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N-Tosylhydrazones and Diazooxindoles as Carbene Precursors

to Access Diverse Molecular Frameworks

Arun prasath
Department of Chemistry
Indian Institute of Technology Madras
INDIA
Content
Chapter I: Introduction

Chapter II: Pd-Catalyzed Domino Carbene Migratory Insertion/Heck-type Cyclization
Strategy for the Synthesis of 3-Aryl-1-indanones

Stereoselective Construction of α-Tetralone-fused Spirooxindoles via
Chapter III:
Carbene Migratory Insertion/Conjugate Addition Sequence

Synthesis of Indanone-fused Spirooxindoles via Pd-Catalyzed Cross-Coupling
Chapter IV:
of Tosylhydrazones with 3-Arylidene oxindoles

Cu-Catalyzed Construction of Indolo[3,2-c]-quinolinones via
Chapter V: N–H Insertion/Aldol Annulation/Unusual Ring-Expansion Sequence

N-Tosylhydrazone-Mediated Carbene Insertion into S-S and Se-Se Bonds:
Chapter VI:
An Access to Thio and Selenoacetals

Chapter VII: Summary 2
Chapter I

Introduction
Carbene Involving Cross-Coupling Reactions

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Carbene and its precursors

A highly reactive intermediate containing a neutral divalent carbon atom with 2 unshared valence electrons

• First prepared by Curtius in 1883
• Diazo compounds readily decomposes thermally or photochemically to give carbene
• Liberation of N2(g) serve as a driving force

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M. P. Doyle, M. A. McKervey, T. Ye, Modern Catalytic Methods for Organic Synthesis with Diazo Compounds Wiley, 1998
Diazo compounds: Types

Diazo compounds are generally classified into three main groups, based on the electronic properties of the substituents

• Difficult to prepare and handle
• Unstable and explosive
• Could not be synthesized in large quantities
• Has to be freshly prepared before use
• Limited scope

M. P. Doyle, M. A. McKervey, T. Ye, Modern Catalytic Methods for Organic Synthesis with Diazo Compounds:
From Cyclopropanes to Ylides, Wiley, 1998 5
N-Tosylhydrazones
Alternative for non-stabilized diazo compounds

Can be intercepted
with metal

W. R. Bamford and T. S. Stevens J. Chem. Soc. 1952, 4735

Aggarwal et al., J. Am. Chem. Soc. 2003, 125, 10926

• Easy access from aldehydes or ketones (One-step synthesis; No column purification)
• In-situ generation of non-stabilized diazo compounds
• One-pot strategy from carbonyl compounds
• N-Tosylhydrazones are bench-stable compounds

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Cross-coupling reactions involving carbene

Barluenga coupling reaction

Barluenga et al., Angew. Chem. Int. Ed. 2007, 46, 5587
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Objectives of the study

• Utilization of N-tosylhydrazones as carbene precursors for the Pd-catalyzed domino reactions
• Merging carbene process with other transformations in an intra-molecular fashion
• Development of carbene insertion reactions into homo-nuclear bonds
• Synthesis of novel cyclic frameworks

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Chapter II

Pd-Catalyzed Domino Carbene Migratory Insertion/Heck-type Cyclization
Strategy for the Synthesis of 3-Aryl-1-indanones

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Carbopalladation Vs Carbene migratory insertion

Known!

Gu et al., Org. Lett. 2013, 15, 4814

Wang et al., Org. Lett. 2013, 15, 5032 10
Carbene migratory insertion Vs Carbopalladation

Unknown!

Initial result

• E-selective product formation was observed
• Selective towards 5-exo-trig cyclization
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Optimization of reaction condition

Tosylhydrazone Temp Yieldb
Entry Pd cat. Solvent
(equiv) (oC) (%)

1 1.2 Pd(OAc)2 THF 60 36
2 1.5 Pd(OAc)2 THF 60 61
3 2 Pd(OAc)2 THF 60 82
4 2 PdCl2 THF 60 71
5 2 Pd2(dba)3 THF 60 67
6 2 Pd(acac)2 THF 60 77
7 2 Pd(OAc)2 THF/TBAC 60 78c
8 2 Pd(OAc)2 THF/H2O 60 96
9 2 Pd(OAc)2 Dioxane/H2O 60 37
10 2 Pd(OAc)2 CH3CN/H2O 60 50
11 2 Pd(OAc)2 DMF/H2O 60 nr
12 2 Pd(OAc)2 THF/H2O 40 76
13 2 Pd(OAc)2 THF/H2O 60 21d
14 2 - THF/H2O 60 nr
15 2 Pd(OAc)2 THF/H2O 60 nre
aReaction conditions: 1a (0.25 mmol), 2a (1.2-2.0 equiv) K2CO3 (0.75 mmol), Pd catalyst (10 mol 12
%), PPh3 (30 mol %). bIsolated yield. cTBAC (2 equiv) was used. dWithout PPh3. eWithout base
Substrate scope

