NHC-Catalyzed Benzylic Csp3–H Bond Activation of Alkylarenes and N-Benzylamines for the Synthesis of 3H-Quinazolin-4-ones: Experimental and Theoretical Study

Article abstract of DOI:10.1002/ejoc.201600792

An N-heterocyclic carbene catalyzed benzylic C_sp3–H bond activation of alkylarenes and N-benzylamines under metal-free conditions was developed. This organocatalyzed oxidative transformation afforded the corresponding carbonyl derivatives in good to excellent yields. A variety of alkylarenes and N-benzylamines were tolerated under the optimized reaction conditions. The established method was further extended to the synthesis of biologically important 3H-quinazolin-4-ones in good yields. For example, NPS 53574, a potent calcium receptor antagonist, was successfully synthesized by using this oxidative protocol. DFT studies show that the benzylic C–H bond activation proceeds through the nucleophilic attack of the free carbene on the benzylic carbon atom.

Full text of DOI:10.1002/ejoc.201600792

A Journal of
Accepted Article
Title: NHC Catalyzed Benzylic sp3 C-H Bond Activation of Alkylarenes and N-
Benzylamines for the Synthesis of 3H-Quinazolin-4-ones - Experimental and
Theoretical Study
Authors: Anitha Alanthadka; Sankari Devi E; Nagarajan Subbiah; Sridharan Vellai-
samy; Suvitha Ambigapathy; C Uma Maheswari
This manuscript has been accepted after peer review and the authors have elected
to post their Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by using the Digital
Object Identifier (DOI) given below. The VoR will be published online in Early View as
soon as possible and may be different to this Accepted Article as a result of editing.
Readers should obtain the VoR from the journal website shown below when it is pu-
blished to ensure accuracy of information. The authors are responsible for the content
of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201600792
Link to VoR: http://dx.doi.org/10.1002/ejoc.201600792
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201600792
FULL PAPER
NHC Catalyzed Benzylic sp3 C-H Bond Activation of Alkylarenes
and N-Benzylamines for the Synthesis of 3H-Quinazolin-4-ones –
Experimental and Theoretical Study
Anitha Alanthadka[a], E. Sankari Devi[a], Subbiah Nagarajan[a], Vellaisamy Sridharan[a], Ambigapathy
Suvitha[b]* and C. Uma Maheswari*[a]
Abstract: N-heterocyclic carbene catalyzed benzylic sp3 C-H bond
activation of alkylarenes and N-benzylamines under metal-free
conditions was reported. The reaction tolerated different alkylarenes
and N-benzylamines to give the corresponding carbonyl derivatives
in good to excellent yields. The established methodology was further
extended for the synthesis of biologically important 3H-quinazolin-4-
ones in good yields. NPS 53574, a potent calcium receptor
are: use of additives, use of base and reagents in stoichiometric
amount, limited substrate scope and/or the poor product
selectivity. Likewise, activation of sp3 C-H bond adjacent to
nitrogen has been extensively explored as the method is
essential for the synthesis of natural products as well as
pharmaceuticals
possessing
the
heteroatoms.
This
transformation was usually aided by transition metal based
antagonist was successfully synthesized using this oxidative protocol. catalyst. There is clearly scope for the development of new
The DFT studies shows that benzylic C-H bond activation takes
place through nucleophilic attack of free carbene.
synthetic strategy for the benzylic sp3 C-H bond activation of
alkylarenes and N-benzyl amines. In this aspect, the use of N-
heterocyclic carbenes (NHC) as organocatalyst for the
aforementioned transformation can be a viable starting point.
NHCs are very stable under oxidative conditions unlike
phosphine ligands and it was even used as a stabilizing ligand in
Pd catalysed oxidation reactions.[13] There were several reports
on oxidative organocatalysis mediated by NHCs like oxidative
esterification of aldehydes,[14] oxidation of aldehydes to
carboxylic acids,[15] oxidation of alcohols,[16] oxidative
functionalization of unactivated aldehydes,[17] and oxidative
amidation of aldehydes (Scheme 1, a-c).[18] Apart from these
reports, there were few reviews which gives a complete account
of development on various oxidation processes catalyzed by
NHCs and its synthetic utility for several transformations.[19]
Introduction
The oxidative transformation of benzylic sp3 C-H bond to
respective carbonyl compounds is one of the important area in
synthetic organic chemistry as it introduces oxygen atom into
organic moiety.[1] This strategy offers direct access to complex
building blocks from readily accessible alkylarenes.[2] Traditional
method involves the usage of stoichiometric amount of metal
oxidants such potassium permanganate or potassium
dichromate under harsh reaction conditions.[3] Due to the
stringent environmental policies, these methods were replaced
by catalytic oxidation where a transition metal was employed as
a catalyst in the presence of stoichiometric terminal oxidants
most commonly, tert-butyl hydroperoxide (TBHP)[4,5] and other
oxidants like KBrO3, N-hydroxyphthalimide (NHPI), H2O2 and
Oxone.[6] In similar lines, there were few reports on
environmental friendly and green oxidant i.e. oxygen as the
terminal oxidant in presence of precious metals like Pt, Rh etc.[7]
However most of the above procedures have limitations such as
usage of toxic metals, low yields of the desired product and
limited substrate scope.
There were few metal-free catalytic oxidations to aide this
[10]
transformation including NBS-H2O,[8] I2-Py-TBHP,[9] NHPI/O2
and DDQ/tert-Butyl nitrite,[11] and more recently a recyclable
TEMPO catalyst for the benzylic oxidation of isochromans and
alkylarenes.[12] The disadvantages of these catalytic systems
Scheme 1. NHC catalysed oxidative transformations.
