Imines Reformatsky reaction

SET reduction of ketones Reductive amination Reductive coupling of imines Reformatsky reaction Ring-opening of strained heterocycles... 

The addition of Reformatsky reagents to imines has been utilized occasionally as an alternative to the Mannich reaction where the enolate is generated by deprotonation. A rhodium-catalyzed imine Reformatsky reaction of menthyl bromodifluoroacetate 378 was used for an asymmetric synthesis of P-lactam 379. 

Scheme 4.82 Rhodium catalyzed difluoro imine Reformatsky reaction of menthyl ester 378 for the synthesis of difluoro p-lactams 379.

In the pilot-plant procedure, the oxidant lead tetraacetate was replaced, for the environmental benign, by sodium periodate, and the salt 385 was obtained after washings with acetone in 48-57% overall yield and >99.7% ee. The imine Reformatsky reaction was performed on a scale that started from 240 kg of the aldehyde 380. After the batch of the adduct 383 had been spht in two, the subsequent steps led to a combined amount of 350 kg of crystalline ester 385. The sequence shown in Scheme 4.83 is suitable to demonstrate that enolate chemistry, when carefully optimized, is applicable in over 100-kg scale. 

Inspired by Cozzi s studies on the imine Reformatsky reaction [164] and guided by Noyori s investigation of reactive zinc species [165], the authors propose an oxygen-initiated radical mechanism for the formation of the Reformatsky reagent and a catalytic cycle that is included in a modified version in Scheme 5.87. First, it is assumed that the reaction of dimethyl zinc with oxygen produces - via the peroxide MeOOZnMe - a-methyl radical that enters the first catalytic cycle A. 

Catalytic Enantioselective Mannich Reactions, Ester Enolate-lmine Condensations, and Imine Reformatsky Reactions... 

Reformatsky reaction has covered aspects of this topic (20b). If analogous pericyclic transition states are involved in these condensations, the added stereochemical control element imposed on the condensation by the imine geometry should provide a more well-defined set of transition states than for the analogous aldehyde condensations. The four diastereomeric chair and boat transition states for ( )- and (Z)-enolates with ( )-imines are illustrated in Scheme 15. 

Enantiomerically pure trans-2-phenylcyclohexanol, first used by Whitesell as a chiral auxiliary has become a popular reagent in a number of asymmetric transformations. Some recent applications include asymmetric azo-ene reactions, [4 + 2]-cycloaddition reactions, ketene-olefin [2 + 2]-reactions, enolate-imine cyclocondensations, Pauson-Khand reactions," palladium annulations and Reformatsky reactions. Despite its potential, use of this chiral auxiliary on a preparative scale is currently limited by its prohibitive cost. 

A Rh-catalyzed Reformatsky reaction of chiral imine (24) led to the stereoselective preparation of the a,a-difluoro-jS-amino acid (25). 25 was converted to difluor-oalkene (26), and subsequently L-Val-i/r[(Z)CF=CH]Gly derivative (23) in greater than 82% for both steps. The samarium diiodide-mediated reductive transformation of the y,y-difluoro-a, S-enoates proceeded via successive two-electron transfers to form a dienolate species which upon kinetically controlled trapping with fert-BuOH formed 23 (Scheme 6). 

Reformatsky reactions of Af-(2-bromoalkanoyl)-l,3-benzoxazin-4-ones 267 and 272 and imines derived from aniline or /)-substituted anilines gave fra j -/3-lactams 273 with complete diastereoselectivity, and the l,3-benzoxazin-4-one auxiliary 269 could also be recycled. However, in the similar transformations of imines containing an o-methoxyphenyl substituent on the nitrogen, no cyclization to azetidinone occurred and /r -/3-aminocarboxamide derivatives 274 were the only products formed (Scheme 51) <2005S725>. 

Inspired by a bright report from Katritzky and coworkers on the use in Reformatsky reactions of a variety of benzotriazolyl aminals121, which in solution are in equilibrium with the corresponding imines, the formaldehyde aminal 61122 was reacted with lc, Zn and TMSC1 to give adducts 62 (equation 39), which can be successively converted into /3-lactams upon treatment with f-BuMgCl. 

The technique of chiral auxiliaries was exploited in a synthesis of cholesterol absorption inhibitors, based on an imino-Reformatsky reaction between bromoacetates of chiral alcohols (e.g. 69a and 69b) and imine 70. Virtual complete asymmetric induction was found with (-)-trans-2-phenylcyclohexanol and (—)-phenyl substituted menthol derived chiral auxiliaries (equation 43)126. 

