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A direct coupling reaction between the vinyl and the aryl groups was attempted, having been inspired by alkene to aryl coupling methods.^139,140 The coupling in the first of these reported methods relied on the use of palladium acetate as the catalyst and a co-catalyst to regenerate the palladium acetate catalyst at the end of the cycle.

The second method reported the synthesis of various carbazoles in a one pot N-arylation and coupling between aryl triflates and aniline in the presence of palladium acetate and acetic acid, with oxygen as the oxidant. The enaminone (as an electron-rich nucleophile) would be able to mimic the role of the electron-electron-rich aromatic nucleophile in the second method, as well as in some alternative methods to be described below.

Compound 161 (prepared as described previously) was transformed into 1-(3,4-dimethoxyphenyl)pyrrolidine-2-thione 302 in moderated yields between 51 – 77%

using phosphorus pentasulphide as the thionating agent in dichloromethane at room temperature overnight (Scheme 68, b). Loss in yield may be due to the tars formed at the bottom of the round bottom flask which were insoluble in dichloromethane. ( E)-Ethyl 2-(1-(3,4-dimethoxyphenethyl)pyrrolidin-2-ylidene)acetate 303 was then achieved in yields between 35 – 60% in an Eschenmoser sulphide contraction reaction of 302 with ethyl bromoacetate in acetonitrile at room temperature overnight after which the salt had precipitated. The reaction was completed by the addition of a solution of triethylamine and triphenylphosphine in acetonitrile and left to react at room temperature overnight to induce sulphur extrusion. A lower equivalence of triphenylphosphine and triethylamine plus leaving the Eschenmoser salt formation step for longer hours ensured higher yields (Scheme 68, c, d). The enaminone 303 was then subjected to a number of coupling reactions utilising reagents in Scheme 68, e.

Wurtz et al. demonstrated an efficient synthesis of indoles from anilines by a palladium-catalysed intramolecular oxidative coupling. They used palladium(II) acetate as the catalyst, copper(II) acetate as the oxidant to reoxidise Pd⁰complexes to Pd^IIand potassium carbonate as the base in N,N-dimethylformamide. The optimal conditions for para-substituted anilines were reacting at 140 °C.^138,138(E)-Ethyl 2-(1-(3,4-dimethoxyphenethyl)pyrrolidin-2-ylidene)acetate 303 was reacted under these conditions for 18 h, returning 86% of compound 303 after purification (Table 28, entry 1). Vinylogous urethane 303 was not a suitable substrate for this transformation under the above reaction conditions. The reason maybe that compound 303 had a tertiary amine while anilines had secondary amine where the NH proton was crucial in reaction mechanism.

Fujiwaraet al. reported the arylation of arenes with olefins by palladium(II) acetate in acetic acid in the presence of air for a few minutes to several hours resulting in high yields of arylated products.¹⁴³The co-catalyst was therefore changed from copper(II) acetate to oxygen gas by heating (E)-ethyl 2-(1-(3,4-dimethoxyphenethyl)pyrrolidin-2-ylidene)acetate 303 under reflux with palladium(II) acetate in acetic acid while bubbling oxygen gas for 1 hour. This also returned compound 303 in high 80% yield (Table 28, entry 2).¹⁴⁰

Table 28: Various coupling reactions of compound303

No. Reagents Conditions Solvents Results

1. (0.1 eq) Pd(OAc)2, (3 eq) Cu(OAc)2, (3 eq) K2CO3

140 °C, 18 h DMF 165 = 0%;

303 = 86%

2. (0.1 eq) Pd(OAc)2, bubbling O2gas

Reflux, 1 h Acetic acid 165 = 0%;

303 = 86%

3. (0.1 eq) Pd(OAc)2, bubbling O2gas

100 °C, 1 h DMF 165 = 0%;

303 = 86%

4. (0.4 eq) Pd(OAc)2, (1.6 eq) P(o-tolyl)³, (10.6 eq) TEA

55 °C, 22 h DMF,

MeCN, H2O

165 = 0%;

303 = 79%

5. (10 eq) FeCl3 r.t. DCM 165 = 0%;

303 = 93%

Changing the solvent from acetic acid to N,N-dimethylformamide had no benefit for the reaction. (E)-Ethyl 2-(1-(3,4-dimethoxyphenethyl)pyrrolidin-2-ylidene)acetate 303 was reacted with palladium(II) acetate in N,N-dimethylformamide while bubbling oxygen gas at 100 °C for 1 hour, but this returned 86% of compound 303 after

purification (Table 28, entry 3). In another attempt, (E)-ethyl 2-(1-(3,4-dimethoxyphenethyl)pyrrolidin-2-ylidene)acetate 303 was reacted with tri-o-tolylphosphine and triethylamine in a mixture of acetonitrile, N,N-dimethylformamide and water as solvents at 55 °C for 22 hours, returning 79% of compound 303 (Table 28, entry 4).

