Bu4NI-Catalyzed, Radical-Induced Regioselective N-Alkylations and Arylations of Tetrazoles Using Organic Peroxides/Peresters

Article abstract of DOI:10.1021/acs.joc.9b02875

Bu₄NI-catalyzed regioselective N²-methylation, N²-Alkylation, and N²-Arylation of tetrazoles have been achieved using tert-butyl hydroperoxide (TBHP) as the methyl source, alkyl diacyl peroxides as the primary alkyl source, alkyl peresters as the secondary and tertiary alkyl sources, and aryl diacyl peroxides as the arylating source. These reactions proceed without pre-functionalization of tetrazole and in the absence of any metal catalysts. Here, peroxides serve the dual role of oxidants as well as alkylating or arylating agents. Based on DFT calculations, it was found that spin density, transition-state barriers (kinetic control), and thermodynamic stability of the products (thermodynamic control) play essential roles in the observed regioselectivity during N-Alkylation. This radical-mediated process is amenable to a broad range of substrates and provides products in moderate to good yields.

Full text of DOI:10.1021/acs.joc.9b02875

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Article
Bu4NI Catalyzed Radical Induced Regioselective N-Alkylations
and Arylations of Tetrazoles Using Organic Peroxides/Peresters
Suresh Rajamanickam, Chitranjan Sah, Bilal Ahmad Mir, Subhendu Ghosh,
Garima Sethi, Vinita Yadav, Sugumar Venkataramani, and Bhisma K. Patel
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02875 • Publication Date (Web): 07 Jan 2020
Downloaded from pubs.acs.org on January 8, 2020
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Bu NI Catalyzed Radical Induced Regioselective N-Alkylations and
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Arylations of Tetrazoles Using Organic Peroxides/Peresters
†
‡
†
†
§
Suresh Rajamanickam, Chitranjan Sah, Bilal Ahmad Mir, Subhendu Ghosh, Garima Sethi,
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Vinita Yadav, Sugumar Venkataramani, * and Bhisma K. Patel *
†Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati-781039, India
‡Department of Chemical Sciences, Indian Institute of Science Education and Research
(IISER) Mohali, Sector 81, SAS Nagar, Knowledge City, Manauli-140306, India
§School of Chemical Sciences, Department of Chemistry, Central University of Haryana,
Haryana-123031, India
Fax: (+91)361-26909762, E-mail: patel@iitg.ac.in
RECEIVED DATE (will be automatically inserted after the manuscript is accepted).
R/Ar
O
N
N
O
R/Ar
N
N
Ar/R
O
CH3
H
O
0.22
N
N
H3C
N
N
N
CH3
CH3
Ar
N
N
O
N
H
O
0.03
Bu NI
4
o
R = (1 ) alkyl (8 examples)
Bu4NI (20 mol %)
00 o
1
C
o
R = Aryl (14 examples)
100 C, CH3CN
Ar
Ar
R
N
N
N
O
1
2 examples
N
O
tBu
thermodynamic
stability
low transition
state barrier
favorable
spin density
R
O



