78 * Neumáticos

To extend the substrate scope of the 2,3 diaryl substituted cyclopropane diesters and in turn the products afforded via the [3+3] cycloaddition reaction, the replacement of aryl halides with heteroaromatic halides were investigated.

The phenyl cyclopropene diester 1d was treated with iodo-pyrazole 180 in presence of

palladium acetate and potassium carbonate expecting to afford the Heck product 181. (Scheme 102)

Scheme 102

However it soon became apparent from the NMR spectrum that the expected Heck product

181 had not been obtained. A split in the chemical shifts for the methyl ester peaks at 3.5

and 3.6 ppm combined with an additional two doublets at 4.2 and 5.0 ppm suggested the presence of a saturated cyclopropane ring. This was further confirmed by mass spectrometry and a crystal structure of product 182a was obtained by X-ray diffraction as

83

Figure 13

This implied that a hydroamination type reaction might have taken place as this reaction often occurs when catalysed by palladium (II) complexes. However this type of palladium mediated hydroamination is typically facilitated using a co-oxidant. In our case, the hydroamination of the cyclopropene was observed while no oxidant was used, and additionally the reaction was performed under anaerobic conditions. To identify whether the palladium source was responsible for the formation of product 182a, the reaction was

performed with a palladium (0) source, Pd2(dba)3. This returned the same trans 2,3

disubstituted cyclopropane 182a which was afforded with a similar yield despite the

palladium source used.

The reaction was attempted with a further three heteroaromatic halides; bromo-pyrazole, imidazole and 3,6 dibromocarbazole. (Scheme 103) The corresponding trans 2,3 disubstituted cyclopropanes 182b-d were isolated again in respectable yields and

84

Entry substrate Product Yield (%)

1 182b 80

2 182c 60

3 182d 50

Scheme 103

In light of these results, the presence of the palladium catalyst was not thought to be essential as the palladium source had no detrimental effect on the yields. Further investigations were carried out using iodopyrazole as the initial reagent in an attempt to optimise the reaction conditions. (Scheme 104)

Entry Solvent Base Temp (°C) Time (h) Product Yield (%)

1 DMF K2CO3 90 20 182a 90 2 DMF K2CO3 r.t. 24 182a 67 3 DMF n/a 90 72 182a SM 4 toluene K2CO3 110 20 182a 18 5 DMF NMM 90 48 182a SM 6 CH3CN K2CO3 80 48 182a 86 7 CH3CN K2CO3 r.t. 21 182a SM Scheme 104

85 The first reaction was performed utilising potassium carbonate as the base in DMF at 90°C without the presence of palladium which successfully afforded the desired product 182a in

90% yield. (entry 1) This proved the presence of palladium was not required within the reaction and as a result a significant increase in the yield was observed from 61 to 90%. To investigate further, a range of solvents, temperatures and bases was explored to see whether these had an adverse effect on the reaction. When the reaction was performed at room temperature (entry 2) a decrease in the yield was observed. It was thought this could be attributed to solubility issues with the potassium carbonate in DMF. A background reaction was performed without the base (entry 3), but no reaction was observed which proved the presence of base was required for the reaction to proceed. Replacement of DMF with a less polar solvent toluene (entry 4) resulted in a diminished yield of only 18% with 50% of the SM retained. This suggested a polar aprotic solvent was complementary to the reaction. To improve the solubility and reactivity of the base in the reaction, N- methylmorpholine was chosen as an alternative to potassium carbonate. However it can be seen from the results that no reaction was observed (entry 5), suggesting the base may have been too strong. This could have resulted in a stabilised anion unable to undergo addition with the cyclopropene. Finally, the reaction was attempted using acetonitrile as the solvent. The results observed were quite interesting as the cyclopropane was afforded in an excellent yield of 86% while heated to reflux (entry 6), although no reaction was observed when the reaction was performed at room temperature (entry 7). This is thought to be associated with the solubility of potassium carbonate in acetonitrile at room temperature and also implied the thermodynamic product was favoured over the kinetic product (entries 1 and 6).

