Hemiaminal dehydration

Forty years after the initial proposal, Sweet and Fissekis proposed a more detailed pathway involving a carbenium ion species. According to these authors the first step involved an aldol condensation between ethyl acetoacetate (6) and benzaldehyde (5) to deliver the aldol adduct 11. Subsequent dehydration of 11 furnished the key carbenium ion 12 which was in equilibrium with enone 13. Nucleophilic attack of 12 by urea then delivered ureide 14. Intramolecular cyclization produced a hemiaminal which underwent dehydration to afford dihydropyrimidinone 15. These authors demonstrated that the carbenium species was viable through synthesis. After enone 13 was synthesized, it was allowed to react with N-methyl urea to deliver the mono-N-methylated derivative of DHPM 15. 

The mechanism was then reexamined 25 years later in 1997 by Kappe. Kappe used H and C spectroscopy to support the argument that the key intermediate in the Biginelli reaction was iminium species 16. In the event, 5 reacted with 3a to form an intermediate hemiaminal 17 which subsequently dehydrated to deliver 16. Iminium cation 16 then reacted with 6 to give 14, which underwent facile cyclodehydration to give 15. Kappe also noted that in the absence of 6, bisureide 8 was afforded as a consequence of nueleophilic attack of 16 by urea (3a). This discovery confirmed the conclusion of Folkers and Johnson in 1933. As far as the proposal from 25 years earlier by Sweet and Fissekis, Kappe saw no evidenee by H and NMR spectroscopy that a carbenium ion was a required species in the Biginelli reaetion. When benzaldehyde (5) and ethyl... 

Furthermore, Shutalev and coworkers reported a two-step modification. Urea 43a or thiourea 43b was condensed with 5 in the presence of p-toluenesulfonic acid to deliver a-tosylderivative 44. The enolate of 6 was then allowed to react with 44 to give a substitution product which then cyclized to give the hemiaminal 45. Dehydration of the hemiaminal with p-toluenesulfonic acid delivered 46. 

Because of their significant electrophilic character, aldehydes are often unstable and will react with nucleophiles. For example, a common reaction of aldehydes is the formation of a hemiaminal with amines. If the amine is a primary amine, the hemiaminal can dehydrate to form an imine as shown in Figure 21. The reaction of aldehydes with primary and secondary amines is a well-studied reaction pathway because it is a common reaction pathway of reducing sugars and amino acids, and this reaction pathway is known as the Maillard reaction (40). In the case of amino acids and sugars, this reaction leads to discoloration, or browning. This reaction will be discussed in greater detail in the Amines-Maillard Reaction section. 

Hemiaminals are available from HFA and amines. A series of similar reactions has been carried out with ammonia (187,189), amines (189), aliphatic, aromatic (258), and fluoroaliphatic acid amides (169). The hemiaminals 95 can be dehydrated with phosphorus oxychloride in pyridine to form 2-hexafluoropropaneimines 96 (187). 

In the reverse case, for the dimethylation with formaldehyde for example (R2 = R3 = H), the dehydration is impossible. Thus, in this last case, the only possible pathway is the hydrogenolysis of the hemiaminal D. The competitive hydrogenation of carbonyl must be considered carefully because it influences the choice of the reaction conditions. We assume that with amides, anilines and alcohols similar mechanisms should be possible. 

The effect of sodium sulfate is not fully understood it can either act as a dehydrating agent to increase the formation of the hemiaminal intermediate or as a catalyst poison to limit carbonyl reduction. 

Fig. 2.3 Reaction of IsoK/LG with primary amines to form stable adducts. Primary amines including lysine react with IsoK/LGs to form a hemiaminal adduct. Unlike most aldehydes which can only form the highly reversible Schiff base adduct, the hemiaminal adduct of y-ketoaldehydes can undergo a second nucleophilic attack to form a pyrrolidine adduct which dehydrates to form an irreversible pyrrole adduct. In the presence of oxygen, the pyrrole is converted to lactam and hydroxylactam adducts. Oxidation of the pyrrole leads to formation of stable crosslinked species...

This is then followed by a tandem attack of the pyrrole-A on C(7), a subsequent dehydration, and a site-selective hydroxylation to give the imidazolone hemiaminal the latter event completes assembly of the natural product. 

There are several possible sequences for the addition, cyclization and dehydration steps involved in the overall transformation. A study of the effect of the size of 3,4-substituents in 2,5-hexanediones showed that rates decreased in the order Me > Et > Ph > Me2CH. Both dl and meso isomers were compared and the dl isomers reacted more rapidly in each case <86JOC62l>. The fact that the stereoisomers do not interconvert under the cyclization conditions and the absence of a primary isotope effect for 3,4-hydrogen atoms have been taken to indicate that the cyclization of the hemiaminal is the rate-determining step <9lJOC6924>. This proposal is consistent with the observed steric effect, since the meso diketones result in cw-stereochemistry in the cyclization step (Scheme 68). 