Ar
2
N -Regioselectivity
o
R = (2 ) alkyl (6 examples)
DFT studies Peroxides / perester as alkyl & aryl source
o
R = (3 ) alkyl (6 examples)
2
2
2
ABSTRACT: A Bu NI-catalyzed regioselective N -methylation, N -alkylation and N -arylation of
4
tetrazoles have been achieved using tert-butyl hydroperoxide (TBHP) as the methyl, alkyl diacyl
peroxides as the primary alkyl, alkyl peresters as the secondary and tertiary alkyls and aryl diacyl
peroxides as the arylating sources. These reactions proceed without pre-functionalization of tetrazole
and in the absence of any metal catalysts. Here, peroxides serve the dual role of oxidants as well as
alkylating or arylating agents. Based on DFT calculations, it was found that spin density, transition
state barriers (kinetic control) and thermodynamic stability of the products (thermodynamic control)
play essentials roles in the observed regioselective during N-alkylation. This radical-mediated process
is amenable to a broad range of substrates and provides products in moderate to good yields.
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INTRODUCTION
Nitrogen center radicals (NCRs) are far less explored than the carbon center radicals due to the
absence of an operationally simple process for their generations. Most of the NCRs are generated
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under a harsh and potentially explosive reaction conditions. Historically, Hofmann-Löffler-Freytag
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reaction produce NCR via the homolytic cleavage of a Nhalogen bond, forming an intramolecular
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CN bond by abstracting a γ-hydrogen atom. Very recently, a NCR is generated via a photo-induced
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cleavage of a NX bond (where X = halogen or oxygen). Even though, these processes are milder but
are not economical. Thus, the search for alternative protocols for the direct conversion of N–H bonds
in general and azoles in particular, to their corresponding NCRs under a mild condition is challenging.
Transformation of azole NH into a NCR and trapping it with appropriate coupling partners would
lead to valuable target molecules. Barring a single report on the functionalization of an amide with an
azole, there is no other report on nitrogen center azole radicals.4
Tetrazole based N-heterocyclic compounds have been investigated extensively owing to its usage in
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biology, pharmaceuticals, and material sciences. Tetrazoles have found applications as ligands, in
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agriculture as herbicides, and fungicides and as a stabilizer in photography. Due to their similar pKa
values, they serve as metabolically stable bioisosteres of carboxylic acid surrogates in medicinal
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chemistry. For example, biphenyl tetrazoles are key intermediates for the preparation of multibillion-
dollar angiotensin-II receptor antagonist, a class of high blood pressure agents such as valsartan,
losartan, candesartan, and irbesartan (Figure 1).10a-d Whereas, pemirolast is an antiallergic, and
azosemide is a diuretic drug (Figure 1).10e,f In the above-mentioned drugs, the tetrazole moiety is
present in its free NH form. Among tetrazole derivatives, Nalkylated tetrazoles are important
synthetic targets as they are found in bioactive compounds, chemical intermediates, and energy-
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intensive materials. Recently, a Nmethylated tetrazole core, tedizolid phosphate (Sivextro) has been
approved by the US FDA for the treatment of acute bacterial skin and skin structure infections caused
by susceptible gram-positive pathogens, including MRSA (Methicillin-Resistant Staphylococcus
Aureus), MSSA (Methicillin-Sensitive Staphylococcus Aureus), VRE (Vancomycin-Resistant
Enterococci) and Hi (Haemophilus influenza) bacterial strains (Figure 1).12 Similarly, N-arylated
tetrazoles HM30181 derivatives are potent and selective inhibitors of breast cancer resistance protein
(
BCRP/ABCG2) (Figure 1).13
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HO
H3C
H3C
O
N
Cl
O
N
NH
N
N
CH3
N
NH
N
OH
N
N
HO
N
NH
N
CH3
NH
N
N
NH
N
O
N
N
N
N
N
N
N
O
N
S
N
O
O
S
CH3
N
3
H C
NH2
Cl
O
(I) Valsartan
(II) Losartan
(III) Candesartan
(IV) Irbesartan
(V) Azosemide
1
1
1
1
1
1
1
1
1
1
2
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NH
O
N
O
N
N
N
N
N
N
N
N
N
N
N
O
N
H3CO
OCH3
OCH3
N
N
H3C
F
CH3
O
H3CO
OH
NH
O
P
(
VI) Pemirolast
(VII )Tedizolid Phosphate
O
(VIII) HM30181
HO
O
O
Figure 1. Representative biologically active tetrazole containing molecules.
The classical method for the synthesis of N-alkylated tetrazole is via the nucleophilic substitution
reaction of tetrazole with an alkyl halide in the presence of a base. Due to the existence of two
1
2
isomeric forms viz. 5-phenyl-1H-tetrazole or N (1x) and 5-phenyl-2H-tetrazole or N (1) (Scheme 1,
Table 1) the selective alkylation of tetrazole is highly challenging as it is reported to give a mixture of
regioisomeric products.12d,e,14a,b The silylated or stannylated derivatives of tetrazoles are alkylated
regioselectively using chloroformates or cyanoformates via the in situ generated urethanes, which
rearranges to a N-alkyl product with concurrent loss of carbon dioxide.14c Regioselective metal-fee
alkylation of tetrazole is accomplished using cheap and readily available methylarenes,14d,e ethers14e-g
2
via oxidative couplings. On the other hand, the regioselective N -arylation of tetrazole has been carried
out by coupling tetrazole with an aryl boronic acid under Cu catalysis.15 Alternatively, a Cu(II)-
catalyzed N-arylation is accomplished by coupling pre-functionalized tetrazoles such as N-
tributylstannyl or its N-sodium salt with a diaryliodonium salt. While the former gave a single
2
16
regioisomer (N -arylation), the latter yielded a mixture of regioisomers. No doubt the metal-catalyzed
reactions are advantageous but are not always appreciated in the synthesis of pharmaceuticals, owing
to the difficulties in the removal of traces of transition-metal residues from the final product.
Therefore, it is essential to develop a regioselective metal-free protocol for the N-arylation of tetrazole.
Recently, tert-butyl hydroperoxide (TBHP),17 diacyl peroxides,18a-d and alkyl perester18b-f have been
utilized for various alkylation procedures. TBHP has been successfully employed as an oxidant cum
methyl source for the oxidative esterification of benzylic alcohols, aryl carbaldehydes, and aryl
carboxylic acids {Scheme 1(i)}.17
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Scheme 1. Radical Mediated Alkylation Strategies
Earlier works
OH
CHO
COOH
O
Copper
quinolate
CH3
or
or
O
TBHP, Bu4NI
ref 17
(i)
O
O
0
1
2
3
4
5
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8
9
0
1
2
3
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0
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0
1
2
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8
9
0
N
N
S
O
O
Alkyl Fe(OTf)3
Alkyl ref 18b
H +
H3C
Alkyl
CH3
(
ii)
S
O
N
N
NH
N
N
N
N
N
O
TBHP
Bu4NI
ref 4
N
+
N
CH3
(
iii)
H3C
CH3
CH3
N
N
N
N
N
This works
H C
3
O
CH3
H3C
O
H
R
H
Ar
Ar
8 h
N
N
N
N
O
R
N
N
N
O
Bu4NI
(20 mol %)
O
R
Ar
O
CH3CN
o
6 h
o
100
C
R = 1 alkyl, aryl
N
N
O
R
N
N
H
N
N
O
h
CH3
CH3
O
6
N
N
R
CH3
Ar
Ar
R = 2 , 3o alkyl
o
Alkyl radicals are generated from diacyl peroxides via the homolytic cleavage of peroxide bond
followed by the extrusion of carbon dioxide (CO ). These alkyl radicals are trapped with various
2
reacting partners leading to useful products. Several fluoroalkanes have been prepared by treating
diacyl peroxides with N-fluorobenzene sulfonimide under thermal or photochemical conditions.18a
Synthesis of 2-alkyl benzothiazoles has been accomplished via a Fe-catalyzed decarboxylative CH
alkylation of benzothiazoles using diacyl peroxides {Scheme 1(ii)}.18b A radical-mediated coupling
2
between a tetrazole and a N,N-dialkyl formamide leads to an exclusive formation of a N -alkylated
1
4
tetrazole without giving any traces of N -alkylation {Scheme 1(iii)}. Thus, it would be interesting to
2
investigate whether regioselective N -alkylation of tetrazole can be achieved using TBHP as the
methyl and diacyl peroxides/peresters as the alkyl sources.
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RESULTS AND DISCUSSION
We initiated our exploration by examining the reaction between an aryl tetrazole (1) and tert-butyl
hydroperoxide (TBHP) in decane (56 M) (3 equiv), in the presence of tetrabutylammonium iodide
(Bu NI) (20 mol %) at 100 °C in DMSO. Interestingly, the reaction provided a Nmethylated product
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
in 39% yield (Table 1, entry 1), which is based on mass spectrometry and IR, H and 13C NMR
1
1
2
spectroscopic analysis of the product (1a). However, whether the product obtained is a N or a N
1
isomer it could not be ascertained. Incidentally, the reported melting point of the methylated N -isomer
2
i.e., 1-methyl-5-phenyl-1H-tetrazole is 103104 °C, whereas, the N -isomer i.e., 2-methyl-5-phenyl-
2
H-tetrazole (1a) melts at 4950 °C.19a The melting point of the isolated compound was found to be
2
5
052 °C, which is in close agreement with the reported methylated N -isomer. Further, all the
spectroscopic data (IR, H and 13C NMR) of the isolated compound (1a) is in agreement with the
1
2
literature reported one, thereby confirming its structure to be a N -isomer, i.e., 2-methyl-5-phenyl-2H-
tetrazole (1a).19b-e To obtain a satisfactory yield of the product (1a) various important reaction
parameters such as solvents, catalysts, methylating source, and the temperature was tuned. By
switching the oxidant from TBHP (in decane) to an aqueous TBHP (aq TBHP) (70% in water) (3
equiv) an improvement in the yield (47%) of (1a) was observed (Table 1, entry 2). Some other
commercially available oxidants such as di-tert-butyl peroxide (DTBP) and tert-butyl peroxybenzoate
(TBPB) were also examined under identical reaction conditions. While DTBP failed to give any trace
of the product, the oxidant TBPB provided only 19% yield of (1a) along with numerous side products
(Table 1, entries 3 and 4). The reaction was found to be extremely solvent dependent. As can be seen
from Table 1, solvents such as DMF, DCE, MeOH were detrimental to the reaction (Table 1, entries
5
7). Pleasingly, the use of acetonitrile (CH CN) provided the desired methylated product (1a) in 60%
3
yield (Table 1, entry 8). The reaction proceeds better in solvents such as (CH ) SO, CH CN (Table 1,
3
2
3
entries 2 and 8). Thus, it is possible that the methyl group present in (CH ) SO or CH CN might be
3
2
3
serving as the possible source of the methyl group in the product (1a). To ascertain this, two reactions
were carried out independently in deuterated DMSO-d and CD CN solvents under otherwise identical
6
3
reaction conditions (Table 1, entries 9 and 10). However, the isolated N-methyl tetrazole (1a) was
found to be devoid of any deuterated methyl (CD ) group, thereby suggesting neither the DMSO nor
3
CH CN as the possible source of the methyl group. Thus, the methyl group is originating from the
3
oxidant TBHP in this reaction. The reaction when performed in normal acetonitrile provided a low
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
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yield of the product (1a) (41%) possibly because of the quenching of radicals by the dissolved oxygen
in acetonitrile (Table 1, entry 11).
Table 1. Screening of the Reaction Conditionsa,b
H
N
N
N
N
N
Catalyst
Solvent
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
Methyl
Source
N
CH3
H
+
N
N
N
N
Oxidant) Temp o
(
C
(
1x)
(1)
(a)
(1a)
entry oxidant
equiv)
catalyst
(mol %)
solvent
yield (%)
(
1
2
3
4
5
6
7
8
9
1
1
dec. TBHP (3)
aq TBHP (3)
DTBP (3)
Bu
Bu
4
NI (20)
NI (20)
DMSO
DMSO
DMSO
DMSO
DMF
39
47
4
Bu
Bu
Bu
Bu
Bu
4
NI (20)
NI (20)
NI (20)
NI (20)
NI (20)
n.d.
19
n.d.
n.d.
n.d.
60
45
59
41
n.d.
19
26
50
42
n.r.
53
62
48
62
47
TBPB (3)
4
4
4
4
aq TBHP (3)
aq TBHP (3)
aq TBHP (3)
aq TBHP (3)
aq TBHP (3)
aq TBHP (3)
aq TBHP (3)
aq TBHP (3)
aq TBHP (3)
aq TBHP (3)
aq TBHP (3)
aq TBHP (3)
aq TBHP (3)
aq TBHP (2)
aq TBHP (4)
aq TBHP (3)
aq TBHP (3)
aq TBHP (3)
aq TBHP (3)
aq TBHP (3)
--
DCE
MeOH
Bu
4
NI (20)
NI (20)
NI (20)
NI (20)
NF (20)
NCl (20)
NBr (20)
CH
3
CN
Bu
Bu
Bu
Bu
Bu
Bu
4
DMSO-d
6
0
4
4
4
4
4
CD
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
1c
12
13
1
1
1
1
1
1
2
21
22d
23e
4
5
6
7
8
9
0
KI (20)
NaI (20)
I
2
(20)
Bu NI (20)
NI (20)
4
Bu
Bu
Bu
Bu
Bu
4
4
NI (10)
NI (30)
NI (20)
NI (20)
4
4
4
61
n.r.
n.r.
2
2
4
5
--
NI (20)
Bu
4
a
Reaction conditions: 5-phenyl-2H-tetrazole (1) (1 mmol), solvent (2 m
00 °C under degassed condition. Isolated yield after 8 h. cN
b
1
d
e
acetonitrile without dried and degassed (AR grade). At 90 °C. At 11
n.d. = not detected. n.r. = no reaction.
Next a genre of quaternary ammonium salts such as Bu NF, Bu NCl and Bu NBr were tested, but
4
4
4
all were found to be ineffective compared to Bu NI for this transformation (Table 1, entries 1214).
4
Other inorganic iodo salts such as KI and NaI when used in lieu of Bu NI, gave the product (1a) in
4
50% and 42% yields respectively, whereas I failed to give any product (Table 1, entries 1517). By
2
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decreasing the quantity of aq TBHP from 3 to 2 equivalents, the product (1a) yield dropped from 60 to
53% but remained practically unchanged (62%) when 4 equivalents of TBHP was used (Table 1,
entries 18 and 19). Similarly, by decreasing the quantity of catalyst Bu NI loading from 20 to 10 mol
4
%
, marginally reduced the yield (48%) of (1a) whereas, a higher catalyst loading (30 mol %) did not
improve the yield any further (Table 1, entries 20 and 21). On decreasing the reaction temperature (90
C), the yield of (1a) dropped to 47% but an increase in the temperature (110 °C), there was no
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
°
significant improvement in the product yield 61% (Table 1, entries 22 and 23). Control experiments
carried out in the absence of the catalyst (Bu NI) or oxidant (TBHP), failed to provide the desired
4
product (1a) (Table 1, entries 24 and 25). After several optimizations (Table 1), it was found that a
combination of aqueous TBHP (3 equiv), Bu NI (20 mol %) at 100 °C in CH CN solvent was found to