Results and Discussion
[a]
[b]
Organic Synthesis group, Department of Chemistry, School of
Chemical and Biotechnology, SASTRA University, Thanjavur-
613401, India.
E-mail: umamaheswaric@scbt.sastra.edu, uma.cchem@gmail.com.
Computational Molecular Biophysics Laboratory, Department of
Chemistry, School of Chemical and Biotechnology,
SASTRA University, Thanjavur-613401, India.
E-mail: suvitha@scbt.sastra.edu
As a part of our ongoing study on organocatalytic oxidative
transformations mediated N-heterocyclic carbenes, we have
recently reported NHC-catalyzed oxidative amidation of
aldehydes with amines.[18e] During this process, when
dibenzylamine was used as the amine variant for amidation of
aldehyde, we obtained the desired amide as major product
along with N-benzylbenzamide as a side product, due to
benzylic C-H oxidation (Equation 1).
Supporting information for this article is given via a link at the end of
the document.

European Journal of Organic Chemistry
10.1002/ejoc.201600792
FULL PAPER
was prolonged for 24 h (entry 25). Thus we arrived at the
optimized reaction NHC
Inspired by this result, the benzylic sp3 C-H bond oxidation
of alkylarenes was attempted. Herein, we report NHC catalyzed
benzylic sp3 C-H bond activation of alkylarenes and N-
benzylamines under metal-free conditions (Scheme 1, d). Finally,
the application of this protocol for the synthesis of 3H-quinazolin-
4-ones, a bioactive heterocyclic compound was demonstrated.
For our initial optimization studies on benzylic sp3 C-H
oxidation, diphenylmethane was taken as the model substrate.
Variation of different NHC-salts A to G as pre-catalyst and Et3N
as base in presence of TBHP in water as oxidant at 80 oC
proved that D gave better results than the other pre-catalysts
(Scheme 2).
Scheme 2. Various N-heterocyclic carbenes used in the benzylic sp3 C-H
bonds oxidation.
Reaction conditions: diphenylmethane (1 mmol), NHC precatalyst (10 mol%),
Et3N (10 mol%), TBHP (3 equiv) in CH3CN (2 mL), 80 oC, 15 h, Isolated yields.
Screening of different oxidants indicated that TBHP was
the oxidant of choice and the yield was better with TBHP in
water than TBHP in decane (Entries 1-9). Once the oxidant was
fixed for this oxidative transformation, we focused our attention
on choice of bases and it was observed that inorganic bases like
K2CO3 and Cs2CO3 decreased the yield (entries 10-13). Diethyl
azodicarboxylate (DEAD) also did not improve the product yield
compared to Et3N. Different solvents were tested and among
them, CH3CN gave the best yield (entries 14-19). When the
reaction was performed at room temperature, the respective
ketone was not detected (entry 20). Gradual increase in the
temperature increases the product yield and the yield was
optimal at 80 oC and further increase in temperature did not
improve the product yield (entries 21 and 22). The yield
decreased dramatically when amount of oxidant was decreased
from 3 to 1 equiv. (entries 23 and 24). There was significant
decrease in the product yield when the amount of NHC pre-
catalyst used was decreased to 5 mol% even when the reaction

European Journal of Organic Chemistry
10.1002/ejoc.201600792
FULL PAPER
pre-catalyst D (10 mol%), Et3N (10 mol%) as base , TBHP in
Table 1. Optimization conditions for NHC catalyzed benzylic oxidation
of alkylarenes.[a]
water as oxidant (3 equiv) in CH3CN as solvent at 80 oC for 15 h.
Entry
1
Base
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
K2CO3
Cs2CO3
t-BuOK
DEAD
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Oxidant
NBS
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
PhCl
Yield (%)[b]
<5
-
NCS
2
H2O2
<5
88
-
3
TBHP[c]
BQ[d]
4
5
AQ[e]
-
6
DTBP
DCP
18
13
22
51
37
54
45
68
70
81
14
<5
12
NR
54
62
51
68
57
<5
7
8
Scheme 3. N-Heterocyclic carbene-catalyzed benzylic oxidation of
TBPB
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP[f]
TBHP[g]
TBHP[h]
TBHP[i]
TBHP[j]
TBHP[K]
TBHP[l]
9
alkylarenes.[a]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
[a] Reaction conditions: 1 (1 mmol), NHC precatalyst D (10 mol%), Et3N (10
mol%), TBHP (3.0 equiv), CH3CN (2 mL), 80 oC, 15 h. Yields refers to isolated
yields. [b] Reaction time = 24 h. [c] Reaction was prolonged for 24 h with 5.0
equiv of TBHP as oxidant.
With the optimized results in hand, the scope of the
benzylic sp3 C-H bond activation is tested for structurally diverse
alkylarenes as summarized in Scheme 3. The reaction
proceeded smoothly to generate the corresponding carbonyl
compounds in good to excellent yields. Ethyl benzene and
1,2,3,4-tetrahydronaphthalene gave the expected product,
DCE
Dioxane
Toluene
DMF
acetophenone
and
3,4-dihydronaphthalen-1(2H)-one
respectively in good yield albeit longer reaction time and excess
of oxidant (entries 2b and 2c). When 3 equiv. of oxidant was
used, the yield of the products 2b and 2c were low even when
the reaction was prolonged for 24 h (69% and 67% respectively).
