Copper(II)-catalyzed-α-C(sp3)-H activation of cyclic amines: A simple and efficient strategy for the synthesis of fused pyrazole derivatives

Article abstract of DOI:10.1016/j.tetlet.2018.10.017

In this paper, we have described a simple and efficient strategy for the synthesis of fused pyrazole derivatives. The key steps of our strategy involves hydroamination, copper-catalyzed cross dehydrogenative coupling (CDC) followed by aromatization (aerial oxidation) in one-pot. Our strategy offers a valuable alternative to known methods for synthesis of fused pyrazole derivatives. Overall, we have synthesized 13 diverse fused pyrazole derivatives in moderate to excellent yields.

Full text of DOI:10.1016/j.tetlet.2018.10.017

Accepted Manuscript
Copper(II)-catalyzed-α-C(sp3)-H activation of cyclic amines: a simple and ef-
ficient strategy for the synthesis of fused pyrazole derivatives
Venkata Reddy Regalla, RamaKrishnam Raju Addada, Anindita Chatterjee
PII:
S0040-4039(18)31225-5
https://doi.org/10.1016/j.tetlet.2018.10.017
TETL 50327
DOI:
Reference:
Tetrahedron Letters
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7 October 2018
10 October 2018
Please cite this article as: Regalla, V.R., Addada, R.R., Chatterjee, A., Copper(II)-catalyzed-α-C(sp3)-H activation
of cyclic amines: a simple and efficient strategy for the synthesis of fused pyrazole derivatives, Tetrahedron
Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.10.017
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Graphical Abstract
Copper(II)-catalyzed-α-C(sp3)-H activation
of cyclic amines: a simple and efficient
strategy for the synthesis of fused pyrazole
derivatives
Leave this area blank for abstract info.
Venkata Reddy Regalla, RamaKrishnam Raju Addada, Anindita Chatterjee*

1
Tetrahedron Letters
Copper(II)-catalyzed-α-C(sp3)-H activation of cyclic amines: a simple and
efficient strategy for the synthesis of fused pyrazole derivatives
Venkata Reddy Regallaa,b, RamaKrishnam Raju Addadaa,b, Anindita Chatterjee a,
a
Department of Chemistry, K L University, Vaddeswaram, Guntur (Dist), A.P, India
b GVK Biosciences Private Limited, Medicinal Chemistry Division 28A, IDA, Nacharam, Hyderabad 500076, Telangana, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
In this paper, we have described a simple and efficient strategy for the synthesis of fused
pyrazole derivatives. The key steps of our strategy involves hydroamination, copper-catalyzed
cross dehydrogenative coupling (CDC) followed by aromatization (aerial oxidation) in one-pot.
Our strategy offers a valuable alternative to known methods for synthesis of fused pyrazole
derivatives. Overall, we have synthesized 13 diverse fused pyrazole derivatives in moderate to
excellent yields.
Available online
Keywords:
Fused pyrazoles
2018 Elsevier Ltd. All rights reserved.
Cross dehydrogenative coupling
Hydroamination
C-H functionalization
Aerial oxidation
The activation of Carbon-Hydrogen (C-H) bond for coupling
reactions is economic, sustainable and environmentally benign;
as these reactions bypass the pre-functionalization or de-
functionalization step. The C-H activation method enables direct
synthesis of complex molecules from simple starting materials
and have been extensively employed in the construction of
Carbon-Carbon and Carbon-heteroatom bonds.1 In particular, the
C-H activation through cross dehydrogenative coupling
(CDC)/oxidative coupling reactions can meet the criterion of
green chemistry and are atom economic as these reactions
produce only water as the byproducts. In recent times, among
CDC reactions, α-C(sp3)-H functionalization of tertiary amines
gained greater importance due to direct access of N-containing
heterocyclic compounds.2 Furthermore, copper-catalyzed aerobic
CDC reaction via α-C(sp3)-H functionalization of N-aryl-
substituted tetrahydroisoquinoline with various reaction partners,
especially electron rich counterparts (Nucleophiles) have been
well established in the literature (Figure 1).3
A large number of catalysts (Ag, Cu, Ru, Rh, Co, Pd, I2 etc.,)
oxidants, and nucleophiles have been reported for this reaction
and are compatible under aerobic oxidative condition.4
Mechanistically, an iminium ion intermediate (A) is generated in
situ on oxidation of the corresponding amine and serves as an
active electrophile for subsequent nucleophilic addition reaction
(Figure 1).
Despite the significant potential of α-C(sp3)-H functionalization
of tertiary amines, CDC reaction suffers from limited substrate
scope because N-arylsubstituted-1,2,3,4-tetrahydroisoquinoline
and N, N-dimethyl aniline (tertiary amine) derivatives have been
reported as suitable substrates.5 And also, aryl or benzyl
substitution on tertiary amine is required to induce CDC reaction
at α-position to nitrogen. However, Xu and Li reported copper-
catalyzed CDC reaction of aliphatic tertiary amines with terminal
alkynes but additive is necessary to carry out the transformation.6
To the best of our knowledge, the direct oxidative
functionalization of both aryl-substituted and aliphatic-
substituted tertiary amines under simple and mild aerobic
conditions using internal/electron deficient alkynes as reaction
partners have not been well investigated.
Dinitrogen-fused heterocyclic frameworks are present in many
pharmaceutical, agrochemical, and biologically active
compounds, and are prominent candidates for new drugs and
functional materials. Especially the molecules containing
pyrazolo[5,1-a]isoquinoline (PIQ) framework shows remarkable
biological activities due to the PIQ hybrid structure (isoquinoline
and pyrazolo[1,5-a]pyridine).7 To mention a few, PIQ derivatives
show activities for inhibition of CDC25B, TC-PTP, and PTP1B.8
Figure 1. CDC reaction of N- aryl substituted tetrahydro-
isoquinoline with nucleophile via iminium ion.
———
 Corresponding author. e-mail: anindita@kluniversity.in (A. Chatterjee).

