Metal-free Cross-Dehydrogenative Coupling of HN-azoles with α-C(sp3)-H Amides via C-H Activation and Its Mechanistic and Application Studies

Article abstract of DOI:10.1021/acs.joc.6b02448

A metal-free one step coupling reaction between various N-azole rings and diverse α-C(sp³)-H containing amides has been developed under oxidative reaction conditions. Commercially available tetrabutyl ammonium iodide (TBAI) in the presence of t

Full text of DOI:10.1021/acs.joc.6b02448

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Article
Metal-free Cross-Dehydrogenative Coupling of HN-azoles with alpha-C(sp3)-
H amides via C-H activation and its Mechanistic and Application studies
Hariprasad Aruri, Umed Singh, Mukesh Kumar, Sumit Sharma, Sravan Kumar Aithagani,
Vivek K Gupta, Serge Mignani, Ram A. Vishwakarma, and Parvinder Pal Singh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02448 • Publication Date (Web): 24 Dec 2016
Downloaded from http://pubs.acs.org on December 25, 2016
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Metalꢀfree CrossꢀDehydrogenative Coupling of HNꢀazoles with αꢀC(sp3)ꢀH
amides via CꢀH activation and its Mechanistic and Application studies
7
Hariprasad Aruri,a Umed Singh,a Mukesh Kumar,a Sumit Sharma,a Sravan Kumar Aithagani,a
Vivek K. Gupta,b Serge Mignani,c Ram A. Vishwakarma,a and Parvinder Pal Singha*
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aMedicinal Chemistry Division, CSIRꢀIndian Institute of Integrative Medicine, Academy of
Scientific and Innovative Research, Canal Road, Jammu, 180001.
bXꢀray Crystallography Laboratory, University of Jammu, Jammu Tawiꢀ180006, India
cUniversité Paris Descartes, PRES Sorbonne Paris Cité, CNRS UMR 860, Laboratoire de Chimie
et de Biochimie Pharmacologiques et Toxicologique, 45, rue des Saints Pères, 75006 Paris,
France
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Abstract
A metalꢀfree one step coupling reaction between various Nꢀazole rings and diverse αꢀ
C(sp3)ꢀH containing amides have been developed under oxidative reaction conditions.
Commercially available tetrabutyl ammonium iodide (TBAI) in the presence of
terbutylhydroperoxide (TBHP), under neat reaction condition, efficiently catalysed the coupling.
Various azole types such as 1Hꢀbenzotriazoles, 1Hꢀ1,2,3ꢀtriazoles, 1Hꢀ1,2,4ꢀtriazoles, 1Hꢀ
tetrazoles, 1Hꢀpyrazoles and 1Hꢀbenzimidazoles and αꢀC(sp3)ꢀH containing amides such as N,Nꢀ
dimethylacetamide, N,Nꢀdimethylbenzamide, Nꢀmethylacetamide, Nꢀmethylbenzamide, Nꢀ
methylpyrrolidine and pyrrolidineꢀ2ꢀone were successfully employed for the coupling. A series
of designed and controlled experiments were also performed in order to study the involvement of
the different intermediates. Based on the evidences, a plausible mechanism is also proposed.
These novel, simple, rapid, attractive and straightforward transformation open the way of the
construction of novel highly functionalized Nꢀazoles via direct covalent NꢀH bond
transformations onto NꢀC bonds. This approach allows to the synthesis of complex molecules
requiring number of steps using classical synthetic ways. In addition, the range of αꢀC(sp3)ꢀH
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containing amide substrates is virtually unlimited highlighting the potential value of this simple
system for the construction of complex heterocyclic molecules such as fused azoles derivatives.
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Introduction:
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CꢀH activation/functionalization methods provide unique and atom economy strategy for
the functionalization and derivatization of sp3, sp2 and sp hybridized bonds.1,2 In the last two
decades, several transitionꢀmetals and metalꢀfree catalytic systems were developed and
successfully employed for such transformation. Among various catalytic systems, TBAI/TBHP
has received significant attention because of its ease availability, economical and versatile redox
potential. This catalytic system has been successful used in the construction of CꢀC, CꢀN, CꢀO
and CꢀS bonds.3ꢀ6 Recently, we have used TBAI/TBHP catalytic system for the activation of αꢀ
C(sp3)ꢀH bond of ethers/thioethers and successfully used for the coupling with azoles.7 More
importantly, activation of αꢀC(sp3)ꢀH bond of amides/amines will be of very high significance
because of their ubiquitous occurrence and their presence in quite all biological systems. Amide
derivatives were associated with broad spectrum of biological activities including, for instance,
anticonvulsant, antituberculosis, antifungal, anticancer, analgesicꢀantiꢀinflammatory etc,
generally coupled with diverse heterocycles.8 According to our knowledge, only one approach is
available for the construction of αꢀNꢀazolylamides, but involved iron catalytic system (Fig. 1).9
As amides are ubiquitously present in both natural and synthetic chemical space for diverse
biological and nonꢀbiological applications.8 Consequently, facile and general methods for their
functionalization are highly required, in order to extend the panel and the diversity of
functionalized amides. While making this manuscript, Lakshman and coꢀworkers also reported a
Ruꢀcatalyzed method for the coupling of HNꢀazoles with αꢀC(sp3)ꢀH bond containing ethers and
also with amides but limited.10 Here, we report metalꢀfree TBAI/TBHP catalyzed method for the
coupling of αꢀC(sp3)ꢀH of amides with azoles via αꢀC(sp3)ꢀH activation with wide and diverse
substrate scope.
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Figure 1. Approaches for functionalization of αꢀC(sp3)ꢀH amides
Results and Discussion:
1HꢀBenzotriazole (1a, Bt) and N,Nꢀdimethylacetamide (2a, DMA) were firstly selected
as a model substrate due to their simple chemical structure. In the first attempt, coupling reaction
was performed in the presence of 2 equivalents of 70% aq. TBHP and 0.1 equivalent of TBAI in
dichloroethane (DCE) as solvent (Table 1, entry a). N1ꢀcoupled product 3a was obtained in an
isolated yield of 48%. In our next attempt, the amount of TBHP was increased to 3 equivalents,
slight improvement in the yield of N1ꢀcoupled product 3a (52%) was observed (Table 1, entry b).
Different solvents such as ethyl acetate (EtOAc), acetonitrile (ACN) didn’t give any
improvement (Table 1, entries cꢀd). Interestingly, when the reaction was performed under neat
condition using DMA 2a as a solvent, 68% of coupled product 3a was observed (Table 1, entry
e). In the further refinement, the reduction in the amount of DMA to 4 equivalents gave better
result, wherein coupled product 3a was observed in a yield of 72% (Table 1, entry f). Moreover,
the reaction with nonꢀaqueous TBHP (5ꢀ6 M in decane) have shown further improvement and
coupled product 3a was observed in a yield of 81% (Table 1, entry g). Further, reduction in the
amount of DMA 2a from 4 equivalents to 2 equivalents shown negative effect and only 36% of
coupled product 3a was noticed (Table 1, entry h). Other oxidants like DTBP and H2O2 did not
give satisfactory results (Table 1, entry iꢀj). When the reaction was performed in the absence of
TBAI, only 20% of product 3a was observed (Table 1, entry k). Next, replacement of TBAI with
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I2, KI and NaI also catalysed the reactions and coupled product 3a was observed in a yield of 76,
75 and 72% respectively (Table 1, entry lꢀn).
Table 1. Optimization studiesa
N
9
O
N
Conditions
N
N
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N
N
+
N
O
N
H
2a
1
3a
Entry
Oxidant (mmol)
Catalyst
DMA
Solvent
T
Yield
(%)b
48
52
42
Trace
68
72
81
36
24
(0.025 mmol) (mmol)
(oC)
90
a
b
c
d
e
Aq. TBHP (0.5)
Aq. TBHP (0.75)
Aq. TBHP (0.75)
Aq. TBHP (0.75)
Aq. TBHP (0.75)
Aq. TBHP (0.75)
TBHP (0.75)
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
ꢀ
2.5
2.5
2.5
DCE
DCE
EtOAc
ACN
neat
90
90
90
100
110
110
110
110
2.5
solvent
1
f
neat
neat
g*
1
0.5
1
1
1
1
1
1
h*
i
TBHP (0.75)
DTBP (0.75)
H2O2 (0.75)
TBHP (0.75)
TBHP (0.75)
TBHP (0.75)
TBHP (0.75)
neat
neat
neat
neat
neat
neat
neat
j
110 Trace
k*
l*
110
110
110
110
20
76
75
72
I2
KI
NaI
m*
n*
*
aAll the reactions were performed with 0.25 mmol of azole 1. TBHP (5ꢀ6 M in decane), 12 h. Isolated
b
yields.
Substituted 1Hꢀbenzotriazole such as 5,6ꢀdichlorobenzotriazole reacted with DMA and
produced N1 coupling product 3b in the yield of 76%. 5ꢀMethylbenzotriazole underwent coupling
with DMA 2a and gave unseperable N1 coupled regioisomers 3c and 3c' in an overall yield of
62%. Besides N,Nꢀdimethylacetamide (DMA 2a), 1Hꢀbenzotriazole 1a also reacted smoothly
with N,Nꢀdimethylbenzamide 2b, oꢀfluoroꢀN,Nꢀdimethylbenzamide 2c and pꢀmethylꢀN,Nꢀ
dimethylbenzamide 2d, afforded the corresponding N1ꢀselective coupled products 3d, 3e, and 3f
in an isolated yield of 66, 54, and 45 respectively. Subsequently, secondary aliphatic amide such
as Nꢀmethylacetamide 2e also reacted with 1Hꢀbenzotriazole 1a and furnished 75% of N1ꢀ
selective coupled product 3g. 1HꢀBenzotriazole 1a also reacted with N,Nꢀdiethylacetamide 2f
gave 3h in a yield of 52%. 1HꢀBenzotriazole 1a on coupling with cyclic amide such as Nꢀ
methylpyrrolidine 2g (NMP) and gave separable mixture of N1 and N2 regioꢀisomers 3i and 3i'
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with an isolated yield of 72 and 15%, respectively. On the other hand, 1Hꢀbenzotriazole 1a also
reacted with 2ꢀpyrrolidinone 2h and gave corresponding N1ꢀselective coupled product 3j in a
yield of 42% along with trace amount of N2ꢀselective other regioꢀisomer 3j' (<5%) (Table 2).
