A diversity-oriented synthesis of polyheterocycles: Via the cyclocondensation of azomethine imine

Article abstract of DOI:10.1039/c9nj02874a

Pd-Catalyzed sequential reactions to afford skeletally diverse molecules are described. The reaction involved azomethine imine formation and a cyclocondensation reaction as individual steps. The methodology provides excellent regio- and stereocontrol. Skeletal diversity was ensured by changing the electrophilic counterpart of azomethine imine. Due to its broader diversity and complexity, the DOS methodology is likely to benefit drug discovery and development in the future.

Full text of DOI:10.1039/c9nj02874a

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Pardasani and D. M. Sawant, New J. Chem., 2019, DOI: 10.1039/C9NJ02874A.
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DOI: 10.1039/C9NJ02874A
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A diversity-Oriented Synthesis of Polyheterocycles via
Cyclocondensation of Azomethine Imine
Arshad J. Ansari,a Ramdas S. Pathare,a Anita Kumawat,b Antim K. Maurya,c Sarika Verma,e Vijai K.
Received 00th January 20xx,
Accepted 00th January 20xx
Agnihotri,c Rahul Joshi,b Ramesh K. Metred Ashoke Sharon,e R. T. Pardasani,a Devesh M. Sawant,*a
DOI: 10.1039/x0xx00000x
Pd-catalyzed sequential reaction to skeletally diverse molecule is
described. The Reaction involved azomethine imine formation and
cyclocondensation reaction as individual steps. The methodology
exhibited excellent regio- and stereocontrol. The skeletal diversity
was ensured by changing the electrophilic counterpart of
azomethine imine. Due to its broader diversity and complexity, the
DOS methodology is likely to benefit drug discovery and
development in the future.
The human genome, a treasure trove of hidden information,
comprised of 25,000 genes that encode hundreds of thousands
of proteins. Modulation of these protein function using small
organic molecules represents the basis for chemical biology and
medicinal chemistry.1 However, exploration of astronomically
huge biologically accessible chemical space (1060 molecules) is
like “searching a needle in haystack.2 Natural product space,
enriched with bioactive structure, is considered as a good
starting point for targeting proteins of human diseases.3
However, natural products are evolved as a defense mechanism
against invaders in the absence of advanced immune response
in plants and marine organisms; thus they tend to target highly
connected and more essential target proteins compared to
genes implicated for human diseases.4 In contrast, protein
targets of marketed drugs exhibited a connectivity distribution
closer to that of human disease genes. Thus, design and
assembly of compound collections based on small molecules,
instead of natural products, play a decisive role in driving drug
discovery research. In this context, diversity and complexity of
small organic molecules are critical to ensure high performance
in the drug discovery. 5
Scheme 1. Transition metal catalyzed cascade reactions for the synthesis of sophisticated
polyheterocycles.
a.School of Chemical Sciences and Pharmacy, Central University of Rajasthan NH-8,
Bandarsindri, Ajmer-305817 (Raj) India,
Diversity-oriented synthesis (DOS), an efficient and
simultaneous generation of chemical space with a high degree
of skeletal diversity, emerged as a popular method in organic
synthesis for generating a diverse compound collection from
readily accessible and common intermediates.6 Nevertheless, a
huge library can be assembled by altering either functional
group or skeletal framework7 of at least one of the precursor.
Owing to its high skeletal diversity, DOS-based on compound
collections contribute meaningfully in the area of drug
b.
Department of Chemistry, University of Rajasthan JLN Marg, Jaipur 302004,
c. Natural product chemistry and process development division, CSIR-IHBT,
Palampur, Himachal Pradesh -176061,
d.Department of Chemistry, Indian Institute of Technology Jodhpur, Karwad,
Jodhpur-342037, Rajasthan, India.
e. Department of Chemistry, Birla Institute of Technology, Mesra, Ranchi 835215,
Jharkhand, India.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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discovery. To this end, a significant volume of research based on
diversity-oriented synthesis was published during the last
decade.8
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DOI: 10.1039/C9NJ02874A
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Recently, we reported
azomethine imine through
a
robust preparation of diverse
three-component reaction
a
promoted by auto-tandem Pd(II) catalysis (Scheme 1a).9 In
continuation of our efforts to develop new EGFR inhibitors by
cyclocondensation of azomethine imines,9 we envisaged that
owing to its ambiphilic nature, azomethine imines could react
with reagents having orthogonal functionality to generate
skeletally diverse compound collections (Scheme 1b).
