14 Parameters for epoxide ring opening by aryl amines.

TBDMSO TBDMSO 4.12 O OH H N Lewis acid/activator H₂N Solvent Temperature R Duration R R = H or CO2Me

Following the reported procedure,102 LiNTf2 was added to a CH2Cl2 solution of

anthranilate methyl ester and the protected epoxide 4.12 (table 4.03, rxn 1). The reaction mixture was stirred under N2 at 4 °C for 20 hours. Although TLC showed no reaction

NMR analysis showed starting materials, which were almost completely recovered to the amount initially used. Repeating the experiment with 0.5 equivalents of LiNTf2, and

allowing the reaction mixture to stir at room temperature did not yield any product (rxn 2). Using a stronger aryl amine nucleophile such as aniline (R = H, rxn 3-5) and increasing the concentration of the CH2Cl2 solution did not produce any product even

after stirring over a 9-day period. Hamoir et al.102 noted that some epoxide ring openings benefit from solvent being excluded from the reaction. This was investigated by stirring the reaction mixture at room temperature as a neat solution of two equivalents of aniline, LiNTf2 and the protected epoxide 4.12 over 22 hours (rxn 5). Again starting materials

were almost completely recovered and 1H NMR or TLC analysis detected no product. Rxn # Aryl amine (Eq) Lewis acid (Eq)

Solvent Temp Duration Yield 1 R = CO2Me, 2.75 LiNTf2, 0.25 CH2Cl2a 4 °C 20 hrs 0%

2 R = CO2Me, 2.75 LiNTf2,0.5 CH2Cl2a rt 15 hrs 0%

3 R = H, 2.0 LiNTf2,0.5 CH2Cl2b rt 20 hrs 0%

4 R = H, 2.2 LiNTf2,0.5 CH2Cl2a rt 9 days 0%

5 R = H, 2.0 LiNTf2,0.5 Neat rt 22 hours 0% a _{1 mL of CH}

2Cl2 per 0.5 mmol of epoxide4.12. b _{1 mL of CH}

2Cl2 per 2.5 mmol of epoxide4.12.

Table 4.03. Reactions using low equivalents of aryl amine at room temperature to

open the TBDMS-protected epoxide 4.12.102

It was clear conditions needed to be more forceful to ring-open the protected epoxide 4.12. Refluxing the protected epoxide 4.12 with aniline 4.24 and LiNTf2 in CH2Cl2 over

14 hours returned only starting materials (table 4.04, rxn 1). Changing the Lewis acid from LiNTf2 to ZnCl2351 and refluxing the protected epoxide 4.12 with aniline 4.24 in

MeCN produced small amounts of the desired secondary aryl amine (rxn 2). An array of spots appeared on TLC four hours after the reagents were refluxed. These spots increased in intensity until the protected epoxide 4.12 spot completely disappeared after 46 hours. Isolation of the numerous spots by flash chromatography afforded unidentifiable by-

products and the desired product (6%, scheme 4.15). Distinguishing NMR features of the secondary amine 4.31 include a downfield shift of hydrogen-2 1H to 3.85 ppm and a shift in carbon-2 13C 52.2 to 70.0, and carbon-1 13C from 47.2 to 50.1 ppm. Changing the solvent to THF and using BF3.Et2O356 instead of ZnCl2 produced similar results as in

reaction 2. A multitude of spots were apparent via TLC after all of the protected epoxide 4.12 was consumed.

Scheme 4.15. Low-yielding opening of TBDMS-protected epoxide 4.12 using

aniline 4.24, and ZnCl2 in refluxing MeCN.

2 TBDMSO TBDMSO 4.12 O OH H N ZnCl₂, MeCN H₂N 6% 4.24 4.31 reflux

Increasing the nucleophilic nature of the amine by using cyclohexylamine 4.32 did not produce the desired product under refluxing conditions with LiNTf2 (rxn 4). Surprisingly

Rxn # Aryl amine (Eq) Lewis acid (Eq)

Solvent Temp Duration Yield 1 R = H, 3.5 LiNTf2, 0.5 CH2Cl2a reflux 14 hrs 0%

2 R = H, 1.0 ZnCl2,0.05 MeCNb reflux 46 hrs 6%

3 R = H, 10 BF3.Et2O,0.5 THFc reflux 19 hrs trace

4 cyclohexylamine, 3.5 LiNTf2,0.5 CH2Cl2a reflux 14 hours 0% a _{1 mL of CH}

2Cl2 per 1 mmol of epoxide4.12. b _{5 mL of MeCNper 1 mmol of epoxide4.12.} c _{5 mL of THFper 1 mmol of epoxide4.12.}

References: 102,351,356

Table 4.04. Reactions using low equivalents of aryl amine at reflux to open the

protected epoxide 4.12.

It was decided to dramatically increase the equivalents of cyclohexylamine 4.32 and remove the solvent. After a few hours stirring at room temperature TLC analysis showed an emergence of a more polar spot and a gradual decline of the protected epoxide 4.12. After 14 hours the protected epoxide 4.12 reacted completely to form a single product, which after isolation was characterised by 1H NMR spectroscopy to be the secondary amine 4.33 (scheme 4.16). Distinguishing NMR features of the secondary amine 4.33 include a downfield shift of hydrogen-2 1H to 3.58 ppm, and a shift in carbon-2 13C from 52.2 to 69.7, and carbon-1 from 47.2 to 56.7 ppm. Excellent regioselectivity was observed in forming the terminal secondary amine 4.33, with none of the other regioisomer isolated. The secondary amine 4.33 was assumed to be a racemic mixture. The parameters of this reaction can be seen in table 4.05, reaction 1.

Scheme 4.16. Cyclohexylamine 4.32 opening of the TBDMS-protected epoxide

4.12. TBDMSO TBDMSO 4.12 O OH H N LiNTf₂, rt H2N 63% 4.32 4.33 2 2

Using aniline 4.24 and the parameters of reaction 1 table 4.05, the secondary aryl amine 4.31 was synthesised in a yield of 55% (rxn 2). This was the only product seen by 1H NMR analysis of the crude reaction mixture apart from trace amounts of the protected epoxide 4.12 (scheme 4.17). A portion of the 1H NMR of secondary aryl amine 4.31 can be seen in graph 4.01. A pair of doublet of doublets is at δ 3.03 and δ 3.23 corresponding to hydrogen-1, the multiplet at δ 3.69 to hydrogen-5 and the multiplet at δ 3.85 to hydrogen-2. The downfield hydrogens between δ 6.6 and δ 7.15 correspond to the aryl hydrogens. Excellent regioselectivity was again observed in forming the terminal secondary aryl amine 4.31 and it was assumed to be a racemic mixture.