3
be the most optimum for this N-methylation protocol (Table 1, entry 8).
Having established an optimized reaction condition, we set out to investigate the substrate scope of
this metal-free regioselective N-methylation of aryl tetrazoles and the results are summarized in
Scheme 2. This methodology was found to be highly successful for electron-neutral tetrazole (1) and a
biphenyl tetrazole (2) providing their N-methylated tetrazoles (1a) and (2a) in 60% and 66% yields,
respectively (Scheme 2). Similarly, aryl tetrazoles bearing electron-donating groups such as p-CH (3),
3
p-OCH (4), p-tert-butyl (5) and m-OCH (6) on the phenyl moiety of the tetrazole reacted smoothly to
3
3
provide the expected products (3a, 61%), (4a, 59%), (5a, 64%) and (6a, 60%) in modest yields.
Moderately electron-withdrawing halo substituents namely, p-Br (7), p-Cl (8), and o-Cl (9)
irrespective of their position of attachments in the phenyl ring remained unaffected giving their N-
methylated products (7a, 65%), (8a, 66%) and (9a, 61%). Further synthetic elaborations such as
Suzuki coupling, Buchwald–Hartwig amination can be carried out at these halo sites of the products
(7a9a), if desired. The compound (7a) was crystallized from a supersaturated solution of chloroform
by the slow evaporation method. The structure of the product (7a) and its regioselectivity has been
unambiguously confirmed by X-ray crystallography (Scheme 2) (see the Supporting Information).
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1
1
1
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 2. Substrate Scope for N-Methylation
of Aryl Tetrazolesa,b
N
N
N
N
H3C
3
O
Bu NI (20 mol %)
N
H
4
N
CH3
OH
+
N
H C
CH CN (2 mL)
N
3
o
Ar
CH3
Ar
1
00 C, 8 h
(112)
(a)
(1a12a)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
N
N
N
N
N
N
CH3
N
CH3
N
N
CH3
CH3
N
N
Ph
H3C
(
1a, 60%)
(2a, 66%)
(3a, 61%)
N
N
N
N
N
N
N
N
N
N
N
CH3
tBu
CH3
N
H3CO
(
(
4a, 59%)
(5a, 64%)
(6a, 60%)
H3CO
N
N
N
N
N
N
N
CH3
CH3
N
Br
Cl
Cl
7a, 65%)
(8a, 66%)
(
7a, CCDC 1897064)
N
N
N
N
N
N
N
N
N
CH3
N
CH3
CH3
N
N
F3C
O2N
(
9a, 61%)
(10a, 70%)
(11a, 73%)
c
(
11a, 67%)
N
O
N
N
CH3
N
CH3
N
N
CH3
H3C
N
O
O
N
H3C
H3C
(12a, 53%)d
(13'a, 57%)e
O
N
N
N
N
O
O
S
N
N
N
N
CH3
CH3
CH3
CH3
CH3
O
(17a, 42%)f
(
14a, 00%) (15a, 00%)
(16a, 00%)
(18a, 68%)
aReaction conditions: aryl tetrazole (1 mmol), Bu
mol %) and aq TBHP (a) (3 equiv) at 100 °C in CH
NI (20
CN (2
mL) under degassed condition. Isolated yields after 8 h.
4
3
b
c
d
Isolated yield reported for 8 mmol (1.53 g) scale. 4-(2H-
tetrazol-5-yl)benzaldehyde was used as the starting
equivalents of aq TBHP. e5-(4-
material with
5
methylbenzyl)-2H-tetrazole was used as starting material
f
with 5 equivalents of aq TBHP, 30 mol % of Bu
benzo[d][1,2,3]triazole (1 mmol), Bu
4
NI. 1H-
4
NI (30 mol %) and
CN (2 mL) under
aq TBHP (a) (4 equiv) at 120 °C in CH
3
degassed condition for 12 h.
Aryl rings of tetrazole possessing strongly electron-withdrawing substituents such as p-CF (10) and
3
p-NO (11) delivered the corresponding N-methylated products (10a, 70%) and (11a, 73%) in good
2
yields. To evaluate the potential and scope of this radical-induced N-methylation reaction, (11) and (a)
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were reacted on 8 mmol scale (1.56 g), which provided 67% of the product 2-methyl-5-(4-
nitrophenyl)-2H-tetrazole (11a) (Scheme 2). Tetrazole possessing an electron-withdrawing formyl
group (12) was found to be extremely sensitive to the reaction. Under the standard reaction condition
i.e., using 3 equivalents of TBHP, the expected N-methylated tetrazole was associated with
peresterification at the aldehydic site and less than 10% yield of the product (12a) could be isolated.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
0
Such esterification of aldehydes using TBHP is well documented in the literature. By increasing the
quantity of TBHP to 5 equivalents, the N-methylated peresterified product (12a) was isolated in 53%
yield. The formation of product (12a) supports a radical-mediated reaction pathway. It is well known
that the aryl methyl groups are susceptible to oxidation under TBHP condition.14d,e But in the substrate
(3), the methyl group remained intact and the alkylation took place at the tetrazole NH site. This is
because all the three equivalents of TBHP are used up during this transformation. Interestingly, a
benzylic tetrazole viz. 5-[(4-methylphenyl)]-2H-tetrazole (13), when reacted with TBHP (a) gave N-
methylated product (13′a) with concurrent oxidation at the benzylic position (Scheme 2).
To ascertain nature of the mechanism, when a reaction of 5-phenyl-2H-tetrazole (1) with TBHP (a)
was performed in the presence of a radical quencher 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO)
2
(
b) (2 equiv) under an identical reaction condition, only traces (9%) of N -methylated tetrazole (1a)
was Isolated. However, the formation of a O-methylated TEMPO adduct (ab) could be detected by
HRMS analysis of the reaction mixture (Scheme 3A). This trapping experiment confirms the
generation of a methyl radical from TBHP in the medium. The use of cumene peroxide (c) in lieu of
tert-butyl hydroperoxide (TBHP) may provide either a methylated tetrazole (1a) or a phenylated
tetrazole (1n) (Scheme 3B). Interestingly, the treatment of cumene peroxide (c) with 5-phenyl-2H-
2
tetrazole (1) provided an equimolar mixture of N -methylated product (1a) and acetophenone (c′′)
2
without giving any trace of N -phenylated product (1n) (Scheme 3B). This observation suggests that
the cleavage of a methyl radical from the intermediate 2-phenyl-2-propoxy radical is more favorable as
2
1
it generates a stable secondary benzylic radical. On the other hand, cleavage leading to a phenyl
radical would leave behind a less stable isopropoxy radical, which is unfavorable. Next, a reaction of
5
-phenyl-2H-tetrazole (1) was carried out with another radical scavenger 1,1-diphenylethylene (DPE)
(d) (Scheme 3C).The reaction provided a 1,1-diphenyl-2-(5-phenyl-2H-tetrazol-2-yl)ethan-1-ol (1d) in
0% isolated yield. Thereby confirming the generation of nitrogen centered radical from tetrazole
during the reaction.
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 3. Control Experiments to Confirm the Radical Nature of the Reaction
N
NH
N
TEMPO (b) (2 equiv)
Bu NI (20 mol %)
4
N
H C
O
CH3
3
OH
+
H C
3
N
O
(A)
CH3
CH CN (2 mL)
3
(3 equiv)
100 °C, 8 h
detected in
HRMS
(
1)
(a)
(ab)
Ph
0
1
2
3
4
5
6
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CH3
OH
O
N
N
N N
CH3
CH3
N
N
N
N
O
CH3
standard
condition
+
+
(B)
(
1) +
(c)
(1a, 42%) (1n, 00%) (c'', 42%)
N
NH
Ph
Ph
N
N
Bu4NI (20 mol %)
TBHP (3 equiv)
Ph CH3CN (2 mL)
N
N
CH2
OH
+
N
N
(C)
Ph
100 °C, 8 h
(
1) (d)
(1d, 60%)
In order to understand the origin of regioselectivity in tetrazole, computations have been performed
at DFT level. A preliminary potential energy surface (PES) scan calculations by varying the
o
N=CCC dihedral angle of phenyl tetrazole in the increments of 10 revealed a planar structure as
minima for both the isomeric tetrazoles 5-phenyl-2H-tetrazole (1) and 5-phenyl-1H-tetrazole (1x) as
well as their corresponding radical isomers (1′ and 1x′) (Figure 2a).22a Indeed, the generation of
2
1
radicals from N -H-tetrazole (1) and N -H-tetrazole (1x) were expected to give two distinguishable N-
centered radicals (1′) and (1x′) via homolytic cleavage of NH bonds. However, both of these lead to
the same tetrazole radical (1′), which was basically a -radical (indistinguishable) (Figure 2). This was
further confirmed by inspecting the spin density and singly occupied molecular orbital (SOMO) (vide
infra) [(Figure 2 (d)]. The scan showed maxima at 90 degrees for all the three species viz. (1), (1x) and
the radical (1′), and the rotational energy barriers were estimated to be 5.4, 3.6 and 15.6 kcal/mol,
respectively. The higher rotational barrier about N=CCC for radical (1′) also favor a coplanar
orientation of the tetrazole ring relative to the phenyl ring (Figure 2). The true minima for each species
have been optimized based on the PES scan calculations, and the resulting structures were further used
22b
for the estimation of bond dissociation energies (BDE). . The NH BDE value corresponding to
homolytic bond scission was found to be 97.2 and 99.5 kcal/mol for (1x) and (1), respectively.
Presumably, the steric release between NH (tetrazole) and the ortho CH (phenyl) in (1x) could be
responsible for lowering in BDE (Figure 2b).
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1
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Figure 2. (a) Potential Energy Surfaces (PES) of 1, 1x and 1′; (b)
Bond Dissociation Energy (BDEs) of 1 and 1x (in kcal/mol); (c) Spin
density and (d) Singly Occupied Molecular Orbital (SOMO) of the
radical 1′ (isovalue 0.05). (All the computations have been
performed at (U)B3LYP/cc-pVTZ level of theory).
In order to obtain further insights into regioselectivity, spin densities have been inspected for the N-
centered radicals 1′ (Figure 2c). The spin densities in the radicals also confirmed that the spin is
delocalized over the -orbitals. Interestingly, the spin density was found to be more localized at the N2-
1
centered radical (1′) (0.22) compared to the N -centered radical (1x') (-0.03) (Figure 2c). Once again,
the SOMO of the tetrazolyl radical (1′) confirmed the -radical character of it (Figure 2d). The larger
2
1
spin density accounts for the higher reactivity at the N -site than at the N -in tetrazole. This could be
2
one of the reasons for the regioselective product formation at the N position.
2
1
Apart from spin density (Figure 2c), the regioselectivity at N -tetrazolyl (1′) compared to N -
tetrazolyl (1x′) can also be explained on the basis of activation barriers for the reactions. In this regard,
1
2
the transition states have been computed for the alkylation reaction with TBHP at N - and N -positions
1
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of the tetrazolyl radical (1′). Computations predicted a barrier of 38.0 kcal/mol for the N -methylation,
2
2
whereas for the N -methylation it is 32.6 kcal/mol. Further, the N -methylated product (1a) is both
1
kinetically and thermodynamically more favored than the N -methylated product (1xa) by 5.4 and 6.1
2
kcal/mol, respectively (Figure 3, Table 2). The lower energy barrier for N -methylation of (1′) is due to
0
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0
marginal entropy preference as well as lower enthalpy contribution, which is also consistent with its
2
2
positive spin density value (0.22) at the N -center (Figure 3). The thermodynamic stability of the N -
methylated product can be due to the release of the steric factor arising between the methyl group and
the phenyl CH at the ortho position.
1
2
Figure 3. Energy profile in the N - and N -methylation of tetrazole radical (1′) with TBHP (All the reactants, products and transition
states have been optimized at (U) B3LYP/cc-pVTZ level of theory).
After demonstrating the compatibility of a variety of aryl and alkyl tetrazoles and understanding the
2
N -regioselectivity, other heterocycles possessing NH sites such as pyrrole (14), indole (15),
benzimidazole (16) and benzotriazole (17) were tested (Scheme 2). All these azoles failed to give any
N-methylated products even in a trace. To understand the failure behind N-methylation for these N-
2
heterocycles (1417) and N -regioselectivity of tetrazole (1), it is essential to understand the detailed
mechanism of N-methylation.
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Scheme 4. Proposed Mechanism for NMethylation of Aryl Tetrazole
1
/ I
2 2
H3C
O
(
1')
CH3
OH
N
N
N
N
H C
CH3
3
N
N
N
t
H
H C
3
2
x BuOOH
O
N
Ph
Ph
OH
(
a)
(1)
(
1a)
H C
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
methyl
-

