Para-Selective Cyanation of Arenes by H-Bonded Template

Article abstract of DOI:10.1002/chem.202001368

The significance of site selective functionalization stands upon the superior selectivity, easy synthesis and diverse product utility. In this work, we demonstrate the para-selective introduction of versatile nitrile moiety, enabled by a detachable and reusable H-bonded auxiliary. The methodology holds its efficiency irrespective of substrate electronic bias. The conspicuous shift in the step energetics was probed by both experimental and computational mechanistic tools, which heralds the inception of para-deuteration. The synthetic impact of the methodology was highlighted with reusability of directing group and post synthetic modifications.

Full text of DOI:10.1002/chem.202001368

A Journal of
Accepted Article
Title: Para-Selective Cyanation of Arenes by H-Bonded Template
Authors: Sandeep Pimparkar, Trisha Bhattacharya, Arun Maji, Argha
Saha, Ramasamy Jayarajan, Uttam Dutta, Gang Lu, David W
Lupton, and Debabrata Maiti
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To be cited as: Chem. Eur. J. 10.1002/chem.202001368
Link to VoR: http://dx.doi.org/10.1002/chem.202001368
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Chemistry - A European Journal
10.1002/chem.202001368
RESEARCH ARTICLE
Para-Selective Cyanation of Arenes by H−Bonded Template
Sandeep Pimparkar,[a,b,c] ‡ Trisha Bhattacharya,[a] ‡ Arun Maji, Argha Saha, Ramasamy Jayarajan,
[a]
[a]
[a]
Uttam Dutta,[a,b,c] Gang Lu,* David W. Lupton* and Debabrata Maiti*[a]
[d]
[b,c]
‡These authors have contributed equally.
[
a]
Sandeep Pimparkar, Trisha Bhattacharya, Dr. Arun Maji, Argha Saha, Dr. Ramasamy Jayrajan, Dr. Uttam Dutta, Dr. Debabrata Maiti
Department of Chemistry
Indian Institute of Technology Bombay
Powai, Mumbai-400076, India.
E-mail: dmaiti@iitb.ac.in
[
[
b]
c]
Sandeep Pimparkar, Dr. Uttam Dutta, Prof. David W. Lupton
IITB-Monash Research Academy,
Near estate office, IIT Bombay Powai, Mumbai-400076, India.
E-mail: david.lupton@monash.edu
Sandeep Pimparkar, Dr. Uttam Dutta, Prof. David W. Lupton
School of Chemistry
Monash University
Clayton, VIC 3168, Australia.
E-mail: david.lupton@monash.edu
Dr. Gang Lu
[
d]
School of Chemistry and Chemical Engineering
Shandong University
Jinan-250100, China.
E-mail: ganglu@sdu.edu.cn
Supporting information for this article is given via a link at the end of the document.
Abstract: The significance of site selective functionalization stands
directed remote C−H activation and thus remains extremely
challenging.[
9]
upon the superior selectivity, easy synthesis and diverse product
utility. In this work we demonstrate the para-selective introduction of
versatile nitrile moiety, enabled by detachable and reusable H-bonded
auxiliary. The methodology holds its efficiency irrespective of
substrate electronic bias. The conspicuous shift in the step energetics
was probed by both experimental and computational mechanistic
tools heralds the inception of para-deuteration. The synthetic impact
of the methodology was highlighted with reusability of directing group
and post synthetic modifications.
