification experiment, cells were imaged using
a 100X oil objective mounted on a Spinning disc confocal microscope
equipped with a Yokogawa CSU and Andor EMCCD cameras.
Analysis and statistical significance
Intensity was measured by making 20X20 pixel or 30X30 regions on
the flat surface of the cell membrane and average intensity from
these boxes were calculated for cells imaged on TIRF. The Area was
measured by drawing regions along the periphery of the cells using
Image J plugin. KS test was performed to compare two distributions
and test for statistical significance.
Acknowledgements
We are grateful to the financial support of CSIR through
research grants MLP-5005 and HCP-0008. M. K. thanks UGC
for the award of fellowship, S. S., P. S. and M.K thanks CSIR for
the award of the fellowship. Authors thank Mr. Rajneesh Anand,
Mrs. Deepika Singh support in recording NMR and Mass
spectroscopy. IIIM communication No. IIIM/2290/2019.
Figure 3. Pentachloropseudilin (PCP, 7b) phenocopies Myosin1 perturbation
in cells: A) Representative TIRF-M images showing cells expressing GFP
tagged GPI (GFP GPI) treated overnight with DMSO or 1, 5, 10 µM PCP,
exhibiting lowering of surface intensity of GPI anchored proteins; B)
Quantification of intensity of regions from TIRF images of cells expressing
GFP GPI (C) Maximum intensity projection images depicting accumulation of
GFP GPI (arrows) in cells treated with PCP for 3.5 hours; D) Representative
images depicting cell spreading on fibronectin-coated surface upon pre-
treatment with DMSO/PCP after 150 minutes of plating; E) Quantification of
cell area in DMSO versus PCP treated cells depicted in D.
Keywords:
Pentabromopseudilin
C-H
arylation Radical
•
Aryl
•
•
Pentachloropseudilin • 2-arylated
pyrroles.
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Experimental Section
Appropriate aniline (1 mmole) was dissolved in 4 mL of DMSO followed
by the addition of (2 mmol) tert-butyl nitrite. Then the reaction mixture
was stirred for 30 min for the generation (in-situ) of the diazonium salt.
The resulting mixture was then degassed by “pump-freeze-thaw” cycles
(×2) via a syringe needle After that, the reaction mixture was cooled to
0°C followed by the slow addition of 2 (Boc-Pyrrole, N-methyl Pyrrole,
NH-Pyrrole) and chlorpromazine hydrochloride. After completion, the
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10.1002/ejoc.201900353
European Journal of Organic Chemistry
COMMUNICATION
Table of Contents
COMMUNICATION: C-H Arylation and Synthesis of Pentabromo/choropseudilins
Mukesh Kumar, Shweta sharma, Parijat
Sil, Manoj Kushwaha, Satyajit Mayor,
Ram A.Vishwakarma and Parvinder Pal
Singh1,*
Page No. – Page No.
C-H Arylation of N-heteroarenes:
Application towards the synthesis of
marine natural product
Here, we have developed a metal-free and mild condition for the synthesis of 2-
arylated heteroarenes. The complex forming property and charge transfer property
of phenothiazine expanded its application towards catalysis The optimized condition
has been successfully employed for the synthesis important marine natural product
namely
pentabromo/chloropseudilins
(PBP/PCP).
The
synthesized
Pentachloropseudilin (PCP) has been shown to phenocopy the effect of Myosin1c
depletion which provides a strong justification for the use of PCP as a specific probe
for Myosin 1 function in cells.
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