Carbonylation of aziridines

Carbonylative ring expansion of aziridines in the presence of palladium or cobalt catalysts has proved to be a useful reaction for the construction of the P-lactam ring of 

Mild reaction conditions, high sdectivities, and compatibility with other functional groups make this type of carbonylation a versatile tool in synthetic organic chemistry and especially in the synthesis of pharmaceuticals. They provide a straightforward route to the synthesis of various a,P-unsaturated carbonyl compounds and carboxylic acid derivatives starting from easily available substrates. 

Atmospheric hydroxycarbonylation was applied as the key step in the synthesis of two 5a-reductase inhibitors SB 209963 (SO) [67] and epristeride (SI) [68]. In both cases a 3-bromo-3,5-diene moiety was converted into the 3-carboxylic acid. 

The method developed by Cacchi and Lupi for the hydroxycarbonylation of various aryl triflates including steroidal substrates [69] was used effectively for the synthesis of an intermediate of the biologically active 8,10-di-O-methylbergenin [70]. The conversion of the rather unreactive aryl triflate substrate was achieved using DMSO as solvent that was shown to play a crucial role in the catalytic cycle by facilitating decomposition of the in situ formed acylpalladium complex and formation of the carboxylic acid product [69]. 

Although alkenyl/aryl halides or triflates are the usual substrates for such carbonylations, there are also a few examples for the conversion of benzyl derivatives. Among them, hydroxycarbonylation of 1-arylethyl chlorides or bromides leading to 2-arylpropionic adds can be of practical importance, but the use of acidic media, elevated temperature (110-125 °C), and high CO pressure (55 bar) is necessary to obtain satisfactory catalytic activity and chemo-selectivity [71]. 

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The carbonylation of epoxides was discovered in the 1960s, and advances have been made more recently. Analogous carbonylations of aziridines have also been studied extensively. The advent of well-defined catalysts creates the potential to bring this process from the synthesis of commodity materials to problems in complex molecule synthesis. This section focuses on modern catalysts for this reaction, the impact these processes can have on synthesis, and the mechanisms of these reactions. 

Efforts to develop aziridine carbonylation have occurred in parallel with efforts to develop epoxide carbonylation. The 3-lactams that are formed by this process are important in medicinal, organic, and polymer chemistry. Important contributions to aziridine carbonylation have been made by Alper, Davoli and Prati, and Coates. " A series of carbonylations of aziridines were developed using [Rh(CO)jCl]j and COj(CO)jas catalyst. More recently, faster rates and expanded scope have been found with catalysts that combine a Lewis acid cation with the [Co(CO)J" anion. 

The carbonylation of several classes of aziridines have been reported. In general, the carbonylation of aziridines containing alkyl or benzyl substituents on the two carbon atoms occurs to insert the CO into the C-N bond containing the less-substituted carbon. Equation 17.53 shows a series of these reactions catalyzed by Co2(CO)g. In contrast, the carbonylation of aziridines containing aryl groups on one of the two carbons occurs at the benzylic position. Examples of these reactions are shown in Equation 17.54. Carbonylation of these phenyl-substituted aziridines catalyzed by [Rh(CO)2Cl]j has also been reported by Alper, and a representative example is shown in Equation 17,55. ... 

Like the carbonylation of epoxides, the carbonylation of aziridines occurs with increased rates and scope in the presence of catalysts containing a Lewis acidic cation and Co(CO) " anion. A particularly active version of fliis catalyst for the carbonylation of aziridines is the uncommon species [CpjTi(THF)2]""[Co(CO)J . As shown in Equation 17.56, this catalyst is substantially more active tiian COj(CO)g for the carbonylation of N-benzyl cyclohexene imine. The carbonylation of N-tosyl-2-methylaziridine has also been accomplished (Equation 17.57), and ttiis reaction is important because of the ability to prepare optically active N-tosyl aziridines. Although the reaction catalyzed by the titanium and cobalt system occurred to only 35% conversion, the carbonylation of the N-tosyl-2-methylaziridine catalyzed by the aluminum and cobalt system occurred to completion under the same reaction conditions. 