I
tBuO
tBuOO
H O
2
scission
CH3
N
CH3
CH3
CH3
O
CH3
CH3
N
N
(
a')
N
O
O
tBuOH
Ph
O H
tBuOOH
(1')
(a)
H

Initially, the oxidation of iodide (I ) by TBHP (a) afforded a tert-butoxyl radical, iodine and a
hydroxyl anion (Scheme 4, red arrows). The in situ generated iodine reacts with another molecule of
TBHP and hydroxyl ion to generate a tert-butylperoxy radical and a molecule of water (Scheme 4,
2
3
green arrows). Any one of these radicals can abstract a hydrogen atom from the tetrazole NH (1), to
provide a persistent nitrogen-centered radical (1′). In order to obtain additional insights, computations
have been performed for the H-abstraction reactions in creating NCR from the 5-phenyl-2H-tetrazole
(1) and 5-phenyl-1H-tetrazole (1x) using iodine atom and tert-butoxy radical. Based on the results, we
predicted a very low barrier for the H-abstraction by tert-butoxyl radical (1.9 kcal/mol) in the case of
2
4
(
1) (Figure S5). Based on the barriers, it is very clear that the hydrogen abstraction is most likely
happened through the tert-butyloxy radical as indicated in the Scheme 4 (See computational details in
the SI-Figure S5). The concerted reaction between the tetrazolyl radical (1′) with TBHP led to a N-
methylated product (1a) along with the formation of a molecule of acetone and an OH radical. Apart
from this, possible concerted mechanism between the tetrazolyl radical and TBHP in the regioselective
methylation, an alternative pathway through -methyl scission from the tert-butoxyl radical (a′)
leading to the fragments acetone and methyl radical, followed by a radical recombination step to the
regioselective product has also been considered (Scheme 4). The barrier for such fragmentation of tert-
butoxyl radical has been estimated to be 11.8 kcal/mol (Figure S7). However, our attempts in locating
the corresponding transition states for the recombination step or a conceted “-methyl scission–radical
coupling” reaction were unsuccessful. The OH radical so generated may abstract a proton from the
tetrazole to generate a tetrazolyl radical (1′), which may participate in the further reaction (Scheme 4,
magenta arrow).
In yet another control experiment, TBHP was treated with TEMPO (in the absence of TBAI) in
13
CD CN under an identical reaction conditions in a sealed tube. The C NMR of the crude reaction
3
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mixture confirmed the generation of a TEMPO methyl adduct (ab, Scheme S1) and acetone which was
ascertained by the appearance of a carbonyl signals at 210.4 ppm. Thus, instead of a tetrazole radical
(
1′) the persistant radical TEMPO can also abstact a CH group from the TBHP either via a concerted
3
fashion (black arrows) or via -methyl scission pathway (in the gray rectangle box). Thus, we
0
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9
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1
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
concluded that both the concerted reaction between NCR and the TBHP, as well as the radical
t
combination between the NCR and methyl radical formed through a -methyl scission of BuO/ tert-
butoxyl radical (in the grey rectangular) might equally be plausible pathways (Scheme 4). Furthermore,
the factors such as lower barrier (kinetic favourability), higher spin density (higher reactivity) and less
2
steric factor (thermodynamic favourability) lead to higher regioselectivity in the N -alkylation.
2
Having understood the regioselective N -methylation in aryl tetrazoles the next objective is to find
out the reason for the unsuccessful N- methylation for azoles (1417) (Scheme 2). The spin density,
activation barriers and thermodynamic stability of the products for all these N-heterocycles (1417)
were calculated at (U)B3LYP/cc-pVTZ level of theory. Based on the calculations, we concluded that
all the three factors viz. high electron spin density around the nitrogen atom, lower activation barrier
and higher thermodynamic stability of the products were found to be responsible for the N-alkylation.
A negative spin density of -0.13 at the nitrogen center for the pyrrolyl radical (14′) suggests a complete