Reaction conditions: 1 (0.25 mmol, 1 equiv), 2 (0.5 mmol. 2 equiv), THF (2.7 mL), H2O (0.3 mL), 60 oC; Isolated yield.
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Arunprasath. D, Muthupandi. P and Sekar. G, Org. Lett. 2015, 17, 5448
One-pot reaction

In-situ
N-tosylhydrazones

In-situ
2'-iodochalcones

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Control experiments

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Proposed mechanism

Arunprasath. D, Muthupandi. P and Sekar. G, Org. Lett. 2015, 17, 5448
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Extension to asymmetric version: Screening of chiral ligands

ee was determined by chiral HPLC using diacel AD-H column; Mobile phase: 10% IPA/Hexanes; 1 mL/min 17
Extension to asymmetric version

Additive
Entry Pd cat. Yield (%) ee (%)
(equiv)
1 Pd(OAc)2 - 85 27
2 Pd(PPh3)4 - 47 rac
3 Pd2(dba)3 - 76 24
4 Pd(dba)2 - 31 05
5 Pd(acac)2 - 31 rac
6 Pd(TFA)2 - 37 03
7 PdCl2dppf.dcm - 34 05
8 PdCl2 - 73 21
9 PdCl2(PPh3)2 - 41 02
10 Pd(OAc)2 Ag(OAc)2 (1) nr --

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Conclusion

• The Pd-catalyzed intermolecular carbene insertion prior to the intramolecular carbopalladation has been
developed for the first time.
• Stable and easily accessible N-tosylhydrazones and 2'-iodochalcones were utilized as starting materials.
• The reaction was found to be selective towards 5-exo-trig cyclization and E-isomer of the double bond.
• One-pot reactions with respect to both the coupling partners 2'-iodochalcones and N-tosylhydrazones has been
successfully demonstrated.
• The attempted chiral version of the developed methodology has resulted in moderate enantioselectivity.

Arunprasath. D, Muthupandi. P and Sekar. G, Org. Lett. 2015, 17, 5448

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Chapter III

Stereoselective Construction of α-Tetralone-fused Spirooxindoles via
Carbene Migratory Insertion/Conjugate Addition Sequence

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Initial attempt for synthesis of spiro compounds

Previous Chapter

Hypothesis!

Choice of cyclic
N-tosylhydrazones

Initial attempt:

Anti (Major) 21
Syn (Minor)
Optimization of reaction condition

Additive Yieldb,c (%) drb
entrya R Pd cat.
(equiv) (3/4) anti:syn
1d Me Pd(OAc)2 - 36/24 72:28
2d Ts Pd(OAc)2 - 15/36 67:33
3d Bn Pd(OAc)2 - 56/28 73:27
4d Bn Pd(OAc)2 - 46/5 86:14
5d H Pd(OAc)2 - 0/20 -
6e Bn Pd(PhCN)2Cl2 - 48/8 73:27
7e Bn Pd2(dba)3 - 56/7 77:23
8 Bn [Pd(cinnamyl)Cl]2 - 62/0 82:18
9 Bn [Pd(η3-allyl)Cl]2 - 69/0 88:12
10 Bn [Pd(η3-allyl)Cl]2 HCOONa (1) 68/0 84:16
11 Bn [Pd(η3-allyl)Cl]2 Proton sponge (1) 61/7 87:13
12 Bn [Pd(η3-allyl)Cl]2 H2O (1) 63/5 85:15

13 Bn [Pd(η3-allyl)Cl]2 TBAC (0.5) 76/0 89:11

14 Bn [Pd(η3-allyl)Cl]2 TBAB (0.5) 80/0 90:10

15f Bn [Pd(η3-allyl)Cl]2 TBAB (0.25) 89(86)/0 91:09

16 Bn [Pd(η3-allyl)Cl]2 TBAB (0.1) 72/0 89:11
17g Bn [Pd(η3-allyl)Cl]2 TBAB (0.25) 31/0 86:14
aReaction conditions: Reactions were performed in 0.1 mmol scale. bDetermined by 1H NMR. cYield of
both the diastereomers. dReaction at 80 oC. eUnreacted 1a was found (18% for entry 6 and 11% for 22
entry 7). fValue in parentheses represents isolated yield. gReaction in dry CH3CN at N2 atm.
Substrate scope with 2'-iodochalcones