Azomethine imines were popular in 1,3 dipolar cycloaddition
reaction.10 In this context, we report the diversity-oriented
synthesis of two classes of quinazoline-based polyheterocycles
from common intermediates, azomethine imine.
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Figure 1. The X-ray crystal structure of compound 4f showing with ORTEP diagram using
50% ellipsoidal plot.
for the synthesis of 1-nitro-2-aryl -1,2,3,10 b-
We embarked our journey by preparing a spectrum of diverse
tetrahydropyrazolo[1,5-c]quinazolin
6 (Table 1). The reaction
azomethine imine
4
from readily available 2-azido
, and aryl sulfonyl hydrazide 3
was carried out in toluene at reflux (method A). The reaction
exhibited excellent substrate scope and diversity, and various
benzaldehyde , isocyanide
1
2
using our reported protocol (scheme 2). Irrespective of
substitution pattern on aryl ring, the corresponding azomethine
substitutions on azomethine imine
4 and 5 were well tolerated
under standard conditions. Various substitutions on the aryl
ring of nitroolefins and sulfonyl hydrazides can be incorporated.
The chemical integrity of functional groups such as Cl and Br,
remained unperturbed in the standard conditions,
imines
substitutions on the aryl ring (R3) of sulfonyl hydrazides
tolerated under the standard reaction condition. However,
diversity on isocyanide was restricted to tert-butyl an iso-octyl
4
were obtained in 65-86% yield. A good diversity of
3
is
2
Table 1: Substrate scope of 4-CR with nitroolefins.
group. Overall, all title compound were obtained as stable solids
at ambient temperature by flash chromatography. Single crystal
X-ray analysis confirmed the structure of the compound 2-(tert-
butylamino)quinazolin-3-ium-3-yl)((4-chlorophenyl)sulfonyl)
amide 4f in Fig 1.
With an assortment of azomethine imine
4 at hand, we
attempted cyclocondensation with various orthogonally
functionalized precursors. We were keen to develop a one-pot.
multicomponent route for generating pharmaceutically active
polyheterocyclic skeletons. We commenced the cyclo-
condensation studies of azomethine imine 4 with nitroolefins 5
Reaction condition: Method A: azomethine imine 4 (0.14 mmol), nitroolefins 5
(0.65 equiv, 0.091 mmol) in toluene and reflux for 2h. Method B: 2-
azidobenzaldehyde 1 (0.51 mmol), isocyanide 2 (1.2 equiv, 0.612 mmol), sulfonyl
hydrazide 3 (1.1 equiv, 0.561 mmol), palladium acetate (7.5 mol %) in toluene, 4 A
MS followed by nitroolefins 5 (0.65 equiv, 0.091 mmol) at 120 oC for 2h.
Scheme 2. Preparation of functional azomethine imine through one-pot three-
component reaction. Reaction condition: 2-azidobenzaldehyde (0.51 mmol),
isocyanide 2 (1.2 equiv, 0.612 mmol), sulfonyl hydrazide 3 (1.1 equiv, 0.561 mmol),
1
palladium acetate (7.5 mol %) in toluene, 4 A MS and stirred at room temperature.
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providing a chemical handle for further functionalization. We be a common platform for the development of a one-pot
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succeeded in the development of a one-step four-component tandem protocol from four different prDeOcuI:r1s0o.1r0s3.9I/nC9cNoJn02tr8a7s4tA,
protocol by developing method B.
reaction with cyclohexanone presented limited substrate scope
The cyclocondensation of azomethine imine
4
was then and reaction failed with pentanone to give the desired product
elegantly extended to allenes for the synthesis of 2- 12c
methylpyrazolo[1,5-c]quinazoline (Table 2). The feasibility of
.