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Table 2. Coupling of un/substituted 1Hꢀbenzotriazoles with αꢀC(sp3)ꢀH containing amides
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aReaction conditions (unless otherwise noted): 1Hꢀbenzotriazole 1 (0.25 mmol), amides 2 (1 mmol),
TBHP (0.75 mmol, 5ꢀ6 M in decane), TBAI (0.025 mmol) at 110 oC, bisolated yields, cRatio was revealed
1
d
e
by H NMR and 13C NMR. Amide 2 (3 mmol) was used. Reaction was performed in chlorobenzene
solvent.
To further explore the diversity of optimized method, un/substituted 1Hꢀ1,2,3ꢀtriazoles,
1Hꢀ1,2,4ꢀtriazoles and 1Hꢀtetrazoles 4 were also explored with αꢀC(sp3)ꢀH containing amides 2
and all the results are summarized in Table 3. 4ꢀPhenylꢀ1Hꢀ1,2,3ꢀtriazole 4a treated with
pyrrolidineꢀ2ꢀone 2h gave regioselective N2 selective coupled product 5a. The structure of 5a is
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unambiguously confirmed by Xꢀray analysis (details given on page No. 2 and 3 of SI). Similarly,
4ꢀ(4ꢀfluorophenyl)ꢀ1Hꢀ1,2,3ꢀtriazole and 4ꢀ(4ꢀmethoxyphenyl)ꢀ1Hꢀ1,2,3ꢀtriazole on coupling
with pyrrolidinꢀ2ꢀone 2h also gave corresponding N2ꢀselective single regioꢀisomers 5b and 5c in
an isolated yield of 56 and 32%, respectively. 4ꢀPhenylꢀ1Hꢀ1,2,3ꢀtriazole 4a also reacted
efficiently with NMP 2g and gave 91% of coupled product 5d. The N2ꢀselectivity in 5d was
confirmed by HMBC and HSQC studies (details given on page No. 27 and 28 of supporting
information). 5ꢀ(4ꢀFluorophenyl)ꢀ1Hꢀ1,2,3ꢀtriazole on coupling with NMP 2g gave an unꢀ
separable mixture of regioꢀisomers 5e and 5e' in a ratio of 2:1 as predicted by NMR analysis.
Similarly, 4ꢀ(4ꢀmethoxyphenyl)ꢀ1Hꢀ1,2,3ꢀtriazole also underwent coupling with NMP 2g and
gave an unꢀseparable mixture of regioꢀisomers 5f and 5f' in a ratio of 1:1 with an overall yield of
51%. 4ꢀPhenylꢀ1Hꢀ1,2,3ꢀtriazole 4a when tried with DMA 2a, 69% of N2 regioselective product
5g was observed, which was confirmed by HMBC and HSQC studies (details given on page No.
33 of supporting information). Similarly, 4ꢀ(4ꢀfluorophenyl)ꢀ1Hꢀ1,2,3ꢀtriazole and 4ꢀ(4ꢀ
methoxyphenyl)ꢀ1Hꢀ1,2,3ꢀtriazole also coupled with DMA 2a and gave 62 and 51% of N2ꢀ
selective products 5h and 5i, respectively. Surprisingly, 1Hꢀ1,2,3ꢀtriazole 4b did not give
coupled product with DMA 2a, but 1Hꢀ1,2,3ꢀtriazole when coupled with NMP 2g, reaction
underwent efficiently and gave the corresponding N2ꢀselective coupled product 5k in an isolated
yield of 82%. 1Hꢀ1,2,3ꢀtriazole also reacted with pyrrolidinꢀ2ꢀone 2h and gave the
corresponding N2ꢀselective products 5l in an isolated yield of 62%. Interestingly, 1Hꢀ1,2,4ꢀ
triazole 4c underwent smooth coupling with both DMA 2a and NMP 2g and gave 54 and 73% of
N1 coupled products 5m and 5n, respectively. Under optimized conditions, 5ꢀphenylꢀ1Hꢀ
tetrazole 4d also reacted with DMA 2a and gave 62% of respective N2ꢀselective coupled product
5o. Under optimised conditions, 5ꢀphenylꢀ1Hꢀtetrazole 4d did not react with NMP 2g and
pyrrolidineꢀ2ꢀone 2h.
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Table 3. Coupling of un/substituted 1Hꢀtriazoles and 1Hꢀtetrazole with αꢀC(sp3)ꢀH containing
amides
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aReaction conditions: azole 4 (0.25 mmol), amide 2 (1 mmol), TBHP (0.75 mmol, 5ꢀ6 M in decane),
b
TBAI (0.025 mmol), 110 oC. Isolated yields. cRatio was revealed by 1H NMR and 13C NMR.
Next, other azoles such as un/substituted 1Hꢀbenzimidazoles and 1Hꢀpyrazoles 6 were
also tried under optimized conditions. To our delight, both the substrates underwent reaction
with αꢀC(sp3)ꢀH containing amides 2 and gave respective coupled products in moderate to good
yields (Table 4). 1HꢀBenzimidazole 6a on reaction with DMA 2a gave 52% of coupled product
7a. 5ꢀBromoꢀ1Hꢀbenzimidazole 6b on reaction with DMA 2a, gave mixture of unꢀseparable
N1/N2 regioꢀisomers 7b and 7b' with overall yield of 56%. Similarly, 5,6ꢀdimethylꢀ1Hꢀ
benzimidazole 6c on reaction with DMA 2a furnished 7c in a yield of 52% respectively. 1Hꢀ
benzimidazole did not work with NMP 2g and pyrrolidinꢀ2ꢀone 2h. Further, 3ꢀphenylꢀ1Hꢀ
pyrazole 6d didn’t couple with DMA 2a but underwent smooth coupling with cyclic amide such
as NMP 2g and gave 58% of corresponding coupled product 7g. 3ꢀ(4ꢀBromophenyl)ꢀ1Hꢀ
pyrazole 6d when tried with NMP 2g and pyrrolidinꢀ2ꢀone 2h, corresponding N1 coupled
products 7h and 7i were formed in a yield of 59 and 56%, respectively.
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Table 4. Coupling of un/substituted 1Hꢀbenzimidazole or 1Hꢀpyrazole with αꢀC(sp3)ꢀH
containing amides
3
4
5
6
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8
9
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12
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aReaction conditions: azole 6 (0.25 mmol), amide 2 (1 mmol), TBHP 5ꢀ6 M in decane (0.75 mmol,),
TBAI (0.025 mmol) 110 oC. bIsolated yields are shown. cratio was revealed by 1H NMR and 13C NMR.
We next examined other nucleophiles 8 such as benzamides 8a and sulphonamide 8b
with αꢀC(sp3)ꢀH containing amides 2 (Table 5). Under optimized conditions, benzamide 8a
didn’t couple with DMA 2a, however, underwent reaction with NMP 2g and gave 61% of
corresponding coupled product 9b. Under optimized conditions, benzamide 8a didn’t couple
with pyrrolidineꢀ2ꢀone 2h. Other substituted benzamide containing both donating (pꢀmethyl and
mꢀmethyl) and electronꢀwithdrawing (pꢀnitro and oꢀfluoro) groups also underwent coupling with
NMP 2g and gave corresponding coupled products 9d, 9e, 9f and 9g in a yield of 57, 52, 32 and
54% respectively. 4ꢀMethylbenzenesulfonamide 8b when tried with NMP 2g, gave a coupled
product 9h in a yield of 61%.
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Table 5. Coupling of un/substituted benzamides with αꢀC(sp3)ꢀH containing amides
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aReaction conditions: benzamide or sulphonamide 8 (0.25 mmol), amide 2 (1 mmol),TBHP 5ꢀ6 M in
decane (0.75 mmol), TBAI (0.025 mmol), 110 oC. bIsolated yields are shown.
The practicality of the present method was also seen by performing a gram scale
synthesis of 3a (0.92 g, 53%), suggesting that the method could also be efficiently scaled up (Fig.
2).
Figure 2. Gram scale synthesis of compound 3a
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Since 1985, after Katritizky’s report, benzotriazolyl (Bt) moiety has been highly
exploited as synthetic auxiliary and has been used in numerous synthetic transformations ranging
from simple functionalization to the construction of heterocycles.11. In the present study, the
synthesized αꢀbenzotriazolyl containing amides have also been further explored for the synthesis
of useful synthetic intermediates and heterocycles (Fig 3). For instances, αꢀbenzotriazolyl
containing DMA 3d when reacted with phenol in the presence of Lewis acid gave Nꢀ
(substituted)benzylꢀNꢀmethylbenzamide 10. Likewise, αꢀbenzotriazolyl containing NMP 3i on
reaction with 1Hꢀindole and 1,3,5ꢀtrimethoxybenzene and gave 5ꢀindolylpyrolidinone 11 and 5ꢀ
arylꢀNꢀmethylpyrrolidinone 12 respectively with excellent yields.
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O
O
OH
R1
N
O
HO
N
O
O
O
Bt
3d
3i
HCl
MeOH
N
AlCl3, DCM
O
O
O
3
10 (64%)
12 (85%)
3i
HCl
MeOH
N
H
O
N
N
H
11 (82%)
Figure 3. Synthetic elaboration of αꢀBt containing amides
During diversity generation, the obtained results indicated that coupling partners
participated through ionic and radical based intermediates and their existence is highly depends
upon the structures of substrates. To ascertain the mechanism involved, and several control
experiments were performed (all results are depicted in Fig. 4. In first instance, the nature of
amide base intermediate were established by performing the experiment in the presence of freeꢀ
radical scavenger viz., 2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀoxyl (TEMPO). The reaction of Bt 1a with
DMA 2a in the presence TEMPO was performed, the yield of coupled product 3a was
significantly suppressed and instead TEMPOꢀDMA adduct 13 was formed (eq. 1). Next, reaction
of Bt 1a with DEA 2f in the presence freeꢀradical scavenger viz., 2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀ
oxyl (TEMPO) was performed, the yield of coupled product 3h was also significantly suppressed
(eq. 2). Surprisingly, when reaction of Bt 1a with NMP 2g in the presence 2 equivalent of
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TEMPO was performed, 62% of TEMPOꢀNMP adduct 14 was obtained along with considerable
amount of coupled product 3i. The formation of coupled product 3i was also noticed even when
5 equivalent of TEMPO was used (eq. 3). These results suggested that open chain amides
participated through purely radical pathway and cyclic amides participated through radical and
ionic path way. In case, the NMP 2g, the formation of coupled products suggested the fast
conversion of radical based intermediate into ionic via second electron transfer reaction. In
another attempts, to confirm the nature of diverse azoles and nucelophiles, reactions in the
presence of another freeꢀradical scavenger, 1,1ꢀdiphenylethylene (DPE) were also performed (eq.
