CAPÍTULO 6. ARQUITECTURA EN HARDWARE
7.1 Métodos de Comparación de Imágenes
As previously mentioned, 1,2,3-triazoles are of interest for the synthesis of P,N-ligands tue to their simple and benign preparation. However, there are only two reports of the application of triazole containing P,N-ligands in Pd-catalyzed allylic substitutions. In 2007 ligands 145 and 146 (Figure 1.42) were evaluated in the asymmetric Pd-catalyzed allylic alkylation of model substrate S10 with dimethyl malonate.139 Ligand 145 afforded the substituted product in moderate enantioselectivity (79% ee), while ligand 146 was not effective for the reaction, giving the product in low enantipurity (10% ee).
Figure 1.42. Triazole-phosphine ligands 145 and 146.
Later, phosphine-triazole ligands 148 (Figure 1.43) were synthesized with the aim of supporting phosphinoimidazoline 147 (Figure 1.43) onto polymer supports for easy recovery and recycling. However, the application of new ligands 148 in allylic substitution reactions showed an improved enantioselectivity with respect to analogous ligands lacking the triazole unit (up to 99% ee vs 80% ee). A combined NMR and DFT study showed that these P,N-ligands most likely coordinate to palladium through the triazole N-3 nitrogen atom. The performance of these ligands was also examined in the alkylation of trisubstituted acetates with dimethyl malonate (up to 99%) and in the amination of substrate S10 with different N-nucleophiles (up to 99%).
Figure 1.43. Phosphinoimidazoline ligands 147 and phosphino-triazole ligands 148. 1.3.2.2. Phosphorus-thioether ligands
Although P-S ligands have been less studied compared with P-N ligands, there are some successful examples of their application in the literature. In the next section, the most successful P-S ligands reported to date will be discussed.
Phosphine-thioeter ligands
Among all the combinations of P-S ligands that have been tested in enantioselective Pd- catalyzed allylic substitutions (e.g. phosphine-thioethers, phosphinite-thioethers or phosphite-thioethers), phosphine-thioether ligands have been the most widely studied. In
particular, several chiral phosphine-thioether ferrocene based ligands has been developed for this process.
The first example of the application of phosphine-thioether ligands containing a ferrocenyl moiety in the Pd-allylic alkylation to the model substrate S10 was developed by Albinati and Pregosin (Figure 1.44) in 1996.140 Ligand 149 bearing a thyoglicose funcionality afforded the alkylated product with an enantioselectivity of 88%. Changing the carbohydrate substituent for a cyclohexyl (150a) or an ethyl group (150b) (Figure 1.44) resulted in a dramatic decrease in the enantioselectivity (67% ee and 34% ee, respectively). Additionally, the replacement of the ferrocene group by a phenyl ring on ligands 151a-b (Figure 1.44) resulted in a low asymmetric induction (ee’s up to 64%).141 Thus, the
combination of the two stereogenic fragments was crucial for achieving good levels of enantioselectivity. Low enanantiomeric excesses were also obtained with a similar thioether-phosphine ligand 152 using a stereogenic norborneol fragment (Figure 1.44), but the authors attributed their catalytic performance to the chain size between the sulphur donor and the stereogenic unit.
Figure 1.44. Chiral phosphine-thioether ligands 149-152.
The catalytic results using ferrocenyl phosphine-thioether ligands 153-157 (Figure 1.45) indicated that enantioselectivity is better when the phosphine group is attached to the Cp ring (ligands 153-155) rather than when is attached to the thioether unit (ligands 157 and
157) (Figure 1.45). Furthermore, by comparing ligands 153-155, it can be seen that
enantioselectivities are not affected by the presence of an additional stereogenic unit or by the length of the thioether chain (Figure 1.45). The structural studies of a 1,3-diphenylallyl palladium complex containing ligand 153a, [Pd(η3-1,3-PhC3H3Ph)(153a)]PF6, indicate that
the small substituents on thioether groups favor the nucleophilic attack in the cis position to the S-donor moiety (Figure 1.45).142
Figure 1.45. Ferrocenyl thioether-phosphine ligands 153-157. This figure also shows the
enantioselectivities obtained in the Pd-catalysed asymmetric allylic alkylation of dimethyl malonate to S10.
