Conclusiones parciales del capítulo

Before investigating the “high” temperature asymmetric lithiation-trapping of N-Boc imidazolidine 36, we carried out our own VT NMR spectroscopic studies. We decided that THF-d8 was a suitable solvent for these experiments and this is important since THF could also be a potential solvent for the lithiation methodology as has been shown for N-Boc pyrrolidine 1. The equilibrium between 36a and 36b shown in Scheme 2.39, is related to rate constant, k, which can be calculated using the Eyring equation (1).

k = (k_B·T/h)·e^{(ΔG‡/RT)} (1)

where k_B is Boltzmann’s constant, h is Planck’s constant, R is the gas constant and ΔG^‡ is the Gibbs free energy of activation. It is known that, when the exchange rate between 36a and 36b is slow, two different sets of signals are observed in the NMR spectrum, one for each rotamer. In contrast, with a fast rate of interconversion, only the average signal is present. Between these two limits a broad and flat peak should appear. The temperature when this happens is called the coalescence temperature, T_c. At T_c, the rate constant k is given by equation (2).

k = (π·Δν₀)/√ (2)

In this equation, Δν0 is the separation in Hertz between the peaks of 36a and 36b at a slow rate of interconversion. At this point, ΔG^‡ can be calculated using equation (3).

ΔG^‡ = RT[ln(k_B·T/h)  lnk] (3)

Knowing ΔG^‡, it possible to calculate the rate constant k at different temperatures using the Eyring equation (1), assuming that the change in entropy is zero on changing the temperature. Finally, the half-life for rotation is given by equation (4).

t_1/2 = ln2/k (4)

Thus, we started our ¹H NMR spectroscopy experiments with a sample of N-Boc imidazolidine 36 in THF-d₈. The methylene signals at δ_H 3.87 and δ_H 3.86 were selected and at 20 °C we measured Δν0 = 6.11 Hz (Figure 2.1, a). This value gives a rate constant k = 13.6 s^1 and a half-life t1/2 = 0.05 s at the Tc. The two signals coalesced at about 38 °C (311 K) (Figure 2.1, e) and therefore, the barrier for rotation, ΔG^‡, was calculated to be 69.5 kJ mol^1. Then, the use of these data in the Eyring equation gives a half-life t1/2 ~200 hours at 78 °C (195 K). At 40 °C (233 K), the value is t1/2 ~10 minutes, while at 30 °C the half-life (t1/2) is ~2 minutes. These results in THF-d8 were fully comparable with those obtained by Coldham in DMSO-d6.

Figure 2.1: VT ¹H NMR spectra of N-Boc imidazolidine 36 in THF-d8

In order to have a deeper insight into the lithiation process of N-Boc imidazolidine 36, we decided to use in situ infra-red (ReactIR™) spectroscopy which is a useful method to monitor the course of the lithiation, as recently demonstrated by our group.^61,63 These studies monitor the decrease in absorbance of the C=O peak of the Boc group after the addition of s-BuLi. The lithiated intermediate that forms has a C=O peak at a different frequency. In Scheme 2.42, the results of the lithiation of N-Boc imidazolidine 36 in the presence of s-BuLi and the (+)-sparteine surrogate in Et₂O at 40 °C are presented. The reaction progress can be evaluated by the disappearance and appearance of new signals in the 3-D plot (a), or by a 2-D plot of the peak intensity of specific peaks (1710 cm^1 and 1645 cm^1 in this case) as a function of time (b). In this example, the addition of s-BuLi caused a decrease in the ν_C=O of N-Boc imidazolidine 36 (1710 cm^1) and an increase in the 1645 cm^1 peak, corresponding to the νC=O of the lithiated intermediate (S)-77∙L*.

(a)

(b) Scheme 2.42

Interestingly, these plots showed a fast initial lithiation of a part of N-Boc imidazolidine 36 in about 2 minutes. However, the lithiation was incomplete and no further change in the concentration of the lithiated species and N-Boc imidazolidine 36 was observed over 1 hour. This could be explained by a slow rate of interconversion of the two rotamers

A reason for the difference between the ReactIR™ data and VT ¹H NMR spectroscopy results could be due to the formation of the pre-lithiation complexes, between the substrate and (+)-sparteine surrogate, 73a and 73b which are equally formed under the lithiation conditions (Scheme 2.43). It might be possible that the rotation of the rotamers is blocked by the increased steric hindrance, once 73a and 73b are formed.

Scheme 2.43

Therefore, in order to allow the rotamers to interconvert, it is necessary that the formation of 73a and 73b is reversible. With Et₂O as lithiation solvent, the formation of the pre-lithiation complexes 73a and 73b could be an irreversible process (Scheme 2.44). This may be due to the incapacity of the Et₂O to displace the chiral ligand from the pre-lithiation complex. Thus, only pre-lithiation complex 73b would be lithiated.

This would lead to a highest theoretical yield of 50%. For clarity, butyl group of s-BuLi is omitted in Schemes 2.44 and 2.45.

Scheme 2.44

In contrast, we reasoned that THF, which is a good coordinating solvent, could displace the chiral ligand on 73a and coordinate to the organolithium to form 79a (Scheme 2.45).

At this point, the rotamers could eventually interconvert due to reduced steric hindrance.

Finally, the chiral ligand should form the reactive pre-lithiation complex 73b and lead to the lithiation of 36.

Scheme 2.45

In addition to these considerations, previous work in our group had shown that THF could give high enantioselectivity in the asymmetric lithiation-trapping protocol, as long as the (+)-sparteine surrogate was used as the chiral ligand (see Scheme 2.9). Therefore, we decided to study the effect of THF with N-Boc imidazolidine 36. First, the progress of the lithiation of N-Boc imidazolidine 36 with s-BuLi and the (+)-sparteine surrogate in THF at 40 °C was monitored using ReactIR™ spectroscopy (Scheme 2.46).

Surprisingly, complete disappearance of the 1705 cm^1 peak corresponding to the ν_C=O of 36 was observed in ~10 minutes, with a parallel formation of the lithiated intermediate (S)-77∙L* peak (at 1646 cm^1). The traces obtained in THF were substantially different from those with Et₂O (see Scheme 2.42). In particular, from the 2-D plot (b), the formation of the lithiated intermediate appeared to proceed more in THF than in Et₂O. In addition, the 2-D plot (b) showed an initial fast lithiation in ~1 minute, followed by a slower lithiation. This was presumably due to the interconversion of unreactive rotamer 73a to rotamer 73b, which was then lithiated.

(a)

(b) Scheme 2.46

Thus, the ReactIR™ results suggested that higher yields of trapped products should be obtained in THF than in Et₂O. Therefore, a range of synthetic experiments were carried out to providing supporting results.