4 to 12). These results suggested that benzoꢀfused azoles and phenyl substitutedazoles
participated through radical based intermediates, as confirmed by the formation of their adducts
with DPE (15, 16, 17, 18 and 19). The structure of compound 16 was also confirmed by Xꢀray
analysis (details given on page No. 3 and 4 of SI). On the other hand, simple azoles and
benzamides and sulphonamides attack as neutral nucleophiles. In order to rule out the
involvement of iodine mediated coupling of azoles with DPE, an experiment was conducted
between 1Hꢀbenzotriazole 1a and DPE in the absence of TBAI (eq. 13). The reaction gave
expected coupled product 15, ruled out the possibility of iodine mediation.
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O
N
N
N
standard conditions
TEMPO (X mmol)
N
O
N
eq. 1
N
N
+
N
N
+
O
N
H
O
6
1a
(0.25 mmol)
2a
(1 mmol)
7
8
9
13
3a
3a
(73%)
13
~10%
73%
95%
TEMPO (0.5 mmol)
TEMPO (1.25 mmol)
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12
13
14
15
16
17
18
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20
21
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23
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27
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30
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<3%
O
N
O
N
N
N
standard conditions
N
+
N
N
N
TEMPO (0.5 mmol)
chlorobenzene
eq. 2
eq. 3
H
2f
(1 mmol)
1a
(0.25 mmol)
3h
(trace amounts)
O
N
O
+
N
N
N
N
N
N
N
N
O
O
N
N
N
standard conditions
TEMPO (X mmol)
+
+
O
N
N
H
1a
(0.25 mmol)
2g
(1 mmol)
3i
3i
3i'
1
4
3i'
14
62%
~30%
trace
TEMPO (0.5 mmol)
TEMPO (1.25 mmol)
~25%
trace
80%
N
N
Ph
N
O
N
N
N
N
N
N
OH
Ph
standard conditions
DPE (0.5 mmol)
+
eq. 4
eq. 5
N
+
N
O
H
1a
1a
2a
(1 mmol)
(0.25 mmol)
15
(72%)
3a
(<5)
N
Ph
N
N
OH
Ph
N
N
N
O
O
N
N
N
N
standard conditions
DPE (0.5 mmol)
N
+
O
N
+
+
N
N
N
H
2g
(1 mmol)
(0.25 mmol)
15
3i'
(trace amounts)
3i
(30%)
(62%
)
N
N
O
N
N
Ph
N
N
N
N
eq. 6
eq. 7
OH
Ph
standard conditions
DPE (0.5 mmol)
N
+
N
+
O
N
H
5g
(<5%)
N
16
(75%)
4a
(0.25 mmol)
2a
(1 mmol)
N
O
standard conditions
DPE (0.5 mmol)
N
N
N
O
N
+
N
N
H
5k
(81%)
2g
(1 mmol)
4b
(0.25 mmol)
N
O
N
N
eq. 8
standard conditions
DPE (0.5 mmol)
N
N
N
+
N
N
H
O
4c
(0.25 mmol)
2a
(1 mmol)
5m
(35%)
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aStandard conditions: azole (0.25 mmol), amide (1 mmol), TBHP (0.75 mmol, 5ꢀ6 M in decane), TBAI
b
(0.025 mmol), 110 oC. Isolated yields are shown
.
Figure 4. Control experiments
Based on the above control experiments, we could postulates that the reactions proceeded
through the involvement of radical and ionic based intermediates and fate is decided by the
nature of azoles and αꢀC(sp3)ꢀH containing amides. Among the diverse azoles tried, it seems that
benzoꢀfused azoles and phenyl substituted azoles such as 1Hꢀbenzotriazole 1a, 4ꢀphenylꢀ1Hꢀ
1,2,3ꢀtriazole 4a, 1Hꢀ1,2,4ꢀtriazole 4c, 1Hꢀtetrazole 4d and 1Hꢀbenzimidazole/3ꢀphenylꢀ1Hꢀ
pyrazoles 6 proceeded through radical based inetrmediates. On the other hand, azoles such as
1Hꢀ1,2,3ꢀtriazole and other nucleophiles such as benzamide and sulfonamide 8 operated through
only ionic pathway. Among αꢀC(sp3)ꢀH amides 2, it seems that DMA 2a operated through only
radical based intermediate and therefore work with azoles capable of generating radical based
intermediates such as 1Hꢀbenzotriazole 1a, 4ꢀphenylꢀ1Hꢀtriazole 4a, 1Hꢀbenzimidazole 6a, 1Hꢀ
1,2,4ꢀtriazole 4c, 5ꢀphenylꢀ1Hꢀtetrazole 4d. On the other hand, NMP 2g is operated through both
radical and iminium based intermadiates and that could be the reason worked with all azoles and
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nucleophiles such as benzamides and sulfonamides 8. The nonꢀcoupling of 1Hꢀbenzimidazole 6a
and 5ꢀphenylꢀ1Hꢀtetrazole 4d with NMP 2g might be due to some steric factor. Furthermore, in
case of cyclic amides, the convesrion of radical based intermediates might be very fast, and
explain the reason why reaction with NMP 2g in the presence of freeꢀradical scavanger didn’t get
completely suppressed, while with DMA 2a, the presence of freeꢀradical scavanger almost
completely supressed the formation of coupled products.
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Based on the control experiments and the literature precedents, the following plausible
pathways are being proposed as shown in the Fig 5. The present reaction is initiated by redox
reaction between TBAI and TBHP, which generates tertꢀbutoxy and tertꢀbutylhydroperoxide
radicals. Under present oxidative conditions, αꢀC(sp3)ꢀH amides generates the corresponding
radical species 2a' and 2' (stepꢀi) via interaction with either tertꢀbutoxy or tertꢀ
butylhydroperoxide radicals (which in turn produced from TBAI and TBHP). The further fate of
the radicals 2a or 2a' depends upon the nature of amides, open chain amides such as N,Nꢀ
dimethylacetamide 2a, N,Nꢀdimethylbenzamide 2b and Nꢀmethylacetamide 2c didn’t generate
iminiun ion and reacted through radicalꢀbased intermediates 2a' with azoles capable of generates
radical. On the other hand, cyclic amides such as NMP 2g and pyrrolidinꢀ2ꢀone 2h underwent
further electron transfer reaction (step ii) and generates iminiun ions 2'', which then coupled
with azoles as well as nucleophilic partners such as benzamides and sulfonamides to furnished
coupled products.
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Figure 5. Plausible mechanism
As the present method generates azoleꢀbased radical, which convert the nucleophilic
azoles into electronꢀdeficient azoles, and also providing the chance of further exploitation. In this
direction, a reaction has been planned for the coupling of azoles with electronꢀrich heteroarenes
such as NHꢀindole. Under TBAI/TBHP conditions, when 1Hꢀbenzotriazole was treated with 1Hꢀ
indole 20, coupling underwent and C2ꢀcoupled product 21 was observed in a yield of 45%
(Table 6).
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Table 6. Coupling of 1Hꢀindole with 1Hꢀ1,2,3ꢀbenzotriazole
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In conclusion, a metal free, TBAI/TBHP mediated crossꢀdehydrogenative coupling
between NHꢀazoles and αꢀC(sp3)ꢀH containing amides has been developed. Apart from azoles,
nucleophiles such as benzamides and sulfonamides also underwent coupling with NMP under
TBAI/TBHP conditions. The synthesized αꢀbenzotriazolyl containing amides were further
exploited for the CꢀC bond formation reactions and prepared DMA and NMP based synthetic
compounds. The present study first time reported the existence of azoleꢀbased radicals, which
umpolung the reactivity of azoles, and further demonstrated its coupling with electronꢀrich
coupling partner 1Hꢀindole.
Experimental section:
General Information:
Analytical thin layer chromatography was performed using TLC preꢀcoated silica gel 60
F254 (20 x 20 cm). TLC plates were visualized by exposing UV light or by iodine vapours or
immersion in an acidic staining solution of pꢀanisaldehyde followed by heating on a hot plate.
Organic solvents were concentrated by rotary evaporation. Column chromatography was
performed on flash silica gel of 100ꢀ200 mesh size using EtOAc and hexane or MeOH and DCM
solvent system. Melting points were recorded on melting point instrument and were uncorrected.
1H NMR spectra were recorded with 400 MHz NMR instrument. Chemical data for protons are
reported in parts per million (ppm, scale) downfield from tetramethylsilane and are referenced to
the residual proton in the NMR solvent (CDCl3: δ 7.26 or other solvents as mentioned). Mass
spectra were recorded with LCMSꢀQTOF instrument. The coupling constant (J) are mentioned in
Hz. ESIꢀMS and HRMS spectra were recorded on LCꢀQꢀTOF and HRMSꢀUHD machines.
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Experimental section:
5
6
7
8
General procedure for the coupling of HNꢀazole (1, 4 and 6) and benzamide or
sulphonamide (8) with αꢀC(sp3)ꢀH amides (2): (Table 2, 3, 4 and 5)
To a 50 ml sealed tube with magnetic bar, HNꢀazoles (1, 4 and 6) and benzamides or
sulphonamides (8) (0.25 mmol) and αꢀC(sp3)ꢀH amides 2 (1 mmol) was loaded. tertꢀ
Butylhydroperoxide (5ꢀ6 M in Decane) 0.75 mmol was added followed by the addition of
9
10
11
12
13
14
15
16
17
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54
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56
57
58
59
60
o
tetrabutylammonium iodide (0.025 mmol). Reaction mixture was allowed to stir at 110 C.
Progress of reaction was monitored by TLC. After completing reaction, required product 3, 5, 7
and 9 was obtained on column chromatography (100ꢀ200 mesh size) using EtOAc and hexane
(6:4) as eluents. Compounds 5m, 5n, 5o, 7a, 7b, 7c, 9b, 9d, 9e, 9f and 9g were purified column
chromatography (100ꢀ200 mesh size) using MeOH and DCM (2:98) as eluents.