Iron(III) chloride has been used as a mild oxidising agent in oxidative carbon-carbon coupling reactions between arenes. Arenes were reacted with iron(III) chloride in dichloromethane at room temperature for 3 hours, resulting in desired products.^123,124 The iron(III) chloride could oxidise the aromatic ring of compound 303 followed by a nucleophilic carbon attack from the enaminone system, coupling the vinyl to the aromatic carbon (C-4). (E)-Ethyl 2-(1-(3,4-dimethoxyphenethyl)pyrrolidin-2-ylidene)acetate 303 was reacted with iron(III) chloride in dichloromethane at room temperature for 23 hours, resulting in the return of compound 303 in 93% yield (Table 28, entry 5).

The IR spectrum of 1-(3,4-dimethoxyphenethyl)pyrrolidine-2-thione 302 revealed the absence of the amide carbonyl peak and had a peak at max = 1456 cm^-1 for the aromatic group. The ¹H NMR spectrum revealed a downfield chemical shift of proton peaks due to stronger electron withdrawing sulphur atom as compared to the oxygen atom, while ring and methoxy proton peaks were not affected by the change. The comparison changes are listed in Table 26. The ¹³C NMR spectrum revealed the absence of the amide carbonyl carbon peak at δ 175.0 ppm and the presence of the thiocarbonyl carbon peak at δ 200.6 ppm. The remainder of the carbon peaks showed a slight downfield chemical shift at seen from Table 29.

Table 29: Comparison of the¹H and¹³C NMR spectra of lactam161 and thiolactam 302

161 ¹H NMR /ppm

302¹H NMR /ppm 161 ¹³C NMR

/ppm

302¹³C NMR /ppm

3.56 – 3.47 (m)

3.95 (t,J = 7.4 Hz, NCH2CH2Ar ) 47.7 55.6 (NCH2CH2Ar)

3.27 (t, J = 7.0 Hz)

3.52 (t,J = 7.3 Hz, γ-protons) 44.1 49.4 (γ-carbon)

2.36 (t, J = 8.1 Hz)

3.05 – 2.87 (m, α-protons) 33.3 44.9 (NCH2CH2Ar)

2.84 – 2.75 (m)

3.05 – 2.87 (m, NCH2CH²Ar) 31.0 31.7 (α-carbon)

The melting point of (E)-ethyl 2-(1-(3,4-dimethoxyphenethyl)pyrrolidin-2-ylidene)acetate 303 was 108 – 109 °C. The IR spectrum revealed peaks at ^max = 1668 and 1585 cm^-1 for the ester carbonyl and the vinyl groups. The ¹H NMR spectrum revealed new peaks, a singlet at δ 4.61 ppm for the vinyl peak and a triplet and a quartet, both withJ = 7.1 Hz at δ 4.11 and 1.27 ppm respectively, for the ethyl side chain, confirming the formation of the unsaturated ester. The reduced electron withdrawing effect from the unsaturated ester produced an upfield chemical shift of the peaks, as shown in Table 30.

Table 30: Comparison of the¹H NMR spectra of thiolactam302 and vinylogous urethane 303

302 ¹H NMR /ppm 303 ¹H NMR /ppm

3.92 3.39 (t, J = 7.3 Hz, NCH²CH2Ar)

3.52 3.16 (m, ε-protons)

3.05 – 2.87 2.80 (t, J = 7.3 Hz, γ-protons) 3.05 – 2.87 3.16 (m, NCH2CH2Ar)

Compound 303 had an E geometry as indicated by the through-space deshielding of γ-protons of the unsaturated ester. The ¹³C NMR spectrum revealed the absence of the thiocarbonyl peak at δ 200.6 ppm and the presence of peaks at δ 169.5, 164.5, 77.6, 58.2 and 14.8 ppm for the ester carbonyl, the quaternary alkene, vinyl and ethyl side chain carbons respectively. The remainder of the carbon peaks remained relatively unchanged except for the CH2CH²Ar peak which shifted up field to 32.7 ppm from 44.9 ppm. The HRMS spectrum found [M+H]⁺ 320.1853 for a molecular formula C18H26NO4+

with an exact calculated mass of 320.1856.

Attempts were made to form five-membered and six-membered rings since forming a seven-membered ring was a challenge under the oxidative coupling reaction conditions. Compounds 304 (with no CH²link between nitrogen atom and aryl group) and 307 (with one CH² link between nitrogen atom and aryl group) would make these transformations possible. Thus (E)-ethyl 2-(1-(3,4-dimethoxyphenyl)pyrrolidin-2-ylidene)acetate 304 (synthesised in section 3.4; see below) was heated under reflux (80 °C) with palladium(II) acetate in acetic acid under oxygen atmosphere (balloon) for 1 hour resulting in formation of an unexpected ethyl 2-(1-(3,4-dimethoxyphenyl)-1H-pyrrol-2-yl)acetate 305 in 14% yield and decomposed tars (Scheme 69, a). The reaction gave the desired ethyl 6,7-dimethoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate 306 in 14% yield and decomposed tars when the reaction temperature was reduced to 55 °C. Further attempts to improve the yields were unsuccessful.