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Arunprasath, D.; Devi Bala, B.; Sekar, G. Org. Lett. 2017, 19, 5280
Scope of the isatin-derived N-tosylhydrazones

Domino synthesis of spiroacenaphthylenes

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One-pot reaction

Diversification of spirooxindoles

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Control experiments

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Mechanism

Rationalization of diastereoselectivity

Arunprasath, D.; Devi Bala, B.; Sekar, G. Org. Lett. 2017, 19, 5280
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Reaction profile

Arunprasath, D.; Devi Bala, B.; Sekar, G. Org. Lett. 2017, 19, 5280
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Conclusion

• A novel Pd-catalyzed carbene migratory insertion/conjugate addition strategy has been developed to access
spirooxindoles with contiguous quaternary and tertiary carbon centers in a diastereoselective fashion.
• The first example of isatin-derived N-tosylhydrazones being utilized in a metal-carbenoid domino process.
• Novel complex molecular spirocycles from readily accessible starting materials with a broad substrate scope.
• Deuterium labelling studies and 1H NMR based reaction profiling were performed.
• The transition state models have been proposed to understand the observed diastereoselectivity.

Arunprasath, D.; Devi Bala, B.; Sekar, G. Org. Lett. 2017, 19, 5280

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Chapter IV

Synthesis of Indanone-fused Spirooxindole via Pd-Catalyzed
Cross-Coupling of Tosylhydrazones with 3-Arylidene oxindoles

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Directing the the Reactivity of η3-Oxoallyl Pd-Intermediate

Previous Chapter

Hypothesis!

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Optimization studies

Entrya Pd cat. (mol%) Base (equiv) Additive (equiv) Yieldb (%)
1 [Pd(allyl)Cl]2 DIPEA (3) - 61
2 PdCl2 DIPEA (3) - 41
3 Pd2(dba)3 DIPEA (3) - 69
4 [Pd(cinnamyl)Cl]2 DIPEA (3) - 55
5 Pd2(dba)3 Et3N (3) - trace
6 Pd2(dba)3 DIPA (3) - trace
7 Pd2(dba)3 KOtBu (3) - 0
8 Pd2(dba)3 K2CO3 (3) - 18
9 Pd2(dba)3 DIPEA (2) - 51
10 Pd2(dba)3 DIPEA (4) - 58
11 Pd2(dba)3 DIPEA (3) H2O (5) 63
12 Pd2(dba)3 DIPEA (3) TBAC (0.25) 76
13 Pd2(dba)3 DIPEA (3) BTAC (0.25) 68
14 Pd2(dba)3 DIPEA (3) TBAB (0.25) 80
15 Pd2(dba)3 DIPEA (3) TBAB (0.50) 77
16 Pd2(dba)3 DIPEA (3) TBAB (0.10) 86 (82)c
17 Pd2(dba)3 DIPEA (3) TBAB (0.05) 82
aReaction conditions: 1 (0.1 mmol), 2 (0.15 mmol), in CH3CN (1 mL) at 50 oC for 6-18 h.
bDetermined by 1H NMR. cValue in parentheses represents isolated yield. 32
Substrate scope

Reaction conditions: Reactions were performed on 0.3 mmol scale in CH3CN (3 mL) at 60 oC. bIsolated yields. a21% of SM was recovered.
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Arunprasath, D.; Devibala, B.; Sekar, G. J. Org. Chem., 2018, 83, 11298–11308
Substrate scope

Scope with benzylidene acenaphthoquinone

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Synthesis of XEN 907 analogue

Possible
mechanism

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Arunprasath, D.; Devibala, B.; Sekar, G. J. Org. Chem., 2018, 83, 11298–11308
Conclusion

• Construction of indanone-fused spirooxindoles was achieved based on the rational designing of 3-arylidene
oxindoles as starting material.
• The η3-oxoallyl Pd-intermediate selectively underwent the 5-exo-trig mode of carbopalladation over 6-endo
trig conjugate addition due to the steric requirements.
• The reaction condition was found to be general as most of the substrates furnished products in good yields.
• Selective towards exclusive E-isomer formation.
• The synthesis of pharmaceutically important XEN 907 analogue was demonstrated.

Arunprasath, D.; Devibala, B.; Sekar, G. J. Org. Chem., 2018, 83, 11298–11308

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Chapter V

Cu-Catalyzed Construction of Indolo[3,2-c]-quinolinones via
N–H Insertion/Aldol Annulation/Unusual Ring-Expansion Sequence

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Attempts to synthesize heterocyclic-fused spirooxindoles

Hypothesis!

