Ideas Toward the Synthesis of S-Aryl Carbamothioates

Lloyd-Jones and co-workers reported a [Pd(^tBu3P)2] catalyzed Newmann-Kwart rearrangement of S-aryl carbamothioates at 100 ^oC. Substrates having electron- withdrawing groups show better reactivity than electron-donating substituents. Mechanistic studies and theoretical calculations suggest that a S-coordinated monophosphine–palladium complex (I), initiates the oxidative addition followed by tautomerization and reductive elimination sequence (Scheme III.2.1).⁷

Scheme III.2.1. Pd(II) catalyzed synthesis of S-aryl carbamothioates.

In 2018, Pittelkow et al. reported a ceric ammonium nitrate (CAN) mediated Newman-Kwart rearrangement of O-thiocarbamate. Substrates having electron-donating substituents gave clean conversion and almost quantitative yield. Computational studies support an intramolecular SET mechanism and formation of thiyl radical cation (Scheme III.2.2).⁸

Scheme III.2.2. CAN-mediated synthesis of S-aryl carbamothioates.

Chapter III S-Allyl Benzoylcarbamothioates Nicewicz et al. disclosed a photoredox-mediated Newman-Kwart rearrangement using 2,4,6-tri(p-tolyl)pyrylium tetrafluoroborate (TPT) as a catalyst. Unlike the thermal NKR route, this process takes place at ambient temperature and is more compatible with electron-rich substituents. Cyclic voltammetry studies show that oxidation of the thiocarbonyl moiety to thiyl radical cation is likely involved in the rearrangement (Scheme III.2.3).⁹

Scheme III.2.3. Photoredox-mediated NKR reaction.

An electrochemical method for the rearrangement of O-aryl thiocarbamates to the equivalent S-aryl thiocarbamates is illustrated by the Francke group. The salient features of this mild approach are ambient temperature, requires only catalytic amounts of both electric charge and metal, and additive free. When the reaction was performed in a flow reactor instead of a batch process, a quantitative yield was obtained without any supporting electrolyte. Compared to the thermal NKR approach, this methodology favors electron-rich substituents (Scheme III.2.4).¹⁰

Scheme III.2.4. Electrochemical approach for NKR reaction.

In 2015, Mao and Zhang’s group demonstrated an AlCl3-promoted thiolation of formamide C−H bonds with arylsulfonyl hydrazides as thiol surrogates. In this strategy, di- tert-butyl peroxide (DTBP) is used as an oxidant (Scheme III.2.5).^5b

Scheme III.2.5. AlCl3-promoted thiolation of formamides.

Chapter III S-Allyl Benzoylcarbamothioates Căproiu and Dumitrascu et al. disclosed an unexpected S-thiocarbamate synthesis via a benzylic Newman-Kwart rearrangement using 5-dibenzosuberol and aroyl isothiocyanates. The structures of these new derivatives were confirmed by elemental analysis, spectroscopic methods (IR, ¹H NMR, ¹³C{¹H} NMR), and X-ray crystallography (Scheme III.2.6).¹¹

Scheme III.2.6. Synthesis of S-thiocarbamate.

Taking cues from the reactivity of aroyl isothiocyanate, we articulated that this could be the precursor to afford S-thiocarbamates upon reaction with Morita-Baylis-Hillman (MBH) alcohol. Thus, a reaction was carried out between methyl 2- (hydroxy(phenyl)methyl) acrylate (1) and benzoyl isothiocyanate (a) in toluene (2 mL) at room temperature. Instead of a S-thiocarbamate, a new allyl thioether (1a) containing two important moieties viz. imide and 2-methylthioacrylate, was isolated in 56% yield possibly via a Mumm type of rearrangement (Scheme III.2.7).

Scheme III.2.7. Synthesis of S-allyl benzoylcarbamothioates.

Despite the remarkable progress made to date, the construction of allylic thioethers via metal-free C−S bond forming reactions is still lacking. Several strategies, including transition metal-catalyzed substitution reaction, thiocarbonylation, insertion reaction, and transition metal-catalyzed or organocatalyzed Michael additions, have been well recognized over the years to construct C–S bonds.¹² Below are some of the examples for the synthesis of S-allyl thioethers.

Chapter III S-Allyl Benzoylcarbamothioates Zhang's group reported a Fe(II) catalyzed cross-coupling reaction of allylic alcohols and thiols using a diphosphite ligand (L). A variety of thiols and alcohols were compatible with this strategy yielding their corresponding product in high yield and selectivity (Scheme III.2.8).¹³

Scheme III.2.8. Fe(II)-catalyzed synthesis of S-allyl thioethers.

