Propargylamine (secondary) as a building block in indole synthesis involving ultrasound assisted Pd/Cu-catalyzed coupling-cyclization method: Unexpected formation of (pyrazole)imine derivatives

Article abstract of DOI:10.1016/j.tetlet.2018.11.037

Propargylamine (secondary) has been explored as a building block in synthesizing indoles via an ultrasound assisted Pd/Cu-catalyzed coupling-cyclization method. Indoles containing a pyrazole moiety at C-2 attached via the –CH₂NH– linker (designed as potential anti-tubercular agents) were synthesized first and then generality/scope of the methodology was expanded by synthesizing other indoles. Unexpected formation of imine side products in first cases helped in synthesizing related (pyrazole)imines via a Cu catalyzed ultrasound assisted aerobic oxidation of precursor amines.

Full text of DOI:10.1016/j.tetlet.2018.11.037

Accepted Manuscript
Propargylamine (secondary) as a building block in indole synthesis involving
ultrasound assisted Pd/Cu-catalyzed coupling-cyclization method: unexpected
formation of (pyrazole)imine derivatives
Gangireddy Sujeevan Reddy, Suresh Babu Nallapati, P.S.V.K. Sri Saranya, B.
Sridhar, Varadaraj Bhat Giliyaru, Raghu Chandrashekhar Hariharapura, G.
Gautham Shenoy, Manojit Pal
PII:
S0040-4039(18)31365-0
https://doi.org/10.1016/j.tetlet.2018.11.037
TETL 50422
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 October 2018
11 November 2018
12 November 2018
Please cite this article as: Sujeevan Reddy, G., Babu Nallapati, S., Sri Saranya, P.S.V.K., Sridhar, B., Bhat Giliyaru,
V., Chandrashekhar Hariharapura, R., Gautham Shenoy, G., Pal, M., Propargylamine (secondary) as a building
block in indole synthesis involving ultrasound assisted Pd/Cu-catalyzed coupling-cyclization method: unexpected
formation of (pyrazole)imine derivatives, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2018.11.037
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Propargylamine (secondary) as a building block in
indole synthesis involving ultrasound assisted Pd/Cu-
catalyzed coupling-cyclization method: unexpected
formation of (pyrazole)imine derivatives
Leave this area blank for abstract info.
Gangireddy Sujeevan Reddy, Suresh Babu Nallapati, P.S.V.K. Sri Saranya, B. Sridhar, Varadaraj Bhat Giliyaru,
Raghu Chandrashekhar Hariharapura, G. Gautham Shenoy and Manojit Pal*
chorismate mutase
NCEs
I
R
NH
NH
air
Cu-cat
Z
N
+
Pd/Cu-cat
H2NOC
N
H
N
Z
Me
R
N
N
R = alkyl, aryl
Z = Ms, Ts etc
N
n-Pr
Z
The rare use of propargylamine has been explored as a building block in the Pd/Cu-catalyzed synthesis of
indoles (and certain imines) under ultrasound.

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Propargylamine (secondary) as a building block in indole synthesis involving
ultrasound assisted Pd/Cu-catalyzed coupling-cyclization method: unexpected
formation of (pyrazole)imine derivatives
Gangireddy Sujeevan Reddy,a,b Suresh Babu Nallapati,a P.S.V.K. Sri Saranya,a B. Sridhar,c Varadaraj Bhat
Giliyaru,b Raghu Chandrashekhar Hariharapura,b G. Gautham Shenoyb and Manojit Pala,*
aDr Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India.
bManipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Madhav Nagar, Manipal, 576 104, Karnataka, India.
cX-ray Crystallography Division, CSIR-IICT, Tarnaka, Hyderabad-500007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Propargylamine (secondary) has been explored as a building block in synthesizing indoles via an
ultrasound assisted Pd/Cu-catalyzed coupling-cyclization method. Indoles containing a pyrazole
moiety at C-2 attached via the -CH2NH- linker (designed as potential anti-tubercular agents)
were synthesized first and then generality / scope of the methodology was expanded by
synthesizing other indoles. Unexpected formation of imine side products in first cases helped in
synthesizing related (pyrazole)imines via a Cu catalyzed ultrasound assisted aerobic oxidation of
precursor amines.