The accepted mechanism for the carbonylation of epoxides is shown in Scheme 17.26, and the basic steps of this cycle are also thought to occur during the carbonylation of aziridines. Alper first proposed a catalytic cycle for the expansion carbonylation of aziridines by [Co(CO)J, and Coates has proposed a similar cycle for epoxide carbonylation catalyzed by complexes containing both Lewis acids and cobalt-carbonyl anions (Scheme 17.26). This mechanism consists of four steps (1) the activation of substrate by coordination to a Lewis acid (2) the S 2 attack on the substrate by [Co(CO)J (3) the insertion of CO into the new cobalt-carbon bond, and the subsequent uptake of CO and (4) ring closing with extrusion of product and regeneration of the catalytic species. 

Piotti ME, Alper H (1996) Inversion of stereochemistry in the C02(CO)g-catalyzed carbonylation of aziridines to p-lactams. The first synthesis of highly strained trans-bicyclic P-lactams. J Am Chem Soc 118 111-116... 

Figure 4.11 Mechanism of Co-catalyzed carbonylation of aziridines or epoxides.

Oxidative cleavage of P-aminoacyl complexes can yield P-amino acid derivatives (320,321). The rhodium(I)-catalyzed carbonylation of substituted aziridines leads to P-lactams, presumably also via a P-aminoacyl—metal acycHc compound as intermediate. The substituent in the aziridine must have 7T or electrons for coordination with the rhodium (322,323). 

Cyclic Carhene Complexes. The reaction of aziridines with carbonyl, thiocarbonyl, or isonitrile ligands in Mn, Re, Fe, Ru, Pd, or Pt complexes leads to formation of cycHc carhene complexes (324—331). 

Azomethine ylides are also frequently obtained by ring opening of aziridines, and the analogous carbonyl ylides from oxiranes. These aspects are dealt with in Section 3.03.5.1. A variety of five-membered heterocycles can also function as masked 1,3-dipoles and this aspect is considered in Section 3.03.5.2. 

Cycloadditions of aziridines to diphenylcyclopropenone lead to 4-oxazolines (36) (70CJC89). A mechanism involving initial addition to the cyclopropenone carbonyl group followed by ring opening and recyclization was suggested. 

It is well known that aziridination with allylic ylides is difficult, due to the low reactivity of imines - relative to carbonyl compounds - towards ylide attack, although imines do react with highly reactive sulfur ylides such as Me2S+-CH2-. Dai and coworkers found aziridination with allylic ylides to be possible when the activated imines 22 were treated with allylic sulfonium salts 23 under phase-transfer conditions (Scheme 2.8) [15]. Although the stereoselectivities of the reaction were low, this was the first example of efficient preparation of vinylaziridines by an ylide route. Similar results were obtained with use of arsonium or telluronium salts [16]. The stereoselectivity of aziridination was improved by use of imines activated by a phosphinoyl group [17]. The same group also reported a catalytic sulfonium ylide-mediated aziridination to produce (2-phenylvinyl)aziridines, by treatment of arylsulfonylimines with cinnamyl bromide in the presence of solid K2C03 and catalytic dimethyl sulfide in MeCN [18]. Recently, the synthesis of 3-alkyl-2-vinyl-aziridines by extension of Dai s work was reported [19]. 

P8 Thermal conrotatory 4tt ring opening of aziridines and epoxides is a well-recognized method of generating azomethine and carbonyl ylidesd (From Johnson, 2003)... 

There are a few reports on the use of oximes as electrophilic amination reagents. Since 1984, ketone O-sulfonyloxknes have found applicability as amino transfer reagents to car-banions. In the reaction of organometaUic compounds with oximes, carbanions attack the carbonyl carbon of the oxime, giving Af-substituted hydroxylamines as addition products (Scheme 53, path a). However, a number of scattered reports have been also published on the formation of aziridines by a-deprotonation, followed by addition (path b) or formation of azirines by a-deprotonation before addition (path c). Addition of carbanions to azirines also yields aziridines, which are hydrolyzed to a-aminoalcohols. 

Since Alper and co-workers reported the first Rh-catalyzed carbonylative ring expansion of aziridines, yielding /3-lactams in 1989, this ring-expansion reaction catalyzed by Rh or Co complexes and its mechanism have been extensively studied. ... 

Dendritic rhodium catalyst systems on a resin have been developed for the carbonylative ring expansion of aziridines. " This catalyst system exhibited same high activity as the homogenous counterpart, that is,... 

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