In 2015, Breit group reported an atom-economic, Rh(I) catalyzed highly regio- and enantioselective hydrothiolation of terminal allenes. Upon further oxidation with m-CPBA, a variety of allylic sulfones were prepared in enantiomerically pure form (Scheme III.2.9).¹⁴

Scheme III.2.9. Asymmetric hydrothiolation with terminal allenes.

In 2010, Wu et al. disclosed a base-mediated synthesis of allylic thioethers by reacting phosphorothioate esters and alcohols in methyl tert-butyl ether (MTBE) as a solvent. This one-step reaction proceeds via the addition of an exogenous alkoxide to the corresponding allylic phosphorothioate ester. This stereospecific process delivers the enantioenriched thioethers in good yields and avoids the use of malodorous sulfur compounds such as thioacetic acid or thiols (Scheme III.2.10).¹⁵

Scheme III.2.10. Base-mediated synthesis of S-allyl thioethers.

Chapter III S-Allyl Benzoylcarbamothioates Imides are significant structural motifs found in various natural products and pharmaceutical agents.^16a,b Figure III.2.1 shows selected examples of biological active imide moiety viz., Diacetazotol (Dermagan),^16c tetraacetylethylenediamine (TAED)^16d and the anxiolytic drug Aniracetam (Ampamet).^16c Such imides motif also appears in certain natural products such as fumaramidmycin,^16e,f coniothyriomycin^16g, and unnatural compound SB-253514.^16h They also appear as precursors in a variety of reactions, such as condensation, alkylation, acylation, and cycloaddition.¹⁷

Figure III.2.1. Examples of biologically active imides.

The classical methodology for the synthesis of imides relies on the condensation of amides with carboxylic acids and their derivatives. N-Acylation of amides using aldehydes as the acyl source is one of the important synthetic tools in the construction of imides. There are limited precedents for the synthesis of imides based on metal-catalyzed cross-coupling strategies such as, (i) Rh(II)-catalyzed sulfamidation of aldehydes;^18a-c (ii) Fe/Cu catalyzed coupling of aldehydes and thioesters with carboxamides;^18d-g (iii) oxidation of N- alkylbenzamides;^18h-j and (iv) ceric ammonium nitrate (CAN)-promoted oxidation of 4,5- diphenyloxazoles.^18k Though the above-mentioned protocols describe elegant methods for the construction of imide motifs but the limitation is, that it is applicable for the derivatization of sulfonamides or carboxamides only.¹⁹ Despite several procedures available for their synthesis, the use of designer substrates, poor yields, cumbersome multi- stepped processes, and inadequate product diversity are some of the limitations. Below are some of the examples for the synthesis of imides.

Chapter III S-Allyl Benzoylcarbamothioates Fu and Jiang's group reported an efficient Fe(II) chloride/N-bromosuccinimide (NBS)-mediated synthesis of imides and acylsulfonamides using thioesters and carboxamides/sulfonamide as coupling partners. This process requires no additional ligands or additives (Scheme III.2.11).²⁰

Scheme III.2.11. FeCl2/NBS-mediated couplings of carboxamides with thioesters.

Singh’s group disclosed a TBHP-mediated direct coupling of NH-amides with methylarenes using iodine as a catalyst. This method also works with benzyl alcohols and benzaldehydes which yields the corresponding imides in good to moderate yields.

Mechanistic investigation suggests a radical pathway. Further, the ¹⁸O-labeled experiment confirmed water to be the source of O-atom in imides (Scheme III.2.12).²¹

Scheme III.2.12. TBHP-mediated synthesis of imides.

A Pd(II) catalyzed synthesis of imides using olefins, NH-amides, and carbon monoxide has been reported by Beller et al. via hydroamidocarbonylation. The imides were synthesized in good yield and good regioselectivity. The synthetic potential of this methodology was demonstrated by synthesizing the anxiolytic drug Aniracetam (Scheme III.2.13).²²

Scheme III.2.13. Pd(II)-catalyzed synthesis of imides.

In 2014, Pan and Liu's group described a base promoted synthesis of imides by reacting -(alkylideneamino)nitriles with molecular oxygen. A wide variety of imides were

Chapter III S-Allyl Benzoylcarbamothioates synthesized in good to moderate yield with a wide range of functional group tolerance (Scheme III.2.14).²³

Scheme III.2.14. Base promoted synthesis of imides.