st
In this context our group has identified and developed 1
generation[ and 2 generation directing templates to allow
para-C−H bond of arenes to be functionalized with superior
selectivity and yield. The feasibility of directed para-
8a]
nd
[8c]
functionalization was demonstrated earlier with Pd(II) catalyzed
para-silylation[8c] and ketonisation[8d] employing the nitrile-based
H-bonded biphenyl template. More recently, a Rh(I) catalyzed
para-C−H olefination was developed.[8e] Despite different non
covalent and electronically assisted approaches for para-
selective functionalizations we recently focused on methods by
which a para-C−H bond can be elaborated to a library of
functionally diverse materials. The nitrile group is a versatile motif
in synthetic chemistry. Furthermore, nitrile groups alter the
molecular properties of the arenes and can be found in the dye
industry, agrochemicals and pharmaceuticals. Many nitrile
containing pharmaceuticals are in clinical development and over
Introduction
[
9]
Site selective C−C bond formation remained a fascinating realm
of synthetic methodology owing to its ubiquitous nature in
molecular frameworks.[1] Construction of such bonds with the
assistance of a directing group has rendered intrinsic electronic
and steric bias redundant, providing a generalized tool for
positional tunability. Initiated with ortho-[2] functionalizations,
template assisted C−H activation of meta-[3-6] position was
explored quite recently, while para functionalization remains in its
infancy. Although exclusive para-selective functionalization is
prevalent in enzymatic systems,[7] synthetic recapitulation is
limited to a handful of systems. In addition, such transformations
are often accompanied by inseparable mixture of regio-isomers.
In this regard the assistance of templates can attenuate such
encumbrance and allow a broader scope.[8] However, designing
the auxiliary, spanning the larger separation of the hinge point and
the para position recurs the intrinsic synthetic challenge of
3
0 are in the market for various conditions. Classically nitrile or
cyanoarenes are generated through substitution or functional
group interconversions which either demands harsh reaction
condition or involves more than one step (Figure 1a).[10] Although
recent efforts in ligand promoted non−directed cyanation of
arenes have been reported (Figure 1b),[ the quest for para-
selective distal cyanation of arenes remains. In this context, the
catalytic synthesis of carbon−nitrile connectivity via C−H
activation is mostly restricted to ortho- and least pronounced for
meta-position of arenes.[12-14]
11]
1
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RESEARCH ARTICLE
Figure 1: (a) Classical approaches for aryl nitrile synthesis (b) Non directed
approach for aryl nitrile synthesis (c) Overview of the present work
Table 1: Evolution of Directing Groups and Nitrile Sources
rate determining step than any other cyanation sources. After
optimizing with DG an overall yield of 70% of cyanation product
with 10:1 para-selectivity was obtained in presence of Pd(OAc)
10 mol%), N-Ac-Gly (20 mol%), Ag CO (2 eq.) and CuCN (1 eq.)
4
2
(
2
3
in hexafluoroisopropanol (HFIP) solvent (see supporting
information for more information). Upon optimization a range of
para-cyano toluene derivatives were synthesized with excellent
yields and selectivity. Notably the methodology remained
unhinged by any electronic and steric inclination of the
arene.Toluene derivatives having both electron donating and
electron withdrawing substituents (2i-2m) delivered para-cyano
products with comparable yield and selectivity (Table 2).
Incorporation of a nitrile group under catalytic conditions poses
several challenges. Specifically, competition for the binding site of
palladium with the directing –CN group and the cyanation source.
The strong binding affinity and π-accepting character of nitriles
tends to saturate the catalytic site of palladium center leading to
deactivation.[15] To overcome the aforementioned problem the
choice of solvent is critical as higher solubility of the cyanide ion
can exceed the initial concentration of the catalyst leading to
catalytic poisoning. Under such circumstances judicial choice of
nitrile source with slower release of nitrile can minimize the
formation of tetracyanopalladate (II) or palladium (II) cyanide
complexes.[16] Systematic understanding and subsequent tuning
of reaction parameters led to the development of directed para-
selective cyanation of arenes which overrides electronic and
steric bias using a para-selective, H-bonding enabled directing
template and employing a Pd(II) catalyst.
However, substrate 1b bearing an ortho methyl group offered a
moderate selectivity compared to other substrates. Under the
optimized reaction conditions bisarenes fused with
a
cycloheptane ring possessing two equivalent para-C−H bonds
was selectively converted to the mono cyanated product 2g in
7
0% yield with good para-selectivity. Arenes with electron
withdrawing substituents were subjected to the established
reaction conditions (Table 3). Scaffolds with fluorine at different
sites were investigated (2p-u, 2y) due to their medicinal
significance. Notably, presence of a highly electron withdrawing
trifluoromethyl(-CF
selectivity (2u-2w). A trifluoromethoxy(-OCF
3
) group could not attenuate the yield or
) group was also
3
compatible with the current protocol, giving synthetically useful
yield and selectivity (2x-y). It is worth to mention that apart from
Results and Discussion
3
electronic effect –OCF can influence the nature of product
formation by distorting its spatial alignment with the benzene ring.