Note: In case of products 5g, 5h, 5i and 5o, rotamers have been noticed. The rotamers leads to
duplication in spectra of 5g, 5h, 5i and 5o.
Spectral data:
Nꢀ((1Hꢀbenzo[d][1,2,3]triazolꢀ1ꢀyl)methyl)ꢀNꢀmethylacetamide 9 (3a, Table 2)
1
TLC Rf=0.5 (40% EtOAc/Hexane); Yield 81% (41 mg); Colorless liquid; H NMR (400 MHz,
CDCl3) δ 7.96 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.30 (t, J =
7.6 Hz, 1H), 6.13 (s, 2H), 3.03 (s, 3H), 2.05 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 171.6,
146.0, 132.3, 127.9, 124.4, 119.5, 111.0, 57.5, 34.9, 21.7; HRMS (ESI+) calcd. for:
C10H12N4NaO 227.0909. (M+ Na), found 227.0904.
Nꢀ((5,6ꢀdichloroꢀ1Hꢀbenzo[d][1,2,3]triazolꢀ1ꢀyl)methyl)ꢀNꢀmethylacetamide (3b, Table 2)
o
1
TLC Rf=0.5 (40% EtOAc/Hexane); Yield 76% (51 mg); Grey color solid; m.p.: 152ꢀ154 C; H
NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 8.01 (s, 1H), 6.03 (s, 2H), 3.04 (s, 3H), 2.04 (s, 3H); 13C
NMR (126 MHz, CDCl3) δ 171.8, 144.9, 133.2, 131.5, 129.4, 120.4, 112.6, 58.0, 35.2, 21.7;
HRMS (ESI+) calcd. for: C10H11Cl2N4O 273.0310. (M+ H), found 273.0297.
NꢀmethylꢀNꢀ((5ꢀmethylꢀ1Hꢀbenzo[d][1,2,3]triazolꢀ1ꢀyl)methyl)acetamide and NꢀmethylꢀNꢀ
((6ꢀmethylꢀ1Hꢀbenzo[d][1,2,3]triazolꢀ1ꢀyl)methyl)acetamide (3c, Table 2)
1
TLC Rf=0.5 (40% EtOAc/Hexane); Yield 62% (33.8 mg); Colorless liquid; H NMR (400 MHz,
CDCl3) δ 7.87 (d, J = 8.5 Hz, 1H), 7.81 – 7.66 (m, 2H), 7.60 (s, 1H), 7.29 (dd, J = 8.5, 1.2 Hz,
1H), 7.18 (dd, J = 8.5, 1.1 Hz, 1H), 6.14 (d, J = 5.3 Hz, 4H), 3.07 (d, J = 6.5 Hz, 5H), 2.49 (d, J
= 8.0 Hz, 6H), 2.10 (d, J = 5.6 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 171.6, 171.6, 146.7,
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144.7, 138.7, 134.5, 132.8, 130.8, 130.1, 126.7, 119.0, 118.4, 110.5, 110.0, 57.5, 57.3, 34.9, 29.7,
22.0, 21.7, 21.5; HRMS (ESI+) calcd. for: C11H15N4O 219.1246. (M+ H), found 219.1249.
Nꢀ((1Hꢀbenzo[d][1,2,3]triazolꢀ1yl)methyl)ꢀNꢀmethylbenzamide 12 (3d, Table 2)
1
TLC Rf=0.6 (40% EtOAc/Hexane); Yield 66% (43 mg); Colorless liquid; H NMR (500 MHz,
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12
13
14
15
16
17
18
19
20
21
22
23
24
25
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CDCl3) δ 8.14 (d, J = 8.4 Hz, 2H), 7.65 – 7.37 (m, 7H), 6.46 (s, 2H), 3.11 (s, 3H); 13C NMR (126
MHz, CDCl3) δ 172.0, 146.2, 134.6, 132.4, 130.5, 128.5, 128.1, 127.0, 124.5, 119.7, 111.0, 58.0,
36.4; HRMS (ESI+) calcd. for: C15H15N4O 267.1246. (M+ H), found 267.1240.
Nꢀ((1Hꢀbenzo[d][1,2,3]triazolꢀ1ꢀyl)methyl)ꢀ2ꢀfluoroꢀNꢀmethylbenzamide (3e, Table 2)
o
TLC Rf=0.6 (40% EtOAc/Hexane); Yield 54% (38 mg); White solid; m.p.: 127ꢀ128 C; 1H
NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.3 Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.56 (t, J = 7.6 Hz,
1H), 7.42 (dd, J = 13.7, 6.5 Hz, 2H), 7.35 (t, J = 7.1 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.09 (t, J =
13
9.0 Hz, 1H), 6.42 (s, 2H), 2.97 (s, 3H); C NMR (126 MHz, CDCl3) δ 167.9, 158.1 (d, J(CꢀF)
=
247.5 Hz), 146.2, 132.3, 132.1 (d, J(CꢀF) = 7.4 Hz), 132.0, 128.9 (d, J(CꢀF) = 3.7 Hz), 128.1, 124.5,
119.7, 115.9 (d, J(CꢀF) = 21 Hz), 111.0, 57.5, 35.0; HRMS (ESI+) calcd. for: C15H14FN4O
285.1152. (M+ H), found 285.1159.
Nꢀ((1Hꢀbenzo[d][1,2,3]triazolꢀ1ꢀyl)methyl)ꢀN,4ꢀdimethylbenzamide (3f, Table 2)
1
TLC Rf=0.6 (40% EtOAc/Hexane); Yield 45% (45 mg); White solid; m.p.:142ꢀ143 oC; H NMR
(400 MHz, CDCl3) δ 8.00 (d, J = 8.4 Hz, 1H), 7.50 – 6.99 (m, 7H), 6.31 (s, 2H), 2.98 (s, 3H),
2.29 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 172.3, 146.2, 140.9, 132.5, 131.6, 129.1, 128.0,
127.3, 124.4, 119.7, 111.0, 58.2, 36.3, 21.4; HRMS (ESI+) calcd. for: C16H17N4O 281.1402. (M+
H), found 281.1406.
Nꢀ((1Hꢀbenzo[d][1,2,3]triazolꢀ1ꢀyl)methyl)acetamide (3g, Table 2)
TLC Rf=0.6 (60% EtOAc/Hexane); Yield 75% (35 mg); White solid; m.p.: 130ꢀ132 oC; 1H NMR
(500 MHz, CDCl3) δ 8.01 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4, Hz, 1H), 7.51 (t, J = 9.4 Hz, 1H),
7.42 – 7.35 (t, 9.2 Hz, 1H), 7.23 (broad singlet, 1H), 6.10 (d, J = 6.9 Hz, 2H), 2.06 (s, 3H); 13C
NMR (126 MHz, CDCl3) δ 170.7, 145.9, 132.4, 128.0, 124.4, 119.4, 111.0, 50.8, 23.1; HRMS
(ESI+) calcd. for: C9H10N4NaO 213.0752. (M+Na), found 213.0759.
Nꢀ(1ꢀ(1Hꢀbenzo[d][1,2,3]triazolꢀ1ꢀyl)ethyl)ꢀNꢀethylacetamide (3h, Table 2)
1
TLC Rf=0.5 (40% EtOAc/Hexane); Yield 52% (30 mg); Colorless liquid; H NMR (400 MHz,
CDCl3) δ 8.05 (d, J = 8.3 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.62 (q, J = 6.9 Hz, 1H), 7.52 – 7.46
(m, 1H), 7.41 – 7.36 (m, 1H), 3.43 (dq, J = 14.4, 7.2 Hz, 1H), 3.32 (dq, J = 14.4, 7.2 Hz, 1H),
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2.15 (s, 3H), 2.10 (d, J = 7.0 Hz, 3H), 0.84 (t, J = 7.2 Hz, 3H); C NMR (101 MHz, CDCl3) δ
171.1, 145.8, 132.6, 127.7, 124.4, 119.6, 110.6, 60.8, 37.5, 21.5, 17.7, 15.5; HRMS (ESI+) calcd.
for: C12H17N4O 233.1402. (M+ H), found 233.1409.
5ꢀ(1Hꢀbenzo[d][1,2,3]triazolꢀ1ꢀyl)ꢀ1ꢀmethylpyrrolidinꢀ2ꢀone 10 (3i, Table 2)
10
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TLC Rf=0.3 (70% EtOAc/Hexane); Yield 72% (39 mg); Colorless liquid; H NMR (400 MHz,
CDCl3) δ 8.12 (d, J = 8.3 Hz, 1H), 7.59 – 7.50 (m, 1H), 7.49 – 7.40 (m, 2H), 6.51 (dd, J = 8.5,
2.7 Hz, 1H), 2.91 (ddt, J = 13.0, 9.0, 4.8 Hz, 2H), 2.74 – 2.63 (m, 4H), 2.54 – 2.43 (m, 1H).13C
NMR (126 MHz, CDCl3) δ 174.4, 146.6, 131.2, 128.4, 124.6, 120.7, 108.9, 74.6, 29.3, 27.6,
25.0; HRMS (ESI+) calcd. for: C11H13N4O 217.1089. (M+ H), found 217.1095.
5ꢀ(2Hꢀbenzo[d][1,2,3]triazolꢀ2ꢀyl)ꢀ1ꢀmethylpyrrolidinꢀ2ꢀone 10 (3i', Table 2)
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TLC Rf=0.6 (70% EtOAc/Hexane); Yield 15% (8 mg); Colorless liquid; H NMR (400 MHz,
CDCl3) δ 7.80 (dd, J = 6.6, 3.1 Hz, 2H), 7.35 (dd, J = 6.6, 3.1 Hz, 2H), 6.23 (dd, J = 7.6, 1.3 Hz,
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1H), 2.96 (dt, J = 12.1, 6.9 Hz, 1H), 2.71 – 2.55 (m, 4H), 2.55 – 2.40 (m, 2H); C NMR (126
MHz, CDCl3) δ 175.6, 144.5, 127.0, 118.4, 80.6, 28.8, 27.8, 25.8; HRMS (ESI+) calcd. for:
C11H13N4O 217.1089. (M+ H), found 217.1093.