The joint effect of substituents and of temperature is clearly evident in imino-Reformatsky reactions of zinc dienolates197. At —78 °C, imines 194a-d react with crotonate derived zinc-dienolate 195, affording the products listed in Table 4. Imine substituents play a fundamental role in controlling the reaction regiochemistry. 

In 2004, the Reformatsky reactions of imine, a-bromoester, zinc dust, and a catalytic amount of iodine in dioxane under high intensity ultrasound (HIU) irradiation have been reported to afford (3-lactam and the corresponding (3-aminoester [178]. The reactions were performed in short reaction times and high yields of both products or a mixture of the two products were obtained, depending on the starting imine and on the a-bromoester (Scheme 79). 

The indium-mediated Reformatsky reaction of phenyl a-bromoalkanoates with ketones or aldehydes gives di-, tri-, and tetrasubstituted /3-lactones (Table 21).327-329 A similar reaction of imines with ethyl bromoacetate gives 3-unsubstituted /3-lactams (Equation (83)).330 331... 

Orsini reported the use of a 10 mol % Sml2-Mg reagent system in the Reformatsky reactions of a-halocarbonyl compounds, nitriles and phospho-nates with ketones, aldehydes and imines.29... 

For the preparation of chiral nonracemic dipeptide isosteres, Otaka and Fujii also reported the use of camphorsultam derivative 49, which was prepared in optically pure form through the Reformatsky reaction of BrCF2C02Et with a chiral imine (see Scheme 10.15) [25]. 

Indium enolates, prepared conveniently by transmetalation of hfhium enolates with IriCl j, react wifh aldehydes to give fhe corresponding -hydroxy esters [80]. Ultrasound irradiation promotes fhe Reformatsky reaction of aldehydes and ethyl bromoacetate wifh indium [81]. Indium-mediated Reformatsky reaction of phenyl a-bromoalkanoates wifh ketones or aldehydes gives di-, tri-, and tetrasubstituted -lactones (Scheme 8.57) [82]. Indium-mediated reaction of imines with ethyl bromoacetate gives 3-unsubstituted -lactams (Scheme 8.58) [83]. An indium-Refor-matsky reagent prepared from 2-(chlorodifluoroacetyl)furan couples with aldehydes (Scheme 8.59) [84]. 

In addition to aldehydes and ketones, organic compounds which are known to react with Reformatsky reagents include esters,nitriles, acid chlorides, organic halides,epoxides, nitrones, azirenes" and imines. This section describes the selectivity reported for Reformatsky reactions with functionally substituted aldehydes or ketones. 

Reactions exhibiting diastereofacial selectivity, which occur when the imine or the enolate contains an endogenous stereocenter or a chiral auxiliary, have important applications for the synthesis of optically active 3-l ctams and 3-amino carboxylic acid derivatives. Early work by Furukawa et al. has demonstrated the viability of preparing optically active 3-amino acids from chiral imines. For example, the Schiff base derived from (5)-a-methylbenzylamine (110) reacts with Reformatsky reagent (111) to give, after hydrolysis and removal of the chiral auxiliary, 3-amino-2,2-dimethyl-3-phenylpropionic acid (112) in 33% ee (Scheme 21). Similar Reformatsky reactions have been performed using (-)-menthyl esters but the enantiomeric excess values are lower. ... 

Reformatsky reaction. Reformatsky reagents are known to react with imines to afford P-lactams. The reaction can he applied to the synthesis of a,a-difluoro-p-lactams, and even chiral products. ... 

Boyer, N. Gloanec, R De Nanteuil, G. Jubault, R Quirion, J.-C. Chemoselective and stereoselective synthesis of gcm-difluoro-P-aminoesters or gcm-difluoro-P-lactams from ethyl bromodifluoroacetate and imines during Reformatsky reaction. Tetrahedron 2007, 65(50), 12352-12366. 

Taguchi, T. Kitagawa, O. Suda, Y. Ohkawa, S. Hashimoto, A. litaka, Y Kobayashi, Y. Synthesis of 3,3-difluoro-2-azetidinones and 2,3-dideoxy-2,2-difluoro-3-amino-sugars through the reformatsky reaction of difluoroacetate with imine. Tetrahedron Lett. 1988, 29, 5291-5294. 

Scheme 79 Reformatsky reaction of imines and a bromoesters affording P lactams and P aminoesters...

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