Carretero et. al. reported a readily available family of enantiopure phosphine-thioether ferrocenes (Figure 1.46), having exclusively planar chirality. Ligands 158 and 159 were efficiently applied in the palladium-catalyzed allylic substitution of the model substrate S10 (ee’s up to 97%).143 Catalytic results showed that ligands 158b-c containing electronwithdrawing phosphines (Figure 1.46) provided high enantioslectivities in significantly shorter reaction times (20 min). A less sterically demanding thioether substituent in ligand 159 (Figure 1.46) resulted in a dramatically drop of the enantioselectivity (40% ee). Ligands 158 and 159 were also applied in the Pd-catalyzed allyllic amination achieving the best ee’s with ligands 158f-g containing bulky phosphines (Figure 1.46) (ee’s up to 99.5%). The authors also performed X-ray diffraction analyses and NMR studies of the Pd-allyl intermediates, proving the formation of a P,S-bidentated ligand and explaining the enantioselectivity obtained. It was concluded that the nucleophilic attack takes place trans to the phosphorus donor atom and the bulky thioether substituent plays an important role in enhancing the reactivity of the endo/exo intermediate that gives the obtained product enantiomer.
Figure 1.46. Ferrocenyl thioether-phosphine ligands 158 and 159 developed by Carretero et. al..
Recently, a new class of ferrocenyl phosphine-thioether ligands with heterocyclic scaffolds has been reported by Chan and coworkers (Figure 1.47). Ligands 160-161 were initially applied in the enantioselective Pd-catalyzed indole alkylation of the 1,3- diphenylated substrate S10, achieving enantioselectivities up to 96% with ligand 161, irrespective of the steric and electronic nature of indoles.144 Later, ligands 160-162 (Figure 1.47) were applied in Pd-catalyzed allylic alkylation reactions using several malonate nucleophiles, providing enantioselectivities up to 96% ee with ligand 161. Privileged ligand
161 was also examined in the Pd-allylic alkylation of cyclic allylic acetates and
unsymmetrical allylic substrates, obtaining enantioselectivities up to 87% ee.145
Figure 1.47. Phosphine-thioether ligands 160-162 based on ferrocene and heterocyic scaffolds.
A novel phosphine-thioether ligand family based on a triazoleferrocenylethyl backbone was synthesized and applied in Pd-catalyzed allylic alkylations, etherifications and aminations. ThioClickFerrophos ligands 163a-f (Figure 1.48), in which the thioether moiety is directly attached to the ferrocene unit, were screened in the Pd-catalyzed allylic alkylation of substrate S10 using dimethyl malonate. The best enantioselectivities were obtained with ligand 163e (up to 90% ee). It should be pointed out that ligand 163e was able to efficiently catalyze the etherification between substrate S10 and different electronically substituted benzyl alcohols (ee’s and yields ranging from 74 to 82% and from 85 to 99%, respectively).146
Figure 1.48. ThioClickFerrophos ligands 163.