delocalization of radical electron, which enhances the stability and lowers the reactivity.25a-c Despite
having a moderately positive spin density values of 0.27, 0.13/0.42, and 0.20/0.47, at different nitrogen
centers for the N-centered indolyl (15′), benzimidazolyl (16′), and benzotriazolyl (17′) radicals,
respectively (Figure 4). The reactions failed in all these cases. Presumably, the delocalization of the
spin (or the radical character in the fused ring system) along with a higher reaction barrier may hinder
the reactivity in all these cases. In this regard, we compared the activation barriers for the N-
methylation of all these species have also been estimated computationally (Table 2).
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
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5
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5
5
5
5
5
5
5
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 4. Spin densities and SOMO of various azole radicals 14′18′ (Computations are performed at (U)B3LYP/cc-pVTZ level of
theory; The MOs are rendered at an isovalue 0.05).
A high activation barrier of 51.1 and 42.7 kcal/mol, respectively were computed for indolyl (15′)
2
and benzimidazolyl (16′) radicals compared to a barrier of 32.6 kcal/mol for N -tetrazolyl radical (1′),
which could be the reason behind their reluctance to participate in the reaction. As can be seen from
Table 2, all the anticipated products 14a17a showed higher stability relative to their respective
reactants indicating thermodynamically favorable reactions. In spite of favorable spin density 0.20 and
high thermodynamic stability (-53.3), benzotriazolyl radical (17′) failed to react under the present
reaction condition, which can be due to higher activation barrier (35.2 kcal/mol) compared to N2-
tetrazolyl (1′) (32.6 kcal/mol). Interestingly, by carrying out the reaction at a higher temperature (120
oC) and high catalyst loading (30 mol %) leads to 42% of the product (17a). A radical-mediated
oxidative imidation of ketones with saccharin (18) has been achieved using a combination of TBHP
2
5d
and Bu NI. A higher positive spin density value 0.73 of saccharin encouraged us to test the
4
feasibility of similar N-methylation on saccharin (18). Interestingly N-methylation of saccharin (18)
(Scheme 2) could be accomplished in 68% yield under the standard reaction condition. For this
reaction, obtaining the kinetic barrier through the location transition state failed even after multiple
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
attempts. However, the larger spin density value (0.73) at the N-centre of saccharin radical (18′) and
the inspection of its SOMO confirmed a more localization of the radical character at the N-center that
can be attributed to its higher reactivity.
Table 2. Computed thermodynamic and kinetic parameters corresponding to the N-methylation
reactions using TBHP for the various N-heterocycles.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
reactant
produc
t
thermodynamic
parametersa,b
kinetic parametersa,b,c
relativ
Go
G‡
H‡
S‡
e
E
a
energy
52.7
(
1′)–N2
(1′)–N1
14′)
(15′)
(1a)
57.6
51.2
47.0
43.3
51.5
57.5
61.0
32.6
38.0
50.3
51.1
42.7
35.2
-
42.2
48.0
60.1
61.9
52.9
45.7
-
32.9
38.3
50.7
51.6
43.1
35.4
-
31.0
32.6
31.7
34.6
32.9
34.4
-
(1xa)
(14a)
(15a)
(16a)
(17a)
(18a)
46.6
42.0
38.9
47.3
53.3
50.9
(
(16′)
(17′)
(18′)
aThe thermodynamic (between products and reactants) and kinetic (between transition states and the reactants)
b
parameters, were calculated at (U)B3LYP/cc-pVTZ level of theory; All the energy values are expressed in kcal/mol;
cS‡ values are expressed in cal/mol.K.
So far, we have delineated the N-methylating capability of commercially available tert-butyl
hydroperoxide as the methyl source. Unfortunately, the higher alkyl analogs of similar reagents for
ethylation, propylation etc. are neither commercially available nor they can be easily synthesized. One
of the reagents, 2-hydroperoxy-2-methylpentane (e) is commercially available, which can be the
source of both methyl and propyl radicals. Assuming similar stability of their corresponding alkyl
(methyl or propyl) radicals there is 2/3rd probability of methylation and 1/3rd probability of
propylation (Scheme 5). Can this reagent deliver regioselective propylation (if the radical stability is
higher than the methyl radical) under the present reaction condition? When 5-phenyl-2H-tetrazole (1)
was treated with 2-hydroperoxy-2-methylpentane (e) in lieu of TBHP under an otherwise identical
condition provided both N-methylated (1a, 20%) and N-propylated (1e, 43%) products (Scheme 5).
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Scheme 5. Regioselective Alkylation using Unsymmetrical Peroxidea,b
H3C CH3
CH3
OH
N N
N
N
CH3
H3C
O
(e)
Bu4NI
20 mol %)
N
N
N
N
(
+
N
+
N
8 h, 100 o
CH CN
C
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
H
3
N
(
1)
(
1a, 20%)
(1e, 43%)
aReaction conditions: 5-phenyl-2H-tetrazole (1) (1
mmol), Bu NI (20 mol %) and 2-hydroperoxy-2-
4
methylpentane (e) (3 equiv) at 100 °C in CH
under degassed condition. Isolated yields after 8 h.
3
CN (2 mL)
b
The success of this N-alkylation reaction is in general dependent on the generation of nitrogen
centered radicals (NCR), as well as alkyl radicals. The higher homologs of alkyl radicals can be
generated via the homolytic cleavage of a diacyl peroxide followed by the extrusion of carbon dioxide
(CO2).18a-g The long-chain N-alkylation of tetrazoles could be achieved by minor modification of the
just established methylation protocol (Scheme 2). When the reaction was carried out using 1
equivalent of diacyl peroxide i.e., dihexanoyl peroxide (f), it provided 56% yield of (1f) (Scheme 6).
However, the yield improved up to 74% using two equivalents of the peroxide (f). Many of the
diacylperoxides are commercially not available and can be prepared by treating alkyl carboxylic acids
2
6
with DCC, H O , DMAP in methylene chloride. It would be advantageous if the same can be
2
2
generated in situ. Thus, in a one-pot strategy all diacyl peroxide precursors (hexanoic acid, DCC,
H O , DMAP), tetrazole and TBAI were added in a 1:1 mixture of DCM and CH CN and the reaction
2
2
3
was allowed to proceed. The reaction did not give any trace of the N-alkylated product (1f). In another
approach initially diacyl peroxide i.e., dihexanoyl peroxide (f) was generated in situ via a DCC
mediated dehydrative condensation with hydrogen peroxide, which was used directly after simple
filtration (without further purification). It leads to the formation of product 2-pentyl-5-phenyl-2H-
tetrazole (1f) in 61% yield, which is 13% lower than when pure isolated peroxide (f) was used. Thus,
we have used pure isolated diacylperoxides throughout the reaction. After few optimization reactions,
it was found that the use of hexanoic peroxyanhydride (f) (2 equiv) and Bu NI (20 mol %) was
4
2
necessary to achieve a decent yield (74%) of the N -alkylation (pentanylation) of aryl tetrazole (1f).
The results of various other alkylations are portrayed in Scheme 6.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 6. Substrate Scope for N-Alkylation of Aryl Tetrazolesa,b
N
N
N
N
O
N
H
+
Bu NI (20 mol %)
N
R
4
O
R
N
R
O
N
CH CN (2 mL)
3
Ar
Ar
o
O
100 C, 6 h
(
1, 5, 10, 19, 20)
(fi)
(1f1i, 5i, 10i, 19i, 20i)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
N
N
N
N
N
N
N
N
N
N
N
H3C
1f, 56%)c
(
(
H3C
H3C
1f, 74%)
(1g, 75%)
(
1h
, 79%)
d
(
1f, 61%)
N
N
N
N
N
N
N
N
N
N
N
N
(
1i, 80%)
(1i, 73%)
tBu
(10i, 89%)
H C
5i, 84%)
3
F3C
3
H C
H3C
e
(
N
N
N
N
N
N
N
N
O
H3C
O
H3C
H3C
(J, 77%)f
(
19i, 82%)
(20i, 74%)
aReaction conditions: aryl tetrazole (1 mmol), Bu
NI (20