Similarly, the reaction was sluggish and required more oxidant in
case of indan and the desired product indanone was obtained in
low yield of 48%, whereas the yield was considerably low (34%)
H2O
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
with
3 equiv. of oxidant (entry 2d). In case of 9,10-
dihydroanthracene, instead of formation of carbonyl compound,
we observed the complete aromatization of the ring due to
oxidative dehydrogenation, leading to the formation of
anthracene in good yield (entry 2e). 9H-xanthene yielded the
required 9H-xanthen-9-one in excellent yield of 95% (entry 2f).
The yields were good when oxygen is present in the ring
adjacent to benzylic position, as witnessed in the case of
isochroman and 1,3-dihydroisobenzofuran (entries 2g and 2h).
Similarly,1,2,3,4-tetrahydroisoquinoline,
a
cyclic secondary
[a] Reaction conditions: diphenylmethane (1 mmol), NHC precatalyst D
(10 mol%), base (10 mol%), oxidant (3.0 equiv), solvent (2 mL), 80 oC,
15 h. [b] Isolated yield. [c] Oxidant = TBHP in decane. [d] BQ:
Benzoquinone. [e] AQ: Anthraquinone. [f] Reaction at r.t. [g] Reaction
at 60 oC. [h] Reaction at 70 oC. [i] 1.0 equiv of oxidant used. [j] 2.0
equiv of oxidant used. [k] NHC precatalyst (5 mol%) and Et3N (5 mol%)
for 24 h. [l] Reaction carried out in the absence of NHC precatalyst with
Et3N (10 mol%) and TBHP ( 3.0 equiv) for 24 h.
amine, gave the desired carbonyl product in good yield (entry
2i), whereas similar trend was not observed with 1,2,3,4-
tetrahydroquinoline. In this case, it was observed that the
substrate underwent oxidative dehydrogenation leading to the
formation of quinoline instead of 2,3-dihydroquinolin-4(1H)-one
and the reaction was found to be slow in spite of using excess

European Journal of Organic Chemistry
10.1002/ejoc.201600792
FULL PAPER
oxidant (entry 2j). In case of fluorene derivatives, the reactivity
depends on the nature of the substituent present (entries 2k-m).
Fluorene gave the required fluorenone in good yield of 91%,
whereas when bromine or amino groups are present on the
aromatic ring, the yield decreased. In case of 9H-fluoren-2-
amine, it underwent chemo-selective oxidation at the benzylic
position and the corresponding –NH2 oxidised product 2-nitro-
9H-fluorene was not observed.
carboxylic acid anhydride followed by further treatment with
amine.[21] Recently, other synthetic routes emerged for the
synthesis of 3H-quinazolin-4-ones.[22] However, these methods
have several drawbacks, in terms of substrate scope, yields and
the reaction conditions. Thus, extension of our NHC catalysed
benzylic oxidation procedure for the synthesis of 3H-quinazolin-
4-ones could be an elegant and useful synthetic strategy.
Scheme 5. Synthetic route for the preparation of 3H-quinazolin-4-ones.
3H-Quinazolin-4-ones was synthesized as described in
Scheme
5.
The
primary
coupling
partner
2-
((alkylamino)methyl)aniline
7
was synthesized from 2-
nitrobenzaldehyde 5 via reductive amination to yield compound
6[23a] followed by further reduction.[23b] Treatment of compound 7
with arylaldehydes in ethanol at ambient temperature afforded
the required precursors 8 in good yields. The optimized reaction
conditions for the benzylic oxidation was then employed for the
synthesis of 3H-quinazolin-4-ones 9 starting from compounds 8
and the results are shown in scheme 6.
Scheme 4. NHC catalysed benzylic oxidation of N- benzylamines.[a]
[a] Reaction conditions: 3 (1 mmol), NHC precatalyst D (10 mol%), Et3N (10
mol%), TBHP (3.0 equiv), CH3CN (2 mL), 80 oC, 15 h. Yields refers to isolated
yields.
The higher reactivity of benzylic C-H bond adjacent to
heteroatom like nitrogen and oxygen prompted us to widen the
scope of this benzylic sp3 C-H bond activation to acyclic
secondary amines viz. N-substituted benzylamines (Scheme 4).
Initially, various N-benzylanilines were made to undergo the
aforementioned reaction. The corresponding N-benzoylaniline
was obtained in moderate to good yield irrespective of the
nature of the substituents present in benzyl part (4a – 4d). The
reaction gave moderate yield when N-benzyl-4-chloroaniline was
used as the substrate (4e). When the reaction was performed
with heteroaromatic N-(thiophen-2-ylmethyl)aniline, the required
product N-phenylthiophene-2-carboxamide (4f) was obtained in
good yield. When dibenzylamine was taken, the corresponding
N-benzylbenzamide was obtained in 68% (4g). In similar lines,
N-butylbenzamide and N-cyclohexylbenzamide were achieved in
good yields from their respective amines viz. N-benzylbutan-1-
amine and N-benzylcyclohexylamine (4h and 4i).
3H-Quinazolin-4-ones show broad range of biological and
pharmaceutical activities including anti-hypertensive,[20a,b]
antidiabetic,[20c]
antibacterial,[20d]
anticonvulsant,[20e]
Scheme 6.Synthesis of 3H-quinazolin-4-ones via NHC-catalyzed oxidation. [a]
antitumor,[20f,g] central nervous system (CNS) depressants,[20h,i]
diuretic activity[20j] and calcium receptor antagonist.[20k]
Traditionally, 3H-quinazolin-4-ones were prepared by coupling
2-aminobenzoic acid or its derivatives with acylchloride or
[a] Reaction conditions: 8 (10 mmol), NHC precatalyst D (10 mol%), Et3N (10
mol%), TBHP (3.0 equiv), CH3CN (2 mL), 80 oC, 12 h.
