Diels-Alder cycloaddition of methylcyclopentadienes to 2,5-dibromo-p-benzoquinone was performed. A single, isomerically pure cycloadduct was isolated, whose structure was assigned via analysis of its 1-D and 2-D NMR spectra. Diels-Alder cycloaddition of methylcyclopentadienes to 2 -methoxy-p-benzoquinone was performed. A single, isomerically pure cycloadduct was isolated, whose structure was assigned via analysis of the 1-D and 2-D NMR spectra of this cycloadduct and its reduction product obtained via stereo-specific reduction with sodium borohydride in the presence of cerous chloride. The structure of Thiele's ester was assigned via analysis of its 1-D and 2-D NMR spectra.

A new approach to fulminic acid cycloadditions has been developed. At reduced temperatures, fulminic acid is generated in situ and undergoes 1, 3-diploar cycloaddition reactions with dipolarophiles to form isoxazolines and/or its dimers. This procedure represents a novel, safe general method for the one-step generation of fulminic acid, which complements existing potentially explosive protocols.

Dipolar (3+2) cycloadditions are extensively utilized by synthetic chemists for accessing important 5-membered heterocyclic structures. After the pioneering work by Rolf Huisgen in the early 1960s, the field greatly matured and found applications in a variety of fields of chemistry. Worthy of mention, the discovery by Meldal, Sharpless, and Folkin of copper-catalyzed azide alkyne cycloadditions (CuAAC), also referred to as a “Click” reaction, was awarded the Nobel Prize in 2022. The finding of this ideal CuAAC reaction originated from the reliability of dipolar (3+2) cycloaddition reactions, whose transformation was rendered extremely kinetically favorable and stereospecific with the use of copper-catalysis. It is therefore of high importance to continue finding novel (3+2) cycloadditions, despite the apparent maturity of the field. The research described in this thesis presents the efforts towards the synthesis of fused pyrroles and thiophenes by means of (3+2) cycloaddition cascades using ynamides and alkynyl sulfides as isoelectronic species to 1,3-dipoles. In Chapter 2, the exploration of different strategies to bridge the in-situ synthesis of alkyne tethered ynamide and our group’s previously described thermally induced (3+2) cycloaddition cascade was investigated. Many challenges were faced when attempting to design one-pot procedures including the unprecedented degradation of yne-ynamides under metal-containing reaction conditions. This impeded the use of copper-catalyzed cross-coupling reactions as a general retrosynthetic disconnection for the in-situ formation of the ynamide functionality. Even an attempt to functionalize an ynamide precursor containing a tethered terminal alkyne by a Sonogashira cross-coupling was unsuccessful. With the aim to find an efficient way of synthesizing these diynes while limiting the use of stoichiometric reagents, the use of a previously unreported ynamide substituted propynal building block was explored. These aldehyde synthons were easily synthesized from accessible ynamide substituted propargyl alcohols using Dess-Martin Periodinane as the oxidant. Upon mixing these propynal derivatives with primary propargyl amines, a rapid condensation reaction takes place as long as the removal of water is done. These in-situ formed yne-ynamides then undergo (3+2) cycloaddition cascades towards fully substituted fused pyrroles at temperatures ranging from 60 to 100 oC. While the method was found to be limited to [3.3.0] fused pyrroles and moderate yields were observed (22-55% yields, 8 examples), this one-pot method permitted an extremely rapid growth of molecular complexity. Collectively, the work described in this chapter further accentuates the utility of ynamides as building blocks for densely functionalized pyrrole heterocycles. In Chapter 3, the reactivity of analogous alkyne tethered alkynyl sulfides (thioalkynes) was investigated. Alkynyl sulfides are an important class of heteroatom-substituted alkynes, whose alkynyl carbons are weakly polarized in contrast to ynamines (N-alkynyl amines) derivatives. While thioalkynes display superior stability in contrast to ynamides, both X-alkynyl species share similar reactivities. Upon heating of S-ester substituted yne-alkynyl sulfides, fully substituted thiophenes were obtained indicating that the reactivity observed with ynamides (as 4 cycloaddition partner) was transferable to thioalkynes. When S-alkyl substituted yne-thioalkynes are used, 5-unsubstituted thiophenes are formed instead. The use of S-tert-butyl substituted alkynyl sulfides enabled a broad scope of 5-unsubstituted fused thiophenes to be obtained via an intramolecular (3+2) cycloaddition and dealkylation cascade. The transient thiophenium ylide cycloadducts formed as a result of (3+2) cyclization were also efficiently trapped with electrophiles generating complex functionalized thiophenes. The use of S-n-propyl substituted yne-alkynyl sulfide was necessary in this case to provide control over product selectivity and to permit the electrophilic trapping to occur before