After successful para-C−H cyanation of toluene derivatives, we
next extended this strategy to other arene systems. To date, C−H
activation reactions with phenol derivatives have predominantly
occurred at the ortho and meta positions in the presence of a
suitable template, or selectivity has been achieved exclusively
based on steric and electronic bias. We reported first para-
selective olefination of phenol
Initially we commenced the cyanation of toluene scaffold using
DG1 (12% yield; p:others = 2:1, Table 1). Systematic studies of
directing templates with strongly coordinating pyridine or
quinoline (DG -DG ) improved the yield, yet compromised the
5 7
selectivity. Modification of the electronic environment around the
nitrile group showed further improvements (DG2/3/4). Best output
4
was obtained with dimethoxy substituted template DG .
Enhanced electron density due to the presence of the dimethoxy
group likely improves metal binding and yield while H−bonding
interactions with the solvent are likely to provide enhanced
structural rigidity to favour specific conformation and necessary
superior para-selectivity.
Cuprous cyanide was found to be the most effective nitrile source
which might be due to its facile nitrile ligand transfer ability in the
2
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RESEARCH ARTICLE
Table 3: Scope of para-Cyanation on Different Electron Neutral and Electron
Table 2: Scope of para-Cyanation on Different Electron Neutral and Electron
Rich Toluene Scaffoldsa
Poor Toluene Scaffoldsa
aAll the reactions were carried out using 0.1 mmol of 1, 0.1 mmol of CuCN and
1
mL of HFIP. Yields are of isolated products. Selectivity was determined by 1
H
NMR analysis of the crude reaction mixture. The ratios in parentheses are for
para/others.
Table 4. Scope of para-Cyanation on Different Phenol Scaffoldsa
aAll the reactions were carried out using 0.1 mmol of 1, 0.1 mmol of CuCN and
1
mL of HFIP. Yields are of isolated products. Selectivity was determined by 1
H
NMR analysis of the crude reaction mixture. The ratios in parentheses are for
para/others.
in 2016.[8b] To promote para-cyanation of phenols we switched the
connecting carbon and oxygen atoms in T
4
to a modified template
4
cyanation of phenol
TP (Table 4). With the template TP
4
substrate 3a was examined under the established reaction
condition for the toluene scaffolds. On our first attempt, the
desired cyanated product of phenol was obtained in 30% yield
with a 3:1 (para:others) selectivity. Subsequently, we optimized
other reaction parameters to obtain maximum output.
A
aAll the reactions were carried out using 0.1 mmol of 3, 0.1 mmol of CuCN and
combination of Pd(OAc) (10 mol%), Fmoc-Gly-OH (20 mol%),
2
1
mL of (1:1) DCE+HFIP. Yields are of isolated products. Selectivity was
AgOAc (2 eq.), NaOAc (2 eq.) and CuCN (1 eq.) in 1:1 mixture of
DCE and hexafluoroisopropanol (HFIP) solvent lead to 55% yield
and 10:1 para selectivity. However, we were unable to elevate the
yield of the desired product further and starting material was left
unreacted. Phenol derivatives having methoxy (3b and 3c) and
ortho- methyl substitution (3d) allowed formation of cyanated
products with moderate yield and greater than 10:1 selectivity.
determined by 1H NMR analysis of the crude reaction mixure. The ratios in
parentheses are for para/others.