Available online
Keywords:
Propargylamine
Indole
2009 Elsevier Ltd. All rights reserved.
Pyrazole
Palladium
Antitubercular
Propargylamines are well known building blocks in the
synthesis of diverse N-heteroarenes including indoles.1 The
transition metal mediated coupling / cyclization (performed either
in the same pot2,3 or separately4) on the other hand has become a
common strategy for the synthesis of 2-substituted indoles.5 The
one-pot coupling-cyclization leading to indole derivatives
typically involves in situ generation of 2-alkynylanilides
followed by spontaneous cyclization in the same pot. The use of
a wide variety of terminal alkynes that are key reactants in these
reactions has been reported till date. While the use of propargyl
alcohol, ether and their derivatives (A, Fig. 1) are also common
in these one-pot reactions the use of propargylamines (B-D, Fig.
1) especially the primary and secondary types (B and C, Fig. 1)
surprisingly remained underexplored for the synthesis of indoles.
For example, the use of propargylamine of type D (Fig. 1) was
explored by Wang et al in the synthesis of indoline derivatives6
(Scheme 1a) that was speculated to involve an initial Pd-
catalyzed Sonogashira coupling followed by several steps
(involving indole cyclization, regio- and chemoselective N-1-
acylation, and finally, a 1,4-Michael addition). Previously,
A; X = OH or OR (explored)
B
X
; X = NH2
(not explored)
C; X = NHR
D; X = NRR' (explored)
Fig. 1. Propargyl alcohol, ethers and amines explored/ not explored for
indole synthesis.
one-pot Pd(II) catalyzed synthesis of cycloalkane-fused indoles
was reported by Lu et al7 (Scheme 1b) where D was used to
prepare the required substrate. While the use of C under
Sonogashira conditions has been reported by Larock et al8 there
is no precedence on the use of B or C for the direct and one-pot
synthesis of indoles. Herein we report the use of propargylamine
of type C for the synthesis of 2-substituted indoles via a one-pot,
ultrasound assisted Pd/Cu-catalysed coupling-cyclization method
(Scheme 1d). An unexpected formation of corresponding imine
derivatives was also observed in certain cases during this study
the details of which are presented.
Over the years compounds containing pyrazole framework have
attracted particular interest because of their natural occurrences
and diverse pharmacological properties including antimicrobial
and antitubercular activities.9 Indoles on the other hand are well
known scaffolds for the design and synthesis of antimicrobial
agents. In continuation of our effort in the discovery of indole-
based novel inhibitors of chorismate mutase (CM) as potential
antitubercular agents10a,b we became interested in constructing a
----------------
* Corresponding author: Tel.: +91 40 6657; fax: +91 40 6657 1581
E-mail address: manojitpal@rediffmail.com (MP)

2
Tetrahedron Letters
(a) Wang et al6 (use of propargyl amine of type
)
indicated two H-bonds involving the linker and the amide –NH-
D
of I-3 with the GLN 64 residue of the protein. It was therefore
necessary to have a direct and convenient access to compounds
based on I-3.
Pd(OAc)2
PPh3
Z
I
R
N
R
NZ
N
+
K2CO3
TBAB
(Z = Ms, Ts etc)
NH
O
O
Initially, the pyrazole-5-carboxamide derivative12 1a and 2-
iodoanilide 2a were used as model substrates (Table 1) and the
reaction was performed in the presence of (PPh3)2PdCl2/CuI in
EtOH at 80 ºC for 5 h when 3a was isolated in moderate yield
(entry 1, Table 1). Interestingly, a side product 4a was isolated
from the same reaction that was characterized as the
corresponding imine derivative of 3a (vide infra for further
details). In order to suppress the formation of 4a the reaction was
performed in different solvents in the presence of different bases
(entries 2-5, Table 1). However, no significant improvement was
observed. Anticipating that 4a was generated from 3a we aimed
for a shorter reaction time hoping that the conversion of 3a to 4a
could be minimized. Accordingly, the reaction was performed at
COCF3
(predominantly Pd(0) catalysis)
(b) Lu et al7 (use of propargyl amine of type
)
D
O
Pd(OAc)2
bpy
N
CN
NTs
Ts
HOAc or
TsOH.H2O
Dioxane, reflux
NH
Ts
N
Ts
(Pd(II)-catalysis)
(c) Larock et al8 (use of propargyl amine of type
)
C
Ph
N
(PPh3)2PdCl2
CuI
H
I
H
+
N
Ph
Et3N, 20 oC
NH2
NH2
o
60 C under ultrasound irradiation using a laboratory ultrasonic
(Pd(0) catalysis)
bath producing irradiation of 35 kHz (entry 6, Table 1). To our
delight the reaction was completed within 30 min affording 3a in
good yield with trace amount of 4a. While formation of 4a was
suppressed completely in solvents like MeCN or DMSO the yield
of 3a was decreased significantly in these cases (entry 7 and 8).