The axially chiral 1-1’-binaphtyl backbone has been also widely used in the ligand design for the asymmetric Pd-catalyzed allylic substitution reaction. Phosphine-thioether ligands
BINAPS 164a-d (Figure 1.49) derived from enantiopure BINOL have been reported by
Kang147, Gladiali148 and Shi149 with different alkyl groups on the sulfur atom. Kang and co- workers reported 91% ee for the product of usual allylic alkylation test by using ligand
164a. Gladiali tested the isopropyl derivative 164b, which led to the corresponding
compound in quantitative yield in 60% ee. Shi obtained 77% and 33% ee, respectively, by using ligands 164c and 164d. Interestingly, they obtained a reversal of enantioselectivity between ligands 164a, 164c, and 164b, 164d. X-ray analyses and NMR studies confirmed a P,S-coordination as a metallocyle in a pseudo-boat-seven-membered arrangement. The steric bulkiness of alkyl groups on the sulfur atom seems to be responsible for the observed reversal of enantioselectivity by favoring one or the other diastereomeric π-allyl complex. Recently, Hagiwara and coworkers have reported for the first time the synthesis of the aryl- thioether substituted BINAPS ligands 164e-h and their alkyl counterpart 164i.150 After a first examination of ligand 164e in the test reaction with S10 (90% yield, 95% ee), ligands
164e-i were tested in the enantioselective Pd-catalyzed allylic alkylation of indoles. Tunning
of the structural properties of the sulfur substituent was an effective stereocontrol tactic. Therefore, 164f provided enantioselectivities up to 95% using different sterically and electronically substituted indoles.
Figure 1.49. Phosphite-thioether BiNAPS ligands 164.
Very recently, the synthesis of another axially chiral thioether-phosphine ligand has been reported.151 Ligands 165 (Figure 1.50), containing an enantiopure biphenyl backbone, have been applied in the asymmetric Pd-catalyzed allylic substitution of model substrate
S10 using dimethyl malonanate and indole as nucleophiles. These ligands showed in both
cases comparable efficiency with regard to their binaphtyl homologues (164) above mentioned (ee’s up to 94% were obtained with ligands 165).
Figure 1.50. Axially chiral biphenyl-based phosphine-thioether ligands 165.
Nakano and Hongo were the first to test the ability of oxathiane-type ligands to perform Pd-catalyzed allylic substitutions. They initially synthesized ligands 166-168 (Figure 1.51) and successfully used them in alkylation and amination reactions of substituted allyl acetates. Norbornane-based phosphine-oxathiane ligand 166 gave the highest level of enantioselectivity (ee’s up to 94%) in the test reaction. Ligand 166 was also useful in the analogous allylic amination with either benzyl amine or potassium phtalamide providing enantioselectivities up to 90%.152 Later, taking into account the good catalytic performance obtained with ligand 166, Nakano et. al reported a novel polymer-supported P-S type ligands 169a-e (Figure 1.51) and applied them in Pd-catalyzed asymmetric alkylations and aminations. Excellent enantioselectivities were obtained in both processes (up to 96 ee% in alkylation reactions and up to 99% ee in amination reactions).153 Additionally, the same authors developed a new xylofuranoside-based phosphinoxathiane ligand 170 (Figure 1.51), that provided also high enantioselectivities in the enantioselective Pd-catalyzed allylic substitution of S10 (ee’s up to 91%).154
Figure 1.51. Phosphinooxathiane ligands 166-170.
Cyclopropane-based phosphine-thioether ligands 17-19 (Figure 1.9) and related ligands
171-175 (Figure 1.52) were applied in the palladium-catalyzed allylic alkylation of S10 with
dimethyl malonate. Varying the ligand substituents on the phosphorus, sulfur and carbon chain revealed ligand 18 (Figure 1.9) to have the optimal configuration for this reaction, giving the product in high yield and with good enantioselectivity (93% ee).29
Figure 1.52. Cyclopropane-based thioether-phosphine ligands 171-175.
A series of (S)-proline-derived phosphine ligands bearing thioether and selenoether functionalities (176-180; Figure 1.53) were prepared and used in the test Pd-catalyzed asymmetric allylic alkylation. It was observed that an increase of the steric hindrance around the sulfur atom in ligands 178a-g resulted in higher values of enantioselectivity, with a maximum of 88% ee for the ligand bearing a sterically hindered naphtyl group (178g). It should be noted that ligands 177 and 179, bearing a selenium atom instead of sulfur, also induced good levels of enantioselectivities (ee’s ranging from 79% to 86%).155
Figure 1.53. (S)-Proline-derived chiral ligands 176-180.
