Remote meta-C–H Cyanation of Arenes Enabled by a Pyrimidine-Based Auxiliary

Article abstract of DOI:10.1002/anie.201706360

An easily removable pyrimidine-based auxiliary has been employed for the remote meta-C?H cyanation of arenes. The scope of this Pd-catalyzed cyanation reaction using copper(I) cyanide as the cyanating agent was demonstrated with benzylsilanes, benzylsulfonates, benzylphophonates, phenethylsulfonates, and phenethyl ether derivatives. The method was utilized for the synthesis of pharmaceutically valuable precursors.

Full text of DOI:10.1002/anie.201706360

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Accepted Article
Title: Remote meta-C−H cyanation of arenes enabled by pyrimidine-
based auxiliary
Authors: SUKDEV BAG, Ramasamy Jayarajan, Uttam Dutta, Rajdip
Chowdhury, Rahul Mondal, and Debabrata Maiti
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706360
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10.1002/anie.201706360
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Remote meta-CH cyanation of arenes enabled by pyrimidine-
based auxiliary
Sukdev Bag,[a] Ramasamy Jayarajan,[a][b] Uttam Dutta,[a] Rajdip Chowdhury,[a] Rahul Mondal,[a] and
Debabrata Maiti*[a]
Abstract: An easily removable pyrimidine-based auxiliary has been
employed for the remote meta-CH cyanation of arenes. The scope
of this Pd-catalyzed cyanation reaction using copper(I) cyanide as
the cyanating agent has been demonstrated with benzylsilanes,
benzylsulfonates, benzylphophonates, phenethylsulfonates and
phenethyl ether derivatives. Present protocol was utilized for the
synthesis of pharmaceutically valuable precursors.
copper(I) cyanide as the cyanating source.
A precise elimination of the electronic and steric bias in
controlling the positional selectivity for chemical transformations
has been successfully attained through a suitable employment
of directing groups that affect functionalization in a highly
regioselective fashion.[1] Recent time has seen an unexpected
rise in the popularity of metal-catalyzed distal C–H bond
functionalization.[2] In this regard, a judicious exhibition of meta-
and para-selective C–H bond activation in aromatic arenes
stand as worthy examples.[3] From the viewpoint of remote C–H
functionalization; 1) judicious design of template, 2) choice of
directing group (i.e., weak vs strong coordination with metal), 3)
proper selection of catalyst and coupling partners are
recognized to be crucial factors. Importantly, the required effort
would be high enough for those transformations where the
reactions proceed through high energy macrocyclic pre-
transition state and reductive elimination step.[3-5] Recently, the
meta-C–H alkylation and alkenylation have been achieved with
the aid of strong coordinating pyrimidine-based template.[5b]
Although a handful of reports on distal C–H activation were
prescient, extension of the strategy towards performing new
functionalization has always continued to be an important goal.
Aromatic molecules containing nitrile groups are found to
be integral constituents of dyes, agrochemicals, natural products,
Figure 1. a) The key features of pyrimidine-based scaffold, b) Previous work
with pyrimidine-DG, c) DG-assisted meta-CH cyanation of arenes, d) Scaffold
variation
As part of our foremost attempt, benzylsilane appended
with 2-cyanophenol scaffold 1 was tested with potassium
hexacyanoferrate(III) (Table 1).[12] Interestingly, the meta-
cyanation product was obtained in 12% yield. However, weak
coordinating ability, intolerance to harsh conditions, strenuous
effort in proper placing and projection of nitrile group led us to
explore alternative directing scaffold.
Table 1: Gradual evaluation of strong coordinating heterocycle-based DGa
7]
pharmaceuticals, and herbicides.[6, Incorporation of a nitrile
group by catalytic transformation suffers from its own limitations.