Notably, the use of CuI alone also afforded 3a in good yield but
the requirement of catalyst was higher and the reaction time was
longer in this case (entry 9, Table 1). Overall, the combination of
(PPh3)2PdCl2-CuI-Et3N-EtOH at 60 ºC under ultrasound
irradiation was optimal for the preparation of 3a and was used for
the synthesis of various analogues of 3a.
C
(d) Current work (use of propargyl amine of type
I
)
R
NH
H
+
N
R
Pd/ Cu-cat
NH
N
Z
Z
[R = alkyl, (het)aryl; Z = Ms, Ts etc]
(when
R = Pz)
(when
R = Pz)
conventional
heating
NPz
Cu-cat
air
Cu-cat
N
(one-pot)
Z
(Pz = 5-carbamoyl-1-methyl-3-propyl-1H-pyrazole-4-yl)
Table 1. Effect of reaction conditions on the coupling-
cyclization of 1a with 2a
Scheme 1. Use of propargyl amines towards construction of
indole ring
Me
NH2
O
Me
NHPz
NHSO2Me
I
NPz
(Het)aryl
L
RO2SHN
N
N
(PPh3)2PdCl2
N
HN
N
+
+
O
O
S
Me
S
Me
N
N
CuI
base solvent
N
O
NHPz Me
O
S
O
S
O
S
O
1a
2a
I-3
3a
O
4a
I-2
I-1
O
O
Pz =
O
NH2
N
N
Me
Entry
Base
Solvent
Temp (ºC);
Time (h)
Yield (%)b
3a
4a
10
12
19
20
10
5
1
2
3
4
5
6
7
8
9
K2CO3
Cs2CO3
Et3N
EtOH
EtOH
EtOH
DMSO
MeCN
EtOH
MeCN
DMSO
EtOH
80; 5
45
80; 5
40
80; 6
45
Et3N
80; 6
40
Et3N
80; 6
35
Fig. 2. Design of new indole derivative I-2 and I-3 from the known indole
framework I-1 and binding mode of I-3 (a representative molecule) with
chorismate mutase (PDB code: 2FP2).
Et3N
60; 0.5
60; 0.5
60; 0.5
60; 2.5
82c
52c
55c
80c,d
Et3N
-
Et3N
-
library of molecules based on the framework I-3 (Fig. 2)
containing indole and pyrazole ring together. Our design mainly
involved the introduction of a linker “L” at the C-2 of known
indole10c I-1 to provide structurally flexible and novel10d I-2
possessing CM inhibiting properties. While a large variety of
compounds can be derived from I-2 by varying “L” and the
“(het)aryl” group initially, we focused on the framework I-3 (also
derived from I-2) where the pyrazole11 moiety as a representative
heteroaryl group was connected to the indole ring via the -
CH2NH- linker. Indeed, this design i.e. introduction of linker and
amide was justified by the in silico docking studies of a
representative compound into the active site of CM (Fig 2) that
Et3N
7
aReactions were carried out using alkyne 1a (1 mmol), 2a (1.2
mmol), base (2.0 mmol), (PPh3)2PdCl2 (1 mol%) and CuI (1 mol
%) in a solvent (10 mL) under nitrogen.
bIsolated yield.
cThe reaction was performed under ultrasound.
dCuI (10 mol%) was used in place of (PPh3)2PdCl2 (1 mol%) +
CuI (1 mol %).

3
A variety of indole-pyrazole derivatives (3) were prepared via
the coupling-cyclization of 1a with a range of 2-iodoanilides (2)
(Table 2). The ultrasound assisted reaction proceeded well in all
these cases affording the desired product in good yields.