Two families of P-chirogenic phosphine-thioether ligands have been developed for the asymmetric Pd-catalyzed allylic substitution process. The first one was reported in 2001 by Imamoto and coworkers (ligands 181, Figure 1.54).156 By changing the substituents on the phosphorus and sulfur atoms, ee’s up to 90% were obtained in the model reaction using different malonates. Very recently, a second family of P-chirogenic phosphine-sulfide has been developed (ligands 182, Figure 1.54).157 Ligands 182 have been applied in the Pd- catalyzed allylic alkylation of substrates S10, S11 and S13 (Figure 1.35). Excellent enantioselectivities were achieved in the alkylation of model substrate S10 (ee’s up to 96%). In contrast, low-to-moderate enantioselectivities were obtained in the case of the more challenging substrates S11 and the S13 (ee’s up to 66% and up to 34%, respectively). These ligands have been also applied in the Pd-catalyzed allylation of benzyl amine, leading to the N-benzyl product with enantioselectivities ranging from 37% to 89% ee. In all cases enantioselectivity was strongly dependent upon the substituents on the phosphorus atom and significantly less dependent upon those on the sulfide moiety.
Figure 1.54. P-chirogenic phosphine-thioether ligands 181 and 182.
Phosphinite-thioether ligands
The first application in the Pd-catalyzed allylic substitution of a family of mixed thioether-phosphinite ligands was reported by Evans and coworkers.158 Ligands 2-4 (Figure 1.4), also applied in the Rh-catalyzed hydrogenation of enamides,24 and related ligands 183-
188 (Figure 1.55) were successfully applied in the allylic substitution of several linear and
phosphorus, and backbone, ligands 2g and 3g were found to be optimal in the Pd-catalyzed allylic substitution of S10 with dimethyl malonate and benzyl amine in high yield and excellent enantioselectivities (91-98% ee) (Figure 1.56). Hence, ligand 3g contains a bulky substituent in both backbone and thioeher group that controls the sulfur inversion. A similar optimization of the ligand structure for the Pd-catalyzed allylic substitution of cycloalkenyl acetates showed that 186c afforded the highest enantioselectivities (91-97% ee) (Figure 1.57). Moreover, sulfur and nitrogen containing heterocyclic substrates underwent enantioselective allylic alkylation and amination using ligand 186c to afford 3- substituted piperidines and dihydrothiopyrans in enantioselectivities up to 94% ee(Figure 1.57). The regioselective allylic alkylation of trisubstituted propenyl acetates was also explored with ligands 2g and 3g, affording high yields and asymmetric induction up to 94% ee (Figure 1.56). The authors could furthermore prove the contribution of sulfur in the coordination of the palladium by X-ray analysis of crystals of these organometallic complexes.
Figure 1.55. Phosphinite-thioether ligands 183-188 developed by Evans and coworkers.
Figure 1.56. Summary of the best results obtained by using ligands 2-3g in the Pd-allylic
Figure 1.57. Summary of the best results obtained by using ligands 186c in the Pd-allylic
alkylation and amination of cyclic and heterocyclic substrates S12-S14 and S18-S19.
The series of above mentioned furanoside phosphinite-thioether ligands 5 (Figure 1.5) and ligands 189 (Figure 1.58) bearing a wider variety of thioether susbtituents, were applied in the Pd-catalyzed allylic substitution of mono- and disubstituted linear and cyclic substrates (ee’s up to 95%).159 These ligands contained several thioether substituents with different electronic and steric properties. The authors found that this substituent has an important effect on catalytic performance. Enantioselectivities were best when the bulkiest ligands 5c and 189a were used.
Figure 1.58. Phosphinite-thioether ligands 189 with a furanoside backbone.