A variety of 3-alkyl-1,2,3,4-tetrahydroquinazolines 8 was
converted into the corresponding 2,3-disubstituted-3H-

European Journal of Organic Chemistry
10.1002/ejoc.201600792
FULL PAPER
quinazolin-4-ones 9. Irrespective of the nature of the
substituents on the 2-aryl moiety the reaction proceeded well to
furnish the products 9 in good yields. The reaction was tolerant
to various alkylarenes and N-benzylamines to give the
corresponding carbonyl derivatives in good to excellent yields.
The reaction was also tolerated n-butyl and phenethyl
substituents. Importantly, the developed protocol was employed
for the synthesis of a potent calcium receptor antagonist NPS
53574 9i.[20k]
slightly increased after attacking the Sub (0.133e to 0.153e)
possibly the reason for the H atom transfer from Sub to Cat.
There is lowering of HOMO-LUMO energy gap from 8.51 to 6.18
eV as Sub forms I1, which was substantiated by the increase in
reactivity of the I1 as compared to the Cat and Sub.
Table 2. Energy of HOMO (EH, in a.u.), energy of LUMO (EL, in a.u.),
Electronic chemical potential
µ
(a.u.), chemical hardness
ɳ
(a.u.),global
electrophilicity ω (eV) and global nucleophilicity indices (eV )
ω
N
EH(a.u)
EL(a.u)
µ(a.u)
ɳ(a.u)
(eV)
0.67
0.66
0.44
0.46
0.33
(ev)
2.95
3.24
5.44
5.06
2.26
Role of NHC:
Sub
Cat
TS1
I1
-0.281
-0.270
-0.189
-0.203
-0.306
0.031
0.028
0.023
0.026
0.107
-0.125
-0.121
-0.083
-0.089
-0.100
0.313
0.299
0.212
0.229
0.413
To get an insight on the role of NHC as catalyst in the
oxidation of diphenylmethane using TBHP as oxidant, we have
carried out a DFT calculation using M06-2X/6-31g (d,p) level of
theory. In the control experiments, we observe the facile
Oxd
conversion
of
diphenylmethane
to
the
intermediate
diphenylmethanol only in the presence of NHC catalyst. Hence
we have considered only the first step of catalysis reaction for
the DFT studies. The optimized structure of the reactants,
intermediates and products without geometrical constraints were
shown in Figure 1.
To understand the role of NHC for our reaction, we have
followed Tang et al. strategy where they used the Global
reactivity index.[24] In similar lines, we have computed the
chemical hardness, global electrophilicity and nucleophilicity for
the NHC (Cat), diphenylmethane (Sub), intermediate (I1),
oxidant (Oxd) and the transition state (TS1) formed during the
course of the reaction. Our calculated results for the nucleophilic
index were shown in Table 2. Nucleophilic index of the Sub
before and after attack of Cat have increased remarkably. The
NBO analysis shows that charge on the carbene carbon of Cat
To understand the reason for titled reaction to occur at
high temperature, we computed the potential energy surface,
which is shown in Figure 3. The formation of TS1 has an
activation barrier of 56.65 kcal mol-1 which may be due to the
formation of three membered ring between hydrogen, benzylic
carbon and carbene carbon. The 1,2-shift of H atom from
benzylic carbon to carbene carbon gives I1 with an energy
release of about 46.09 kcal mol-1. The second step involves a
simultaneous reaction in which TBHP (Oxd) abstracts H atom
from carbene carbon of I1, and transfer of hydroxyl group to
benzylic carbon of the Sub. This leads to the regeneration of
NHC from I1 yielding diphenylmethanol R2 and t-butylalcohol
TBA via TS2.

European Journal of Organic Chemistry
10.1002/ejoc.201600792
FULL PAPER
Figure 1. Optimized geometries of all the stationary points involved in the NHC catalysed oxidation of diphenylmethane
Figure 2. Gibbs free energy profile NHC catalysed oxidation of diphenylmethane
the formation of I1 can be the rate determining step as shown in
Figure 2. The reaction did not proceed at room temperature
The computed energy barrier for the above step was 4.74
kcal mol-1, much lower than the first step. Thus in this reaction,

European Journal of Organic Chemistry
10.1002/ejoc.201600792
FULL PAPER
possibly due to high free energy barrier for the formation of
intermediate.
Hydrogen transfer in TS1. By taking into account of various
electron density distributions and NCI, we can conclude that the
catalyst can improve the efficiency of substrate reactivity by the
formation of I1 through TS1.
Table 4. Summary of Types of Interaction, (ρbcp), (Gb), (Vb), (Hb), and (∇2ρ) at
the Bond Critical Points (BCPs) along the Bond Paths in TS1.
-2
ρbcpx10-
Gb x10
Vb
Hb x10-
-1
∇2ρ x10
BCP Type of
index interaction
1
3
x10-2
1
2
3
4
5
6
7
π…. Π
CH…. π
CH…. π
CH…. π
CH…. π
lp…. π
0.0093
0.0066
0.0105
0.0059
0.0110
0.2737
0.2750
-0.0071
-0.0057
-0.0089
-0.0042
-0.0087
0.2013
0.1909
0.0059 0.0047 -0.0011
0.0045 0.0034 -0.0011
0.0073 0.0058 -0.0015
0.0034 0.0026 -0.0008
0.0075 0.0062 -0.0012
0.1480 0.3494
0.1933 0.3842
0.4974
0.5775
lp…. π
In order to arrive at plausible reaction mechanism, several
control reactions were performed. The reaction of
diphenylmethane in the absence of NHC precatalyst D and in
presence of oxidant (Oxd) gave 7% of the desired product.
