Optimization of the reaction conditions

Once the possibility of carrying out the reaction in the presence of a Brønsted acid catalyst was verified, we next proceeded to evaluate the effect of different BINOL-based chiral Brønsted acids on the reaction.

Table 2.1: Chiral BINOL-derived Brønsted acid catalyst survey.a

Entry Catalyst Yield 3a (%)b _{ee 3a (%)}c

1 4a 53 25 2 4b 52 23 3 4c 54 68 4 4d 53 15 5 4e 61 8 6 4f 74 0 7d _{4f 48 -2}

a _{The reaction was performed in 0.26 mL of toluene and 0.13 mmol scale of 1a, using 1.2 eq. of 2a at rt.}b _Isolated

product yield of 3a after flash column chromatography.c _{Determined by HPLC analysis of the pure product.}d _Reaction

carried out at -78 ºC.

As shown in Table 2.1, when the chiral phosphoric acid possessed a bulky substituent at the 3,3’-position (4a-c), adduct 3a was achieved in moderate yield and enantiocontrol, being the case of (R)-3,3′-Bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate (TRIP) 4c the most promising one with 68% of enantiomeric excess (Entries 1-3). A most acidic phosphoric acid 4d could not improve the results previously obtained, which suggested us that more acidic catalysts could not be appropriate in this reaction. Nevertheless, and in order to verify our hypothesis, two different BINOL-derived N-triflyl phosphoramides (4f-g) were tested which are known to be 5-6 pka (in CH3CN) units more acidic than their corresponding phosphoric acids.6 In both cases the reaction was faster and the yield of the

Table 2.2: Evaluation of different solvents in the reaction.a

Entry Solvent Yield 3a (%)b _{ee 3a (%)}c

1 toluene 54 68 2 benzene 53 65 3 o-xylene 43 67 4 CH2Cl2 52 49 5 CHCl3 27 26 6 EtOAc 83 57

a _{The reaction was performed in 0.26 mL of solvent and 0.13 mmol scale of 1a, using 1.2 eq. of 2a for 14h.}b _Isolated

product yield of 3a after flash column chromatography.c _{Determined by HPLC analysis of the pure product.}

Initially, non-polar solvents were examined, such as benzene and o-xylene trying to maintain a close chiral contact ion pair, however, they did not afford better results than those obtained with toluene (Entries 2-3 vs Entry 1). Next, we moved on to test polar solvents, which could stabilize ions in the medium (Entries 4-6), but these showed no ability to control the enantioselectivity of the process.

With toluene as the best performing solvent, we proceeded to study the effect of other parameters on the reaction, such as temperature and drying agents (Table 2.3).

Table 2.3: Influence of temperature and drying agents in the reaction.a

Entry T (ºC) Additive Yield 3a (%)b _{ee 3a (%)}c

1 rt - 54 68 2 -5 - 43 74 3 -15 - 30 71 4 -20 - - - 5d _{-5 MgSO4 45 76} 6d _{-5 4 Å MS 40 82} 7d,e _{-5 4 Å MS 42 86}

a _{The reaction was performed in 0.26 mL of toluene and 0.13 mmol scale of 1a, using 1.2 eq. of 2a for 14h.}b _Isolated

product yield of 3a after flash column chromatography.c _{Determined by HPLC analysis of the pure product.}d _{27 mg of}

additive was added.e _{Reaction carried out with dry toluene.}

When lowering the reaction temperature to -5 ºC the enantioselectivity of the product was slightly increased (Entry 2), though compromising the yield of the process. However, at lower temperature, we could not observe any improvement, affording the product in low yield and even halting the reaction at -20 ºC (Entries 3-4). The use of MgSO4 showed no significant improvement (Entry 5), however, when using 4 Å molecular sieves, the product was obtained with 82% of enantioselectivity, albeit in similar yield (Entry 6). Additionally, when running the reaction with dry toluene, the enantioselectivity was even increased to 86%, though the yield was still an issue to bear in mind (Entry 7).

Depending on the reaction conditions, the generated azo intermediate was not able to reach the final product through [1,3]-hydride shift process at the same rates. Therefore, quenching and purifying the products at longer times, we could improve the enantioselectivity of the process. We carried out different experiments, trying to promote the [1,3]-H shift more rapidly, such as, the addition of acidic additives, however, in all cases the enantioselectivity decreased. We also tested leaving the reaction for longer time, and this was found to be the most optimal choice, without observation of the azo intermediate (Scheme 2.26).