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Optimization studies

Temp Yieldb (%)
Entry Cat. (mol%) Solvent
(oC) 1 2
1c Rh2(OAc)4 (1) DCM 40 65 0
2 Rh2(OAc)4 (1)/Yb(OTf)3 (20) DCM 40 0 42
3 Rh2(OAc)4 (1)/BPA (20) DCM 40 5 35
4 Rh2(OAc)4(1)/Cu(OTf)2 (20) DCM 40 0 58
5 Cu(OTf)2 (20) DCM 40 0 65
6 Cu(OTf)2 (20) DCE 40 0 81
7 Cu(OTf)2 (20) CH3CN 40 0 28
8 Cu(OTf)2 (20) CHCl3 40 0 86
9 Cu(OTf)2 (20) CHCl3 60 0 93
10 Cu(OTf)2 (20) CHCl3 50 0 89
11 Cu(OTf)2 (20) CHCl3 rt 0 45
12 (CuOTf)2·tol (20) CHCl3 60 0 75
13 Y(OTf)3 (20) CHCl3 60 8 20
14 Zn(OTf)2 (20) CHCl3 60 0 nr
15 Fe(OTf)3 (20) CHCl3 60 12 33
16 Cu(OAc)2 (20) CHCl3 60 0 0
17 CuCl (20) CHCl3 60 0 0
18 Cu(OTf)2 (15) CHCl3 60 0 93
19 Cu(OTf)2 (10) CHCl3 60 0 93 (91)d
20 Cu(OTf)2 (5) CHCl3 60 <5 76
21 - CHCl3 60 0 nr
aReaction conditions: Reactions were performed in 0.1 mmol scale and diazo compound was
added over 1 h by a syringe pump. bDetermined by 1H NMR. c100 mg of 4 Å molecular sieves was
used. dValue in parentheses represents isolated yield. BPA= Binol-Phosphoric Acid. 39
Substrate scope with 2-aminochalcones

Reaction conditions: 1 (0.3 mmol), Cu(OTf)2 (10 mol %) in CHCl3 (1.5 mL) at 60 oC. 2 (0.45 mmol) in CHCl3 (1.5 mL) was added over 1 h by a syringe pump.

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Arunprasath, D.; Sekar, G. Org. Lett., 2019, Just accepted, DOI: 10.1021/acs.orglett.8b035578
Substrate scope study Control experiments

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Possible reaction pathway

Arunprasath, D.; Sekar, G. Org. Lett., 2019, Just accepted, DOI: 10.1021/acs.orglett.8b035578

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Conclusion

• Synthesis of novel heterocyclic scaffold indolo[3,2-c]-quinolinones was demonstrated using Cu-catalyst with
good to excellent yields.
• The developed reaction proceeds via domino N–H insertion/aldol/ring expansion sequence.
• Readily synthesizable/available 2'-aminochalcones and 2-aminobenzophenones were utilized.
• Control experiments suggested that the reaction proceeds via N–H insertion and in-situ generated TfOH
catalyzed the intramolecular aldol reaction and subsequent 1,2-carbonyl migrations.
• Indirect evidence for the involvement of spirooxindole intermediate was also obtained.

Arunprasath, D.; Sekar, G. Org. Lett., 2019, Just accepted, DOI: 10.1021/acs.orglett.8b035578
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Chapter VI

N-Tosylhydrazone-Mediated Carbene Insertion into S-S and Se-Se Bonds:
An Access to Thio and Selenoacetals

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Carbene insertion reactions

• Carbene insertion reactions have proven to be a powerful strategy for the synthesis gem-
metallated or non-metallated compounds
• Carbene insertion process is well-known with C-H and X-H bonds where X = N, O, S, Si, P

Wang et al., J. Am. Chem. Soc. 2015, 137, 12800

Murakami et al., J. Am. Chem. Soc. 2014, 136, 7217

Wang et al., Org. Lett. 2014, 16, 448 45
Objective and initial result

 Thiol-free thioacetal synthesis
 Transition metal-free

Traditional method  Usage of nasty thiol
for thioacetal synthesis  Long reaction time

Initial result

Optimized condition

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Substrate scope with various N-tosylhydrazones

Reaction conditions: 1 (1.0 mmol), 2a (1.5 mmol) and KOtBu (2.0 equiv) in DMSO (3 mL) at 100 oC for 10-30 min. Isolated yields.