5ꢀ(1Hꢀbenzo[d][1,2,3]triazolꢀ1ꢀyl)pyrrolidinꢀ2ꢀone (3j, Table 2)
TLC Rf=0.3 (70% EtOAc/Hexane); Yield 42% (21 mg); Colorless liquid; 1H NMR (400 MHz,
CDCl3) δ 7.95 (d, J = 8.3 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.30 (dd, J
= 8.1, 7.1 Hz, 1H), 6.44 (d, J = 6.1 Hz, 1H), 2.77 (dq, J = 13.4, 8.1 Hz, 2H), 2.66 – 2.53 (m, 1H),
2.50 – 2.34 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 178.5, 146.3, 131.4, 128.0, 124.4, 120.2,
109.4, 68.6, 29.0, 27.6; HRMS (ESI+) calcd. for: C10H11N4O 203.0933. (M+ H), found
203.0939.
5ꢀ(4ꢀphenylꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)pyrrolidinꢀ2ꢀone (5a, Table 3)
TLC Rf=0.2 (60% EtOAc/Hexane); Yield 59% (33 mg); White solid; m.p.: 124ꢀ125 C; 1H
o
NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.76 (d, J = 7.3 Hz, 2H), 7.4 (m, 2H), 7.36 (m, 1H),
7.01 (broad, 1H), 6.19 (d, J = 6.7 Hz, 1H), 3.01 – 2.81 (m, 1H), 2.68 (dd, J = 16.2, 8.9 Hz, 2H),
2.43 (ddd, J = 16.9, 8.9, 2.9 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 176.6, 146.7, 129.9, 128.0,
127.0, 126.9, 124.0, 71.2, 26.5, 25.7; HRMS (ESI+) calcd. for: C12H13N4O 229.1089. (M+ H),
found 229.1085.
5ꢀ(4ꢀ(4ꢀfluorophenyl)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)pyrrolidinꢀ2ꢀone (5b, Table 3)
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TLC Rf=0.2 (60% EtOAc/Hexane); Yield 56% (34 mg); White solid; m.p.: 131ꢀ133 oC; 1H NMR
(400 MHz, CDCl3) δ 7.81 (s, 1H), 7.73 (dd, J = 8.5, 5.4 Hz, 2H), 7.11 (t, J = 8.6 Hz, 2H), 7.14
(broad, 1H), 6.17 (d, J = 6.8 Hz, 1H), 2.95 – 2.82 (m, 1H), 2.77 – 2.60 (m, 2H), 2.42 (ddd, J =
16.8, 8.9, 2.8 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 178.7, 163.0 (d, J(CꢀF) = 246.2 Hz), 147.7,
131.5, 127.7 (d, J(CꢀF) = 8.7 Hz), 126.1 (d, J(CꢀF) = 3.7 Hz), 116.0, 73.2, 28.4, 27.5; HRMS (ESI+)
calcd. for: C12H11FN4NaO 269.0815 (M+ H), found 269.0806.
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5ꢀ(4ꢀ(4ꢀmethoxyphenyl)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)pyrrolidinꢀ2ꢀone (5c, Table 3)
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TLC Rf=0.2 (60% EtOAc/Hexane); Yield 32% (21 mg); White solid; m.p.: 141ꢀ142 C; 1H
NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.70 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 6.66
(s, 1H), 6.16 (dd, J = 5.3, 2.7 Hz, 1H), 3.85 (s, 3H), 2.99 – 2.85 (m, 1H), 2.77 – 2.66 (m, 2H),
2.44 (ddd, J = 16.9, 8.1, 4.4 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 178.3, 160.1, 148.5, 131.3,
127.3, 122.5, 114.3, 72.8, 55.3, 29.7, 27.5; HRMS (ESI+) calcd. for: C13H14N4NaO2 281.1014.
(M+ H), found 281.1003.
1ꢀmethylꢀ5ꢀ(4ꢀphenylꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)pyrrolidinꢀ2ꢀone 10 (5d, Table 3)
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TLC Rf=0.3 (60% EtOAc/Hexane); Yield 91% (55 mg); Colorless liquid; H NMR (400 MHz,
CDCl3) δ 7.91 (s, 1H), 7.83 – 7.75 (m, 2H), 7.41 (t, J = 8 Hz, 2H), 7.38 (m, 1H), 6.05 (dd, J =
13
7.5, 1.3 Hz, 1H), 3.03 – 2.89 (m, 1H), 2.75 (s, 3H), 2.70 – 2.41 (m, 3H); C NMR (126 MHz,
CDCl3) δ 175.4, 148.6, 131.9, 129.8, 128.9, 128.8, 126.0, 78.8, 28.9, 27.6, 25.2; HRMS (ESI+)
calcd. for: C13H15N4O 243.1246. (M+ H), found 243.1251.
5ꢀ(4ꢀ(4ꢀfluorophenyl)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)ꢀ1ꢀmethylpyrrolidinꢀ2ꢀone and 1ꢀ((4ꢀ(4ꢀ
fluorophenyl)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)methyl)pyrrolidinꢀ2ꢀone (5e and 5e', Table 3)
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TLC Rf=0.3 (60% EtOAc/Hexane); Yield 62% (40 mg); Colorless liquid; H NMR (400 MHz,
CDCl3) δ 7.84 (d, J = 6.8 Hz, 2H), 7.77 (ddd, J = 6.6, 4.3, 1.1 Hz, 3H), 7.18 – 7.05 (m, 3H), 6.04
(dd, J = 7.5, 1.6 Hz, 1H), 5.85 (s, 1H), 3.53 – 3.43 (m, 1H), 3.03 – 2.87 (m, 1H), 2.74 (s, 3H),
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2.68 – 2.56 (m, 2H), 2.5 (m, 4H), 2.11 – 1.98 (m, 1H); C NMR (126 MHz, CDCl3) δ 175.6,
175.4, 163.0 (d, JCꢀF = 246.2 Hz), 163.0 (d, JCꢀF = 247.4 Hz, 5e'), 147.8, 147.7, 131.7, 131.6,
127.8, 127.7, 126.1, 126.0, 116.0 (d, JCꢀF = 21.2 Hz), 115.9 (d, JCꢀF = 21.2 Hz, 5e'), 78.9, 60.0,
46.2, 30.5, 28.9, 27.6, 25.2, 17.7; HRMS (ESI+) calcd. for: C13H14FN4O 261.1152. (M+ H),
found 261.1151.
5ꢀ(4ꢀ(4ꢀmethoxyphenyl)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)ꢀ1ꢀmethylpyrrolidinꢀ2ꢀone and 1ꢀ((4ꢀ(4ꢀ
methoxyphenyl)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)methyl)pyrrolidinꢀ2ꢀone (5f and 5f', Table 3)
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TLC Rf=0.3 (60% EtOAc/Hexane); Yield 52% (34.5 mg); Colorless liquid; H NMR (400 MHz,
CDCl3) δ 7.82 (s, 1H), 7.81 (s, 1H), 7.73 (t, J = 2.2 Hz, 1H), 7.71 (t, J = 2.2 Hz, 1H), 6.97 (d, J =
3.6 Hz, 1H), 6.96 – 6.94 (m, 1H), 6.02 (dd, J = 7.5, 1.7 Hz, 1H), 5.84 (s, 1H), 3.85 (s, 1H), 3.85
(s, 1H), 3.47 (dd, J = 8.9, 5.3 Hz, 1H), 3.02 – 2.87 (m, 1H), 2.74 (s, 1H), 2.67 – 2.58 (m, 1H),
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2.52 (ddd, J = 10.9, 4.8, 2.8 Hz, 1H), 2.49 – 2.41 (m, 1H), 2.04 (dt, J = 11.3, 7.5 Hz, 1H); C
NMR (101 MHz, CDCl3) δ 175.4, 175.3, 160.0, 160.0, 148.6, 148.4, 131.5, 131.3, 127.4, 127.3,
122.7, 122.5, 114.3, 114.3, 78.7, 59.9, 55.3, 46.2, 30.5, 28.9, 25.2, 17.7.; HRMS (ESI+) calcd.
for: C14H17N4O2 273.1352. (M+ H), found 273.1347.
NꢀmethylꢀNꢀ((4ꢀphenylꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)methyl)acetamide (5g, Table 3)
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TLC Rf=0.2 (50% EtOAc/Hexane); Yield 69% (40 mg); Colorless liquid; H NMR (400 MHz,
CDCl3): (mixture of rotamers) δ 7.82 (s, 1H), 7.72 (t, J = 6.4 Hz, 1H), 7.37 (dd, J = 13.8, 6.9 Hz,
2H), 7.33 – 7.27 (m, 2H), 5.9, 5.7 (2Xs, 2X2H), 3.05, 2.99 (2Xs, 2X3H), 2.40, 2.10 (2Xs,
2X3H).13C NMR (126 MHz, CDCl3): (mixture of rotamers) δ 170.4, 147.7, 147.3, 130.9, 130.8,
129, 128.7, 127.9, 127.8, 127.6, 125.0, 124.9, 66.8, 62.6, 34.2, 32.2, 28.6, 20.7; HRMS (ESI+)
calcd. for: C12H15N4O 231.1242. (M+ H), found 231.1225.
Nꢀ((4ꢀ(4ꢀfluorophenyl)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)methyl)ꢀNꢀmethylacetamide (5h, Table 3)
TLC Rf=0.2 (50% EtOAc/Hexane); Yield 59% (38 mg); Colorless liquid; 1H NMR (400 MHz,
CDCl3): (mixture of rotamers) δ 7.84 (d, J = 2.8 Hz, 1H), 7.81 – 7.73 (m, 2H), 7.12 (dd, J = 15.7,
8.6 Hz, 2H), 5.96, 5.83 (2Xs, 2X2H), 3.13, 3.06 (2Xs, 2X3H), 2.47, 2.17 (2Xs, 2X3H); 13C
NMR (101 MHz, CDCl3): (mixture of rotamers) δ 170.5, 170.4, 163 (d, J(CꢀF) = 308.7 Hz), 161.9
(J(CꢀF) = 307.5 Hz), 146.9, 146.5, 130.7, 130.5, 126.8, 126.7, 115.0, 114.9, 114.8, 114.7, 66.8,
62.7, 34.3, 32.2, 20.7, 20.6; HRMS (ESI+) calcd. for: C12H14FN4O 249.1152. (M+ H), found
249.1142.