Similarly in absence of oxidant only 4% of carbonyl product was
observed. These blank reactions emphasizes the role of both
NHC and oxidant for this benzylic C-H activation. As discussed
in optimization condition (Table 1, entry 26), the reaction doesn’t
proceed in presence of base and TBHP only. When
diphenylmethanol (R2) was subjected to benzylic oxidation with
TBHP in absence of NHC, quantitative formation of
benzophenone was observed. This confirmed that the
secondary alcohol was formed during the course of the reaction.
Figure 3. Bond critical points (BCPs, colored red) along the bond paths
(colored white) for topological analysis of TS1
The natural bond orbital (NBO) charge values on the C−H
bond for various species involved in the reactions are
summarized in Table 3. The negative charge on the benzylic
carbon of Sub decreases from -0.494 to -0.354 e, which readily
facilitates the attack of hydroxyl group of TBHP oxidant, resulting
in the lowering of energy barrier as illustrated in Figure 2.
To confirm that the reaction occurs through TS1, we
carried out Atom in molecule (AIM) analysis on the transition
state structures. Topology analysis of electron density is a main
component of Bader’s AIM theory.[25] In Figure 3, the topological
diagram for TS1 is provided with the bond critical points along
the bond paths. Correspondingly, the electron densities (ρbcp),
Lagrangian kinetic energies (Gb), potential energy densities Vb,
energy densities (Hb), and Laplacian of electron densities (∇2
ρ) at the bond critical points (BCPs) along the bond paths are
summarized in Table 4.
Table 3. Values of NBO charges (e) on atoms Ccarbene, Cben H1 and H of Sub,
Cat, TS1 and TS2
C-H1
C-H2
Ccarb
Cben
Sub
Cat
TS1
TS2
0.260
-
0.260
-
-
-0.494
-
0.133
0.153
0.135
0.281
0.225
0.271
0.493
-0.354
0.0890
The additional stabilization to favor the transition state TS1
happens through a network of noncovalent interactions (NCI)
such as CH---π (methyl C-H bond interaction with aromatic π
cloud), lp---π (lone pair of nitrogen atom with aromatic π cloud)
and π---π between the phenyl rings of catalyst and the substrate.
These interactions lead to a conformation, which facilitates the
Scheme 7: Plausible mechanism for the benzylic sp3 C-H bond activation.
Based on the aforementioned theoretical studies and the
control experiments, we propose a plausible mechanism as

European Journal of Organic Chemistry
10.1002/ejoc.201600792
FULL PAPER
one negative frequency. Natural bond orbital (NBO) analyses were
performed with the same level of theory to assign atomic charges. To
know the role of NHC (Cat) in C-H activation, we have calculated and
analysed the nucleophilicity index (N) and electrophilicity index (ω) as
global reactivity indices. Specifically, the nucleophilicity index (N)
introduced by Domingo and co-workers can be used to estimate the
global nucleophilicity index, which is based on HOMO energies obtained
within the Kohn–Sham scheme[28a] and defined as N = EHOMO(Nu) -
EHOMO(TCE). In the nucleophilicity scaling. Tetracyanoethylene (TCE)
is taken as a reference to compute the nucleophilicity of organic
compounds.[28b] The global electrophilicity character of a molecule is
measured by the electrophilicity index, ω, following equation, ω = µ2/2ɳ,
in terms of the electronic chemical potential µ and the chemical hardness
ɳ. Both quantities may be obtained in terms of the one-electron energies
of the frontier molecular orbital HOMO and LUMO, EH and EL, as µ =
(EH + EL)/2 and ɳ= EL - EH.
shown in Scheme 7. The initial step is the generation of free
carbene Cat from imidazolium salt precursor D by treating with
base. NHC activates the benzylic position of the alkylarene to
generate intermediate I1 through the transition state TS1. The
intermediate I1 further reacts with TBHP (Oxd) to generate
secondary alcohol R2 via the transition state TS2. R2 on
oxidation with TBHP generates the desired product along with
the regeneration of free carbene, thus making this reaction
catalytic.
Conclusions
In conclusion, we have developed a novel method for benzylic
sp3 C-H bond activation of alkylarenes and N-benzylamines
under metal free conditions by oxidative NHC catalysis. The
reaction was tolerant to various alkylarenes and N-benzylamines
to furnish the corresponding carbonyl compounds in good to
excellent yields. This oxidative strategy was extended to the
synthesis of an important bioactive 3H-quinazolin-4-ones,
including NPS 53574, a potent calcium receptor antagonist. The
theoretical studies shows that benzylic C-H bond activation
takes place through nucleophilic attack of carbene on the
benzylic carbon of the substrate with hydrogen transfer.
Acknowledgements
C. U thanks DST, SERB, New Delhi for the award of a research
grant for young scientist (no. SB/FT/CS-108/2012), New Delhi and
SASTRA University for infrastructure and for NMR analysis.
Keywords: N-Heterocyclic Carbene
Quinazolin-4-ones Alkylarene Benzylamine
functional calculation
•
Oxidation
•
3H-
•
•
• Density
Experimental Section
[1]
a) R. G. Bergman, Nature 2007, 446, 391-393; b) K. Godula, D. Sames,
Science 2006, 312, 67-72; For representative reviews, see: c) R. H.
Crabtree, J. Organomet. Chem. 2004, 689, 4083-4091; d) V. Ritleng, C.
Sirlin, M. Pfeffer, Chem. Rev. 2002, 102, 1731-1770; e) C. Jia, T.
