Recent contributions to the Diversity-Oriented Synthesis (DOS) mediated by iminium ions through multicomponent Mannich-type reactions

This short account summarizes the most recent contributions of the author and his collaborators to the Diversity Oriented Synthesis (DOS) mediated, at least in a step of the process, by Mannich-type reactions (MTR) and using formaldehyde as common starting material in all cases. Through this strategy, diverse nitrogen-containing acyclic and heterocyclic systems were synthesized, whether in straightforward or multicomponent approaches


Introduction
It is well-known that multicomponent reactions (MCRs) are convergent reactions, in which three or more starting materials react in a single chemical step to form a product that incorporate substantial portions of all components, 1 (e.g.Mannich, 2 Strecker, 3 Hantzsch, 4 Ugi, 5 Biginelli, 6 Passerini, 7 Willgerodt-Kindler, 8 etc., among other reactions).In a MCR, a product is assembled according to a cascade of elementary chemical reactions.Thus, there is a network of reaction equilibria, which all finally flow into an irreversible step yielding the product.Applications of MCRs in all areas of applied chemistry are very popular because they offer a wealth of products, while requiring only a minimum of effort.As opposed to the classical way to synthesize complex molecules by sequential synthesis, MCRs allow the assembly of complex molecules in a one-pot manner.Unlike the usual stepwise formation of individual bonds in the target molecule, the defining attribute of MCRs is the inherent formation of several bonds in one operation without isolating the intermediates (referred to as the bond-forming efficiency, BFE), [9][10][11] changing the reaction conditions, or adding further reagents.
The Mannich reaction is a classical reaction, belonging to the multicomponent reactions (MCR´s) family, 12 which typically have been used for the synthesis of β-aminocarbonyl compounds (i.e.Mannich bases) 5.These latter compounds are key intermediates in the synthesis of different pharmaceutical and natural occurring products as well as Michael acceptor precursors. 13The typical Mannich reaction involves the reaction between enolizable aldehydes or ketones 1, formaldehyde 2 and primary/secondary amine hydrochlorides 3 in a protic solvent, as shown in Scheme 1, the iminium ion 4 being the key species in this process.Scheme 1. Classical approach for the Mannich reaction.
Modern variants of Mannich reaction (called Mannich-type reactions-MTR), are carried out in simplest ways and short reaction times through pre-formed electrophiles such as iminium salts, imines or benzotriazolyl aminals, as well as diverse nucleophiles instead of enolizable aldehydes and ketones like enolates, vinyl ethers or enamines.
5] This approach is analyzed in the direction of chemical reactions, i.e. from reactants to products, using forward synthetic analysis, Figure 1. 16Although complexity and diversity can be analyzed separately, the design of the synthetic pathway should integrate both features as a final step in the analysis.In this sense, the goals of DOS include the development of pathways leading to the efficient (three-to fivestep) synthesis of collections of small molecules having skeletal and stereochemical diversity with defined coordinates in the chemical space.Although the DOS do not permit the application of retrosynthetic concepts and thinking (like Target-Oriented Synthesis (TOS) or Combinatorial Chemistry), these foundations are being built on, by using parallel logic, to develop the complementary procedure known as forward-synthetic analysis, which facilitates the synthetic planning, communication, and teaching in this evolving discipline of the organic chemistry.
In consequence, we initially evaluated the reactivity of benzotriazolyl derivatives of pyrazoles (acting as pre-formed electrophiles) with activated alkenes (acting instead of enolizable aldehyde or ketone) as it is presented below:

An Efficient Catalyst-Free Four-Component Synthesis of Novel γ-Aminoethers Mediated by a Mannich-Type Reaction
9][30] In the past years, a series of selective serotonine (5-HT)-reuptake inhibitor (SSRI) antidepressants (e.g.Fluoxetine and Paroxetine) and selective norepinephrine (NE)-reuptake inhibitor antidepressants (e.g.Tomoxetine and Viloxazine), have been developed. 31Structural examination of such compounds revealed that several of them contain the γ-amino ether functionality in their structures, Figure 3. Based on some previous studies, we planned the synthesis of the 2-benzazepine 22 via a one-pot threecomponent Mannich-type reaction.Thus, reaction of N-benzylmethylamine 19{1} (1 equiv), polyformaldehyde 2 (1.2 equiv), N-vinyl-2-pyrrolidone 10{1} (1 equiv) in methanol (MeOH) 20{1} as solvent, at room temperature, should afford our expected product 22.Contrary to our expectations, the γ-aminoether 21{1,1,1} was isolated instead as unique product.This result indicates that MeOH acted not only as the solvent but also as nucleophile (reagent), Scheme 6. 32 Scheme 6. Synthesis of the novel γ-aminoether 21{1,1,1} from the N-benzylmethylamine 19{1}. 32sed on the literature and our experimental observations, it may be suggested that synthesis of the γaminoether 21{1,1,1} started with the formation of the well-known iminium ion type 4 from the reaction of the secondary amine 19{1} with polyformaldehyde 2. This species is then trapped by the electron-rich alkene 10{1} via a Mannich-type reaction affording a new cationic species 23 (stabilized by a resonant effect with the free electronic pair of the N atom).Finally, the nucleophilic intermolecular attack of the hydroxyl group of the MeOH over the species 23 led the γ-aminoether 21{1,1,1}, Scheme 7. Scheme 7. Proposed mechanistic sequence for the formation of the products 21{1,1,1} via the iminium ion type 4. 32 Although, initially we expected an intramolecular cyclization process (ring closure), involving the orthocarbon atom of the Ph-ring in the intermediate species 23 (stabilized by a resonant effect with the free electronic pair of the X substituent), to afford the 2-benzazepinic framework 22, see Scheme 6, such product was not formed.This fact may indicate that the intermolecular nucleophilic attack of the hydroxyl group of the respective MeOH over the species 23 proceeded faster than the intramolecular ring closure.Steric and conformational factors should be determinant features in this process.
It is also remarkable, that in this one-pot protocol three new bonds were formed in sequence during the process.0][11] Moreover, in the overall process only a molecule of water is removed as by-product, providing also an environmentally friendly character to our four-component procedure. 32

A Facile Synthesis of Stable β-Amino-N-/O-Hemiacetals through a Catalyst-Free Three-Component Mannich-Type Reaction
5][36][37] Reaction proceeds in an equilibrium and contrary to the stability displayed by their five-/ sixmembered intramolecular cyclic analogues (called lactols), 33,34 in the most cases, the open chain hemiacetals are intrinsically unstable and the equilibrium tend to favor the parents aldehyde and alcohol. 35,36There are just few examples of stable and isolable open chain hemiacetals, especially from aldehydes bearing electronwithdrawing groups, [37][38][39][40][41] particularly, several of them derived from chloral. 41rying to overcome the drawback suffered with protic solvents in our failed attempt to obtain the desired 2-benzazepines 22, as described in Scheme 6 (section 3), we decided to repeat the same experiment but using a non-nucleophilic aprotic solvent (i.e.dry acetonitrile, ACN) instead of methanol in order to avoid competition by the cation 23, Scheme 8, and address the reaction toward the desired product 22.After 72 h of stirring (monitored by TLC), a dense oily material was obtained.Analysis by spectroscopic techniques indicated that the formation of the expected product 22 did not occur again, and instead the unexpected β-amino-Nhemiacetal (also called γ-aminoalcohol) 24{1,1} was obtained as the unique product in 71% isolated yield (Scheme 8, route 2). 42heme 8. Synthesis of the novel β-amino-N-hemiacetal 24{1,1}. 42lthough, the aza-hemiacetal 24{1,1} in principle, was not our expected product, owing to the practical usefulness of its structural parents γ-aminoalcohols, [43][44][45][46][47] we decided to explore in more detail, reproducibility and scope of this process.Thus, a chemset of diversely substituted secondary amines 19{1-21} and activated alkenes 10{1,3-4} was evaluated under the established reaction conditions.Satisfactorily, the corresponding βamino-N-hemiacetals type 24 were obtained with yields in the range of 51-93%, Table 2, except for compound 24{21,1} (see Table 2 foot note).
According to the results, it was suggested that the synthesis of the hemiacetals 24 commenced with the formation of a hemiaminal 25 from the reaction of the secondary amine 19 and formaldehyde 2, which should be simultaneously in equilibrium with the aminal 26 and the iminium species type 4 (its counter ion Y = OH -if comes from 25 or (R 1 CH 2 )R 2 N -if comes from 26), as shown in Scheme 9.In all cases during the course of the reactions, it was detected by TLC the partial transformation of the secondary amines 19 into aminals type 26 although they were completely re-consumed during the reaction.Subsequently, the iminium species type 4 should be trapped by the alkene 10 via a Mannich-type reaction leading to the carbocationic species type 23 (stabilized by a resonant effect with the free electronic pair of the X-substituent), through an irreversible process affording the new C-C bond.The intermolecular attack of the hydroxyl counter ion or a water molecule over the species type 23 should led the isolated β-amino-N-/O-hemiacetals 24. 42Scheme 9. Proposed mechanistic sequence for the formation of the β-amino-N-/O-hemiacetals 24 via the iminium species type 4. 42 In order to confirm unequivocally the structure and stability of the obtained β-amino-N-/O-hemiacetals 24, the growing of single crystals suitable for X-ray diffraction analysis of compound 24{16,1} in ethyl ether as solvent at room temperature was performed, see Figure 5.

