Aminoacetaldehyde dimethyl acetal

Toward the end of the 19 century both Pomeranz and Fritsch independently reported the preparation of isoquinolines by the reaction of aminoacetaldehyde dimethyl acetal 2 (R = Me) with aromatic aldehydes 1 followed by cyclisation in acidic media. " Unfortunately yields were often poor and not always reproducible. This has prompted the search for various improvements and modifications on the original theme, including the use of reagents other than strong mineral acid which tends to destroy the intermediate imine. ... 

Aldehyde 22 and aminoacetaldehyde dimethyl acetal 23 (3eq.) were heated to reflux in toluene (Dean-Stark apparatus) until all of the starting material was consumed. The crystalline product was collected and washed with solvent to yield imine 24, which was used without further purification. 

Pyrazino[l,2-z]pyrimidine-6,8-dionc was prepared from [3+3] atom fragments by reacting 6-hydroxypyrimidine-4-carboxylic acid with 2-aminoacetaldehyde dimethyl acetal <2005W02005/016927>. 

Aminoacetaldehyde diethyl acetal, d306 Aminoacetaldehyde dimethyl acetal, d506 1-Aminoadamantane, a64 Aminoanisoles, m48 thru m50 / -Aminoazobenzene, p88... 

The acid-catalyzed cyclization of properly substituted aminoacetaldehyde dialkyl acetals was shown to be a suitable method in the construction of a homo-isopavine (Scheme 39) (132a,172). Treatment of 7V-[l,3-bis(3,4-dimethoxy-phenyl)propyl]aminoacetaldehyde dimethyl acetal (175) with concentrated hydrochloric acid afforded the 7V-norhomoisopavine 176 in 39% yield. This cyclization was also accompanied by some O-demethylation. Product 176 could be readily N-methylated using formaldehyde and sodium borohydride to afford the homoisopavine ( )-177 (772). 

A modification of the Pomeranz-Fritsch synthesis <1983JCXI3344> is used in the preparation of thieno[2,3- l-pyridine and its 2-substituted derivatives. An aryl aldehyde undergoes condensation with aminoacetaldehyde dimethyl acetal giving a Schiff base which cyclizes to form an imine product. The imine is treated with ethyl chloroformate followed by triethyl phosphate to form an intermediate carbonate-phosphonate, which then cyclizes to the thienopyr-idine product (Scheme 22) <2004S1935>. Very low product yields (2-17%) are obtained for alkyl- and phenyl-substituted thieno[2,3- ]pyridines however, the unsubstituted product and 2-halogenated derivatives give moderate yields (28-44%). 

Aminoacetaldehyde dimethyl acetal, d440 1-Aminoadamantane, a66 Aminoanisoles, m42, m43, m44 p- Aminoazobenzene, p87... 

The early antimicrobial compounds such as lucosit (219 R = Me) and globucid (219 R = Et) can be prepared by treatment of the 2-amino-l,3,4-thiadiazole with (V-acetylsulfonyl chloride in pyridine followed by deacetylation. A more recent antimicrobial compound (224) can be efficiently synthesized by the route shown in Scheme 35. The thiadiazole (220) is obtained by the usual cyclization procedure and then oximated to (221). Dehydration and the Pinner amidine synthesis followed by treatment with aminoacetaldehyde dimethyl acetal yields (222). Sulfuric acid cyclization furnishes the thiadiazoloimidazole derivative (223) which is further methylated, acetylated, nitrated and hydrolyzed to the desired (224) <69JHC(6)835). 

A solution of ethyl benzimidate hydrochloride (496.9 mmol) in 300.0 ml methyl alcohol was cooled to 0°C, then treated with a solution of aminoacetaldehyde dimethyl acetal (670.9 mmol) in 75 ml methyl alcohol at such a rate that the temperature was kept below 5°C. The solution was stirred 3 days at or below 5°C, then concentrated, and an yellow oil isolated. The residue was dissolved in 750 ml 1M NaOH, then extracted four times with 250 ml CH2C12, dried with MgS04, concentrated, and 108.13 g of crude /V-(2,2-dimethoxyethyl)benzamidine was isolated as an yellow oil. It was used without further purification. 