Scheme 69: Reagents and Conditions: (a) Pd(OAc)2(0.1 eq), O₂balloon, acetic acid, 1 h at relfux (80°C),305 = 14%; (b) Pd(OAc)2(0.1 eq), O₂balloon, acetic acid, 1 h at 55 °C, 305 = 14%.

305 304 306

a b

O

The IR spectrum of ethyl 2-(1-(3,4-dimethoxyphenyl)-1H-pyrrol-2-yl)acetate 305 had

1H NMR spectrum revealed the absence of the vinyl peak which was at δ 4.65 ppm in306’s ¹H NMR spectrum and the presence of a singlet at δ 3.56 ppm for α-protons of the ethyl ester. The pyrrole ring was represented by a multiplet at δ 6.80 – 6.75 ppm for the ε-proton and a multiplet at δ 6.31 – 6.14 ppm for the γ and δ-protons of the ethyl ester revealing the absence of the pyrrolidinyl ring proton peaks which were at δ 3.63, 3.23 and 2.02 ppm of 304’s ¹H NMR spectrum. The ¹³C NMR spectrum revealed the absence of the vinyl and quaternary carbon peaks which were at δ 80.7 and 164.8 ppm in 304’s ¹H NMR spectrum and the presence of pyrrol peaks at δ 125.8, 122.7, 110.4 and 109.3 ppm for the β, ε, γ and δ carbons of the ethyl ester respectively. The α-carbon peak to the ester group registered at δ 32.7 ppm. The HRMS found [M+H]⁺equal to 290.1319 for a molecule with a molecular formula C16H20NO4+

with an exact calculated mass of 290.1387.

The IR spectrum of ethyl 6,7-dimethoxy-2,3-dihydro-1 H-pyrrolo[1,2-a]indole-9-carboxylate 306 showed peaks at ^max = 1678 and 1579 – 1427 cm^-1 for the ester carbonyl and aromatic groups. The ¹H NMR spectrum revealed the absence of the vinyl singlet at δ 4.65 ppm in 304’s ¹H NMR spectrum. The aromatic peaks resolved to two singlets at δ 7.63 and 6.75 ppm for 8-H and 5-H protons, from three proton peaks previously observed in 304’s ¹H NMR spectrum. The ¹³C NMR spectrum revealed the absence of the vinyl carbon peak at δ 80.7 ppm in 306’s ¹H NMR spectrum and the presence of a quaternary alkene carbon peak at δ 99.0 ppm for C-6. The newly formed quaternary aromatic carbon peak C-9 was at δ 124.1 ppm, a downfield shift from δ 117.5 ppm in 304’s ¹³C NMR spectrum due to added electron delocalisation by the ester group. The aromatic carbon peaks C-8 and C-5 shifted up field to δ 103 and 93.5 ppm respectively from 111.6 and 109.0 ppm in 304’s ¹³C NMR spectrum. The remainder of the quaternary and pyrrolidinylidene ring carbon peaks slightly shifted up field except for δ-carbon peak which shifted downfield. The HRMS found [M+H]⁺ equal to 290.1389 for a molecule with molecule formula C16H20NO4+

and exact calculated mass of 290.1387.

(E)-Ethyl 2-(1-(3,4-dimethoxybenzyl)pyrrolidin-2-ylidene)acetate 307 (synthesised in section 3.4; see below) was also reacted with palladium(II) acetate to observed whether it would give the desired products 308 (E)-ethyl

2-(1-(3,4-dimethoxybenzyl)pyrrolidin-2-ylidene)acetate 307 was heated under reflux (80 °C) with palladium(II) acetate in acetic acid under oxygen atmosphere for 24 hours resulting in unidentified by-products (Scheme 70, a). The reaction of compound 307 returned tars and 18% of starting material when the temperature was reduced to 50

°C (Scheme 70, b).

The coupling reactions for compounds 303 and 307 in Scheme 64 and Scheme 66 respectively may have failed due to difficulties in creating six-membered and seven-membered rings as compared to making five-seven-membered rings via arylation, even though the synthesis of compound 306 was demonstrated in significantly poor yields.

The lack of CH2link between the nitrogen atom and the aryl group on 306 influences the electronics of the aryl group. The nitrogen atom together with OMe (C-3) activate C-6 on the aryl group making it more nucleophilic as compared to C-6 from compounds 307 and 303 which have carbon linkers between the nitrogen atom and aryl group.