Arunprasath, D.; Sekar, G. Adv. Synth. Catal. 2017, 359, 698 47
Substrate scope with various diaryl disulfides

Reaction conditions: 1 (0.5 mmol, 1.0 equiv), 2 (1.5 equiv), base (2.0 equiv) and solvent
(2 mL); Isolated yields.

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One-pot reaction

Carbene insertion across Se-Se bond

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Control experiments

Possible mechanism

Arunprasath, D.; Sekar, G. Adv. Synth. Catal. 2017, 359, 698 50
Conclusion

• Carbene insertion into S-S and Se-Se bonds have been developed using N-tosylhydrazone as a
safe, stable and readily synthesizable carbene precursor.
• Thio- and selenoacetals under thiol and selenol-free conditions in good to excellent yields.
• Featured with short reaction time, high functional group tolerance and wide substrate scope.
• Scale-up reaction and one-pot synthesis involving in situ generation of tosylhydrazone were
demonstrated.

Arunprasath, D.; Sekar, G. Adv. Synth. Catal. 2017, 359, 698

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Summary

Chapter III Chapter II

Arunprasath, D., Devi Bala, B., Sekar, G. Arunprasath. D, Muthupandi, P., Sekar. G,
Org. Lett. 2017, 19, 5280 Org. Lett. 2015, 17, 5448

Chapter IV

Arunprasath, D., Devi Bala, B., Sekar, G. J. Org. Chem., 2018, 83, 11298

Chapter V

Arunprasath, D.; Sekar, G. Org. Lett. 2019, Just accepted

Chapter VI

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Arunprasath, D.; Sekar, G. Adv. Synth. Catal. 2017, 359, 698
List of Publications

1. Stereoselective Construction of α-Tetralone-Fused Spirooxindoles via Pd-Catalyzed Domino Carbene Migratory
Insertion/Conjugate Addition Sequence. Arunprasath, D.; Devibala, B.; Sekar, G. Org. Lett., 2017, 19, 5280.
2. A Transition-Metal-Free and Base-Mediated Carbene Insertion into S-S and Se-Se Bonds: An Easy Access to Thio- and
Selenoacetals. Arunprasath, D.; Sekar, G. Adv. Synth. Catal. 2017, 359, 698.
3. Palladium-Catalyzed Intermolecular Carbene Insertion Prior to Intramolecular Heck Cyclization: Synthesis of 2-Arylidene-
3-aryl-1-indanones. Arunprasath, D.; Muthupandi, P.; Sekar, G. Org Lett., 2015, 17, 5448.
4. An Efficient Synthesis of Pyrido[1,2-a]indoles through Aza-Nazarov Type Cyclization. Karthikeyan, I.; Arunprasath, D.;
Sekar, G. Chem. Commun., 2015, 51, 1701-1704.
5. Phosphine-Free and Reusable Palladium Nanoparticles Catalyzed Domino Strategy: Synthesis of Indanone Derivatives.
Saha, R.; Arunprasath, D.; Sekar, G. J. Org. Chem, 2018, 86, 4692-4702.
6. Dictating the Reactivity of η3-Oxoallyl Pd-Intermediate toward 5-exo-trig Cyclization: Access to Indano-spirooxindoles,
Arunprasath, D.; Devibala, B.; Sekar, G. J. Org. Chem., 2018, 83, 11298–11308.
7. Copper(II)-Catalyzed Domino Synthesis of Indolo[3,2-c]quinolinones via Selective Carbonyl Migration. Arunprasath, D.;
Sekar, G. Org Lett., 2019, Just accepted.
8. Luxury of N‐Tosylhydrazones in Transition‐Metal‐Free Transformations. Arunprasath, D.; Devibala, B.; Sekar, G. Adv.
Synth. Catal. 2019, Accepted, DOI: 10.1002/adsc.201801031 (Review article).
9. Surface Enriched Pd on Metal-Carbon Bonds Stabilized Pd/Cu Bimetallic Nanoparticles: An Efficient Catalyst for Synthesis
of Polycyclic Triazoles Saha, R.; Arunprasath, D.; Sekar, G. (Manuscript is under preparation)
Acknowledgements

• Prof. G. Sekar
• IIT Madras
• IC&SR (IITM) for funding through Research Scholars Innovative Project
• CSIR, India for SPM fellowship

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Major
c b a

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Minor

a
b c

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Helvetica Chemica Acta, 1987, 70, 607

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Types of diazo compounds

Bamford–Stevens reaction

W. R. Bamford and T. S. Stevens J. Chem. Soc. 1952, 4735

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