Kitamura, Y. Fujiwara, Acc. Chem. Res. 2001, 34, 633-639; f) G. Dyker,
Angew. Chem., Int. Ed. 1999, 38, 1698-1712..
1) General procedure for benzylic oxidation: A mixture of NHC (0.1
mmol) and base (0.1 mmol) in CH3CN (2 mL) was stirred at 25 oC for 30
min. To this solution, alkylarene (1.0 mmol) followed by 70% TBHP in
H2O (3.0 mmol) was added and stirring was continued at 80 oC for 15 h.
Progress of the reaction was monitored by TLC. After the completion of
the reaction, the mixture was washed with water and extracted with ethyl
acetate. The extract was washed with brine solution and dried over
anhydrous Na2SO4. Removal of the solvent under vacuum afforded the
crude product, which was purified by column chromatography using
hexane/ethyl acetate mixture.
[2]
a) R. A. Sheldon, Top. Curr. Chem. 1993, 164, 20-43; b) R. A. Sheldon,
J. K. Kochi in Metal Catalyzed Oxidations of Organic Compounds,
Academic Press: New York, 1981; c) P. C. Bulman Page, T. J.
McCarthy, in Comprehensive Organic Synthesis, Vol. 7 (Eds.: B. M.
Trost, I. Flemming), Pergamon: Oxford, New York, NY, Seoul, Tokyo,
1991, 83-117; d) L. Kesavan, R. Tiruvalam, M. H. Ab Rahim, M. I. Bin
Saiman, D. I. Enache, R. L. Jenkins, N. Dimitratos, J. A. Lopez-
Sanchez, S. H. Taylor, D. W. Knight, C. J. Kiely, G. J. Hutchings,
Science 2011, 331, 195-199; e) A. Aguadero, H. Falcon, J. M. Campos-
Martin, S. M. Al-Zahrani, J. L. G. Fierro, J. A. Alonso, Angew. Chem.,
Int. Ed. 2011, 50, 6557-6561.
2) General procedure for the synthesis of 3H-Quinazolin-4 ones (9 a-
i): A mixture of NHC (0.1 mmol) and base (0.1 mmol) in 2 mL of CH3CN
was stirred at 25 oC for 30 min. To this reaction mixture 3-alkyl-1,2,3,4-
tetrahydroquinazolines was added followed by TBHP (3 mmol) and
stirred at 80 oC for 12 h. Progress of the reaction was monitored by TLC.
Similar work-up procedure was employed as mentioned previously. The
crude product was purified by column chromatography using
hexane/ethyl acetate mixture. All the 3H-quinazolin-4 ones given below
are synthesized using general procedure.
[3]
a) M. Hudlicky, Oxidations in Organic Chemistry; ACS Monograph No.
186; American Chemical Society: Washington, DC, 1990; b) M.
Meciarova, S. Toma, A. Heribanova, Tetrahedron 2000, 56, 8561-
8566; c) T. Dohi, N. Takenaga, A. Goto, H. Fujioka, Y. Kita, J. Org.
Chem. 2008, 73, - d) H. ichter, O. . Manche o, Eur. J.
Org. Chem. 2010, 23, 4460-4467; e) C. Zhang, P. Srivastava, K. E.
Guardiola, J. C. Lewis, Tetrahedron 2014, 70, 4245-4249 and
references cited therein.
Computational details:
[4]
For Metal catalyzed benzylic oxidations, see: a) B. M. Choudary, A. D.
Prasad, V. Bhuma, V. Swapna, J. Org. Chem. 1992, 57, 5841-5844; b)
M. Jurado-Gonzalez, A. C. Sullivan, J. R. H. Wilson, Tetrahedron Lett.
2003, 44, 4283-4286; c) G. Blay, I. Fernandez, T. Gimenez, J. R. Pedro,
R. Ruiz, E. Pardo, F. Lloret, M. C. Munoz, Chem. Commun. 2001,
2102-2103; d) M. D. Nikalje, A. Sudalai, Tetrahedron 1999, 55, 5903-
5908; e) Y. Bonvin, E. Callens, I. Larrosa, D. A. Hederson, J. Oldham,
A. J. Barton, A. G. M. Barrett, Org. Lett. 2005, 7, 4549-4552; f) A. J.
Catino, J. M. Nichols, H. Choi, S. Gottipamula, M. P. Doyle, Org. Lett.
2005, 7, 5167-5170 and references cited therein.
The DFT studies were carried out using M06-2X functional as
implemented in Gaussian 09.[26] M06-2X functional is proved to be
efficient and reliable for organic systems.[27] All the reactant,
intermediates and product structures were energy minimized using 6-31g
(d, p) basis in the solvent acetonitrile solvent simulated by the integral
equation formulism polarizable continuum model (IEF-PCM). There is no
significant effect of solvent on energtics. Harmonic frequency analysis
was carried out at the same level of theory to confirm optimized geometry
as minima with no negative frequency, or transition state structures with

European Journal of Organic Chemistry
10.1002/ejoc.201600792
FULL PAPER
[5]
For some selected examples on Fe-catalyzed benzylic oxidation, see:
a) C. Pavan, J. Legros, C. Bolm, Adv. Synth. Catal. 2005, 347, 703-
705; b) M. Nakanishia, C. Bolm, Adv. Synth. Catal. 2007, 349, 861-864;
c) F. Szabó, B. Petho, Z. Gonda, Z. Novák, RSC Adv. 2013, 3, 4903-
4908; d) N. François, K. Raphaëlle, J. -G. Ludivine, G.-H. Catherine, D.