Substituents like F, Cl, Br and Me on the anilide ring and groups
such as mesyl, p-tosyl, benzenesufonyl and 2-thienosulfonyl at
the anilide nitrogen were tolerated under the conditions
employed. Notably, the use of a bis-propargylated amine (1b)
under this reaction condition was also successful as 1b
participated in dual coupling-cyclization when reacted with 2c
affording an interesting bis-indole derivative 5 (Scheme 2).
irradiation (Table 3) when the corresponding indoles (6a-f)
were obtained in good yields. Indeed, propargylamines 1d and 1e
also participated well and afforded the expected indole derivative
6g-i in high yield (Table 3). While 2-(aminomethyl)indoles have
been synthesized13 via an elegant 3-component reaction
(involving 2-ethynylanilides, paraformaldehyde and secondary
amines in the presence of CuBr) the methodology appeared to be
suitable for accessing indoles possessing a tertiary aminoethyl
group rather than a secondary aminoethyl moiety (like 3 or 4) at
C-2.
Table 3. Use of propargylamine 1c-e in indole synthesis.a
R1
R1
+
I
HN R
Table 2. Cu-catalysed synthesis of indole-pyrazole
derivatives (3) under ultrasound irradiation.a
(PPh3)2PdCl2
N
NH
R2 SO2R3
2
NH
R
SO2R3
CuI, Et3N
EtOH, 60oC
30 min
R2
NH2
O
1a
6
1
Me
N
N
R1
I
R1
HN
1
2
Products (6)
%yieldb
(PPh3)2PdCl2
CuI, Et3N
EtOH, 60oC
30 min
N
NH
SO2R3
R =
R1
H
Br
H
Cl
H
F
R
R3
SO2R3
R2
R2
1c; o-(NH2CO)C6H4
2b
2c
2g
2j
H
H
H
H
H
H
H
H
H
p-MeC6H4 6a
p-MeC6H4 6b
78
80
82
77
75
79
83
80
82
2
3
1c
2-Iodoanilides (2)
Products (3)
%Yieldb
1c
Me
p-MeC6H4 6d
Ph 6e
6c
R1
R2
H
H
H
H
H
H
H
Me
H
H
H
H
R3
1c
2a
2b
2c
2d
2e
2f
Me
H
Me
3a
3b
3c
3d
3e
3f
82
81
80
74
73
75
82
70
70
74
73
80
1c
2k
2l
p-MeC6H4
p-MeC6H4
2-thienyl
Ph
1c
p-MeC6H4 6f
p-MeC6H4 6g
p-MeC6H4 6h
p-MeC6H4 6i
Br
Cl
Cl
Br
H
1d; Ph
2b
2b
2l
H
H
F
1e; Cyclohexyl
1e
2-thienyl
Me
aReactions were performed using a mixture of 1c-e (1.0
mmol), 2 (1.2 mmol), (PPh3)2PdCl2 (1 mol%), CuI (1 mol %) and
Et3N (2.0 mmol) in EtOH (10 mL) under ultrasound irradiation
(35 KHz) at 60 °C under nitrogen.
2g
2h
2i
3g
3h
3i
Me
Cl
Cl
H
Me
Me
bIsolated yield.
2j
p-MeC6H4
Ph
3j
2k
2l
3k
3l
Finally, the importance of imine compounds (Schiff bases) as
antimicrobial agents14 intrigued us to prepare 4a (Table 1) and its
analogues. Our initial attempt to synthesize 4a as a sole or major
product via the Cu-catalysed reaction of 1a with 2a in a single-
pot under conventional heating was not successful. Indeed 4a
was isolated in ~ 40% yield when the reaction was performed for
a longer time (24h). Considering 3a as an in situ precursor of 4a,
we used 3a as the substrate and the reaction was performed under
ultrasound for 4h in the presence of air. To our satisfaction the
yield of 4a was improved significantly in this case (Table 4).
Thus a number of imines (4b-f) were synthesized using this
method in good yield (Table 4) whereas the one-pot method (i.e.
the reaction of 1 with 2 for 24h) afforded these compounds in 35-
58% yield. Notably all these reactions were performed using
excess of Et3N (5 mmol) as the conversion was slow when 2
mmol of Et3N was used. The reaction was also sluggish in the
absence of air or ultrasound and did not proceed in the absence of
CuI indicating their key role in this transformation. Notably, our
attempt to prepare the corresponding imine derivatives from
indoles 6 was not successful under the condition employed.
Perhaps the N-methylpyrazole moiety played a key role in
oxidation of amine 3 to the imine 4 (see later for mechanistic
discussion).