4
mol %) and alkyl diacyl peroxide (2 equiv) at 100 C in
b
CH
3
CN under degassed condition (2 mL). Isolated yield
c
after 6 h. One equivalent of dihexanoyl peroxide was used.
d
In situ generated dihexanoyl peroxide, simply filtered
e
used for the reaction without purification. Isolated yield
reported for 8 mmol (1.17 g) scale. f2-phenylacetic
peroxyanhydride was used as the starting material.
Treatment of alkyl peroxyanhydrides, such as octanoic (g), decanoic (h) and dodecanoic (i) with 5-
2
2
phenyl-2H-tetrazole (1) smoothly afforded their anticipated N -heptanyl (1g, 75%), N -nonyl (1h,
2
7
9%) and N -undecanyl (1i, 80%) products (Scheme 6). To further explore the synthetic potential of
2
this peroxyanhydrides mediated regioselective N -alkylation strategy, a variety of substituted aryl
tetrazoles were investigated. Aryl tetrazoles substituted with electron-releasing group on para-position,
namely p-tert-butyl (5), and electron-withdrawing p-CF (10) groups, all successfully provided their
3
2
corresponding N -undecylated products (5i, 84%), and (10i, 89%) in good yields. A 5-(naphthalen-2-
yl)-2H-tetrazole (19) with dodecanoic peroxyanhydride (i) gave the targeted compound (19i) in
synthetically useful yield (82%) (Scheme 6). Further, a meta-methyl substituted tetrazole successfully
2
provide its N -undecanyl product (20i) in 74% yield. Judging from the trends in the yields of all the
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preceding set of substrates in Scheme 6, long chain alkyl peroxyanhydrides delivered higher yields
2
than short chain alkyl peroxyanhydrides. In an attempt to synthesize N -benzylated tetrazole following
a similar strategy, tetrazole (1) was reacted with 2-phenylacetic peroxyanhydride (j), which failed to
give any benzylated product. Under the reaction condition, the 2-phenylacetic peroxyanhydride
decomposed to give a benzyl 2-phenylacetate (J) product (Scheme 6). Such decomposition of 2-
phenylacetic peroxyanhydride (J) is well documented in the literature.27
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
After multiple attempts, secondary and tertiary alkyl diacyl peroxides could not be prepared as they
tend to decompose even under extreme care.28 On the other hand, Hongli Bao group have used
o
o
secondary and tertiary alkyl peresters as 2 or 3 alkyl radical synthons in various systems instead of
peroxides, as they are relatively easier to synthesize.18c-g Interestingly, the reaction between 5-phenyl-
2
H-tetrazole (1) and tert-butyl 2-ethylhexaneperoxoate (k) under the optimized reaction condition
2
smoothly provided secondary N -alkylated tetrazole (1k). To demonstrate the versatility of this
2
regioselective N -alkylation a variety of tetrazoles were tested. As can be seen from Scheme 7, aryl
tetrazoles bearing electron-donating (p-OMe) (4) and electron-withdrawing [o-Cl (9), p-CF (10), and
3
p-NO (11)] substituents afforded their corresponding products (4k, 71%), (9k, 73%), (10k, 82%), and
2
(11k, 85%) in good to excellent yields. Apart from aryl tetrazoles, a thiophene attached tetrazole i.e.,
2
5-(thiophen-2-yl)-2H-tetrazole (21) also underwent N -alkylation with perester (k) giving the
corresponding product (21k) in 74% yield (Scheme 7). After regioselective installation of a secondary
alkyl group onto aryl tetrazoles, we wish to install tertiary alkyl groups. Under the identical reaction
conditions treatment of tert-butyl-2,2-dimethylpropaneperoxoate (l) with phenyl tetrazole (1) furnished
2
the corresponding N -t-butylated product (1l) in 87% yield. Two other tetrazoles, one possessing an
EDG, p-OMe (4) and another an EWG group p-NO (11), both successfully underwent t-butylation at
2
2
the N -position giving products (4l) and (11l) in 81% and 92% yields, respectively. Following this
strategy, a tricyclic adamantyl group was successfully incorporated into a variety of aryl tetrazoles (1),
2
(
10), and (11) providing tertiary N -adamantyl tetrazoles (1m, 85%), (10m, 89%), and (11m, 90%),
respectively (Scheme 7).
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 7. Substrate Scope for N-Secondary and Tertiary Alkylation of Aryl Tetrazolesa,b
N
N
N
N
O
Bu4NI (20 mol %)
N
H
N
R
O
CH3
CH
N
R
O
CH CN (2 mL)
N
3
Ar
+
o
Ar
3
CH3
100 C, 6 h
(1, 4, 911, 21)
(km)
(1k, 4k, 9k11k, 21k)
(
1l, 4l, 11l, 1m, 10m, 11m)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H3C
H3C
H3C
N
N
N
N
N
N
Cl
N
N
N
N
N
N
H3CO
H3C
H3C
H3C
(
1k, 77%)
(4k, 71%)
(9k, 73% )
H3C
H3C
H3C
N
N
N
N
N
N
N
N
N
N
N
N
S
F3C
O2N
3
H C
H3C
H3C
(10k, 82%)
(11k, 85%)
(21k, 74%)
c
(
11k, 74%)
N
N
N
CH3
CH3
CH3
N
CH3
CH3
CH3
N
N
N
N
CH3
CH3
CH3
N
N
N
N
H3CO
O2N
(
1l, 87%)
(4l, 81%)
(11l, 92%)
N
N
N
N
N
N
N
N
N
N
N
N
F3C
10m
O2N
(11m, 90%)
(1m, 85%)
(
, 89%)
aReaction conditions: aryl tetrazole (1 mmol), Bu
NI (20

4
mol %) and tert-butyl alkylperoxoate (2 equiv) at 100 C in
b
CH
3
CN under degassed condition (2 mL). Isolated yield
c
after 6 h. Isolated yield reported for 8 mmol (1.53 g) scale.
A Pd(II) catalyzed ortho-arylation of directing arene has been successfully demonstrated using
2
9
aroyl peroxyanhydride via a decarboxylative radical pathway. After the efficacious alkylation using
alkyl peroxyanhydrides ((RCO) OO) (Scheme 6) and taking cues from the ortho-arylation, we were
2
2
encouraged to attempt various N -arylation using a number of aroyl peroxyanhydrides. Employing
benzoic peroxyanhydride (n) as the aryl surrogate, its reaction with 5-phenyl-2H-tetrazole (1) under
2
the optimized reaction condition afforded the N -phenyl substituted tetrazole (1n) in a satisfactory
yield of 61% (Scheme 8). Similarly, aryl tetrazoles bearing various electron-donating p-CH (3), m-
3
OMe (6) and electron-withdrawing p-Br (7), o-Cl (9), p-CF (10), and p-NO (11) groups, all lead to
3
2
2
their regioselective N -phenylation products (3n, 58%), (6n, 54%), (7n, 62%), (9n, 56%), (10n, 65%),
and (11n, 67%) in modest yields, when treated with benzoic peroxyanhydride (n) (Scheme 8). Besides,
aryl tetrazoles, 5-(thiophen-2-yl)-2H-tetrazole (21) also smoothly underwent coupling with benzoic
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peroxyanhydride (n) exhibiting good compatibility providing the product (21n) in 63% yield. A di-
substituted 5-(2-bromo-4-methylphenyl)-2H-tetrazole (22) reacted successfully with benzoic
peroxyanhydride (n) giving its N-phenylated tetrazole (22n).
Scheme 8. Substrate Scope for N-Arylation of
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Aryl Tetrazolesa,b
N
N
N
N
O
N
H
Bu NI (20 mol %)
N
4
Ar
N
O
Ar
N
1Ar
(
CH3CN (2 mL)
1Ar
Ar
O
+
o
100 C, 6 h
O
1, 3, 6, 7,
11, 21, 22)
(1n, 3n, 6n, 7n, 9n11n,
21n, 22n, 1o1s)
(
ns)
9
N
N
N
N
N
N
N
N
N
N
N
N
(
(
1n, 61%)
(3n, 58%)
(6n, 54%)
H3C
1n, 54%)c
OCH3
N
N
N
N
N
N
N
N
Cl
N
N
N
N
Br
(7n, 62%)
(9n, 56%) F3C
(10n, 65%)
N
N
N
N
N
N
N
N
N
N
N
N
Br
S
N
(
11n, 67%)
(21n, 63%)
(22n, 58%)
O2N
H C
3
H3C
N
N
N
N
N
N
N
N
N
OCH3
N
C2H5
N
N
(1q, 57%)
(
1o, 54%)
(1p, 53%)
N
N
N
N
N
N
F
Br
N
(1r, 60%)
(1s, 61%)
(1s, CCDC 1897066)
aReaction conditions: aryl tetrazole (1 mmol), Bu
NI (20

4
mol %) and diaryl acyl peroxide (2 equiv) at 100 C in
b
CH
3
CN under degassed condition (2 mL). Isolated yield
c
after 6 h. Isolated yield reported for 10 mmol (1.46 g
scale).
To further demonstrate the synthetic utility of
this protocol, a diverse array of aryl peroxyanhydrides (os) were examined. Benzoic
peroxyanhydrides bearing electron-releasing groups, such as o-methyl (o), p-methoxy (p), and p-ethyl
2
(
q) all reacted competently with 5-phenyl-2H-tetrazole (1), furnishing their respective N -arylated
products (1o, 54%) (1p, 53%) and (1q, 57%) in modest yields. The scope of this decarboxylative N-
arylation reaction was further extended to benzoic peroxyanhydrides possessing electron-withdrawing
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halogen functionality such as p-F (r) and p-Br (s) both lead to their respective arylation products (1r)
and (1s) in 60 and 61% yields (Scheme 8). The compound (1s) was crystallized from a supersaturated
2
solution of chloroform by the slow evaporation method. Here also, the N regioselectivity of the
arylation product (1s) was unequivocally confirmed by X-ray crystallographic analysis (Scheme 8)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(see the Supporting Information). As can be seen from Scheme 8, no absolute correlation could be
drawn from the yields of the product obtained with the presence of either electron-donating or
electron-withdrawing groups present in any of the reacting partners.
2
To gain insight into the reaction pathway of this N -regioselective alkylation and arylation, a series
of control experiments were conducted. At first, to ascertain the nature of the mechanism, a reaction
between 5-phenyl-2H-tetrazole (1) and dodecanoic peroxyanhydride (i) under the standard condition
was performed in the presence of radical scavenger 2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO,
2
1
.2 equiv). The TEMPO-undecanyl adduct (bi, 72%) along with 15% of the N -undecanylated product
(1i) was isolated {Scheme 9 (D)}. This result confirms the radical nature of the reaction.
Scheme 9. Control Experiments to Confirm the Radical Nature of the Reaction
C11H23
TEMPO (b)
N NH C11H23
N N
(2 equiv)
C11H23
O
N
N
N
N
Bu NI (2 mmol)
N O
4
O
O
+
+
(D)
CH3CN (5 mL)
100 °C, 4 h
O
C11H23
(
1)
(i)
(1i, 15%)
(bi, 72%)