Micheline, A. Bruno, Tetrahedron Lett. 2015, 56, 2517-2520 and
references therein.
[19] a) C. E. I. Knappke, A. Imami, A. J. von Wangelin, ChemCatChem.
2012, 4, 937-941; b) S. D. Sarkar, A. Biswas, R. C. Samanta, A.
Studer, Chem. -Eur. J. 2013, 19, 4664-4678.
[20] a) H. J. Hess, T. H. Cronin, A. Scriabine, J. Med. Chem. 1968, 11,
130-136; b) M. Ishikawa, Y. Eguchi, Heterocycles 1981, 16, 31; c) M.
S. Malamas, J. Millen, J. Med. Chem. 1991, 34, 1492-1503; d) P. P.
Kung, M. D. Casper, K. L. Cook, L. Wilson-Lingard, L. M. Risen, T. A.
Vickers, R. Ranken, L. B. Blyn, R. Wyatt, P. D. Cook, J. Ecker, J. Med.
Chem. 1999, 42, 4705-4713; e) A. Mannscherck, H. Koller, G. Stuhler,
M. A. Davis, J. Traber, Eur. J. Med. Chem. 1984, 19, 381-383; f) J.
Felter, T. Czuppo, G. Hornyak, A. Feller, Tetrahedron 1991, 47, 9393-
9410; g) L. A. Sorbera, J. Bolos, N. Serradell, M. Bayes, Drugs future
2006, 31, 778-787; h) M. L. Gujral, P. N. Saxena, R. S. Tiwari, Indian.
J. Med. Res. 1955, 43, 637-641; i) B. L. Chenard, A. R. Reinhold, W.
M. Welch, European Patent Application EP 0884310A1, 1998; j) E.
Cohen, B. Klarberg, J. R. Vaughan, J. Am. Chem. Soc. 1960, 82,
2731-2735; k) I. Shcherbakova, M. F. Balandrin, J. Fox, A. Ghatak, W.
L. Heaton, R. L. Conklin, Bioorg. Med. Chem. Lett. 2005, 15, 1557-
1560.
[6]
[7]
a) Y. J. Xie, Y. Z. Yang, L. H. Huang, X. B. Zhang, Y. H. Zhang, Org.
Lett. 2012, 14, 1238-1241; b) A. V. Biradar, T. Asefa, Appl. Catal. A:
Gen. 2012, 435-436, 19-26; c) K. Moriyama, M. Takemura, H. Togo,
Org. Lett. 2012, 14, 2414-2417; d) C. S. Yi, K. H. Kwon, D. W. Lee, Org.
Lett. 2009, 11, 1567-1569; e) S. I. Murahashi, N. Komiya, Y. Oda, T.
Kuwabara, T. Naota, J. Org. Chem. 2000, 65, 9186-9193.
a) A. Sen, M. Lin, L. C. Kao, A. C. Hutson, J. Am. Chem. Soc. 1992,
114, 6385-6392; b) A. K. Fazlur-Rahman, J. C. Tsai, K. M. Nicholas, J.
Chem. Soc., Chem. Commun. 1992, 1334-1335.
[8]
[9]
C. He, X. H. Zhang, R. F. Huang, J. Pan, J. Q. Li, X. G. Ling, Y. Xiong,
X. M. Zhu, Tetrahedron Lett. 2014, 55, 4458-4462.
J. T. Zhang, Z. T. Wang, Y. Wang, C. F. Wan, X. Q. Zheng, Z. Y. Wang,
Green Chem. 2009, 11, 1973-1978.
[21] a) E. C. Taylor, R. J. Knopf, A. L. Borror, J. Am. Chem. Soc. 1960, 82,
3152-3157; b) B. L. Chenard, W. M. Welch, J. F. Blake, T. W. Butler, A.
Reinhold, F. E. Ewing, F. S. Menniti, M. J. Pagnozzi, J. Med. Chem.
2001, 44, 1710-1717; c) S. Xue, J. McKenna, W. C. Shieh, O. Repic, J.
Org. Chem. 2004, 69, 6474-6477 and references cited therein.
[22] a) J. F. Liu, J. Lee, A. M. Dalton, G. Bi, L. Yu, C. M. Baldino, E.
McElory, M. Brown, Tetrahedron Lett. 2005, 46, 1241-1244; b) A.
Dandia, R. Singh, P. Sarawgi,Org. Prep. Proced. Int. 2005, 37, 397-
402; c) P. Salehi, M. Dabiri, M. A. Zolfigol, M. Baghbanzadeh,
Tetrahedron Lett. 2005, 46, 7051-7053; d) Z. Zheng, H. Alper, Org.
Lett. 2008, 10, 829-832; e) R. A. Kumar, C. U. Maheswari, S.
Ghantasala, C. Jyothi, K. R. Reddy, Adv. Synth. Catal. 2011, 353, 401-
410.
[10] a) Y. Ishii, K. Nakayama, M. Takeno, S. Sakaguchi, T. Iwahama, Y.
Nishiyama, J. Org. Chem. 1995, 60, 3934-3935; b) G. Yang, Q. Zhang,
H. Miao, X. Tong, J. Xu, Org. Lett. 2005, 7, 263-266.
[11] J. Ma, Z. Hu, M. Li, W. Zhao, X. Hu, W. Mo, B. Hu, N. Sun, Z. Shen,
Tetrahedron 2015, 71, 6733-6739.
[12] Z. Zhang, Y. Gao, Y. Liu, J. Li, H. Xie, H. Li, W. Wang, Org. Lett. 2015,
17, 5492-5495.