Subsequently we intended to gain better insight into the
mechanistic pathway. The crucial role of the solvent HFIP was
4
examined by considering H-bonding interaction between DG and
the –OH group of HFIP. Evidence for such interactions was
provided by NMR titrations (Figure 2a)8c and also an X-ray crystal
structure (CCDC 1837260) reported herewith. Unlike other para
functionalizations on the same platform, C−H activation step is not
associated with the product determining step of the
transformation (Figure 2b) and thus representing reversible C−H
activation step. Upon use of d
2
-HFIP decreased yield of the
desired para-cyanation product was observed. Most importantly,
3
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RESEARCH ARTICLE
partially deuterated starting material was recovered which further
supports the existence of a reversible C−H activation step (Figure
1
2
c). We were unable to determine k
H
/k
D
value by H NMR analysis
due to lack of distinguishable proton peak in the product. Product
distribution study was feasible and P /P value ~1 further
H
D
supports a non rate limiting C−H activation pathway.
Figure 3: DFT Computed Energy Profile of para C–H Cyanation with Substrate
1a
barrier of rate-determining CN ligand exchange with AgCN
TS2b) is 4.6 kcal/mol higher than that with CuCN (TS2a). This is
(
in agreement with the experimentally observed lower reactivity in
the reaction with AgCN (Figure 4). The distortion/interaction
analysis[ indicates that the interaction between the palladacycle
fragment and the MCN (M = Cu or Ag) fragment in transition
states is the dominated factor to differentiate the reactivity (Figure
17]
Figure 2: (a) Template-Solvent Interaction (b) Product Distribution Study (c)
Control Experiment
4
).
The energy profile for the para-C−H cyanation of substrate 1a
(
Figure 3) was calculated using density functional theory (DFT)
and is in agreement with the experimental findings (Figure 2).
Similar to other para-functionalizations,[8] the mono-N-protected
amino acid (MPAA) ligand promotes para C–H activation via the
CMD mechanism with the N-acyl group on the MPAA ligand
serving as a base (TS1 ΔG‡ = 24.7 kcal/mol with respect to
2
separated 1a, monomeric Pd(OAc) and N-Ac-Gly; (Figure 5; see
details in supporting information). The formed intermediate A then
tautomerizes and rearranges to the more stable palladacycle B
2
with the carboxylic group bound to the Pd center in κ fashion. A
series of possible CuCN complexes with anions were also
2
-
computed. Among these, CuCN(CO
3
)
is the most stable species
(
see details in supporting information). With respect to
2
-
3
CuCN(CO ) , the CuCN coordination to the carboxylic group in
palladacycle B to form C1 is endothermic by 14.0 kcal/mol. This
leads to an overall barrier of 29.0 kcal/mol for the subsequent
ligand exchange via a 4-membered σ-bond metathesis transition
state (TS2a Figure 3 & 5). The resulting palladacycle D smoothly
undergoes C−C reductive elimination to form the cyanation
product. In the overall catalytic cycle, the C–H activation was
found reversible, which is consistent with the experimental
observation (Figure 2 & 5). In addition, the partial solubility of
[
15]
CuCN is critical for the reactivity.
Due to the favorable
t
interaction with BuOH (ΔG = –7.3 kcal/mol), CuCN is soluble in
BuOH with a relatively high –CN concentration. This increases
t
the possibility of catalyst deactivation, leading to a low yield with
t
BuOH (See Table S7 in Supporting Information). In contrast, the
interaction of CuCN with HFIP is thermodynamically neutral (ΔG
Figure 4: Transmetalation transition states with CuCN and AgCN.
=
0.2 kcal/mol), which provides the optimum cyanide
Energies are computed at the M06/SDD–6-311+G(d,p)/SMD (HFIP) level of
theory with geometries optimized at the B3LYP/SDD–6-31G(d) level. ΔEint is the
interaction energy between the Pd(II) fragment and MCN (M = Cu or Ag) in the
transmetallation transition states. Calculated ΔEdist(Pd) and ΔEdist(MCN) are the
concentration for the reactivity rather than catalyst deactivation.
We further investigated the origin of reactivity difference when
employing the CuCN and AgCN as cyano source. The computed
4
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Chemistry - A European Journal
10.1002/chem.202001368
RESEARCH ARTICLE
energy difference of Pd(II) and MCN fragments between transition states and
ground states respectively.
interconversions strategies and by avoiding requirement of pre-
installation of functional moieties.