F
p-MeC6H4
aReactions were performed using a mixture of 1a (1.0 mmol),
2 (1.2 mmol), (PPh3)2PdCl2 (1 mol%), CuI (1 mol %) and Et3N
(2.0 mmol) in EtOH (10 mL) under ultrasound irradiation (35
KHz) at 60°C under nitrogen.
bIsolated yield.
Br
Ts
2c
N
Br
N
N
N
(PPh3)2PdCl2
O
N
N
N
CuI, Et3N, EtOH
60oC, 30 min
80%
NH2
N
Me
Ts
O
Me
1b
5
H2N
Scheme 2. Ultrasound assisted coupling-cyclization of 1b
with 2c under Pd/Cu-catalysis.
Having prepared a range of pyrazole containing novel indole
derivatives (3) we focused on assessing generality of the present
ultrasound assisted Pd/Cu-catalyzed reaction by using simpler
propargylamines. Accordingly, 1c (the benzene analogous to 1a)
were prepared and employed in Pd/Cu-catalyzed coupling-
cyclization with a number of 2-iodoanilides (2) under ultrasound

4
Tetrahedron Letters
Table 4. Ultrasound assisted synthesis of imines (4).a
NH2
NH2
O
O
Me
Me
N
N
R1
N
N
R1
N
HN
air
N
N
CuI, Et3N
SO2R3
R2
SO2R3
R2
EtOH, 60oC
4h
4
3
Amines (3)
R1
Products
(4)
%yieldb
R2
H
H
H
H
H
H
R3
3a
3b
3d
3j
Me
H
Me
4a
4b
4c
4d
4e
4f
67
65
68
69
70
78
p-MeC6H4
2-thienyl
p-MeC6H4
Ph
Cl
Cl
H
Fig. 3. A view of 3a, showing the atom-labelling scheme. Displacement
ellipsoids are drawn at the 30% probability level and H atoms are represented
by circles of arbitrary radii.
3k
3l
F
p-MeC6H4
aReactions were performed using a mixture of 3 (1.0 mmol),
CuI (10 mole %) and Et3N (5.0 mmol) in EtOH (10 mL) under
ultrasound irradiation (35 KHz) at 60°C for 4h in the presence of
air.
bIsolated yield.
All the compounds (3-6) synthesized were characterized by
spectral data. Briefly, a singlet near ~6.3–6.7  and a doublet near
1
4.2  in the H NMR spectra of 3 were due to the C-3 indole
1
proton and the –CH2NH- moiety, respectively. A similar H
NMR data were obtained for 6. However, the compound 4 was
1
characterized by presence of the imine proton near 9  in the H
NMR spectra. Nevertheless, the molecular structure of two
representative compounds e.g. 3a (amine) and 4b (imine) was
confirmed unambiguously by their respective single crystal X-ray
data (Fig. 3 and 4).15 The data suggested anti –CH=N- geometry
for 4b and an intramolecular H-bond between the imine nitrogen
and the amidic hydrogen (Fig. 4).
Fig. 4. A view of 4b, showing the atom-labelling scheme. Displacement
ellipsoids are drawn at the 30% probability level and H atoms are represented
by circles of arbitrary radii. Intramolecular hydrogen bond is shown as
dashed lines. Minor disordered atoms (ClD/Cl2D/Cl3D) of trichloromethane
solvate have been omitted for clarity.