In general, the oxidation of (I ) with benzoyl peroxide (n) leads to a benzoate anion (PhCOO ) and a
phenyl hypoiodate (PhCOOI).30a,b To check the active role of benzoate anion (PhCOO) and phenyl
hypoiodate (PhCOOI) in the reaction, four different reactions were carried out. A reaction of 5-phenyl-
2
H-tetrazole (1), with a stoichiometric amount of benzoate anion (sodium benzoate) and iodine in
DMSO (in CH CN sodium benzoate is insoluble) failed to provide the desired product (1n) thereby
3
suggesting benzoate ion not to be the active species in the reaction {Scheme 10 (E)}. However,
reactions between the in situ generated phenyl hypoiodate (PhCOOI) or acyl hypoiodate
3
1a-d
(
C H COOI)
upon treatment with 5-phenyl-2H-tetrazole (1) provided the phenylated product
1
1
23
(1n) and undecylated product (1i) {Scheme 10 (FH)} thereby implying the active involvement of
hypoiodate species.
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Scheme 10. Control Experiments to Confirm Involvement of Hypoiodate Species
Ph
N NH
N N
O
N
N
N
N
Na
DMSO)
+
I2
+
(E)
O
o
1
00 C, 12 h
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
t)
(
1)
(1n, 00%)
Ph
N N
COOAg
COOI
N
N
I2 (1.0 equiv)
(1) CH CN)
3
+
(F)
o
CCl (2 mL)
100 C, 5 h
4
(u)
(V)
(1n, 42%)
N N
Ph
O
OH
O
OI
NaI (1.1 equiv)
1
) CH CN
N
N
t
(
3
BuOCl (1.1 equiv)
+
o
(G)
rt to 100 C
CH CN (4 mL)
3
6
h
rt, 20 mins
(
W)
(V)
(
1n, 53%)
C11H23
N N
tBuOCl (1.1 equiv)
O
OH
O
OI
N
N
NaI (1.1 equiv)
(1) CH3CN
+
o
(H)
C11H23 CH CN (4 mL)
C11H23 rt to 100 C
3
rt, 20 mins
6 h
(
y)
(z)
(1i, 53%)
Naked phenyl radicals are not stable enough to participate in this reaction. It is possible that the
reaction may proceed either via a decarbonylation or a decarboxylation path. Accordingly, two
additional controlled experiments were carried out to ascertain the mechanistic path Failure to detect
carbon monoxide by PdCl -PMA strip test rule out any decarbonylation path (Figure S1, see the
2
Supporting Information).31e,f On the other hand, the evolution of CO as confirmed by lime water test
2
(Figure S2, see the Supporting Information) suggest a decarboxylation path. To reassertain, the
possible decarboxylation path, 5-(m-tolyl)-2H-tetrazole (20) was treated with benzoic peroxyanhydride
(n) and Bu NI at a lower temperature (80 °C). After 4 h the reaction was stopped and an intermediate
4
(
20n′) was isolated in 73% yield, which was confirmed to be 5-(m-tolyl)-2H-tetrazol-2-yl benzoate
20n′). When the isolated product (20n′) was further heated at 100 °C in acetonitrile for 3 h, it
(
provided the product 2-phenyl-5-(m-tolyl)-2H-tetrazole (20n) in 51% yield with concurrent evolution
of CO thereby confirming a decarboxylative path {Scheme 11 (I)}. Based on the results of control
2
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2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
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5
5
5
5
5
5
5
5
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experiments (Schemes 911) and cues from the literature,30,31 a plausible mechanism has been
proposed as depicted in Scheme 12.
Scheme 11. Control Experiments to Confirm the Decarboxylation Path
Ph
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
Ph
Ph
O
N NH
N N
N N
O
O
N
N
N
N
N
N
Bu NI (20 mmol)
4
CH CN
3
+
O
(
I)
CH CN (20 mL)
3
100 °C, 3 h
O
80 °C, 4 h
Ph
CH3 (n)
H C
3
H C
3
(
20)
(20n', 73%)
(20n, 51%)
So far as the phenylation using benzoyl peroxide is concerned, a mechanism as shown in Scheme

1
2 is proposed. The oxidation of iodide (I ) by benzoyl peroxide (n) afforded a benzoate anion (IV)
and a hypoiodate species PhCOOI (V). Formation of a similar intermediate has been proposed by
Tokumaru, K.30a Subsequently, the in situ generated PhCOOI (V) collapse to PhCOO (VI) and iodine
radicals. Similar homolytic cleavage is well documented in the literature32 The iodine radical then
abstract the tetrazole NH to furnish a persistent nitrogen-centered radical (20′) and releasing a
molecule of HI. The liberated HI reacts with the benzoate anion (IV) to provide benzoic acid (w) as the