[13] a) S. S. Stahl, J. L. Thorman, R. C. Nelson, M. A. Kozee, J. Am. Chem.
Soc. 2001, 123, 7188-7189; b) M. M. Konnick, I. A. Guzei, S. S. Stahl, J.
Am. Chem. Soc. 2004, 126, 10212-10213; c) M. Yamashita, K. Goto, T.
Kawashima, J. Am. Chem. Soc. 2005, 127, 7294-7295.
[14] For NHC catalyzed esterification of aldehydes: a) J. Guin, S. D. Sarkar,
S. Grimme, A. Studer, Angew. Chem., Int. Ed. 2008, 47, 8727-8730; b)
B. E. Maki, K. A. Scheidt, Org. Lett. 2008, 10, 4331-4334; c) C.
Noonan, L. Baragwanath, S. J. Cannon, Tetrahedron Lett. 2008, 49,
4003-4006; d) B. E. Maki, A. Chan, E. M. Phillips, K. A. Scheidt,
Tetrahedron 2009, 65, 3102-3109; e) S. D. Sarkar, S. Grimme, A.
Studer, J. Am. Chem. Soc. 2010, 132, 1190-1191; f) C. A. Rose, K.
Zeitler, Org. Lett. 2010, 12, 4552-4555; g) B. Maji, S. Vedachalan, X.
Ge, S. Cai, X.-W. Liu, J. Org. Chem. 2011, 76, 3016-3023; h) E. E.
Finney, K. A. Ogawa, A. J. Boydston, J. Am. Chem. Soc. 2012, 134,
12374-12377; i) P. Arde, B. T. Ramanjaneyulu, V. Reddy, A. Saxena,
R. V. Anand, Org. Biomol. Chem. 2012, 10, 848-851; j) T. Uno, T.
Inokuma, Y. Takemoto, Chem. Commun. 2012, 48, 1901-1903; k) I. N.
C. Kiran, K. Lalwani, A. Sudalai, RSC Adv. 2013, 3, 1695-1698; l) L.
Mohlmann, S. Ludwig, S. Blechert, Beilstein J. Org. Chem. 2013, 9,
602-607; m) J. Zhao, C. Mück-Lichtenfeld, A. Studer, Adv. Synth.
Catal. 2013, 355, 1098-1106.
[23] a) F. Ishikawa, Y. Watanabe, J. Saegusa, Chem. Pharm. Bull. 1980,
28, 1357-1362; b) M. -A. Mori, M. Inque. T. Nunozawa, T. Miyahara, H.
Kozuka, Chem. Pharm. Bull. 1986, 34, 4859-4861.
[24] Y. Wang, D. Wei, Y. Wang, W. Zhang, M. Tang, ACS Catal. 2016, 6,
279-289.
[25] R. F. W. Bader, Chem. Rev. 1991, 91, 893−928.
[26] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J.
R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson,
H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J.
Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R.
Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H.
Nakai, T. Vreven, J. A. Montgomery Jr., J.E. Peralta, F. Ogliaro, M.
Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, T.
Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C.
Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M.
Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R.
Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C.
Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski,
G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A.D. Daniels,
O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox,
Gaussian 09, Gaussian, Inc. Wallingford, CT2010
[15] a) V. Nair, V. Varghese, R. R. Paul, A. Jose, C. R. Sinu, R. S. Menon,
Org. Lett. 2010, 12, 2653-2655; b) P.-C. Chiang, J. W. Bode, Org. Lett.
2011, 13, 2422-2425.
[16] a) B. E. Maki, A. Chan, E. M. Phillips, K. A. Scheidt, Org. Lett. 2007, 9,
371-374; b) D.- F. Yu, P. Xing, B. Jiang, Tetrahedron 2015, 71, 4269-
4273.
[27] a) Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120,
215-241; b) Y. Zhao, D. G. Truhlar, Acc. Chem. Res. 2008,
41, 157-167.
[17] a) J. Mo, R. Yang, X. Chen, B. Tiwari, Y. R. Chi, Org. Lett. 2013, 15,
50-53; b) S. Gundala, C. L. Fagan, E. G. Delany, S. J. Connon, Synlett.
2013, 24, 1225-1228.
[28] a) W. Kohn, L. J. Sham, Phys. Rev. 1965, 140, 1133-1138; b) L. R.
Domingo, E. Chamorro and P. Pérez, J. Org. Chem. 2008, 73, 4615-
4624.
[18] For NHC catalyzed oxidative amidations: a) J. W. Bode, S. S. Sohn, J.
Am. Chem. Soc. 2007, 129, 13798-13799; b) H. U. Vora, T. Rovis, J.
Am. Chem. Soc. 2007, 129, 13796-13797; c) F. T. Wong, P. K. Patra,
J. Seayad, Y. Zhang, J. Y. Ying, Org. Lett. 2008, 10, 2333-2336; d) S.
D. Sarkar, A. Studer, Org. Lett. 2010, 12, 1992-1995; e) A. Anitha, C.
U. Maheswari, Adv. Synth. Catal. 2015, 357, 1199-1203.

European Journal of Organic Chemistry
10.1002/ejoc.201600792
FULL PAPER
FULL PAPER
sp3 C-H Activation
Anitha Alanthadkaa, E. Sankari Devia,
Subbiah Nagarajana, Vellaisamy
Sridharana, Ambigapathy Suvithab* and
C. Uma Maheswaria*
Page No. – Page No.
Text for Table of Contents
NHC Catalyzed Benzylic sp3 C-H
Bond Activation of Alkylarenes and
N-Benzylamines for the Synthesis of
3H-Quinazolin-4-ones – Experimental
and Theoretical Study