dealkylation. Collectively, the reactivity cascades of thermally formed thiophenium ylides cycloadducts were studied in detail revealing a modulable and controllable reactivity by judicious choice of alkynyl sulfide substitution and reaction condition. In Chapter 4 the use of coinage metals for catalyzing the (3+2) cycloaddition of yne-alkynyl sulfides at room temperature was presented. Our group established that metal-induced low-energy pathways are accessible when alkynyl sulfides are tethered with terminal alkynes. Application of the new set of reaction conditions to an S-phenyl substituted yne-thioalkyne substrate revealed the formation of a thiophenium cycloadduct intermediate. The screening of alternative reaction conditions enabled the successful isolation of this S-phenyl thiophenium cycloadduct by precipitation from the reaction crude enabling structure confirmation by NMR and X-ray crystallography. The reactivity of this previously undescribed S-phenyl thiophenium salt was also evaluated under thermolysis and (metallo)photoredox conditions. The synthesis of S-(hetero)aryl yne-thioalkynes derivatives was first tackled revealing an incompatibility of the current methods described in the literature for a broad range of (hetero)aryl substituted alkynyl sulfides. Despite the numerous challenges encountered, the synthesis of para-substituted electron-poor and rich phenyl derivatives was successfully achieved using sulfur umpolung methods. A one-pot strategy was applied to these S-phenyl derivatives involving the in-situ formation of thiophenium cycloadducts which readily underwent a [1,5]-sigmatropic rearrangement and aromatization upon mild heating (70 oC) towards 2-aryl substituted fused thiophenes. Lastly, the compatibility of the S-phenyl thiophenium cycloadduct in (metallo)photoredox transformations for new CPh-C bond formation was evaluated. In contrast to electrophilic S-aryl sulfonium reagents commonly employed, this first generation of thiophenium salt was not efficient in providing high yields for the desired cross-coupled products. It was postulated that undesired HAT side reactivity was detrimental to the reaction efficacy. These preliminary studies allowed us to gain crucial insight into the inherent reactivity of an S-phenyl thiophenium salt with the hope to guide the next generation of potentially useful electrophilic reagents.

The thesis entitled "Structure and reactivity in bridged polycyclic systems: cis-trans enantiomerism, fulvene cycloadditions and crystallographic studies of bridgehead β-ketoacids " consists of two parts. Part I contains 3 chapters, and deals with cycloaddition reactions of 6-arylfulvenes with maleic anhydride and nitrones (The products in the case of maleic anhydride display cis-trans enantiomerism). Part II contains 2 chapters, and deals with resolution of racemic primary amines, racemic amino acids and the relative decarboxylation propensities of bicyclic β-ketoacids in solid state. Part I Chapter 1: A new case of the uncommon cis-trans enantiomerism is presented in the Diels-Alder cycloadducts (3 & 4) of 6-arylfulvenes (1) with maleic anhydride (2).1 The resolution of the cis-trans enantiomers were accomplished via the formation of diastereomeric imides 6 and 7 with (1S)-(naphth-1-yl)ethylamine (5), and their subsequent hydrolysis and recyclisation (Scheme 1). The enantiomers 3 and 4 were characterized spectrally, polarimetrically (including CD) and by chiral HPLC. The chiral anhydrides were also stereospecifically converted to the corresponding imides by treatment with aq. ammonia in excellent yields. The crystal structure of one of the diastereomeric imides (derived from 6-phenylfulvene) was determined, and based on the known S configuration of the naphthylethylamine moiety, the configurations of the original anhydride adducts could be assigned.2 Scheme 1 Chapter 2: In this chapter tricyclic imides (8a-c) were prepared by Diels-Alder reaction of 6-arylfulvenes (1a-c) and maleic anhydride (2),2 followed by treatment with aq. NH3. The exo isomers were found to exist as conglomerates when the aryl group was p-tolyl or p-anisyl (although not phenyl). Triage of the p-tolyl racemate (Scheme 2), followed by reaction with p-toluenesulphonyl chloride in CH2Cl2/Et3N, led to the crystalline enantiopure N-tosylimides 9 (These were also found to be conglomerates). X-ray diffraction analysis of the N-tosylimides (9) via the anomalous dispersion technique led to the assignment of the absolute configurations (as either E or Z).3, 4 The original p-tolyl imide enantiomers were found to racemise upon UV irradiation in CHCl3. Based on this, a possible second order asymmetric transformation under photochemical conditions was attempted, and indeed led to the isolation of crystalline imide with a small ee (~15%).5 Scheme 2 Chapter 3: This chapter deals with the fulvene-nitrone cycloadditions. The possibility of discovering examples of the rare (6π + 4π) cycloaddition prompted an exploration of the reaction between electron-rich nitrones and pentafulvenes. In previous reports of such cycloadditions, diazomethane or benzonitrile oxide was used as 4π component.6 Building on