byproduct, liberating the I for the subsequent cycle. The coupling between the tetrazole nitrogen
radical (20′) and a PhCOO radical (VI) would form a 5-(m-tolyl)-2H-tetrazol-2-yl benzoate
intermediate (20n'). When the reaction was carried out at a lower temperature (80 °C) it was possible
to isolate and characterize the intermediate (20n'). But at a higher temperature (100 °C) the
intermediate (20n') undergoes extrusion of carbon dioxide leading to the formation of product (20n).
For understanding whether this observation is controlled by the kinetic or thermodynamic factors,
computations have been attempted at the estimation of barriers. However, the transition state could not
be located even after several attempts. On calculating the energy difference between the product of
decarboxylation reaction with respect to the intermediate (20n'), we estimated a value of -57.4
kcal/mol indicating a high thermodynamic favorability of the product (20n).
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Scheme 12. Proposed Mechanism for Radical Induced NArylation of Aryl Tetrazole
O
Ph
O O
(
n)
O
Ph
OH
O
I
I
Ph
O
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(v)
Ph
O
Ph
O
O
O
(iv)
Ph
O
(
w)
(
vi)
I
HI
H
N
N
N
N
(
20)
H C
H C
3
N
N
O
+
Ph
N
N
O
3
20')
(vi)
(
H C
3
H C
3
N
N
N
N
N
N
O
N
O
Ph
N
Ph
(
Isolated, (20n'))
CO2
(20n)
In this manuscript, we have provided a solution to the long-standing problem of regioselective N2-
alkylation, and arylation of tetrazoles, which is otherwise associated with the formation of a mixture of
1
2
N and N -isomers. This is achieved via the generation of nitrogen centered radical (NCR) in the
presence of iodides and organic peroxides/peresters. Here, the organic peroxides/peresters serve the
dual role of oxidants and alkyl or aryl sources. While tert-butyl hydroperoxide (TBHP) is the source of
methyl group, alkyl diacyl peroxides as the primary alkyl, alkyl peresters as the secondary and tertiary
alkyls and aryl diacyl peroxides as the arylating sources. These reactions proceed under a metal-free
condition without the requirement of any pre-functionalization. Based on the control experiments
carried out a concerted radical mechanism has been proposed. Barring an aldehyde functionality that
forms a perester with peroxide several other functional groups are well-tolerated giving products in
2
modest to good yields. The experimental findings, in particular the regioselectivity in the N -alkylation
and the proposed mechanism have been confirmed by several control experiments, and also supported
by the computations. Through DFT calculations, the estimated spin density, activation barriers for the
reactions and thermodynamic parameters of the reactants and products clearly demonstrated the
involvement of both kinetic and thermodynamic control in the regioselectivity.
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EXPERIMENTAL SECTION
General information:
All the reagents were commercial grade and purified according to the established procedures. All
the reactions were carried out in oven-dried glassware under a degassed atmosphere. Highest
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
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8
9
0
1
2
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9
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2
3
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
commercial quality reagents were purchased and were used without further purification unless
otherwise stated. Aryl tetrazoles were prepared according to the literature procedure.33a,b Reactions
were monitored by thin layer chromatography (TLC) on a 0.25 mm silica gel plates (60F ) visualized
2
54
under UV illumination at 254 nm. Organic extracts were dried over anhydrous sodium sulfate
Na SO ). Solvents were removed using a rotary evaporator under reduced pressure. Column
(
2
4
chromatography was performed to purify the crude product on silica gel 60120 mesh using a mixture
1
13
1
of hexane and ethyl acetate as eluent. All the isolated compounds were characterized by H, C{ H}
NMR and IR spectroscopic (HRMS-spectrometric) techniques. NMR spectra for all the samples were
1
13
1
recorded in deuterochloroform (CDCl ) or deuterated dimethyl sulfoxide (DMSO-d6). H, C{ H}
3
were recorded in 600 (151) or 400 (101) MHz spectrometer and were calibrated using
1
13
tetramethylsilane or residual undeuterated solvent for H NMR, deuterochloroform for C NMR as an
1
13
internal reference {Si(CH ) : 0.00 ppm or CHCl : 7.26 ppm for H NMR, 77.16 ppm for C NMR or
3
4
3
1
(
CH ) SO: 2.50 ppm for H NMR, 39.52 ppm for 13C NMR}. 19F NMR was calibrated using
3
2
hexafluorobenzene as internal standard. The chemical shifts are quoted in δ units, parts per million
1
(
ppm). H NMR data is represented as follows: Chemical shift, multiplicity (s = singlet, d = doublet, t
=
triplet, q = quartet, p = pentat, m = multiplet, br = broad, dd = doublet of doublet, tt = triplet of
triplet), integration and coupling constant(s) J in hertz (Hz). High resolution mass spectra (HRMS)
were recorded on a mass spectrometer using electrospray ionization-time of flight (ESI-TOF)
reflection experiments. FT-IR spectra were recorded in KBr or neat and reported in frequency of
-1
absorption (cm ). Compounds (7a) and (1s) both were crystallized from a supersaturated solution of
chloroform by the slow evaporation method. [Caution: peroxides are potentially explosive, so any
peroxide involved reaction (as product or substrate) should be carried out with precautions!]
Computational Details:
All the geometrical optimization for reactants, products and their corresponding transition states have
been performed at density functional theory with B3LYP34a functional using cc-pVTZ34b,c basis set.
The optimized geometries have been verified to minima/transition state34d,e by frequency calculations
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(
i.e., Zero and one imaginary frequency corresponding to minima and transition state, respectively)and
the energies have been corrected for zero-point energy.34f For obtaining true minima; potential energy
surface scan calculation have been performed by varying the N=CCC dihedral angle at every 10
degrees. Bond dissociation energy (BDE), transition state barrier and spin density calculations have
been performed for the better understanding of regioselectivity. All these calculations were performed
using Gaussian 09 suite of program.34g
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
General Procedure for the Synthesis of Alkyl Diacylperoxide (fh).
These alkyl peroxides can be prepared following the literature procedure.26 However, we have
adopted the following modified procedure: To a 100 mL round bottom flask, the corresponding alkyl
carboxylic acid (hexanoic acid) (1.16 g, 10 mmol, 1 equiv) was charged with an efficient magnetic
stirring bar and diluted with methylene chloride (20 mL). The reaction vessel was immersed into a low
temp bath (-15 °C). Then 1.2 equivalent of hydrogen peroxide (30% aqueous solution) (1.36 g, 1.22
mL) and 4-(dimethylamino)pyridine (0.12 g, 0.1 equiv) were added sequentially. After 15 minutes of
stirring a solution of N,N'-dicyclohexylcarbodiimide (DCC, 2.47 g, 1.2 equiv) in methylene chloride
(25 mL) was added dropwise into the reaction mixture. The resulting mixture was allowed to stir
continuously for 3 h. Then, the crude reaction mixture was directly loaded into a short silica column
and purified using methylene chloride as the eluent to afford 1.52 g of hexanoic peroxyanhydride (f)
(66% yield).
General Procedure for the Synthesis of perester (km).
These alkyl peroxides can be prepared following the literature procedure.18e However, we have
adopted the following modified procedure: To a 100 mL round bottom flask, the corresponding alkyl
carboxylic acid (2-ethylhexanoic acid) (2.88 g, 20 mmol, 1 equiv) was charged with an efficient
magnetic stirring bar and diluted with methylene chloride (25 mL). The reaction vessel was immersed
into a low temp bath (-15 °C). Then 0.1 equivalent of 4-(dimethylamino)pyridine (0.24 g, 2.0 mmol)
and 70% aq TBHP (24 mmol, 1.2 equiv) were added sequentially. After 15 minutes of stirring a
solution of N,N'-dicyclohexylcarbodiimide (3.09 g, 15 mmol, 0.75 equiv) in methylene chloride (25
mL) was added dropwise into the reaction mixture. The resulting mixture was allowed to stir
continuously for 3.5 h. Then, the crude reaction mixture was directly loaded into a short silica column
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and purified using 3% of ethyl acetate in hexane as the eluent to afford tert-butyl 2-
ethylhexaneperoxoate (k) (2.80 g, 65% yield).
General Procedure for the Synthesis of Aryl Diacylperoxide (os).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
9
0
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
These compounds can be prepared following the literature procedure as reported.35a However, we
have adopted the following modified procedure: To a 25 mL round bottom flask hydrogen peroxide
(0.58 mL, 0.57 equiv, 30% aqueous solution) and sodium hydroxide (0.51 g, 1.27 equiv) were added in
an ice bath for 20 minutes with vigorous stirring to generate sodium hydroperoxide. Separately, in
another 100 mL round bottom flask was charged with 4-methoxybenzoyl chloride (1.70 g, 10 mmol,
1.0 equiv) and diethyl ether (30 mL). Then, the reaction mixture was immersed into a low temperature
ice bath (-10 °C). The generated sodium hydroperoxide was added dropwise to the flask containing 4-
methoxybenzoyl chloride over a period of 20 minutes and was allowed to stir for two hours. The
resulting white precipitate was collected, washed sequentially with water (3 x 10 mL) and diethyl ether
(3 x 10 mL). The solid product was recrystallized from cold acetone and water (1:3 v/v, 10 mL)
provided 2.57 g of 4-methoxybenzoic peroxyanhydride (p) (85% yield).
General Procedure for the Synthesis of 2-Methyl-5-phenyl-2H-tetrazole (1a) from 5-Phenyl-2H-
tetrazole (1).
To an oven-dried Schlenk tube equipped with a magnetic stir bar 5-phenyl-2H-tetrazole (146 mg, 1
mmol, 1.0 equiv), tetrabutylammonium iodide (Bu NI) (74 mg, 20 mol %), acetonitrile (2 mL) and an
4
aqueous solution of TBHP (70%) (a) (411 µL, 3 equiv) was slowly added using a micropipette at room
temperature. The resulting reaction mass was degassed using the freeze-pump-thaw method. Then the
reaction mass was brought to room temperature. Maintaining the inert atmosphere, it was transferred to
an oil bath and the temperature was raised to 100 C from room temperature by increasing the
temperature at the rate of 5 C per minute and maintained for 8 h. The reaction mixture was removed
from the oil bath and cooled to room temperature. The solvent acetonitrile was removed under reduced
pressure. The reaction mixture was admixed with ethyl acetate (3 x 10 mL) and transferred into a
separating funnel. The ethyl acetate layer was washed sequentially with 5% solution of sodium
thiosulphate (2 x 10 mL) and brine solution (1 x 10 mL). The combined organic layer was dried over
anhydrous Na SO , filtered and concentrated in vacuo. After the removal of the solvent, the crude
2
4
product so obtained was purified over a column of silica gel using 5% ethyl acetate in hexane as the
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eluent afforded pure 2-methyl-5-phenyl-2H-tetrazole (1a) (96 mg, yield 60%). The identity and purity
of the product were confirmed by spectroscopic analysis.
General Procedure for the Synthesis of 2-Pentyl-5-phenyl-2H-tetrazole (1f) from 5-Phenyl-2H-
tetrazole (1).
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To an oven-dried Schlenk tube, charged with a stirring bar were added 5-phenyl-2H-tetrazole (1)
(
146 mg, 1 mmol, 1.0 equiv), tetrabutylammonium iodide (Bu NI) (74 mg, 20 mol %), and hexanoic
4
peroxyanhydride (f) (460 mg, 2 mmol, 2 equiv). The reaction mass was degassed using a vacuum
pump. Then dry and degassed acetonitrile (2 mL) was added to the reaction. Maintaining the inert
o
atmosphere, the reaction mixture was heated at 100 C for 6 h. After completion of the reaction. The
reaction mixture was cooled to room temperature. The acetonitrile was removed from the reaction
mixture using a rotary evaporator under reduced pressure. Then, the reaction mass was diluted with
ethyl acetate (3 x 10 mL) and transferred to a separating funnel. The ethyl acetate layer was washed
sequentially with 5% solution of sodium thiosulphate (2 x 10 mL) and brine solution (1 x 10 mL). The
combined organic layer was dried over anhydrous Na SO , filtered and concentrated in vacuo. After
2
4
removal of the solvent, the crude reaction mixture was purified over a column of silica gel using 4%
ethyl acetate in hexane as the eluent afforded pure 2-pentyl-5-phenyl-2H-tetrazole (1f) (160 mg, yield
7
4%). The identity and purity of the product were confirmed by spectroscopic analysis.
General Procedure for the Synthesis of 2-(heptan-3-yl)-5-phenyl-2H-tetrazole (1k) from 5-
Phenyl-2H-tetrazole (1).
To an oven-dried Schlenk tube, charged with a stirring bar were added 5-phenyl-2H-tetrazole (1)
(
146 mg, 1 mmol, 1.0 equiv), tetrabutylammonium iodide (Bu NI) (74 mg, 20 mol %), and tert-butyl
4
2
-ethylhexaneperoxoate (k) (432 mg, 2 mmol, 2 equiv). The reaction mass was degassed using a
vacuum pump. Then dry and degassed acetonitrile (2 mL) was added to the reaction. Maintaining the
inert atmosphere, it was transferred to an oil bath and the temperature was raised to 100 °C from room
temperature by increasing the temperature at the rate of 5 °C per minute and maintained for 6 h. After
completion of the reaction, the reaction mixture was cooled to room temperature. The acetonitrile
solvent was removed from the reaction mixture using a rotary evaporator under reduced pressure.
Then, the reaction mass was admixed with ethyl acetate (2 x 25 mL) and transferred to a separating
funnel. The ethyl acetate layer was washed sequentially with 5% solution of sodium thiosulphate (2 x
30 mL) and brine solution (1 x 20 mL). The combined organic layer was dried over anhydrous
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