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(The) Rich Legacy of Isothiocyanates and Arene Diazonium Salts in Metal-Free Cascade Reactions

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This thesis was submitted by me to the Department of Chemistry, Indian Institute of Technology Guwahati for the award of the degree of Doctor of Philosophy. Special thanks to my sweet grandma and my cousin Akshey for their endless love and tireless smile.

S YNOPSIS

The stepwise synthesis of a target organic compound consists of purification/isolation of the intermediates at each step. In 1997, Zanardi's group reported a synthesis of benzothienoquinoxalines via a [3 + 2] radical cascade annulation reaction using o-cyano-arendiazonium salts and aryl isothiocyanates.

Figure IA.1. Differential reactivity of aroyl isothiocyanates.
Figure IA.1. Differential reactivity of aroyl isothiocyanates.

CHAPTER II: Catalyst and Solvent Free Domino Ring Opening Cyclization: A Greener and Atom Economic Route to 2-Iminothiazolidines

In this context, the development of greener and atom-economical approaches for the synthesis of imothiazolidine is considered worth investigating. Will it form a thiazolidine unit via a [3 + 2] cycloaddition similar to aryl isothiocyanates or undergo a double group transfer similar to oxirane.

Differential reactivity of aroyl isothiocyanates

Electron-donating substituents (EDG) on the phenyl ring of aroyl isothiocyanates were found to provide relatively lower yields of the corresponding products. However, the presence of EDG on the phenyl ring of the aziridines increases the yield of the product.

Plausible mechanism for the synthesis of 2-iminothiazolidines

The reaction of benzoyl isothiocyanate with activated aziridine, namely 2-phenyl-1-tosylaziridine, gave only 17% of the expected product. Due to the nucleophilicity of aziridine, its lone pair first attacks the sp carbon of the heterocumule NCS, forming a thiourea intermediate A.

CHAPTER III: A Cascade Synthesis of S-Allyl Benzoylcarbamothioates via Mumm-type Rearrangement

In summary, we have established an elegant catalyst-free domino ring-opening approach for the synthesis of 2-iminothiazolidine. In the former, a concomitant transfer of a thiocyanate (as a nucleophile) and an aroyl moiety (as an electrophile) occurs (Scheme III.1a) while in the latter a domino ring-opening cyclization of the aziridine occurs (Scheme III.1b).

Differential reactivity of aroyl isothiocyanates

Using signals from the reactivity of aroyl isothiocyanate, we articulated that it could be the precursor to yield S-allylbenzoylcarbamothioate upon reaction with MBH alcohol. This observation suggests that the carbonyl oxygen comes from the –OH of MBH alcohol.

Plausible mechanism for the synthesis of S-allyl benzoylcarbamothioates

13CNMR analysis of 18O-labeled S-allylbenzoylcarbamothioate shows two signals and 169,658 ppm) due to both labeled and unlabeled carbonyl group in carbamothioate. Synopsis To demonstrate the applicability of our protocol, the S-allylbenzoylcarbamothioate (1a) was subjected to a few useful organic transformations (Scheme III.3).

Synthetic utility of S-allyl benzoylcarbamothioates

An acid hydrolysis of (1a) was performed which afforded (1ab) by cleavage of the imide bond. Quaternization of the nitrogen atom is the most common route to improve the solubility of commercially available drugs which is important for the oral absorption and bioavailability.

Various approaches for the synthesis of isoindolinones

Finally, single X-ray crystallographic diffraction study of one of the derivatives reestablished its structure as methyl 2-(2-(naphthalen-2-yl)-3-oxoisoindolin-1-yl)acetate. With the optimized condition in hand, the stability of the reaction was then applied to various o-alkenylanilines using different isocyanides.

Intermolecular competitive experiment and mechanistic investigations

Finally, the intermediate (G) abstracts a proton from the conjugate acid of base (B−H) to give the corresponding isoindolinone (1a) (Scheme IV.3). Based on the control experiment {Scheme IV.2d (v)}, it is clear that without photochemical conditions, an anionic reaction pathway cannot be completely ruled out (path-II).