Nꢀ((4ꢀ(4ꢀmethoxyphenyl)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)methyl)ꢀNꢀmethylacetamide (5i, Table 3)
TLC Rf=0.2 (50% EtOAc/Hexane); Yield 52% (32 mg); Colorless liquid; 1H NMR (400 MHz,
CDCl3): (mixture of rotamers) δ 7.81 (s, 1H), 7.74 – 7.69 (m, 2H), 6.99 – 6.94 (m, 2H), 5.95,
5.81 (2Xs, 2X2H), 3.85 (2Xs, 2X3H), 3.11, 3.05 (2Xs, 2X3H), 2.47, 2.17 (2Xs, 2X3H); 13C
NMR (126 MHz, CDCl3) δ (mixture of rotamers) 171.4, 160.0, 159.9, 148.6, 131.4, 131.4, 127.3,
127.3, 122.7, 122.4, 114.3, 114.3, 67.7, 63.5, 55.3, 35.2, 33.2, 29.7, 21.8, 21.7; HRMS (ESI+)
calcd. for: C13H17N4O2 261.1352. (M+ H), found 261.1346.
1ꢀmethylꢀ5ꢀ(1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)pyrrolidinꢀ2ꢀone (5k, Table 3)
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TLC Rf=0.3 (60% EtOAc/Hexane); Yield 82% (34 mg); Colorless liquid; H NMR (400 MHz,
CDCl3) δ 7.68 (s, 2H), 6.07 (d, J = 7.5 Hz, 1H), 2.92 (dt, J = 18.1, 9.2 Hz, 1H), 2.69 (s, 3H), 2.66
– 2.41 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 175.2, 135.0, 78.6, 28.8, 27.4, 25.0; HRMS
(ESI+) calcd. for: C7H11N4O 167.0933. (M+ H), found 167.0947.
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5ꢀ(1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)pyrrolidinꢀ2ꢀone (5l, Table 3)
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TLC Rf=0.2 (60% EtOAc/Hexane); Yield 62%; Colorless liquid (23 mg); H NMR (400 MHz,
CDCl3) δ 7.68 (broad, 1H), 7.65 (d, J = 17.8 Hz, 2H), 6.20 (d, J = 6.9 Hz, 1H), 2.93 – 2.76 (m,
1H), 2.76 – 2.50 (m, 2H), 2.39 (dd, J = 16.4, 9.4 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 178.9,
134.9, 73.0, 28.4, 27.4; HRMS (ESI+) calcd. for: C6H9N4O 153.0776. (M+ H), found 153.0779
Nꢀ((1Hꢀ1,2,4ꢀtriazolꢀ1ꢀyl)methyl)ꢀNꢀmethylacetamide (5m, Table 3)
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TLC Rf=0.5 (5% MeOH/DCM); Yield 54%; Colorless liquid (21 mg); H NMR (400 MHz,
CDCl3) δ 8.34 (s, 1H), 7.92 (s, 1H), 5.64 (s, 2H), 3.20 (s, 3H), 2.12 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ 171.9, 151.6, 144.4, 59.5, 36.3, 21.6; HRMS (ESI+) calcd. for: C6H11N4O 155.0933.
(M+ H), found 155.0939.
1ꢀmethylꢀ5ꢀ(1Hꢀ1,2,4ꢀtriazolꢀ1ꢀyl)pyrrolidinꢀ2ꢀone (5n, Table 3)
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TLC Rf=0.5 (5% MeOH/DCM); Yield 73% (30 mg); Colorless liquid; H NMR (400 MHz,
CDCl3) δ 8.25 (s, 1H), 8.02 (s, 1H), 5.83 (dd, J = 7.8, 1.7 Hz, 1H), 2.86 (dd, J = 16.1, 7.8 Hz,
1H), 2.71 (s, 3H), 2.58 (m, 2H), 2.36 (ddd, J = 15.4, 7.2, 2.1 Hz, 1H); 13C NMR (126 MHz,
CDCl3) δ 175.0, 153.1, 142.4, 74.5, 28.7, 27.3, 25.6; HRMS (ESI+) calcd. for: C7H11N4O
167.0933. (M+ H), found 167.0944.
NꢀmethylꢀNꢀ((5ꢀphenylꢀ2Hꢀtetrazolꢀ2ꢀyl)methyl)acetamide (5o, Table 3)
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TLC Rf=0.6 (5% MeOH/DCM); Yield 62%; Colorless liquid (36 mg); H NMR (400 MHz,
CDCl3) (mixture of rotamers): δ 8.22 – 8.08 (m, 2H), 7.54 – 7.39 (m, 3H), 6.17, 6.07 (2Xs,
2X2H), 3.19, 3.08 (2Xs, 2X3H), 2.48, 2.18 (2Xs, 2X3H); 13C NMR (126 MHz, CDCl3) (mixture
of rotamers): δ 171.6, 171.2, 165.7, 165.4, 130.7, 130.5, 129.0, 128.8, 127.0, 126.9, 126.9, 126.8,
66.3, 62.3, 35.7, 33.3, 21.7, 21.6; HRMS (ESI+) calcd. for: C11H13N5NaO 254.1018. (M+ Na),
found 254.1019.
Nꢀ((1Hꢀbenzo[d]imidazolꢀ1ꢀyl)methyl)ꢀNꢀmethylacetamide 9 (7a, Table 4)
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TLC Rf=0.6 (5% MeOH/DCM); Yield 52% (26 mg); Colorless liquid; H NMR (400 MHz,
CDCl3) δ 8.14 (s, 1H), 7.81 (d, J = 6.2 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.32 (dd, J = 9.7, 5.4
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Hz, 2H), 5.75 (s, 2H), 3.01 (s, 3H), 2.13 (s, 3H); C NMR (101 MHz, CDCl3) δ 171.5, 143.5,
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133.2, 123.6, 122.6, 120.2, 110.3, 55.1, 35.0, 21.8; HRMS (ESI+) calcd. for: C11H14N3O
204.1137. (M+ H), found 204.1128.
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Nꢀ((6ꢀbromoꢀ1Hꢀbenzo[d]imidazolꢀ1ꢀyl)methyl)ꢀNꢀmethylacetamide and Nꢀ((5ꢀbromoꢀ1Hꢀ
benzo[d]imidazolꢀ1ꢀyl)methyl)ꢀNꢀmethylacetamide (7b and 7b', Table 4)
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TLC Rf=0.6 (5% MeOH/DCM); Yield 56% (39 mg); Colorless liquid; H NMR (400 MHz,
CDCl3) δ 8.06 (d, J = 3.2 Hz, 2H), 7.94 (d, J = 1.3 Hz, 1H), 7.81 – 7.74 (m, 1H), 7.65 (d, J = 8.6
Hz, 2H), 7.54 – 7.48 (m, 2H), 7.41 (ddd, J = 8.6, 3.0, 1.8 Hz, 1H), 5.72 (s, 2H), 5.69 (s, 2H),
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3.05 (s, 3H), 3.02 (s, 3H), 2.15 (s, 3H), 2.14 (s, 3H); C NMR (126 MHz, CDCl3) δ 171.6,
171.6, 144.9, 144.4, 144.2, 142.5, 134.4, 132.2, 126.7, 126.1, 126.0, 123.1, 121.5, 117.0, 115.8,
113.4, 111.8, 55.3, 35.3, 35.0, 21.8; HRMS (ESI+) calcd. for: C11H13BrN3O 282.0242. (M+ H),
found 282.0241.
Nꢀ((5,6ꢀdimethylꢀ1Hꢀbenzo[d]imidazolꢀ1ꢀyl)methyl)ꢀNꢀmethylacetamide (7c, Table 4)
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TLC Rf=0.6 (5% MeOH/DCM); Yield 52% (30 mg); Colorless liquid; H NMR (400 MHz,
CDCl3) δ 7.95 (s, 1H), 7.56 (s, 1H), 7.33 (s, 1H), 5.69 (s, 2H), 2.99 (s, 3H), 2.39 (s, 3H), 2.37 (s,
3H), 2.13 (s, 3H).13C NMR (126 MHz, CDCl3) δ 171.4, 142.8, 142.2, 132.8, 131.7, 131.6, 120.3,
110.3, 54.9, 34.8, 21.9, 20.6, 20.2; HRMS (ESI+) calcd. for: C13H18N3O 232.1450. (M+ H),
found 232.1459.
1ꢀmethylꢀ5ꢀ(3ꢀphenylꢀ1Hꢀpyrazolꢀ1ꢀyl)pyrrolidinꢀ2ꢀone (7g, Table 4)
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TLC Rf=0.3 (60% EtOAc/Hexane); Yield 58% (34 mg); Yellow color liquid; H NMR (400
MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 2.3 Hz, 1H), 7.32 (t, J = 7.5 Hz, 2H), 7.23
(t, J = 7.3 Hz, 1H), 6.54 (d, J = 2.3 Hz, 1H), 5.65 (dd, J = 7.7, 2.2 Hz, 1H), 2.85 – 2.72 (m, 1H),
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2.64 (s, 3H), 2.55 – 2.45 (m, 2H), 2.36 – 2.23 (m, 1H); C NMR (101 MHz, CDCl3) δ 175.0,
152.6, 133.0, 128.7, 128.6, 127.9, 125.6, 103.6, 76.5, 29.1, 27.3, 25.9; HRMS (ESI+) calcd. for:
C14H15N3ONa 264.1113. (M+ Na), found 264.1116.
5ꢀ(3ꢀ(4ꢀbromophenyl)ꢀ1Hꢀpyrazolꢀ1ꢀyl)ꢀ1ꢀmethylpyrrolidinꢀ2ꢀone (7h, Table 4)
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TLC Rf=0.3 (60% EtOAc/Hexane); Yield 59% (47 mg); Yellow color liquid; H NMR (400
MHz, CDCl3) δ 7.66 – 7.55 (m, 2H), 7.48 – 7.36 (m, 2H), 7.19 (s, 1H), 6.53 (d, J = 2.4 Hz, 1H),
5.65 (dd, J = 7.7, 2.3 Hz, 1H), 2.84 – 2.72 (m, 1H), 2.66 (s, 3H), 2.56 – 2.39 (m, 2H), 2.34 – 2.25
13
(m, 1H); C NMR (126 MHz, CDCl3) δ 174.9, 151.5, 131.9, 131.7, 128.9, 127.2, 121.9, 103.6,
76.6, 29.0, 27.4, 26.0; HRMS (ESI+) calcd. for: C14H15BrN3O 320.0398. (M+H), found
320.0389.