One of the existing issues for cyanation reaction is the
deactivation of the transition metal catalyst by formation of highly
stable metal-cyano complex.[8]
A defined concentration of
dissolved cyanide ions can prevent the deactivation of transition
metal catalyst.[9] Chelation-assisted C–H bond activation
approach has emerged as a convenient and atom economical
method by averting higher temperature and hazardous nitrile
sources.[10] Regardless, appropriate selection of cyanide source
is thought to be crucial for the directed C–H cyanation
method.[11] Consequently, development of a methodology aimed
to effectuate a selective incorporation of nitrile groups, not as
part of the directing group anymore but now as the protagonist
nucleophile, would be a worthy feat. Herein, we describe a
highly selective meta-C–H cyanation reaction of arenes using
[a]
[b]
S. Bag, Dr. R. Jayarajan, U. Dutta, R. Chowdhury, R. Mondal, Prof.
Dr. D. Maiti
Department of Chemistry, Indian Institute of Technology Bombay
Powai, Mumbai-400 076 (India)
E-mail: dmaiti@chem.iitb.ac.in
Dr. R. Jayarajan
A substantial variation of the scaffolds showed that
biphenyl pyridine-based template 2 predictively yields meta-
cyanated product in comparatively good yield (Table 1). Notably,
silyl bridged directing groups were effectively used owing to the
easy installation/removal and modification features.[13] The two-
geminal isopropyl groups in quaternary silyl center serve to bring
the target meta-C–H bond towards the close proximity of metal
Department of Biosciences and Bioengineering, IIT Bombay,
Mumbai-400 076 (India)
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10.1002/anie.201706360
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COMMUNICATION
center (i.e., Thorpe–Ingold effect). Upon transmetalation of
cyanide ion, palladium metal centre is expected to be more
electron dense and therefore, the appropriate -acidic ligand is
required to stabilize the short-life intermediate.[4, 9] Accordingly,
we have examined fluorinated pyridyl directing groups (as in 3
and 4) and relatively improved yield than the parent pyridyl-
based directing group was obtained. The lowering in yield and
selectivity was observed when isoquinoline-based directing
group (as in 5) was employed. Interestingly, recently developed
biphenyl pyrimidine-based directing group as in 6 provided most
promising yield and meta-selectivity (42%; m:others = 15:1).
Hydrogen-bonding interaction with pyrimidine and HFIP likely
decreases the basicity of DG and synergistically increases -
acidity towards the palladium centre.[14]
7j) and sterically-encumbered para-substituted subsrate such as
4-Bu (7k) were well tolerated. Selective mono-cyanation
products have been detected in case of ,-diphenyl scaffolds
(7m and 7n).
In order to achieve the highest synthetic yield of meta-C–H
cyanation product, we have first tested various cyanating
reagents. We found that the usual organic cyanating reagents
were completely inactive. Among various metal cyanides,
copper(I) cyanide has remarkably increased the yield with
exclusive meta-selectivity. As a bridging metal and oxidant silver
carbonate along with copper(I) chloride ameliorate the yield
significantly. The remarkable effect of solvent has also been
observed when equivalent amount of HFIP was added to DCE.
This combination drastically improved the yield (see the SI).
Partial solubility of CuCN in HFIP/DCE likely helps to release the
cyanide ions slowly which prevent the deactivation of Pd(II)-
catalyst and subsequently facilitate the reductive elimination.
Figure 2. a) Scope with phenylmethanesulfonyl esters. b) Meta-cyanation of
benzylphosphonates. c) Scope with phenethylsulfonyl esters.[12]
Scheme 1. Meta-cyanation of benzylsilane scaffolds.[12]
After successful implementation of cyanation in
benzylsilane scaffolds, we have examined benzylsulfonyl ester
motifs (Figure 2a). The compatibility of substituents on aromatic
ring has been examined with electron donating (9b and 9d),
electron withdrawing (9c and 9e) and sterically encumbered
para-substituted benzylsulfonates (9j-9l). Interestingly, selective
With the optimized reaction conditions in hand, we have
probed the effect of aromatic substitutions in benzylsilane
scaffold. We were delighted to find that the present reaction
protocol provides selective mono-cyanation product (Scheme 1).