Post-synthetic modification of isoindolinone

Summary To demonstrate the synthetic utility of isoindolinone products, 1a was transformed into a useful analogue (1ab) of a GABA (I) receptor antagonist {Scheme IV.4 (i)}. To check the scalability of the present protocol, a standard reaction was performed on a 5 mmol scale.

C ONTENTS

Chapter III A Cascade Synthesis of S-Allyl Benzoylcarbamothioates via Mumm-type

Visible-Light-Driven Isocyanide Insertion to o-Alkenylanilines: A Route to

An Overview of Isothiocyantes and

Arenediazonium Salts in Metal-Free Cascade Reactions

C HAPTER IA

IA.1. Introduction

Thus, it can be expected that the intermediate will be a stable species that can be isolated and characterized. The utility of each reaction is correlated with its bond-forming activity, increase in structural complexity, and its suitability for general application.

IA.2. Historical Background

Chapter IA Cascade Reactions of Isothiocyanates from Acetate presents a beautiful example of a natural cascade reaction. The first synthesis of the seminal cascade was reported by Schöpf and Robinson (1917) by reacting succindialdehyde, acetone dicarboxylic acid and methylamineropinones via double Mannich reactions to give tropinones. Later typical examples of cascade reactions include the synthesis of progesterone via cationic polyolefin cyclization developed by Johnson and co-workers.6 This approach is based on Stork–.

IA.3. Classifications of Cascade Reactions

Chapter IA Cascade reactions of isothiocyanates Br2 gave 1-tolyl-3-aryl-4-methylimidazole-2-thiones in reasonable yields (Scheme IA.5.3.4).39. Chapter IA Cascade reactions of isothiocyanates forming a plethora of diversely functionalized 2-phenyl-2-thiocyanatoethylbenzoates (Scheme IA.5.4.4).43.

Figure IA.4.1. The principle of ideal synthesis as proposed by Wender et al.
Figure IA.4.1. The principle of ideal synthesis as proposed by Wender et al.

IA.6. Refrences

This metal- and base-free strategy simultaneously constructs C−O and C−S bonds at α- and β-positions with 100% atom economy (Scheme IA.4.4.5).44. Miller, in Connectivity Analysis and Multiple Bond Formation Processes in Organic Synthesis: Theory and Applications (ed. Hudlicky, T.) 27–66 (JAI Press, 1993).

C HAPTER IB

IB.1. Introduction

Chapter IB Arenediazonium salts counteranions with low nucleophilicity viz. tetrafluoroborate, hexafluorophosphate, tosylate and disulfonimide are the best anions in stabilizing the arenediazonium cations. Another substitute for arendiazonium salt are aryltriazenes which can be easily generated by the reaction of arendiazonium salts with secondary amines.4.

IB.2. Historical Background

From this point of view, organic nitrites (RONO2) in the presence of BF3.Et2O appeared as a mild and simple synthetic route for the preparation of diazonium salts (Scheme IB.1.1b). Thus, the extension of diazotization to water-incompatible substrates.10 In 1977, Kikukawa and Matsuda established transition metal-catalyzed cross-coupling of arenediazonium salts, which opened new avenues for further progress in cross-coupling chemistry using aryl diazonium salts as an alternative. in aryl halides.11 In the late 19th century, when methods for aromatic functionalization were practically limited, the chemistry of diazonium salts heralded a new era in aromatic substitution and cross-coupling chemistry for the construction of C-C and C-heteroatomic bond formation.

IB.3. Reactivity and Modern Applications

Furthermore, arenediazonium salts have found synthetic applications in the synthesis of complex carbocycles and nitrogen-containing heterocyclic compounds. Chapter IB Mediation of arenediazonium salts followed by electrophilic aromatic substitution (SEAR) together with the previously reported HAS (Scheme IB.4.1.3).17. In this methodology, arenediazonium salts act as two nitrogen units instead of aryl radical sources, which provide an alternative class of N source for the synthesis of bioactive 1,2,4-triazoles (Scheme IB.4.3.9). .

The group of Wang and Zhang realized the synthesis of aryl trimethylstannane derivatives using in situ diazotized arylanilines.