According to a plausible mechanism2,3 (Scheme 3) the initial
step (Sonogashira coupling) involved the generation of organo-
Pd(II) species E-1 [via oxidative addition of Pd(0) to 2] that on
transmetalation with Cu(I)-acetylide (generated in situ from 1)
afforded E-2. On reductive elimination E-2 produced E-3 with
the regeneration of Pd(0)-catalyst thereby completing the first
catalytic cycle. Next, the Cu(I)-catalyst participated in the second
catalytic cycle via promoting the intramolecular cyclization of E-
3. Indeed, the interaction of Cu(I) with the alkyne moiety of E-3
seemed to be favoured by the coordination with the proximate
amino group leading to E-4 followed by E-5 that afforded the
desired indole 3. The regeneration of Cu(I)-catalyst completed
the second catalytic cycle. In the absence of ultrasound the Cu-
catalyst participated further to afford imine 4 as a side product
(Table 1) via E-6 (path a) though less efficiently perhaps due to
the low conversion rate of Cu(0) generated to the Cu(I) species in
the absence of a proper oxidizing agent. However, efficiency of
this step was improved in the presence of aerial oxygen16 when
E-6 was generated from 3 via path b (Table 4). Moreover, the
formation of E-6 appeared to be more facile in case of 3 over 6
perhaps due to the enhanced resonance stabilization caused by
the N-methylpyrazole ring that was absent in case of 6 (Fig. 5). It
is worthy to mention that while one or more steps of these
catalytic cycles e.g. oxidative addition, trans-metalation,
reductive elimination of Pd(0), or cyclization etc were
accelerated by ultrasound, the ultrasound played an important
role in driving the reaction towards completion within short
duration.17
Pd(II)
RHN
2
Pd(0)
B
BH
CuI
N
Z
oxidative
addition
E-3
(
)
RHN
Cu
I
Z= Ms, Ts etc
B = Et3N
reductive
elimination
(II)
I
Pd
BH
N
Z
E-1
(
)
N
BH
NHR
E-4
(
)
Z
CuI + B
transmetalation
Cu
BH
I
cyclization
Cu
1
(II)
I
Pd
RHN
B
3
BH
N
Z
N
RHN
E-2
(
)
(E-5)
Z
Path b
Cu
BH
Cu(0)
RN
Path a
air
4
N
H
(E-6)
Z
Scheme 3. The plausible reaction mechanism for ultrasound
assisted Pd/Cu-catalysed coupling-cyclization of
propargylamine (1) with 2-iodoanilides (2).
.
that involved measurement of catalytic activity of enzyme (CM)
in the conversion of chorismate (substrate) to prephenate. A
known inhibitor i.e. 4-(3,5-dimethoxyphenethylamino)-3-nitro-5-
sulfamoylbenzoic acid19 was used as a reference compound (IC50
< 10 mM). The compound 3c showed significant inhibition (57.4
Most of the pyrazole containing compounds i.e. 3 and 4 were
tested for their CM inhibitory properties in vitro18 using an assay

5
Poondra, R. R.; Iqbal, J.; Pal, M. Org. Biomol. Chem., 2011, 9,
3808; (e) Prasad, B.; Adepu, R.; Sandra, S.; Rambabu, D.;
Krishna, G. R.; Reddy, C. M.; Deora, G. S.; Misra, P.; M. Pal,
± 3.70%) of CM when tested at 50 µM. This was supported by
the initial docking of 3c into the CM that showed H-bond
between –CONH2 group of 3c with ILE 67 and TYR 110 residue
of CM. While detailed pharmacological studies of this class of
compounds are currently ongoing the compound 3c appeared to
be of further interest in view of the fact that tuberculosis is a
leading cause of death worldwide.
Chem. Commun., 2012, 48, 10434; (f) Oskooie, H. A.; Heravi, M.
M.; Behbahani, F. K. Molecules 2007, 12, 1438.
4.
(a) Hiroya, K.; Itoh, S.; Sakamoto, T. Tetrahedron, 2005, 61,
10958; (b) Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem., 2004,
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NH2
NH2
O
O
Me
Cu
Me
Cu
N
N
R1
N
N
R1
N
N
N
N
SO2R3
R2
SO2R3
R2
Fig. 5. Resonance stabilization of E-6 generated from 3.
In conclusion, we have described the rare use of
propargylamine (secondary) as a building block in the synthesis
of 2-substituted indoles. Accordingly, ultrasound assisted
methodology has been developed to prepare (i) indoles via
Pd/Cu-catalyzed coupling-cyclization strategy and (ii) certain
imines via Cu-catalyzed aerobic oxidation of precursor amines.
Initially indoles containing a pyrazole moiety at C-2 attached via
the -CH2NH- linker were synthesized that were originally
designed as potential anti-tubercular agents. Thus 1-methyl-4-
(prop-2-ynylamino)-3-propyl-1H-pyrazole-5-carboxamide was
coupled for the first time with a variety of 2-iodoanilides to
afford novel indoles in 70-82% yield. Subsequently, the scope
and generality of this methodology was expanded by preparing
similar but simpler indole derivatives in 75-83% yield. The
unexpected formation of imine side products in certain cases
helped in synthesizing related (pyrazole)imines in 65-78% yield.