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5ꢀ(3ꢀ(4ꢀbromophenyl)ꢀ1Hꢀpyrazolꢀ1ꢀyl)pyrrolidinꢀ2ꢀone (7i, Table 4)
TLC Rf=0.2 (60% EtOAc/Hexane); Yield 56% (42 mg); White solid; m.p.: 156ꢀ158 oC; 1H NMR
(500 MHz, CDCl3) δ 7.65 (dd, J = 6.7, 1.8 Hz, 2H), 7.50 (dd, J = 6.7, 1.9 Hz, 3H), 7.25 (s, 1H),
6.89 (s, 1H), 6.55 (d, J = 2.4 Hz, 1H), 5.89 (d, J = 7.4 Hz, 1H), 2.88 – 2.56 (m, 1H), 2.56 – 2.27
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6
7
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9
10
11
12
13
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15
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19
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59
60
13
(m, 2H); C NMR (126 MH , CDCl3) δ 178.2, 151.5, 132.0, 131.7, 128.3, 127.2, 121.9, 103.6,
70.7, 29.7, 28.5; HRMS (ESI+) calcd. for: C13H13BrN3O 306.0242. (M+ H), found 306.0245.
Nꢀ(1ꢀmethylꢀ5ꢀoxopyrrolidinꢀ2ꢀyl)benzamide 13 (9b, Table 5)
TLC Rf=0.5 (5% MeOH/DCM); Yield 61% (33 mg); White solid; 1H NMR (400 MHz, CDCl3) δ
7.85 (d, J = 7.4 Hz, 2H), 7.76 (s, 1H), 7.44 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.5 Hz, 2H), 5.84 –
13
5.72 (m, 1H), 2.73 (s, 3H), 2.50 – 2.35 (m, 2H), 2.32 – 2.20 (m, 1H), 1.96 – 1.84 (m, 1H); C
NMR (101 MHz, CDCl3) δ 174.7, 167.5, 133.4, 131.9, 128.5, 127.3, 66.0, 29.3, 27.3, 25.8;
HRMS (ESI+) calcd. for: C12H15N2O2 219.1134. (M+ H), found 219.1138.
4ꢀmethylꢀNꢀ(1ꢀmethylꢀ5ꢀoxopyrrolidinꢀ2ꢀyl)benzamide 13 (9d, Table 5)
TLC Rf=0.5 (5% MeOH/DCM); Yield 57% (33 mg); White solid; 1H NMR (400 MHz, CDCl3) δ
7.74 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 9.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 5.79 (td, J = 8.8, 3.4
Hz, 1H), 2.73 (s, 3H), 2.50 – 2.36 (m, 2H), 2.32 (s, 3H), 2.07 (dd, J = 14.1, 6.9 Hz, 1H), 1.94 –
1.83 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 174.7, 167.4, 142.5, 130.4, 129.2, 127.3, 65.9,
29.3, 27.3, 25.8, 21.5; HRMS (ESI+) calcd. for: C13H17N2O2 233.1290. (M+ H), found 233.1303.
3ꢀmethylꢀNꢀ(1ꢀmethylꢀ5ꢀoxopyrrolidinꢀ2ꢀyl)benzamide 13 (9e, Table 5)
1
TLC Rf=0.5 (5% MeOH/DCM); Yield 52% (30 mg); Colorless liquid; H NMR (400 MHz,
CDCl3) δ 7.78 – 7.61 (m, 2H), 7.46 (s, 1H), 7.33 (d, J = 6.1 Hz, 2H), 5.86 (td, J = 8.7, 3.6 Hz,
1H), 2.82 (s, 3H), 2.60 – 2.45 (m, 2H), 2.43 – 2.29 (m, 4H), 2.03 – 1.85 (m, 1H); 13C NMR (101
MHz, CDCl3) δ 174.6, 167.6, 138.5, 133.3, 132.7, 128.4, 128.0, 124.2, 65.9, 29.2, 27.3, 25.9,
21.3; HRMS (ESI+) calcd. for: C13H17N2O2 233.1290. (M+ H), found 233.1303.
Nꢀ(1ꢀmethylꢀ5ꢀoxopyrrolidinꢀ2ꢀyl)ꢀ4ꢀnitrobenzamide 13 (9f, Table 5)
TLC Rf=0.5 (5% MeOH/DCM); Yield 32% (21 mg); White solid; 1H NMR (400 MHz, CDCl3) δ
8.24 (d, J = 8.9 Hz, 2H), 8.08 (d, J = 8.9 Hz, 2H), 7.76 (d, J = 9.0 Hz, 1H), 5.83 (td, J = 8.7, 2.8
13
Hz, 1H), 2.79 (s, 2H), 2.56 – 2.18 (m, 4H), 1.93 (tdd, J = 10.7, 6.1, 3.2 Hz, 1H); C NMR (126
MHz, CDCl3) δ 175.1, 165.2, 149.9, 138.7, 128.6, 123.8, 66.5, 29.2, 27.6, 25.9; HRMS (ESI+)
calcd. for: C12H14N3O4 264.0984. (M+ H), found 264.0989.
3ꢀfluoroꢀNꢀ(1ꢀmethylꢀ5ꢀoxopyrrolidinꢀ2ꢀyl)benzamide 13 (9g, Table 5)
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TLC Rf=0.5 (5% MeOH/DCM); Yield 54% (31 mg); Colorless liquid; H NMR (400 MHz,
CDCl3) δ 7.96 (td, J = 7.8, 1.6 Hz, 1H), 7.44 (dd, J = 14.3, 6.5 Hz, 1H), 7.21 (t, J = 11.2 Hz,
1H), 7.13 – 6.94 (m, 2H), 5.78 (dt, J = 11.4, 5.5 Hz, 1H), 2.78 (s, 3H), 2.54 – 2.41 (m, 2H), 2.40
– 2.24 (m, 1H), 1.91 – 1.79 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 174.2, 162.5, 160.5 (d, J(CꢀF)
= 248.2 Hz), 133.9 (d, J(CꢀF) = 8.7 Hz) 131.9, 124.9, 120.5, 116.1 (d, J(CꢀF) = 25 Hz), 65.8, 29.1,
27.3, 26.1; HRMS (ESI+) calcd. for: C12H14FN2O2 237.1039. (M+H), found 237.1049.
4ꢀmethylꢀNꢀ(1ꢀmethylꢀ5ꢀoxopyrrolidinꢀ2ꢀylidene)benzenesulfonamide (9h, Table 5)
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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31
32
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49
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53
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55
56
57
58
59
60
1
TLC Rf=0.5 (40% EtOAc/Hexane); Yield 61% (40 mg); Colorless liquid; H NMR (400 MHz,
CDCl3) δ 7.79 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 3.36 – 3.26 (m, 2H), 2.96 (s, 3H),
2.68 – 2.61 (m, 2H), 2.37 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 177.1, 172.6, 143.6, 138.3,
129.5, 126.9, 27.9, 26.6, 26.3, 21.5; HRMS (ESI+) calcd. for: C12H15N2O3S 267.0803. (M+H),
found 267.0806.
Procedure for the synthesis of compound 10 (Fig. 3):
In a 25 ml round bottom flask with magnetic bar, compound 3d (0.13 mmol) was dissolved
in 5 ml of dry DCM under N2 atmosphere. Phenol (0.13 mmol) was added followed by the
o
addition of 0.26 mmol anhydrous AlCl3. Reaction mixture was allowed to reflux at 40 C and
progress of reaction was monitored by TLC. After completion of reaction, solvent was
evaporated and neutralized crude product with saturated NaHCO3 solution. Required product 10
was purified on column chromatography (100ꢀ200 mesh size) using EtOAc and hexane (2:8) as
eluents.
Spectral data of Nꢀ(2ꢀhydroxybenzyl)ꢀNꢀmethylbenzamide (10, Fig. 3)
1
TLC Rf=0.5 (20% EtOAc/Hexane); Yield 64% (20 mg); Colorless liquid; H NMR (400 MHz,
CDCl3) δ 9.80 (s, 1H), 7.39 (m, 2H), 7.34 (m, 3H), 7.24ꢀ7.15 (m, 1H), 7.09 (d, J = 7.4 Hz, 1H),
6.92 (d, J = 8.0 Hz, 1H), 6.76 (t, J = 7.3 Hz, 1H), 4.54 (s, 2H), 2.96 (s, 3H);13C NMR (126 MHz,
CDCl3) δ 173.2, 156.4, 134.2, 131.9, 130.6, 130.5, 128.4, 127.7, 121.2, 119.2, 117.7, 49.1, 37.1;
HRMS (ESI+) calcd. for: C15H16NO2 242.1181. (M+ H), found 242.1186.
Procedure for the synthesis compound 11 (Fig. 3):
In a 50 ml round bottom flask with magnetic bar, compound 3i (0.37 mmol) was dissolved
in 8 ml of methanol. 1Hꢀindole (0.37 mmol) was added to the reaction mixture. Con. HCl (0.7
ml) in 2 ml of water was added. Reaction mixture was refluxed and progress of the reaction was
monitored by TLC. After completion of reaction, solvent was evaporated and neutralized crude
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product with saturated NaHCO3 solution. Required product 11 was purified on column
5
6
chromatography (100ꢀ200 size) using EtOAc and hexane (70:30) as eluents.
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8
Spectral data of 5ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀ1ꢀmethylpyrrolidinꢀ2ꢀone 14 (11, Fig. 3)
9
1
TLC Rf=0.2 (70% EtOAc/Hexane); Yield 82% (65 mg); Yellow solid; H NMR (400 MHz,
10
11
12
13
14
15
16
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60
CDCl3) δ 9.04 (s, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.16 – 7.10 (m, 1H),
7.07 – 6.99 (m, 2H), 4.79 (t, J = 7.2 Hz, 1H), 2.62 (s, 3H), 2.59 – 2.53 (m, 1H), 2.51 – 2.32 (m,
2H), 2.18 – 2.07 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 175.4, 137.0, 125.2, 122.9, 122.4,
119.8, 118.7, 114.8, 111.8, 58.0, 30.8, 28.1, 26.9; HRMS (ESI+) calcd. for: C13H15N2O 215.1184
(M+ H), found 215.1167.
Procedure for the synthesis of compound 12 (Fig. 3):
In a 50 ml round bottom flask with magnetic bar, compound 3i (0.37 mmol) was
dissolved in 8 ml of methanol. Trimethoxy benzene (0.37 mmol) was added to the reaction
mixture. Con. HCl (0.7 ml) in 2 ml of water was added. Reaction mixture was refluxed and
progress of the reaction was monitored by TLC. After completion of reaction, solvent was
evaporated and neutralized crude product with saturated NaHCO3 solution. Required product 12
was purified on column chromatography (100ꢀ200 mesh size) using EtOAc and hexane (60:40)
solvents.