Retrosynthetically, a base-catalyzed dimerization of 127 would afford stephacidin B. Avrainvillamide (127) was simplified as vinyl iodide 128 by cleavage of the dihydropyrano [2,3-g]indole-l-oxide moiety and palladium mediated coupling. An aminoacyl radical addition from 129 gave access to 128, while 129 could be derived from cyanide 130 through a hemiaminal formation/dehydration and conjugate addition. Finally, Strecker-like reaction of ketone 131 would fulfill nitrile 130 [55] (Scheme 22). 

Dehydration of the hemiaminal gives the imine. Now there is some need for catalysis acid must be added so that the OH group can become a good leaving group. This step resembles the conversion of hemiacetals to acetals. The difference is that the iminium ion can lose a proton... 

In Zhu s approach, the advanced intermediate 34 was subjected to Swern oxidation and tetra- -butyIammonium fluoride (TBAF)-mediated deprotection of the silyl ether, yielding a mixture of aldehyde 35 and hemiaminal 36. Treatment of this mixture with 0.01% v/v methanesulfonic acid in dichloromethane initiated a process consisting of acyhminium formation, deprotonation, and domino P-elimination/cydization. Thus, dehydration of hemiaminal 36 initially led to iminium ion 37, which formed enamide 38 under loss of a proton. Elimination of the sulfur side chain then resulted in conjugated iminium ion 39, which was set up to undergo a phenolic Mannich cych2ation. 

Finally, the aminal undergoes an internal condensation involving ring closure by nucleophilic attack of the primary amine group on the carbon of the carbonyl followed by dehydration of the hemiaminal to yield the diazabicyclo[3.1.0]hex-3-ene ring system, again catalyzed by ammonium bromide. A reasonable scheme is shown below ... 

This method affords an easy access to this privileged scaffold by a [3 + 2+1] annulation catalyzed by EtjN. The mechanism of the reaction is shown in Scheme 11.22. First, the Knoevenagel reaction of aromatic aldehydes 53 with 2-hydroxy-1,4-naphthoquinone 113 affords 116 that undergoes the aza-ene reaction with the ketene aminal 114 rendering 117. Next, the intramolecular hemiaminal 118 formation and dehydration afford the corresponding benzolylimidazo [l,2-a]quinolinediones 115 in good yields (60-88%). 

As a special case, the formation of hemiacetals 2 (lactolization) during the hydroformylation of hydroxy-functionalized olefins, such as allyl or homoallyl alcohols, has to be mentioned (1, Y= O, Scheme 5.70). With these substrates, the reaction occurs in an intramolecular manner. In the presence of an external alcohol, the cyclic hemiacetal can further react to give a nonsymmetric cyclic acetal 3. Hemiacetals can be subjected to hydrogenation to afford diols 4. Under reducing conditions and in the presence of amines, amino alcohols 5 are formed both are valuable building blocks in fine chemistry. Alternatively, oxidation gives lactones 6 [5]. By dehydration of hemiacetals, cychc vinyl ethers 7 are formed. The same transformation with allylamines (Y=NR) gives cyclic hemiaminals, A/ ,0-acetals, lactames, or vinyl amines. 

Hemiaminals were intermediates on the way to optically enriched piperidines (Scheme 5.86) [78]. When the hydroformylation at 28bar was conducted in a regioselective manner, exclusively chiral piperidines were obtained. Regioisomeric aldehydes afforded the corresponding pyrrolidines. The reaction sequence could be coupled with an asymmetric hydrogenation step prior to the hydroformylation-hemiacetaUzation-dehydration sequence proceeding in a one pot reaction. 

Mechanism 17.5 describes the reaction between benzaldehyde and methylamine given in the first example. The first two steps lead to the hemiaminal the last three show its dehydration to the imine. Step 4, the key step in the dehydration phase, is rate-determining when the reaction is carried out in acid solution. If the solution is too acidic, however, protonation of the amine blocks step 1. Therefore there is some optimum pH, usually about 5, at which the reaction rate is a maximum. Too basic a solution reduces the rate of step 4 too acidic a solution reduces the rate of step 1. 

Sample Solution A hemiaminal is formed by nucleophilic addition of the amine to the carbonyl group. Its dehydration gives the imine product. 

Step 3 The dehydration stage begins with protonation of the hemiaminal on oxygen. 

Secondary amines are compounds of the type R2NH. They add to aldehydes and ketones to form hemiaminals that can dehydrate to a stable product only in the direction that leads to a carbon-carbon double bond ... 

Sample Solution (a) Nucleophilic addition of dimethylamine to the carbonyl group of propanal gives a hemiaminal that undergoes dehydration to form an enamine. 

Isolated product is an imine, formed by dehydration of a hemiaminal intermediate. 

Nucleophilic addition of amines to aldehydes and ketones (see Sections 17.10,17.11) Primary amines undergo nucleophilic addition to the carbonyl group of aldehydes and ketones to form hemiaminals, which dehydrate under the conditions of their formation to give Af-substituted imines. Secondary amines yield enamines. 

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