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Synthesis of n-heterocyclic compounds by

C-N BOND FORMATION REACTIONS

Research Student: Mr. Dewal S. Deshmukh

Research Supervisor: Prof. B. M. Bhanage
Date: 04/08/2017
introduction
 C–H functionalization is a type of reaction in which a less active carbon-hydrogen bond is cleaved and replaced with a
carbon-X bond (where X is usually carbon, oxygen, or nitrogen)
 Generally catalyzed by transition metals e.g. Pd, Rh, Ru, Co, Ni, Fe, Cu, Ir, etc.

 It provides original disconnections of complex molecules by avoiding additional prefunctionalization of simple starting
material
 Improves the overall efficiency of the desired transformations using cheapest and abundant feedstock so providing more
greener and economical strategies than conventional cross coupling reactions
 Sufficient reactivity for the cleavage of the strong C–H bond and the control of site selectivity are two main challenges

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Established protocols by C-H functionalization

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General mechanism

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Directing groups employed for synthesis of N-heterocyclic compounds

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Directing groups employed for synthesis of N-heterocyclic compounds

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Directing groups employed for synthesis of N-heterocyclic compounds

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 Molecular Iodine Catalyzed Benzylic sp3 C-H Bond
Amination for Synthesis of 2-Aryl Quinazolines

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Prior art
Synthesis of Quinazolines from different precursors

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Drawbacks of previous reports:

Use of excess of non renewable oxidant

Poor yields with 2-aminobenzaldehydes
Use of TEMPO in toxic solvent
Longer reaction time

Our advantages:

Molecular oxygen as a green & renewable oxidant

Solvent free
Excellent yields
Wide substrate scope
Short reaction time

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Plausible mechanism

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Optimization:

Sr. No. Molecular Iodine conc. Solvent Temp. Time. Yield

1 20 mol % DMSO 80 oC 24 h 84 %

2 20 mol % DMSO 80 oC 12 h 83 %

3 20 mol % DMSO 80 oC 6h 71 %

4 20 mol % DMSO 80 oC 8h 74 %

5 20 mol % DMSO 90 oC 12 h 84 %

6 20 mol % DMSO 70 oC 12 h 76 %

7 20 mol % DMSO 130 oC 3h 84 %

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Cont…
Sr. No. Molecular Iodine conc. Solvent Temp. Time. Yield

8 20 mol % DMSO 120 oC 3h 77 %

9 15 mol % - 130 oC 3h 82 %

10 10 mol % - 130 oC 3h 82 %

11 5 mol % - 130 oC 3h 64 %

12 10 mol % (without O2) - 130 oC 3h 42 %

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Substrate study

82% 87% 89%

82% 80% 81 %

83% 76% 88%

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Cont…

89% 91% 86%

72%

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Optimization

Sr. No. Molecular Iodine conc. Solvent Temp. Time. Yield

1 10 mol % - 130 oC 3h 63 %

2 10 mol % - 130 oC 6h 76 %

3 10 mol % - 130 oC 8h 86 %

4 10 mol % - 130 oC 10 h 87 %

5 15 mol % - 130 oC 8h 86 %

6 5 mol % - 130 oC 8h 58 %

7 10 mol % - 140 oC 8h 85 %
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8 10 mol % - 120 oC 8h 78 %
Substrate study

86 %
88 % 91 %

80 % 81 %
85 %

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88 % 77 %
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Prior art

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Prior art
Failed attempt

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Advantages:

 Tosylhydrazone as a novel directing group

 Excellent yields
 Wide substrate scope
 Mild reaction conditions

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Plausible mechanism

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Optimization

Sr. No. Ru-p-cymene AgSbF6 Solvent Temp. Time. Yield

1 10 mol% 20 mol% 1,2-DCE 120 oC 24 h -

2 10 mol % 20 mol% 1,2-DCE 100 oC 24 h -

3 10 mol % 20 mol% 1,2-DCE 80 oC 24 h -

4 10 mol % 20 mol% 1,2-DCE 60 oC 24 h -

5 5 mol % 10 mol% 1,2-DCE 60 oC 24 h -

6 10 mol % 20 mol% PEG-400 60 oC 24 h 25 -

 Different products in different solvent systems

Substrates attempted

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Future plan

 To explore same protocol for tosylhydrazones of aldehydes and other ketones

 To attempt same reaction with economical Co catalyst
 To aim one pot synthesis system for starting as well as product
 Switching annulation to another side

 To explore novel directing groups with different nucleophiles and new catalytic systems for synthesis of N-
heterocyclic compounds using C-H functionalization reactions

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