Spectral data of 1ꢀmethylꢀ5ꢀ(2,4,6ꢀtrimethoxyphenyl)pyrrolidinꢀ2ꢀone 15 (12, Fig. 3)
1
TLC Rf=0.3 (70% EtOAc/Hexane); Yield 85% (82 mg); White solid; H NMR (400 MHz,
CDCl3) δ 6.05 (d, J = 8.0 Hz, 2H), 5.16 (dd, J = 9.6, 4.6 Hz, 1H), 3.75 (s, 3H), 3.71 (s, 6H), 2.58
– 2.50 (m, 1H), 2.47 (s, 3H), 2.43 – 2.32 (m, 2H), 2.24 (dt, J = 16.5, 11.4 Hz, 1H), 2.02 – 1.87
(m, 1H).13C NMR (126 MHz, CDCl3) δ 175.7, 160.9, 108.1, 55.8, 55.3, 54.2, 31.1, 27.5, 23.7;
HRMS (ESI+) calcd. for: C14H20NO4 266.1392 (M+ H), found 266.1394.
Procedures for the free radical scavenger experiments with TEMPO (Fig. 3, eq. 1, 2 and 3):
To a 100 ml sealed tube with magnetic bar, azole 1 (0.25 mmol) and amide 2 (1 mmol)
was loaded. Free radical scavenger TEMPO (0.5 mmol and 1.5 mmol) was added to the reaction
mixture. tertꢀButylhydroperoxide (5ꢀ6 M in Decane) 0.75 mmol was added followed by the
addition of tetrabutylammonium iodide (0.025 mmol). Reaction mixture was allowed to stir at
o
110 C. Progress of reaction was monitored by TLC. After completion of reaction, required
products 13 and 14 were isolated on column chromatography (100ꢀ200 mesh size) using EtOAc
and hexane (40:60) solvents.
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Spectral data of NꢀmethylꢀNꢀ(((2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀyl)oxy)methyl)acetamide16
(13) (eq. 1, Fig. 4)
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8
9
TLC Rf=0.5 (40% EtOAc/Hexane); Yellow liquid. Yield 73% (90 mg, when 0.5 mmol of
TEMPO was taken, yield was calculated with respect to TEMPO). Yield 96% (220 mg, when
10
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1.25 mmol of TEMPO was taken, yield was calculated with respect to DMA); H NMR (400
MHz, CDCl3) δ 4.84 (s, 2H), 2.97 (s, 3H), 2.15 (s, 3H), 1.40 (s, 6H), 1.1 (m, 6H), 1.04 (m, 6H);
13C NMR (126 MHz, CDCl3) δ 171.8, 85.5, 60.0, 39.8, 34.1, 33.1, 29.7, 22.1, 21.5, 20.0, 17.0;
HRMS (ESI+) calcd for: C13H27N2O2 243.2073. (M+H), found 243.2075.
Spectral data of 1ꢀmethylꢀ5ꢀ((2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀyl)oxy)pyrrolidinꢀ2ꢀone (14)
(eq. 3, Fig. 4)
TLC Rf=0.5 (40% EtOAc/Hexane); Yellow liquid. Yield 62%. (78 mg, when 0.5 mmol of
TEMPO was taken, yield was calculated with respect to TEMPO); Yield 65%. (81 mg, when
1.25 mmol of TEMPO was taken, yield was calculated with respect to TEMPO); Yield 80% (208
1
mg, when 1.25 mmol of TEMPO was taken, yield was calculated with respect to NMP); H
NMR (400 MHz, CDCl3) δ 5.31 (d, J = 6.0 Hz, 1H), 3.08 (s, 3H), 2.57 (dt, J = 17.6, 9.0 Hz, 1H),
13
2.33 – 2.20 (m, 2H), 2.14 – 1.96 (m, 1H), 1.45 (d, J = 11.6 Hz, 6H), 1.37ꢀ1.14 (m, 12H); C
NMR (126 MHz, CDCl3) δ 176.6, 93.6, 60.3, 60.0, 59.7, 40.1, 39.6, 34.2, 32.7, 30.8, 29.0, 25.8,
20.3, 20.2, 17.1; HRMS (ESI+) calcd. for: C14H27N2O2 255.2073. (M+ H), found 255.2078.
Procedures for the free radical scavenger experiments with 1,1ꢀdiphenylethylene (DPE)
(Fig. 4, eq. 4 to eq. 12):
To a 100 ml sealed tube with magnetic bar, azole 1, 4, and 6 (0.25 mmol) and amide (1
mmol) was loaded. Free radical scavenger 1,1ꢀdiphenylethylene (0.5 mmol) was added to the
reaction mixture. tertꢀButylhydroperoxide (5ꢀ6 M in Decane) 0.75 mmol was added followed by
the addition of tetrabutylammonium iodide (0.025 mmol). Reaction mixture was allowed to stir
at 110 oC. Progress of the reaction was monitored by TLC. After completion of reaction, required
products 15, 16, 17and 19 were isolated on column chromatography (100ꢀ200 mesh size) using
EtOAc and hexane (20:80) as eluents. Compound 18 was isolated on column chromatography
(100ꢀ200 mesh size) using MeOH and DCM (2:98) as eluents.
Spectral data of 2ꢀ(1Hꢀbenzo[d][1,2,3]triazolꢀ1ꢀyl)ꢀ1,1ꢀdiphenylethanꢀ1ꢀol (15) (Eq. 4, 5,
Fig. 4)
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TLC Rf=0.5 (30% EtOAc/Hexane); Yield 72% (56 mg, yield was calculated based on the 1Hꢀ
1
benzotriazole); Colorless liquid; H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.3 Hz, 1H), 7.39 –
13
7.33 (m, 3H), 7.21– 7.06 (m, 11H), 5.23 (s, 2H); C NMR (126 MHz, CDCl3) δ 145.1, 143.4,
134.0, 128.4, 127.7, 127.5, 127.4, 126.4, 126.2, 123.9, 119.8, 109.7, 78.5, 57.3; HRMS (ESI+)
calcd. for: C20H18N3O 316.1450. (M+ H), found 316.1455.
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11
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Spectral data of 1,1ꢀdiphenylꢀ2ꢀ(4ꢀphenylꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)ethanꢀ1ꢀol (16) (Eq. 6, Fig.
4)
TLC Rf=0.6 (30% EtOAc/Hexane); Yield 75% (63 mg, yield was calculated based on the 4ꢀ
o
1
phenylꢀ1Hꢀ1,2,3ꢀtriazole); White solid; m.p.: 180ꢀ181 C; H NMR (500 MHz, CDCl3) δ 7.72 –
7.67 (m, 2H), 7.53 (s, 1H), 7.47 – 7.43 (m, 5H), 7.41 – 7.27 (m, 9H), 5.15 (s, 2H); 13C NMR
(126 MHz, CDCl3) δ 147.2, 143.0, 130.3, 128.8, 128.5, 128.4, 128.1, 127.9, 126.4, 126.1, 125.6,
121.3, 59.5; HRMS (ESI+) calcd. for: C22H20N3O 342.1606. (M+ H), found 342.1610.
Spectral data of 1,1ꢀdiphenylꢀ2ꢀ(5ꢀphenylꢀ2Hꢀtetrazolꢀ2ꢀyl)ethanꢀ1ꢀol (17) (Eq. 9, Fig. 4)
TLC Rf=0.6 (20% EtOAc/Hexane); Yield 75% (53 mg, yield was calculated based on the 5ꢀ
phenylꢀ1Hꢀtetrazole) Colorless liquid; 1H NMR (400 MHz, CDCl3) δ 8.08 (ddd, J = 8.2, 4.0, 2.3
Hz, 2H), 7.44 – 7.38 (m, 3H), 7.31 – 7.26 (m, 6H), 7.12 (ddd, J = 5.1, 3.9, 2.0 Hz, 5H), 4.76 (d, J
13
= 7.2 Hz, 2H); C NMR (126 MHz, CDCl3) δ 164.4, 139.1, 130.6, 128.9, 128.6, 128.4, 128.2,
127.0, 126.9, 78.7, 69.1; HRMS (ESI+) calcd for: C21H19N4O 343.1559. (M+ H), found
343.1561.
Spectral data of 2ꢀ(1Hꢀbenzo[d]imidazolꢀ1ꢀyl)ꢀ1,1ꢀdiphenylethanꢀ1ꢀol (18) (Eq. 10, Fig. 4,)
TLC Rf=0.5 (5% MeOH/DCM); Yield 42% (32 mg, yield was calculated based on the 1Hꢀ
o
1
benzimidazole); White solid; m.p.:171ꢀ173 C; H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.5
13
Hz, 1H), 7.43 (s, 1H), 7.35 – 7.19 (m, 10H), 7.17 – 7.06 (m, 4H), 4.86 (s, 2H); C NMR (126
MHz, CDCl3) δ 143.9, 128.9, 128.5, 127.8, 126.2, 122.7, 121.8, 119.6, 110.0, 78.2, 54.7; HRMS
(ESI+) calcd. for: C21H19N2O 315.1497. (M+ H), found 315.1493.
Spectral data of 2ꢀ(3ꢀ(4ꢀbromophenyl)ꢀ1Hꢀpyrazolꢀ1ꢀyl)ꢀ1,1ꢀdiphenylethanꢀ1ꢀol (19) (Eq.
11, Fig. 4)
TLC Rf=0.5 (40% EtOAc/Hexane); Yield 12% (13 mg, yield was calculated based on the 1Hꢀ(3ꢀ
o
(4ꢀbromophenyl)ꢀ1Hꢀpyrazole); White solid; m.p.:193ꢀ195 C; 1H NMR (400 MHz, CDCl3) δ
7.55 (d, J = 8.6 Hz, 2H), 7.47 – 7.35 (m, 6H), 7.24 (t, J = 7.4 Hz, 4H), 7.16 (ddd, J = 8.5, 2.5, 1.3
Hz, 2H), 7.11 (d, J = 2.3 Hz, 1H), 6.29 (d, J = 2.4 Hz, 1H), 6.07 (s, 1H), 4.77 (s, 2H); 13C NMR
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