Scheme 2.26

After intensive screening of different concentrations, additives, equivalents, etc. we were unable to improve neither the yield nor the enantioselectivity of the process. So, we decided to optimize the structure of hydrazone and dihydropyrrole reagents (Table 2.4).

Table 2.4: Study of the effect of the structure of the hydrazone and dihydropyrrole.a

Entry R1 _R2 _{Prod. 3 Yield 3 (%)}b _{ee 3 (%)}c

1 Boc (1a) 4-OMeC6H4 (2a) 3a 60 86

2 Boc (1a) 4-SMeC6H4 (2b) 3b 53 92

3 Boc (1a) Ph (2c) 3c 63 88

4 Boc (1a) 4-NO2C6H4 (2d) 3d n.r.d _n.r.

5 Boc (1a) tBu (2e) 3e 87 72

6e _{Boc (1a) Ph (2c) 3c 96 93}

7f _{Fmoc (1b) Ph (2c) 3f 93 92}

8 Ph (1c) Ph (2c) 3g n.r.d _n.r.

9g _{CSNHBn (1d) Ph (2c) 3h 95 92}

10h _{CSNHAr (1e) Ph (2c) 3i 98 >99}

a _{The reaction was performed in 0.26 mL of dry toluene and 0.13 mmol scale of 1a, using 1.2 eq. of 2 and 27 mg of}

MS for 24h.b _{Isolated product yield of 3 after flash column chromatography.}c _{Enantioselectivity determined by HPLC}

analysis of the pure product.d _{No reaction.}e _{Reaction carried out with 1.5 eq. of 1a added in six portions every 1h 30}

min and 1.0 eq. of 2c.f _{Reaction carried out at 10 ºC.}g _{dr = 5.8:1.}h _{Ar: 3,5-(CF}

We checked the behaviour of the reaction when introducing substituents of different nature at the nitrogen position in the hydrazone moiety. With a more electron-donor substituent at the nitrogen atom of the hydrazone, the reaction worked with lower yield, though reaching 92% of enantioselectivity (Entry 2). If we introduced a phenyl ring, the reaction worked with slightly better yield and very good enantioselectivity (Entry 3). However, when using an electron-withdrawing group, the reaction could not take place (Entry 4). If we introduced a tert-butyl substituent, the desired adduct was obtained in high yield, albeit with lower enantioselectivity (Entry 5). At this point, however, the yield of the reaction was still an issue to solve and we proceeded to study the effect of other parameters on the reaction like the stoichiometric ratio between different reagents, observing that very good yield and enantioselectivity could be obtained when using hydrazone 2c as limitant substrate and N-Boc-2,3-dihydro-1H-pyrrole added in portions (Entry 6). Next, we decided to examine the outcome of the reaction with diverse dihydropyrroles and using hydrazone 2c. As outlined in Table 2.4, cyclic enecarbamates were able to promote the reaction in excellent yields and enantioselectivities even at 10 ºC for N-Fmoc-2,3-dihydro-1H-pyrrole 1b (Entries 6-7). However, when using a phenyl enamine the reaction could not take place (Entry 8). Finally, when employing the cyclic enethiourea 1d, having an N-H group in the structure for an additional point of interaction with the catalyst, the reaction worked very well, affording the final compound in 98% yield and 92% of enantioselectivity as two diastereoisomers (Entry 9). We realized that the N-H group on the cyclic enethiourea scaffold was responsible for the better results obtained. We considered that the N-H group of the thiourea moiety would form an additional hydrogen-bond with the phosphoryl oxygen of the catalyst, generating a more strongly bound ion pair intermediate to promote higher asymmetric induction. In fact, to our pleasure, we could afford excellent yield in 2 hours and perfect enantioselectivity, though as a mixture of diastereoisomers (Scheme 2.27). However, this was not an issue, because the cleavage of the hydrazone moiety to afford the carbonyl compound is one of the objectives to confirm their usefulness as acyl anion equivalents. Furthermore, when using the more acidic cyclic enethiourea 1e, the results were improved obtaining the final product with complete enantioselectivity although with 5:1 dr (Entry 10).

Scheme 2.27

In addition, the reaction could be performed with 5.0 and 2.5 mol% of catalyst without erosion of yield or enantioselectivity, and the amount of catalyst could be reduced to 1 mol% affording the product in 86% yield and >99% ee. Therefore, the optimal conditions were established to be 5 mol% of catalyst 4c, in dry toluene, at -5 ºC and in the presence of 4 Å MS.