While this finding seemed to be uncommon the results however
indicated that the imine formation was favored by the presence of
N-methylpyrazole moiety. The initial chorismate mutase
inhibitory properties of these indole derivatives highlighted their
potential for further Med Chem effort. Overall, the current
research related to propargylamine / indole chemistry could
attract further interest.
5.
6.
Liu, Y.; Huang, Y.; Song, H.; Liu, Y.; Wang, Q. Chem. - Eur. J.
2015, 21, 5337.
7.
8.
Xia, G. Q.; Han, X. L.; Lu, X. Y. Org. Lett. 2014, 16, 2058.
Zhang, X.; Campo, M. A.; Yao, T.; Larock, R. C. Org. Lett. 2005,
7, 763 - 766
9.
Karrouchi, K.; Radi, S.; Ramli, Y.; Taoufik, J.; Mabkhot, Y. N.;
Al-aizari, F. A.; Ansar, M. Molecules 2018, 23, 134;
doi:10.3390/molecules23010134
10. (a) Due to its absence in animals but not in bacterial
Mycobacterium tuberculosis H37Rv chorismate mutase (CM) is
considered as a promising target for the identification of new and
potential antitubercular agents, for a review, see: Khanapur, M.;
Alvala, M.; Prabhakar, M.; Kumar, K. S.; Edwin, R. K.; Saranya,
P. S. V. K. S.; Patel, R. K.; Bulusu, G.; Misra, P.; Pal, M. Bioorg.
Med. Chem. 2017, 25, 1725; (b) see also: End to killer TB?
Scientists identify an enzyme that may hold clue;
https://researchmatters.in/article/end-killer-tb-scientists-identify-
enzyme-may-hold-clue; (c) Nakhi, A.; Prasad, B.; Reddy, U.; Rao,
R. M.; Sandra, S.; Kapavarapu, R.; Rambabu, D.; Krishna, G. R.;
Reddy, C. M.; Ravada, K.; Misra, P.; Iqbal, J.; Pal, M. Med.
Chem. Commun. 2011, 2, 1006; (d) The discovery and
development of novel chemical class of molecules / agents is
considered as one of the powerful approaches to overcome
existing resistance mechanisms and combat life-threatening
infections caused by bacteria.
Acknowledgements
GSR thanks DST, India for
a INSPIRE fellowship
11. Indeed, the pyrazolecarboxamide derivatives have been explored
as potential antifungal agents, see: Mu, J.-X.; Shi, Y.-X.; Yang,
M.-Y.; Sun, Z.-H.; Liu, X.-H.; Li, B.-J.; Sun, N.-B. Molecules
2016, 21, 68.
(IF160590). Authors thank the Management of DRILS,
Hyderabad, India and Manipal University, Manipal, India for
encouragement and support and DBT, New Delhi, India for
financial assistance (Grant No. BT/PR12817/COE/34/23/2015).
Authors also thank Prof P. Misra and Ms. R. Edwin of DRILS,
Hyderabad for in vitro assay.
12. The propargyl amine 1a was prepared in 80% yield via the
reaction of 4-amino-1-methyl-3-propyl-1H-pyrazole-5-
carboxamide with propargyl bromide in the presence of K2CO3 in
DMF at room temp for 5h.
13. (a) Ohno, H.; Ohta, Y.; Oishi, S.; Fujii, N. Angew. Chem., Int. Ed.,
2007, 46, 2295; (b) Ohta, Y.; Chiba, H.; Oishi, S.; Fujii, N.; H.
Ohno, J. Org. Chem., 2009, 74, 7052.