A Straightforward and Efficient Method for the Synthesis of Diversely Substituted β-Aminoketones and γ-Aminoalcohols from 3-(N,N-Dimethylamino)propiophenones as Starting Materials through a Mannich-Type Strategy
Amino-ketones are compounds with superior importance not only for their practical applications displayed by themselves but also because they have been found forming part of the structure of synthetic and naturally occurring compounds of diverse practical interest. 48,49Thus, Falicain (a local anesthetic and bronchomotor), 50 compound BE-2254 (antihypertensive and very selective α 1 -adrenoceptor antagonist, precursor of the 3-[ 125 I]derivative), 51 Moban (a neuroleptic) 52,53 and the benzylamine derivative 27 (a potent Jak3 kinase inhibitor), 54 worth be mentioned as representative examples of this large family of amino-compounds, Figure 6.Due to the importance of the γ-aminoalcohols described in Table 2 of our previous section 4, we envisioned an alternative and simple (just one-and two-steps) approach for the synthesis of new β-aminoketones type 30 (by a Mannich-type strategy), and their subsequent reduction process toward the corresponding novel γtertiary-aminoalcohols type 31, from secondary benzylamines 19 and 3-(N,N-dimethylamino)propiophenone derivatives 29, as easily accessible starting materials, Scheme 10. 55 Scheme 10.Proposed sequence for the synthesis of the novel β-aminoketones 30 and γ-aminoalcohols 31 from the benzylmethylamine derivatives 19 through a Mannich-type strategy. 55 start with our purposes, as a model reaction, a mixture of benzylmethylamine 19{1} (R = Me) (1 mmol) and N,N-dimethylaminopropiophenone hydrochloride 29{1} (Ar = Ph) 56,57 (1 mmol) was subjected to different reaction conditions in order to obtain the β-aminoketone product 30{1,1} (i.e step (i), Scheme 10).The best result (88% yield of product 30{1,1}), was achieved when the starting materials were refluxed in a mixture 5:1 v/v of p-dioxane:TEA.Once established the better reaction conditions and in order to determine its scope and general character, this approach was extended to the benzylamines chemset 19{1-3,8,22} and propiophenones chemset 29{1-4}, see Table 3. 55 Satisfactorily, the corresponding β-aminoketones 30{1,1} through 30{22,2} were fairly obtained in 62-90% isolated yields, as shown in the Table 3. Once the β-aminoketones 30 were efficiently obtained, we proceeded with the reduction process of the carbonyl groups, (i.e.step (ii)).The reduction process of ketones 30 was efficiently performed by two different approaches: (a) by a catalytic hydrogenation on a Parr apparatus in the presence of Nickel-Raney as catalyst, methanol as solvent at room temperature, 58,59 and (b) by a chemical reduction with NaBH 4 in methanol at room temperature to afford the expected γ-aminoalcohols 31 in (72-93%) or (57-96%) isolated yields, respectively, Table 3. 55 Table 3. Synthesis of the novel β-aminoketones 30{1,1} through 30{22,2} and γ-aminoalcohols 31{1,1} through 31{22,2} 55 a Values in parentheses correspond to the isolated yields of alcohols obtained by catalytic hydrogenation.
{22,10} According to experimental details and the results depicted in Table 4, the temperature plays an important role in the regioselectivity of this reaction, as well as, the nature of the (hetero)aromatic ring (i.e.R 1 ) attached to the secondary carbon atom holding the hydroxyl group in 31, to afford selectively either 1,4-oxazepanes 36 or the side-product allylamines 38. 74

Summary
Through this review, libraries of diverse nitrogen-containing structures have been reported whose synthesis started from the simple molecule of formaldehyde (pure or masked) as common precursor, in all cases, involving the Mannich-type reaction in any step of their processes.These results correspond to a humble contribution of the author and his collaborators to the Diversity Oriented Synthesis (DOS), considered by many as an emerging, fascinating and powerful tool, currently disposable for the Organic Synthesis as well as for the Medicinal Chemistry.

Figure 1 .
Figure 1.Schematic sequence for a DOS strategy. 6

Figure 2 .
Figure 2. Activated terminal alkenes 10 employed for reacting with the starting compounds 8 and 9.23

Figure 4 .
Figure 4. Employed diverse benzylamines 19, terminal alkenes 10 and alcohols 20 reagents for the synthesis of products 21.32