IB.6. References

Chapter IB Arenediazonium salts Tyrosine is an attractive site for chemo- and site-selective protein modification. This method uses 64Cu and 68Ga labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid diazonium salts as building blocks. Aryldiazonium salts: new coupling agents in polymer and surface science, Wiley-VCH, Weinheim, Germany, 2012, 334.

Syntheses, Properties and Applications of Organic Dyes and Pigments, Wiley-VCH, Zurich, 3rd revised ed., 2003.

Catalyst and Solvent Free Domino Ring Opening Cyclization: A Greener and Atom

Economic Route to 2-Iminothiazolidines

C HAPTER II

Catalyst and Solvent Free Domino Ring Opening Cyclization: A Greener and Atom Economic Route to 2-

  • Introduction
  • Differential Strategies Towards the Synthesis of 2- Iminothiazolidines
    • Synthesis of 2-iminothiazolidines via ring-opening cyclization (DROC) of aziridines
    • Synthesis of 2-iminothiazolidines via ring-opening cyclization (DROC) of thiiranes
    • Synthesis of 2-iminothiazolidines using propargylamines
    • Miscellaneous approach for the synthesis of 2-iminothiazolidines
  • Present Work

Inversion at the benzylic position confirms that the reaction takes place via the SN2 pathway (Scheme II.2.1.7).15. The nature of heterocumulene dictates the enantiomeric excess of this cyclization reaction (Scheme II.2.3.1).18. Unlike aroyl isothiocyanates (ArCO−NCS), the complete failure of the reaction in the case of PhNCS (l) suggests that the former may be a catalyst-free protocol due to the ambident nature of aroyl isothiocyanate (Scheme II.3.4).10-14 .

Since there is no other reagent in the reaction medium that can stabilize (A), which is responsible for the partial in situ racemization of chiral substrates (13) and (14), (Scheme II.3.5).30.

Table II.3.1 .  Optimization of the reaction conditions a,b
Table II.3.1 . Optimization of the reaction conditions a,b

Plausible mechanism for the synthesis of 2-iminothiazolidines

Experimental Section

After completion of the reaction, the crude product thus obtained was then purified by column chromatography on silica gel (column chromatography was not required for compounds 7a–7f and 9a–9f ) using EtOAc/hexane as eluent to obtain product (1a) (149 mg, 88%). It was then equipped with a condenser and the resulting reaction mixture was stirred in a preheated oil bath maintained at 85 oC. After completion (the color changes from white to yellow), the reaction mixture was cooled to room temperature.

Then it was mixed with ethyl acetate (30 ml) and washed sequentially with saturated sodium bicarbonate solution (2 x 5 ml) and brine solution (2 x 5 ml).

Spectral data of product

Representative Spectra

  • HPLC Chromatogram of the Products

Catalyst and Solvent Free Domino Ring Opening Cyclization: A Greener and Atomic Opening Cyclization: A Greener and Atomic Opening. Summary: A catalyst- and solvent-free synthesis of S-allylbenzoylcarbamothioates has been achieved from the in situ generated benzoylcarbonimidothioates obtained by reacting MBH alcohols with aroyl isothiocyanates. An intramolecular thia-Michael addition of the in situ generated adduct causes a Mumm-type rearrangement leading to a stereoselective synthesis of highly functionalized S-allylbenzoylcarbamothioates.

C HAPTER III

A Cascade Synthesis of S-allyl Benzoylcarbamo- thioates via Mumm-type Rearrangement

  • Introduction
  • Ideas Toward the Synthesis of S-Aryl Carbamothioates
  • Present Work

In this strategy, di-tert-butyl peroxide (DTBP) is used as an oxidant (Scheme III.2.5).5b. After further oxidation with m-CPBA, a variety of allylic sulfones were prepared in enantiomeric pure form (Scheme III.2.9).14. The synthetic potential of this methodology was demonstrated by synthesizing the anxiolytic drug Aniracetam (Scheme III.2.13).22.

As can be seen from Scheme III.3.1, variously functionalized aroyl isothiocyanates bearing electron-neutral −H (a), electron-donating groups (b−d), and electron-withdrawing groups reacted smoothly with (1), giving the desired products (1a). -1k) with good to excellent returns.

Figure III.2.1. Examples of biologically active imides.
Figure III.2.1. Examples of biologically active imides.