Supplementary data
14. For a review on antimicrobial activities of Schiff bases, see: da
Silva, C. M.; da Silva, D. L.; Modolo, L. V.; Alves, R. B.; de
Resende, M. A.; Martins, C. V. B.; Fátima, Â. J. Adv. Res. 2011,
2, 1-8
Supplementary data associated with this article can be found,
in the on line version, at xxxxxxxxx
15. (a) Crystal Data for 3a: C19H25N5O3S (M =403.50 g/mol):
monoclinic, space group P21/c (no. 14), a = 12.012(2) Å, b =
12.463(2) Å, c = 14.490(3) Å, β = 109.11(3)°, V = 2049.6(7) Å3,
Z = 4, T = 294.15 K, μ(MoKα) = 0.188 mm-1, Dcalc =
1.308 g/cm3, 56864 reflections measured (4.42° ≤ 2Θ ≤ 55.348°),
4772 unique (Rint = 0.0232, Rsigma = 0.0126) which were used in
all calculations. The final R1 was 0.0497 (I > 2σ(I)) and wR2 was
0.1515 (all data). CCDC 1867683 contains supplementary
Crystallographic data for the structure. (b) Crystal Data for 4b:
C25H26N5O3SCl3 (M =582.92 g/mol): monoclinic, space group
P21/n (no. 14), a = 14.0837(3) Å, b = 8.9510(2) Å, c =
21.8716(4) Å, β = 101.1726(6)°, V = 2704.95(10) Å3, Z = 4, T =
294.15 K, μ(MoKα) = 0.453 mm-1, Dcalc = 1.431 g/cm3, 46657
reflections measured (4.93° ≤ 2Θ ≤ 56.828°), 6746 unique (Rint =
0.0578, Rsigma = 0.0410) which were used in all calculations. The
final R1 was 0.0505 (I > 2σ(I)) and wR2 was 0.1290 (all data).
CCDC 1867705 contains supplementary Crystallographic data for
the structure.
References and notes
1.
2.
For an in depth review, see: Lauder, K.; Toscani, A.; Scalacci, N.;
Castagnolo, D. Chem. Rev., 2017, 117, 14091.
(a) Cacchi, S.; Fabrizi, G.; Parisi, L. M. Org. Lett., 2003, 5, 3843;
(b) Cacchi, S.; Fabrizi, G.; Parisi, L. M.; Bernini, R. Synlett, 2004,
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Org. Lett., 2004, 6, 2909; (d) Liu, F.; Ma, D. J. Org. Chem., 2007,
72, 4844.
3.
(a) Pal, M.; Subramanian, V.; Batchu, V. R.; Dager, I. Synlett,
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Reddy, U.; Rao, R. M.; Sandra, S.; Kapavarapu, R.; Rambabu, D.;
Krishna, G. R.; Reddy, C. M.; Ravada, K.; Misra, P.; Iqbal, J.; Pal,
M. Med. Chem. Commun., 2011, 2, 1006; (d) Rao, R. M.; Reddy,
U.; Nakhi, A.; Mulakayala, N.; Alvala, M.; Arunasree, M. K.;

6
Tetrahedron Letters
16. Patil, R. D.; Adimurthy, S. RSC Adv., 2012, 2, 5119.
these cavitation-induced overall effects are responsible for
facilitating the key steps in the present reaction.
17. The role of ultrasound in the present reaction can be explained as
follows: The cavitation caused by ultrasound is involved with the
growth, oscillation, and collapse of bubbles under the action of an
acoustic field, see: (a) Mason, T.J.; Peters, D. Practical
18. (a) Kim, S. K.; Reddy, S. K.; Nelson, B. C.; Vasquez, G. B.;
Davis, A.; Howard, A. J.; Patterson, S.; Gilliland, G. L.; Ladner, J.
E.; Reddy, P. T.; J. Bacteriol., 2006, 188, 8638; (b) Sasso, S.;
Ramakrishnan, C.; Gamper, M.; Hilvert, D.; Kast, P. FEBS J.,
2005, 272, 375.
Sonochemistry; Ellis Horwood: New York, NY, USA, 1991 and
(b) Mason, T.J. Sonochemistry and the environment - providing a
"green" link between chemistry, physics and engineering.
Ultrason. Sonochem. 2007, 14, 476. On the other hand the
cavitational collapse creates drastic conditions (e.g. the
19. Agarwal, H.; Kumar, A.; Bal, N. C.; Siddiqi, M. I.; Arora, A.
Bioorg. Med. Chem. Lett., 2007, 17, 3053.
temperature of 2000–5000 K and pressure up to 1800 atmosphere)
inside the medium within an extremely short period of time. Thus,
.
Highlights
 Explored the rare use of propargylamine
as a building block in the Pd/Cu catalyzed
synthesis of indoles under ultrasound.
 Indoles containing a pyrazole moiety at C-
2 attached via the -CH2NH- linker were
synthesized as anti-tubercular agents.
 Synthesized related (pyrazole)imines via a
Cu catalyzed ultrasound assisted aerobic
oxidation of precursor amines.