2
The another important class of dinitrogen-fused heterocyclic
frameworks, fused-pyrazoles derivatives display a broad
spectrum of biological activities including antibiotic, kinase
inhibitor, and anticonvulsant activities.
8h, provided diethyl 5,6-dihydropyrazolo[5,1-a]isoquinolines-
1,2-dicarboxylate (3) in 91% isolated yield.
Table 1. The Screening of reaction conditionsa
Recently, Zhu and coworkers described an interesting Iridium-
catalyzed [4+1] annulation of hydrazone with diethyl 2-
bromomalonate under the influence of visible light (Scheme 1,
eq. 1). Unfortunately, this method demonstrated a rather narrow
substrate scope.9a A Copper-catalyzed tandem reaction of 2-
alkynylbromobenzene with pyrazole provides a facile route to
pyrazole[5,1-a]isoquinolines. This method involves
Catalyst
Yield
Entry
Solvent
Time (h)
(%)b
(equiv)
hydroamination followed by C-H activation to provide desired
products in low to moderate yields (Scheme 1, eq. 2).9b In 2007,
Alper and co-workers reported the synthesis of pyrazolo[5,1-
a]isoquinolines through regioselective cycloaddition of stable
aroyldiaziridines of 3,4-tetrahydroisoquinolines with both mono
and disubstituted alkynes (Scheme 1, eq. 3).9c But the difficulty
in preparation of diaziridine compounds and handling reactive
1,3-dipolar intermediates often limits their synthetic application.
1
2
3
4
5
6
7
8
9
10
AgOAc (0.5)
AgOAc (1.0)
AgOAc (1.0)
Ag2CO3(1.0)
Ag2O (1.0)
CuBr (1.0)
Cu(OAc)2
--
DCEc
16
16
8
--d
DCEc
10
48
xylene
xylene
xylene
xylene
xylene
xylene
AcOH
xylene
16
16
16
8
19
trace
trace
91
16
16
16
--d
--
31
AcOH
trace
aAll reactions were carried out on 1 mmol scale.
bIsolated yields.
cReactions were performed in a sealed tube.
dStarting material was recovered.
With the optimized condition established (Table 1, entry 7),
we examined the scope of substrate 1a with various alkynes
(Scheme 2). The results listed in Scheme 2 show that various
internal / electron deficient alkynes (2a-h) bearing different
substituents underwent this cascade reaction smoothly to afford
the corresponding products (3-10) in good to excellent yield. The
various internal / electron deficient alkynes, from aryl or alkyl
substitution to electron withdrawing substitution, were very
compatible under the reaction condition. Even though the
electronic nature of alkynes did have an influence on reaction
time but could not show the significant effect on the yield of
respective PIQ derivatives.
Scheme 1. Selected literature approaches to fused pyrazoles.
Numerous metal-catalyzed and organo-catalyzed cycloaddition of
azomethine imines have been reported for the synthesis of
diverse dinitrogen-fused heterocycles and these literature
procedures are generally efficient and reliable, often involve
preformed azomethine imines.10 However, the direct oxidative α-
functionalization of tertiary amines with various reaction partners
provides a sustainable alternate route for the synthesis of
nitrogen-fused heterocycles. Considering the above-mentioned
factors, we envisioned a novel synthesis of dinitrogen-fused
heterocycles via tandem/cascade hydroamination, CDC reaction
followed by aerial oxidation approach from commercially
available starting materials under simple, mild and facile
operational condition.
Scheme 2. Scope for synthesis of 5,6-dihydropyrazolo[5,1-a]iso-
quinolines-1,2-dicarboxylate derivativea
For our initial studies, we have selected commercially
available 3,4-dihydroisoquinolin-2(1H)-amine (1a) and diethyl
acetylenedicarboxylate (2a) as model substrates. Treatment of 1a
with 2a in presence of catalytic amount of AgOAc in DCE at
110oC for 16h (Table 1, entry 1), did not result in the formation
of any detectable product (3). The subsequent increase in both
catalyst loading and temperature (Table 1, entry 2) led to 10%
formation of desired product and the further change of the
solvent to xylene enhanced the product formation to 48% yield
(Table 1, entry 3). Experimentation with various Ag-catalysts
(Table 1, entry 4 & 5) and Cu-catalysts (Table 1, entry 6 & 7)
revealed that the choice of Cu(OAc)2 could dramatically improve
the yield to 91% and shortens the reaction time to 8h (Table 1,
entry 7). Attempts to further improve the efficiency of product
formation by screening different solvents and catalysts were
unsuccessful (Table 1, entry 8-10). Therefore, the optimum
reaction condition comprised of 1 equiv. of 1a with 1.1 equiv. of
2a in the presence of 1 equiv. of Cu(OAc)2 in xylene at 140oC for
aReaction condition: 1a (5 mmol), 2a-h (5.5 mmol), Cu(OAc)2 (5 mmol),
xylene (25 mL) at 1400C. The reaction time varied from 8-16h.