Condensation of benzaldehyde with aminoacetaldehyde dimethyl acetal, followed by reduction of the resulting imine, gives the precursor 296, which could be further reacted with malonitrile providing the pyrrole 297 in 35% overall yield (Equation 89) <2004OL2857>. 

The guanine-related heterocycle (270) has been prepared by treatment of (627) with aminoacetaldehyde dimethyl acetal to produce (628), followed by deblocking and acid-catalyzed cyclization (78JMC883). 

Condensation of aryl-derived imidate 1279 with a-aminoacetaldehyde dimethyl acetal gives amidine 1280, which cyclizes in the presence of TiCU to yield iV-aryl imidazoles 1281 (Scheme 325) <2004BML333>. 

The precursor to amidoacrolein 64, 1,3-dioxin 66, was prepared as follows [39] the imine derived from the condensation of 2,2-dimethyl-l,3-dioxan-5-one with aminoacetaldehyde dimethyl acetal was acetylated with acetic anhydride/triethylamine to afford dioxin 66 in 83% yield (Scheme 24). Retro Diels-Alder of dioxin 66 in warm benzonitrile (120 C, 16 h) generated the amidoacrolein 64, which was trapped in situ with the silyloxydiene 65 to afford the desired cycloadduct 63 (64%). An aldol cyclization between the acetamide and neighboring aldehyde functionalities within 63 proceeded smoothly (2 equiv. of KCh-Bu, 10 equiv. of EtOAc, THF, 0 °C, 40 min) and directly afforded the corresponding conjugated lactam. This product was of sufficient purity for the second aldol reaction, which was best accomplished under acidic conditions, presumably proceeding through the achiral keto aldehyde intermediate 62 enroute to the desired, but racemic, (3-hydroxy ketone 61 obtained in 79% yield after the two consecutive ring closures. 

A soln. of 5-acetamido-l,3,4-thiadiazole-2-carbonitrile in tetrahydrofuran treated with methanol, ice-cooled, satd. with anhydrous HCl, kept 22 hrs. at 5°, the crude imino ether hydrochloride obtained added to an ice-cooled mixture of aminoacetaldehyde dimethyl acetal and methanol, refluxed 19 hrs., coned, under reduced pressure, the resulting crude dry amidine hydrochloride added portion-wise to coned. H2SO4 with water-cooling if necessary, and the product isolated after a complete soln. has been obtained -> 2-acetamido-5-(2-imidazolyl)-l,3,4-thiadiazole. Y 56%. W. A. Remers, G. J. Gibs, and M.J. Weiss, J. Heterocyclic Chem. 6, 835 (1969). 

Super polyphosphoric acid (PPA 4- P2O5) is an effective reagent in the Pomeranz-Fritsch cyclization, replacing the usual 6N HCl. Thus when imine acetal 4, prepared from o-methylacetophenone and aminoacetaldehyde dimethyl acetal, was heated briefly with super PPA, a 30% yield of 1,8-dimethylisoquino-line was obtained. The product was then oxidized and decarbonylated to supply 8-methylisoquinoline. ... 

Dyke and Tiley have successfully used the Bobbitt modification of the Pomeranz-Fritsch cyclization in a synthesis of berberastine. The deoxybenzoin 21 was condensed with aminoacetaldehyde dimethyl acetal and the resulting Schiff base was reduced with borohydride to give amine 22. The remaining key steps were a Mannich condensation and a Pomeranz-Fritsch acid-catalyzed cyclization ... 

The combination of the Ugi-Smiles coupling with the reduction of the nitro group of the aryl group has been used for the synthesis of benzimidazolopiperazines 128 [110]. Thus, the use of aminoacetaldehyde dimethyl acetal 125 with 2-nitrophenol 107 in the Ugi-Smiles reaction yielded the piperazine 127 (Scheme 7.53) throngh the opened intermediate 126. Then, the hydrogenolysis of the piperazine 127 provided the fused system 128 at 60 C in the presence of acetic acid to ensure a faster cycUzation. 

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