8
Table 3: Substrate scope of 4-CR -halo hydroxamates 9 and cyclicketones 10 with
azomethine imine 4.
cyclocondensation reaction was explored in various solvents
(refer to ESI). The reactions carried out in toluene at 100 C
o
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temperature furnished best yields of 2-methyl pyrazolo[1,5-
c]quinazoline
substrate scope and applicability. Various substitutions on
azomethine imine and allenoates were well tolerated under
8 (Method C). The reaction exhibited a broader
4
7
standard conditions. Since toluene was a common solvent for
the reaction of azomethine imine and allenoates, and
preparation of azomethine imine itself, a one-pot 4-CR protocol
for the synthesis of
8 from four different precursors was
successfully established (method D).
Table 2: Substrate scope of 4-CR with allenoates
Reaction condition: Method E: azomethine imine
4 (0.14 mmol), -halo
hydroxamates 9 (1.2 equiv, 0.168 mmol) K2CO3 (2.0 equiv) in toluene as solvent
(1.0 mL) stirred at 70 oC. Method F: 2-azidobenzaldehyde 1 (0.51 mmol), isocyanide
2 (1.2 equiv, 0.612 mmol), sulfonyl hydrazide 3 (1.1 equiv, 0.561 mmol), palladium
acetate (7.5 mol %) in toluene, 4 A MS followed by -halo hydroxamates (1.2 equiv)
K2CO3 (2.0 equiv) in toluene as solvent (1.0 mL) stirred at 70 oC for 3-4 h. Method
G: Azomethine imine 4 (0.51 mmol) reacted with cyclohexanone (1.02 mmol) in
EtOH 1.0 ml with K3PO4 (1 equiv) at 80 oC 3 h.
Reaction condition: Method C: azomethine imine 4 (1 equiv, 0.51 mmol),
allenoates 7 (2 equiv, 0.612 mmol) in toluene, DABCO at 100 oC for 4h. Method D:
2-azidobenzaldehyde 1 (0.51 mmol), isocyanide 2 (1.2 equiv, 0.612 mmol), sulfonyl
hydrazide 3 (1.1 equiv, 0.561 mmol), palladium acetate (7.5 mol %) in toluene, 4 A
MS followed by allenoates 7 (1.2 equiv, 0.612 mmol) and DABCO at 100 oC for 4 h.
a Ethyl 2,3-pentadienoate is used as allenoates.
With the successfully venturing into the functional diversity
employing allenoates and nitroolefins, we turned our attention
on expanding the scaffold diversity by reacting azomethine
Conclusions
imine
reaction furnished rather an interesting scaffold, 1,3,4,11b-
tetrahydro-2H-[1,2,4]triazino[2,3-c]quinazolin-2-one 11 The
4 with-halo hydroxamates 9 and cyclic ketones 10. The
In conclusion, we successfully demonstrated that
cyclocondensation of azomethine imine and electrophilic
reactant could be effectively utilized for generating skeletal
diversity. As azomethine imine can be generated via three-
.
reaction with-halo hydroxamates displayed broader
substrate scope and diversity (Table 3). Toluene again proved to
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component reaction, the protocol was further transformed to
the sequential one-pot four-component methodology. The
optimal 4-CR protocol ensured a high degree of step/atom
economy. The reaction demonstrates excellent regio- and
stereoselectivity, good functional group tolerance, and good
conversion. A compound collection based on diverse and
intricate molecular architecture plays a crucial role in drug
discovery and development in the future.
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DOI: 10.1039/C9NJ02874A
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Devesh M. Sawant and R. T. Pardasani are grateful to the Central
University of Rajasthan, DST [EMR/2016/008016] and DST
[EMR/2016/003969], for funds. AS thanks CIF, BIT Mesra for X-
ray Diffraction Data Collection. Arshad J Ansari is thankful to the
Indian Council of Medical Research for providing fellowship
(45/20/2018-BIO/BMS).
Conflicts of interest
“There are no conflicts to declare.”
Notes and references
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