previous work from this laboratory,7 the reaction between a set of substituted fulvenes and electron rich nitrones were studied. Theoretical calculations indicate that the (6π + 4π) mode would be favored when the fulvene-nitrone cycloaddition is controlled by the LUMO (fulvene) – HOMO (nitrones) interaction.8 Electron withdrawing groups on the fulvene would lower the LUMO and facilitate the above orbital interaction. Therefore the reaction between electron poor fulvenes and nitrones was taken up for further study. In particular, fulvene (10) was reacted with nitrones (11). However, only a (2π + 4π) mode was observed, involving one of the endocyclic double bond of the fulvene, in moderate yields (Scheme 3). Structures of these adducts were assigned based on NMR and X-ray crystal structure determination. The failure to observe the (6π + 4π) mode (14) is intriguing, and it is not clear whether this is due to electronic or steric reason. Scheme 3 Part II Chapter 1 describes the resolution of racemic primary amines and racemic amino acids (16) via the formation of diastereomeric imides. For this purpose D-camphoric anhydride (15) was chosen as the chiral auxiliary for the following reasons: it is of low-molecular weight with a rigid backbone, and is also easily prepared and purified.9 Primary amine (16) was treated with D-camphoric anhydride (15) in presence of CHCl3/DCC to form the corresponding diastereomeric imides 17 and 18. (In the case of amino acids, the corresponding methyl esters were treated with D-camphoric anhydride (15) in presence of triethylamine in chloroform). The resulting diastereomeric imides 17 and 18 were separated by silica gel column chromatography (Scheme 4), and hydrolyzed to the chiral amines (or amino acids). (The by-produced camphoric acid could be reconverted to D-camphoric anhydride (15). Scheme 4 Chapter 2: The relative ease with which β-ketoacids tend to lose CO2 is intriguing and has been the focus of numerous mechanistic studies.10-12 It is generally believed that the decarboxylation of β-ketoacids occurs via a six-centered hydrogen bonded transition state (19), which leads to the formation of the enol tautomer (20) of the final ketone product (Scheme 5). Scheme 5 Scheme 6 The initial formation of the enol is apparently supported by the high thermal stability of bicyclic β-ketoacids, in which the carboxylic acid functionality is at bridgehead. In these the formation of the enol would be disfavored by Bredt’s rule, which forbids the formation of a double bond at the bridgehead (particularly in the smaller bicyclic compounds). Also, it may be expected that these trends would be manifested in the ground state. This is because there would be a stereoelectronic requirement for the decarboxylation reaction, by which the bond to the carboxylic group would need to be parallel to the C=O π bond of the keto group. Therefore, it was of interest to study the crystal structures of suitable β-ketoacids in the hope of evidencing the above structural trends (Structure for the analogs 21-23 have been reported previously (Scheme 6)).13-15 In fact, the approach pioneered by Dunitz was of particular interest in this regard. 16 In this approach crystal structures of a series of analogs were studied; these analogs possess varying degrees of strain that could be considered as leading to the transition state of a certain reaction. The bond length and related data are then employed to ‘map’ the reaction dynamics. Compound Bond* lengths (Å) Increase in the bond length compared to ketopinic acid (%) Decarboxylation temp.17 * fine bond at the bridgehead to the COOH group. In the case of the decarboxylation of β-ketoacids, a correlation between the lengthening of the bond to the COOH group and the ease of decarboxylation was sought. Therefore the set of analogs 24-26 were prepared (Scheme 6) and their crystal structures determined by X-ray diffraction (at 100K). In the case of 26, an increase of 2.47% relative to 21 in the Cα-COOH bond length was observed. However, no evidence for an intramolecular O=C-O-H…O=C H-bonding, was observed in the crystal structures of 24-26. Instead, the COOH moieties were seen to participate in intermolecular O-H…O hydrogen bonding via the well known carboxylic acid dimer motif. The β-ketoacids were also converted into their corresponding S-benzylisothiouronium salts (Scheme 6), to study the effect of destroying the COOH dimer motif. The salts 27 and 28 could be obtained in a form suitable for single crystal X-ray diffraction. The crystal structures revealed an increase in the Cα-COO- bond length to an extent of 1.97% in case of 28 relative to 27. Also, there is an increase in the relevant bond length of ~0.8% on going from 24 (m.p. 145 °C) to 26 (m.p. 132 °C). Note also that these compounds melts with decompositions. Therefore, it appears that the ease of decarboxylation of these analogs is reflected in the relative lengthening of the bond to the COOH group. Thus, this study represents an application of the Dunitz crystallographic approach to reaction dynamics,16 to the case of the decarboxylation of β-ketoacids.(For structural formula pl see the pdf file)