The optimised conditions were applied to a range of nitrogen heterocycles and amines to test the substrate specificity of the reaction. (Scheme 105) With great success, a variety of halogenated and non-halogenated N-heterocycle substituted cyclopropanes were synthesised in a selective manner in respectable yields as depicted in Scheme 105.

86

Entry Heterocycle Product Yield (%)

1 4-iodopyazole 182a 90 1 2 4-bromoimidazole 182b 85 3 4-bromopyrazole 182c 62 4 3,6 dibromocarbazole 182d 68 5 pyrazole 182e 53 6 1,2,4 triazole 182f 50 7 imidazole 182g 62 8 benzotriazole 182h 60 9 4-nitropyrazole 182i 50 10 3-trifluoromethylpyrazole 182j 82 1

11 tetrazole 182k trace amount

12 phthalimide n/a decomposition

13 N-boc amine 1d >99

14 di N-boc amine 1d >99

15 N-boc ethyl oxamate 1d >99

1

No purification was required

Scheme 105

In the majority of cases the cyclopropanes were afforded within a high degree of diastereoselective control where the amine was added to the least hindered side to exclusively afford the trans isomer. (entries 1 to 10) However it can be seen from the results that the reaction was limited to mainly azoles where little or no reaction was

87 observed with primary and secondary amines. (entries 13-15) N-boc amine was used in an attempt to form the amino cyclopropane to enable further functionalisation of the ring, but unfortunately no reaction took place. To increase the acidity of the amine the di boc protected amine and N- boc ethyl oxamate were tested, however in both cases the starting cyclopropene was retained. The reason for di boc amine to not undergo addition could be associated with steric hindrance as a result of the bulky t-butyl group.

As mentioned previously it is believed that the pKa of the amine combined with the

stability of the ammonium intermediate formed in situ had a significant influence on the yield of the cyclopropane obtained. This was evident in the results shown in Scheme 105 where amines with a lower pKa value (entries 1-3, 10) afforded the cyclopropane in a

higher yield compared to amines with a higher pKa value. (entries 5 and 7) A list of pKa

values of the azoles used is shown in Table 4.

Substrate pKa H2O (DMSO) imidazole 14.4 (18.9)80 pyrazole 14.2 (20.4)80 4-bromopyrazole 12.780 4-iodopyrazole 12.981 4-nitropyrazole 9.680 3-trifluoromethylpyrazole 10.681 4-bromoimidazole 12.281 1,2,4 triazole 10.0 (13.9)80 benzotriazole 8.2 (11.9)81 carbazole (19.9)81 phthalimide 8.381 primary amine (24.8)81 Table 4

88 However there was some anomalies with this explanation as 1,2,4 triazole, benzotriazole and 4-nitropyrazole (entry 6, 8, 9) afforded the cyclopropane in 50%, 60% and 50% yield respectively. It is believed in these examples that the diazole anion is stabilised by its mesomer form and in turn has limited its reactivity to undergo a conjugate addition with the cyclopropene. (Scheme 106)

Scheme 106

As with these amines the potassium carbonate is strong enough to abstract the proton to afford the stabilised anion which is therefore less likely to add to the cyclopropene. However the amines with a pKa value higher than 10 are too basic to have their protons

abstracted by potassium carbonate and therefore the amine acts as a nucleophile to undergo addition with the cyclopropene. This was further confirmed by the result obtained for tetrazole (entry 11) where only trace amounts of the desired product were observed. This was associated with the stability of the tetrazolate anion which has pronounced aromatic character. The diastereoselectivity observed for the cyclopropanes were confirmed by nOe experiments where no direct couplings were observed between the CH protons of the cyclopropane.

The results obtained for this reaction led us to believe that the addition reaction would take place with a conjugated alkene (e.g. styrene) as well as with the strained cyclopropene. Thus the addition reaction was attempted using styrene 155 which was allowed to react with iodopyrazole 180 in the presence of potassium carbonate in DMF at 90°C (Scheme 107).

89 Unfortunately no reaction was observed and the alkene was retained which suggested that the combination of a strained cyclopropene with an activating group like phenyl was essential for the addition reaction to take place.