Compared to the disfavored TS2b with AgCN, the favored TS2a
with CuCN shows more favorable interaction energy (ΔEint, Figure
4
). This is evidenced by the shorter Pd‧‧‧Cu and Cu‧‧‧O
distances in TS2a than the Pd‧‧‧Ag and Ag‧‧‧O distances in
TS2b. The results reveal that the effectiveness of CuCN serving
as cyano source is mostly because of the favorable interaction
between copper and palladacycle which significantly stabilize the
transition state of CN ligand exchange.
Figure 6: (a) Synthetic Diversification and Sequential C−H Functionalization (b)
Large Scale Synthesis
Figure 5: Plausible Catalytic Cycle for para-C−H Cyanation
To show the synthetic utility of para-cyanated toluenes 2a and 2w,
at first directing group was removed under ambient condition
(
4
Figure 6a). The directing template T was recovered in
quantitative yield along with para-cyano toluenes (5a and 5w).
These aryl nitriles can be transformed to different functional
groups and heterocycles. Hydrolysis of 2a in presence of TsOH
gave para-cyanated silanol 6, which is a valuable substrate for
directed ortho-functionalization and late stage modifications. The
silanol was used as directing group for ortho-olefination[18] and
meta-alkylation[19] by installing a pyrimidine based directing group.
To demonstrate practical efficacy of this protocol the large scale
synthesis of 2w was successfully performed under otherwise
identical reaction conditions (Figure 6b).
Figure 7: Iterative C−H Bond Functionalization
Conclusion
After successful para-cyanation of phenol, the template was
m
removed in situ using TBAF (Figure 7) and DG was installed to
obtain further C−H functionalized phenols 10. The strong electron
withdrawing influence of the cyano group in 10 led to preferential
formation of ortho-alkylated phenol 11.[19] Subsequently, this tri-
substituted sterically hindered compound 11 was further alkylated
and olefinated to obtain tetra-substituted arenes 12 and 13. Such
iterative C−H functionalization reactions can demonstrate the
utility of direct protocol without involving functional group
In summary, we have disclosed a Pd(II) catalyzed H-bonded
template assisted para-selective cyanation through C−H
activation. Discovery of electron rich template allowed us to
override the bias present on the aromatic ring. Interestingly C−H
activation is not the rate determining step during the cyanation
reaction which is further supported by DFT studies. This is in stark
contrast with our previous attempts of para-C−H functionalization
wherein macrocyclic TS for C−H activation was always rate
5
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Chemistry - A European Journal
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RESEARCH ARTICLE
[
4]
For selected examples on Ir catalyzed meta-C−H functionalization, see:
limiting. Distal para-C−H cyanation followed by iterative ortho- and
meta-C−H bond functionalization demonstrated the utility of direct
protocol over traditional functional group interconversions
strategy.
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Acknowledgements
This research is supported by SERB (CRG/2018/003951) India.
G. L. thanks the financial support from National Natural Science
Foundation of China (No. 21973055) and the Natural Science
Foundation of Shandong Province (ZR2019MB049). Financial
support received from IITB-Monash Research Academy (SP and
UD), CSIR-India (AM, AS), UGC (TB) and DST-India (Fast Track
Scheme for RJ (YSS/2014/000530).
7972-7979.
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5]
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Entry for the Table of Contents
‡
‡
Sandeep Pimparkar , Trisha Bhattacharya , Arun Maji, Argha Saha, Ramasamy Jayarajan, Uttam Dutta, Gang Lu,* David W. Lupton* and Debabrata
Maiti*
Para-Selective Cyanation of Arenes by H−Bonded Template: Site selectivity for distal para C−H bond of arene has always remain strenuous challenge
compare to proximal –ortho/-meta C−H bonds. A Comprehensive experimental and computational study on distal para-C−H cyanation concreted new
way to introduce versatile nitrile selectively by a detachable directing group. Iterative multi-functional decoration of arenes makes method more appealing.
The notable shift in the step energetics was probed by both experimental and computational mechanistic tools heralds the inception of para-deuteration.
8
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