At the same time, the phosphinite-thioether ligands 6 and 7 with a pyranoside backbone (Figure 1.6) were successfully applied in the Pd-catalyzed allylic substitution of 1,3-diphenylprop-2-enyl acetate (ee’s up to 96%). Highest enantioselectivities were obtained when bulky tert-buthyl group was present in the thioether moiety. Both enantiomers of the products were obtained by using ligand 7b.26a,b,160
More recently, Pericàs and coworkers applied the previously mentioned phosphinite- thioether ligands 9a-n (Figure 1.7) and related ligands 190a-f and 191a,e (Figure 1.59), to Pd-catalyzed allylic substitution reactions.161 After an iterative optimization of four different structural parameters (the skeletal aryl group, the thioether substituent, the ether moiety and the relative configuration of the chiral centers), highly active and enantioselective ligands were identified. In this way, ligands 190a and 191b provided excellent enantioselectivities in the reaction of S10 using dimethyl malonate (up to 99%), benzyl amine (up to 95%), and a much less common O-nucleophile, such as benzyl alcohol (up to 94%), in very short reaction times (20 min-4h, 2h-16h and 3h, respectively).
Phosphite-thioether ligand
Several combinations of P-S ligands, mainly phosphine thioether and phosphinite- thioether, have been studied and proven to be effective, but less attention has been paid to catalysts containing phosphite-thioether ligands.
The first one was the binaphtylphosphite-thioether ligand 192 (Figure 1.60), reported by Pregosin and coworkers. Yields up to 70% were reached, but in all cases, both the regio- and enantioselectivities were moderate.162
Figure 1.60. Binaphtylphosphite-thioether ligand 192.
In 2001 thioether-phosphite ligands 56-58a and 56d with a furanoside backbone (Figure 1.25) were applied in the Pd-catalyzed allylic alkylation and amination substitution reactions providing only moderate enantioselectivities (up to 58% and 67% ee, respectively).163 It was not until 2014 that the high efficiency of this sugar-based backbone has been demonstrated in this catalytic process. Ligands bearing bulkier thioether substituents (62, Figure 1.25; 193, Figure 1.61) and enantiopure biaryl-phosphite moieties (e and f, Figure 1.25) and also their analogous ligands having the opposite configuration in C-3 (63 and 66, Figure 1.25) have been successfully applied in the Pd-catalyzed allylic substitution.5c Ligand 193f was found to have the optimal ligand parameters for the Pd-
allylic substitution of both linear and cyclic substrates S10 and S13 using dimethyl malonate (>99% and 96% ee, respectively). The privileged ligand 193f has been efficiently used in the Pd-allylic substitution of different hindered and unhindered substrates with a large number of nucleophiles, including synthetically useful functionalized malonates, β-diketones, and allyl alcohols (ee’s up to >99%) (Figure 1.62). Furthermore, the potential application of this P,S-system has been proven by simple tandem reactions, involving allylic alkylation/ring- closing metathesis or allylic alkylation/cycloisomerization of 1,6-enyne reactions, with no loss of enantiomeric excess.
Figure 1.62. Summary of the excellent enantioselectivities obtained in the Pd-allylic substitution
of hindered and unhindered substrates with several C-, N- and O-nucleophiles, using Pd-193f system.
N-phosphine-thioether ligands
In 2006 Chan and coworkers developed a series of ferrocene N-phosphine-thioether ligands 194a-c (Figure 1.63) and successfully applied them in the asymmetric allylic substitution of S10 (ee’s up to 93%).164 Later, the same authors expanded this family with ligands containing bulkier thioether substituents (194d-e) (Figure 1.63). Ligands 194a-e were tested in the Pd-catalyzed allylic substitution of substrate S1 with aliphatic alcohols. Ligand 194e was found to be highly efficient in terms of activity and enantioselectivities. Thus, high yields and excellent enantioselectivities (from 77 to 96% ee) were obtained in the Pd-catalyzed allylic etherification of S10 with a broad range of aliphatic alcohols.165
Figure 1.63. Ferrocene N-thioether-phospine ligands 194.