Plausible reaction mechanism

Synthetic transformations of 1a

Experimental Section

  • Crytallographic Description
  • General Procedure for the Synthesis of (Z)-methyl 2- (((benzoylcarbamoyl)thio)methyl)-3-phenylacrylate (1a): Methyl 2-
  • General Procedure for the Synthesis of Methyl 2- (hydroxy(phenyl)methyl)acrylate (1-18): The synthesis of all the MBH alcohols (1-18,
  • NOE Experiment

After completion of the reaction (indicated by the formation of white solid), the crude product thus obtained was then purified by silica gel column chromatography using EtOAc and hexane (20:80) as eluent to remove all the by-product and the final product ( 1a ) was obtained under using 100% DCM as eluent (170 mg, 96%). After completion, the reaction mixture was mixed with ethyl acetate (30 mL) and washed successively with a saturated solution of sodium bicarbonate (2 x 5 mL) and brine (2 x 5 mL). After completion of the reaction, the mixture was diluted with EtOAc (10 mL), washed with saturated NaHCO3 solution (1x10 mL) and finally washed with saturated NaCl solution (1x10 mL), dried over anhydrous sodium sulfate (Na2SO4) and evaporated under reduced pressure , the crude product thus obtained was then purified by silica gel column chromatography using EtOAc and hexane (19:81) as 1ab (25.30 mg, 72%).

After completion of the reaction, the mixture was diluted with EtOAc (10 mL), washed with saturated NaHCO 3 .

Figure III.4.8.1.  1 H NMR spectra of 2b (DMSO-d 6 , 400 MHz).
Figure III.4.8.1. 1 H NMR spectra of 2b (DMSO-d 6 , 400 MHz).
  • References
  • Spectral data of product
  • Representative Spectra

1H NMR study to detect reaction intermediates: To detect the intermediate species in the reaction mixture for this transformation, 1H NMR spectroscopy was performed. The crude product thus obtained was used for 1H NMR study in DMSO-d6 with tetramethylsilane as the internal standard for 1H NMR (400 MHz). The crude mixture thus obtained was used for the 13C{1H} NMR study in DMSO-d6 with tetramethylsilane as internal standard for 13C{1H} NMR (150 MHz).

The formation of the labeled S-allyl benzoylcarbamothioate (1a′′) was confirmed by spectroscopic and HRMS analysis (Figures III.4.10.1 and III.4.10.2).

Figure III.4.10.1.  HRMS spectrum of  18 O labeled 1a′′.
Figure III.4.10.1. HRMS spectrum of 18 O labeled 1a′′.

Methyl 2-((((4-methylbenzoyl)carbamoyl)thio)methyl)-3-phenylacrylate (1b)

Methyl 2-((((4-fluorobenzoyl)carbamoyl)thio)methyl)-3-phenylacrylate (1e)

Synthesis

C HAPTER IV

  • Introduction
  • Differential Strategies for Synthesis of Isoindolinones
    • Synthesis of isoindolinones via lactamization
    • Synthesis of isoindolinones via C−H activation
    • Synthesis of isoindolinones via carbonylation
    • Synthesis of isoindolinones via metal-catalyzed isocyanide insertion
  • Present Work

Huang group reported a four-component Ugi reaction for the synthesis of isoindolinones using 2-furaldehydes, amines, isocyanides, and 2-(phenylselenyl)acrylic acids. One of the earliest examples of Ru(II)-catalyzed synthesis of isoindolinones is disclosed by Hashimoto and co-workers. Several groups have employed this strategy for the synthesis of isoindolinones using different CO surrogates.24.

To the best of our knowledge, this is the unique report on the visible light-mediated synthesis of isoindolinones using 2-alkenylanilines and isocyanides (Scheme IV.2.5.2).

Figure IV.1.1. Representative examples of bioactive isoindolinones.
Figure IV.1.1. Representative examples of bioactive isoindolinones.

Figure

Figure IA.1. Differential reactivity of aroyl isothiocyanates.
Figure IA.1.1. Cascade or domino reaction.
Figure IA.4.1. The principle of ideal synthesis as proposed by Wender et al.
Figure IA.5.2. Differential reactivity of acyl isothiocyanates.
+7

References

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