Topics in Current Chemistry (2020) 378:1
1 3
be considered as active Lewis acids in water, are quite suitable for organocatalytic reactions. Some metals like Mn(II), Ag(I), and In(III) feature parameters close to the limit
values, nevertheless such “borderline metals” can still be considered compatible Lewis
acids. It is difficult to establish a quantitative prediction for the Lewis acidity in aqueous
media. The two above-mentioned criteria can serve to arrange suitable combinations
for organocatalysis in the presence of Lewis acids. Another aspect that requires further
comments is the counterion associated with the Lewis acid. Non-coordinating counterions (such as triflate, PF 6
−
, BF 4
−
) need to be tested first. Among the results obtained
by Kobayashi, it is important to mention the possibility to stabilize water-hydrolyzable
Lewis acids like Bi(OTf) 3 with tailored ligands [35]. Ga(OTf) 3 is another metal salt
that is known to rapidly decompose in the presence of water with the release of protons, but it was adapted to promote Lewis acid reactions with enolsilanes in the presence of adapted ligands inhibiting its hydrolysis [36]. Despite the difficulties to quantify
the content of water in organocatalytic reactions, water is also capable of enhancing
the Lewis acidity of compatible acids. Studies reported by Kobayashi clarified that the
amount of water is crucial to form “naked” active Lewis acids [37]. The principles (fast
rate exchange and high pK h ) established by Kobayashi can give an idea about the type
of Lewis acids that should be chosen for the organocatalytic processes. The presence
of secondary or primary amines, generally used in 20 mol% amounts, also need to be
considered for the choice of the Lewis acid. Lewis acids that can coordinate amines in
irreversible manners need to be avoided. Finally, organocatalytic amino processes are
generally performed with a large amount of the aldehyde, in order to have a reasonable
concentration of the enamine. A large excess of the aldehyde can compete with the
activation of the electrophile for an effective synergic action. Despite the limitations
and shortcomings, the use of Lewis acids in enamine catalysis has found applications in
several interesting reactions here summarized.
1.3 Principal Organocatalysts Employed in Synergistic Catalysis in the Presence
of Lewis Acids
The principal, most-used organocatalysts like proline, proline derivatives, or other
five-membered heterocycles, used in combination with Lewis acid are illustrated in
Fig. 3.
Diaryl-pyrrolidine derivatives, i.e., the Hayashi–Jørgensen organocatalysts (1),
and the imidazolidinone MacMillan-type catalysts (2) are often used in stereoselective catalysis via enamine or iminium ion. They are readily prepared from available starting materials. The Hayashi–Jørgensen organocatalysts are obtained using
the inexpensive D or L proline as starting material, after simple protection, addition of an aryl Grignard reagent, and final silylation step [38]. The MacMillan-type
catalysts are obtained from commercially available amino acids, after the formation
of the corresponding methyl amide derivative. Then, a cyclization reaction with a
ketone or an aldehyde takes place in the presence of Brønsted or Lewis acids. Historically, the MacMillan catalysts obtained by reaction with acetone were described
first [39]. In subsequent generations of MacMillan catalysts, aldehydes were utilized in the cyclization step. In these cases, the separation of the two so-formed
Reprinted from the journal
34
1 3
be considered as active Lewis acids in water, are quite suitable for organocatalytic reactions. Some metals like Mn(II), Ag(I), and In(III) feature parameters close to the limit
values, nevertheless such “borderline metals” can still be considered compatible Lewis
acids. It is difficult to establish a quantitative prediction for the Lewis acidity in aqueous
media. The two above-mentioned criteria can serve to arrange suitable combinations
for organocatalysis in the presence of Lewis acids. Another aspect that requires further
comments is the counterion associated with the Lewis acid. Non-coordinating counterions (such as triflate, PF 6
−
, BF 4
−
) need to be tested first. Among the results obtained
by Kobayashi, it is important to mention the possibility to stabilize water-hydrolyzable
Lewis acids like Bi(OTf) 3 with tailored ligands [35]. Ga(OTf) 3 is another metal salt
that is known to rapidly decompose in the presence of water with the release of protons, but it was adapted to promote Lewis acid reactions with enolsilanes in the presence of adapted ligands inhibiting its hydrolysis [36]. Despite the difficulties to quantify
the content of water in organocatalytic reactions, water is also capable of enhancing
the Lewis acidity of compatible acids. Studies reported by Kobayashi clarified that the
amount of water is crucial to form “naked” active Lewis acids [37]. The principles (fast
rate exchange and high pK h ) established by Kobayashi can give an idea about the type
of Lewis acids that should be chosen for the organocatalytic processes. The presence
of secondary or primary amines, generally used in 20 mol% amounts, also need to be
considered for the choice of the Lewis acid. Lewis acids that can coordinate amines in
irreversible manners need to be avoided. Finally, organocatalytic amino processes are
generally performed with a large amount of the aldehyde, in order to have a reasonable
concentration of the enamine. A large excess of the aldehyde can compete with the
activation of the electrophile for an effective synergic action. Despite the limitations
and shortcomings, the use of Lewis acids in enamine catalysis has found applications in
several interesting reactions here summarized.
1.3 Principal Organocatalysts Employed in Synergistic Catalysis in the Presence
of Lewis Acids
The principal, most-used organocatalysts like proline, proline derivatives, or other
five-membered heterocycles, used in combination with Lewis acid are illustrated in
Fig. 3.
Diaryl-pyrrolidine derivatives, i.e., the Hayashi–Jørgensen organocatalysts (1),
and the imidazolidinone MacMillan-type catalysts (2) are often used in stereoselective catalysis via enamine or iminium ion. They are readily prepared from available starting materials. The Hayashi–Jørgensen organocatalysts are obtained using
the inexpensive D or L proline as starting material, after simple protection, addition of an aryl Grignard reagent, and final silylation step [38]. The MacMillan-type
catalysts are obtained from commercially available amino acids, after the formation
of the corresponding methyl amide derivative. Then, a cyclization reaction with a
ketone or an aldehyde takes place in the presence of Brønsted or Lewis acids. Historically, the MacMillan catalysts obtained by reaction with acetone were described
first [39]. In subsequent generations of MacMillan catalysts, aldehydes were utilized in the cyclization step. In these cases, the separation of the two so-formed
Reprinted from the journal
34