3
In order to explore the scope and limitations of our
methodology, we have next selected aliphatic cyclic tertiary
amine, piperidin-1-amine (1b) and conducted the experiment
with diethyl acetylenedicarboxylate (2a) under optimized
reaction condition (Table 1, entry 7). To our delight fused-
pyrazole (11) was obtained in 75% isolated yield, indicating that
cross dehydrogenative coupling of unactivated/inactivated
aliphatic tertiary amines could be possible under this aerobic
oxidative condition. Then another alkyne 2g was treated with 1b
under the same reaction condition and the corresponding fused-
pyrazole 12 was obtained in 71% isolated yield (Scheme 3).
Encouraged by these results, we have further determined the
scope of a substrate, azepan-1-amine (1c) as reaction partner with
various alkynes (2a, 2d & 2g). The fused-pyrazole 13-15 were
obtained in 70%, 55% & 69% isolated yield respectively
(Scheme 3). The results in Scheme 3 demonstrates that the
electronic and steric nature of substrate did not have an obvious
effect on yield of 11-15 and are very tolerable under tandem
aerobic oxidative condition.
Scheme 4. Plausible mechanism.
Acknowledgments
VRR thanks K L University for constant encouragement
during this research program. VRR is also grateful to GVK
Biosciences for providing basic research facility.
Scheme 3. Scope for synthesis of tetrahydropyrazolo[1,5-
a]pyridine or azepine-2,3-dicarboxylate derivativea
Supplementary Material
All the experimental details, spectral data, 1H and 13C NMR
spectra for the compounds 3-15 are available in the Supporting
Information.
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aReaction condition: 1b or 1c (5 mmol), 2a, 2c-e or 2g (5.5 mmol), Cu(OAc)2
(5 mmol), xylene (25 mL) at 140oC for 16h.
Here in, we are not exploring the mechanism, but assume that
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hydroamination with diethyl acetylenedicarboxylate (2a) under
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synthesis of fused pyrazole derivatives from easily accessible or
commercially available starting materials. Our method also
demonstrates the importance of α-C(sp3)-H functionalization of
tertiary amines for the synthesis of biologically important
dinitrogen-fused heterocyclic frameworks.
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Highlights

Simple and efficient strategy for synthesis of
fused pyrazole derivatives

Our strategy demonstrates various aspects of
α-C(sp3)-H functionalization of tertiary amines
which have not been explored earlier
Our strategy open the possibility to design
coupling reactions with suitable substrates
towards targeted products