The electron-rich (7c, 7d, and 7h), electron-poor (7e, 7f, 7g, and
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meta-cyanation of 3-substituted (aryl/heteroaryl)-benzylsulfonyl
derivatives has been achieved successfully (9f-9i). Meta-C–H
cyanation has also been documented in benzylphosphonate
derivatives (Figure 2b).
converted to the corresponding stilbene derivative resulting from
reaction of 4-methoxy benzaldehyde by modified Julia-type
olefination (Figure 3b). Direct meta-C–H cyanation of toluene
derivatives and modifiable silyl linkage can lead to the
preparation of antidepressant drug citalopram (Figure 3c).[15]
We have performed the systematic NMR studies by
varying the amount of HFIP in presence of substrate 8d in CDCl3.
The NMR studies revealed the hydrogen bonding between
pyrimidine-DG (8d) and HFIP (see the SI).[12] To gain insight into
the reaction mechanism, we carried out kinetic isotope effect
(KIE) experiment (Figure 4a).[16] The average of three parallel
experiments with 8a and 8a-d5 (kH/kD) provided 1.24 and
intermolecular competition experiment, PH/PD is found to be 1.15.
The ESI-MS studies of reaction mixture in absence of cyanide
source suggested formation of macrocyclic palladacycle
intermediate (see the SI).[12] Detailed mechanistic investigations
and in-silico studies are underway in our laboratory.
Scheme 2. Scope with phenethyl ether derivatives.[12]
The scope of the reaction has been further investigated with the
elongated backbone such as phenethylsulfonyl esters, which
afforded the desired meta-cyano product in good yields (Figure
2c). To strengthen the backbone, we have also introduced
simple ether linked phenethyl derivatives. The later provided
synthetically useful yields under slightly modified conditions
(Scheme 2).[12]
Figure 4. a) The experiment of primary kinetic isotope effect. b) Plausible
mechanistic cycle
Probable catalytic cycle has been outlined in Figure 4b.
The pyrimidine DG coordinates with mono-protected amino acid
(MPAA)-ligated palladium catalyst (intermediate I) and the close
proximity activates the meta-C–H bond (most probably via
concerted metallation-deprotonation) to afford the macrocyclic
transition state II. The ligand exchange of CN– between
copper(I) cyanide and cyclopalladated intermediate forms III.
The reductive elimination from III via a complex transition state
IV is presumed to provide the desired cyanation product.[4]
In summary, we have demonstrated a Pd(II)-catalyzed
directing group assisted meta-C–H cyanation of arenes.[17] The
directing group approach and the use of stoichiometric amount
of copper(I) cyanide has greatly facilitated the access to
selective formation of meta-cyano products, which are key
building blocks for synthesis of complex natural products and
drug molecules. A broad substrate scope presented by variation
of synthetically useful linkers such as silyl, sulfonyl,
phosphonates, ethers and electronically/sterically unbiased
substituents has made the strategy attractive.
Figure 3. a) Post synthetic application of benzylsilane and conversion of
cyano to useful functional groups. b) Removal of DG by Julia-type olefination.
c) Synthetic route to citalopram.
Benzylsilane moiety is easily cleaved by fluoride source
and produces meta-cyano toluene derivatives. The broad utility
of nitrile group has been delineated by converting benzonitrile to
corresponding benzaldehyde, benzamide, and tetrazole
derivatives (Figure 3a).[10b] The benzylsulfonyl scaffold has been
Acknowledgements
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10.1002/anie.201706360
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This activity was supported by SERB, India. Financial support
from UGC-India (fellowship to S.B.) and DST-India (Fast Track
Scheme for R.J., YSS/2014/000530) is gratefully acknowledged.
D. M. thanks Prof. Samir K. Maji (BSBE, IITB) for insightful
discussions.
Keywords: pyrimidine • meta-C–H activation • cyanation •
copper(I) cyanide • palladium
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Table of Contents
COMMUNICATION
Pyrimidine-based
directing
S. Bag, Dr. R. Jayarajan, U.
Dutta, R. Chowdhury, R.
Mondal, Prof. Dr. D. Maiti*
group has been employed for
meta-C–H cyanation of arenes
using copper(I) cyanide as
cyanating reagent. The broad
substrate scope has been
presented by varying different
linkers such as silyl, sulfonyl,
phosphonate, ether.
Page No. – Page No.
Remote meta-CH cyanation
of arenes enabled by
pyrimidine-based auxiliary
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