Cyclopropanones, synthesis

Cyclopropanone Synthesis. The literature procedures (jj,6) for the synthesis of cyclopropanone utilize the reaction of a 2-3 fold excess of ketene with diazomethane at -78°C as shown in Equation 5. 

There are several mechanistically related ring expansion reactions of cyclopropanones which lead to /3-lactams. The conversion of cyclopropanone to /3-lactam (174) via the cyclopropanolamine (173) (75JOC1505) is just one modification, but it illustrates the strategy of this type of approach (73TL4855, 69JA2375) which has been applied to the synthesis of 3-amino-nocardicinic acid (81JOC2999). 

Materials. Ketene was synthesized as described by Andreades and Carlson ( ) from diketene. Diazomethane was synthesized from N-methyl-N-nitroso-pi-toluenesulfonamide as outlined by Hudlicky (10). A typical synthesis of cyclopropanone involved the slow addition of 400 mL of a 1.0 M diethyl ether solution diazomethane to a 2-3-fold molar excess of ketene at -78°C. This synthesis was based on the... 

Due to their physiological importance, considerable efforts are currently devoted towards the total synthesis of 2,3-methanoamino acids (ACCs). The parent compound ACC 71 has been readily prepared from acrolein, through the base-induced (K2CO3) cyclization of 2-amino-4-chlorobutyronitrile [96] or from one-pot Strecker reaction of cyclopropanone hemiacetal [97]. 

The configuration of cleonine 106 appears to be S from a biosynthetic viewpoint [139] its synthesis from the readily available cyclopropanone cyanohy-drine has been reported [140,141]. 

Ketenes rarely produce [3+ 2]-cycloaddition products with diazo compounds. The reaction possibilities are complex, and nitrogen-free products are often obtained (5). Formation of a cyclopropanone represents one possibihty. Along these lines, the synthesis of (Z)-2,3-bis(trialkylsilyl)cyclopropanones and (Z)-2-trialkylsilyl-3-(triethylgermyl)cyclopropanones from diazo(trialkylsilyl)methanes and appropriate silyl- or germylketenes has been reported (256,257). It was found that subsequent reaction of the cyclopropanone with the diazoalkane was not a problem, in contrast to the reaction of diazomethane with the same ketenes. The high cycloaddition reactivity of diazomethylenephosphoranes also extends to heterocumulenes. The compound R2P(C1)=C=N2 (R = N(/-Pr)2) reacts with CS2, PhNCO and PhNCS to give the corresponding 1,2,3-triazole derivative (60). 

Cyclopropanones deserve special comment, not because of their practical importance (they have no commercial value at this time), but because of their novel behavior and reactivity. No unambiguous synthesis of cyclopropanones was known prior to 1965, and the older textbooks usually contained statements such as cyclopropanones apparently cannot exist. However, they had been postulated as intermediates in various reactions (see, for example, the Favorskii rearrangement, Section 17-2C and Exercise 17-15), but until recently had defied isolation and identification. The problem is that the three-ring ketone is remarkably reactive, especially towards nucleophiles. Because of the associated relief of angle strain, nucleophiles readily add to the carbonyl group without the aid of a catalyst and give good yields of adducts from which the cyclopropanone is not easily recovered ... 

To avoid destructive side reactions, cyclopropanones have to be prepared at low temperatures in the absence of nucleophiles. A good example is the synthesis of cyclopropanone itself from ketene and diazomethane (see Section 16-4 A) ... 

Cyclopropanon.es are highly reactive organic systems containing a number of labile sites on a small carbon skeleton. They represent valuable substrates for studying theoretical aspects of the chemistry of small strained ring systems and are of special interest in synthesis because of the variety of transformations in which they take part. 

A significant step in studying the chemistry of cyclopropanones has resulted from the discovery that many labile carbonyl derivatives such as hemiacetals and carbinol amines are useful precursors of the parent ketone. 4-6> Such derivatives may be isolated, purified and used as cyclopropanone substitutes or, alternatively, may be generated in solution and used as in situ precursors. As a result of these advances, exploration of cyclopropanone chemistry has recently been accelerated. The aim of this article is to review some of this chemistry, noting areas where there may be potential applications in synthesis. 

A versatile synthesis of cyclopropanones and closely related derivatives is provided by the diazoalkane-ketene reaction as shown in Scheme 2. Using this method, the parent ketone 2>3> and alkyl-substituted cyclopropanones 1()) have been prepared in yields of 60—90% based upon the concentration of diazoalkaneb) (Table 2). The reaction is rapid at Dry Ice-acetone temperatures and is accompanied by evolution of nitrogen. Although most cyclopropanones are not isolable, dilute solutions of 3 (0.5—0.8 M) may be stored at — 78 °C for several days or at room temperature in the presence of suitable stabilizing agents.15) The hydrate and hemiketal derivatives are readily prepared by the addition of water or alcohols to the solutions of. .2>8>5)... 

As shown in Table 2, the application of this method to the synthesis of aryl-substituted cyclopropanones 16> and cyclopropanone acetals 17>18> has been moderately successful, although products other than the expected ketones may be obtained. For example, the oxadiazoline 4 and not tetraphenylcyclopropanone is formed when diphenylketene is allowed to react with diphenyldiazomethane.19>... 

Carbon monoxide may be eliminated from cyclopropanones either by thermal or photochemical processes (Table 12). In fact, decarbonylation is sometimes an undesirable side reaction in the synthesis of cyclopropanones. For example, the reaction of dimethylketene and ethyl diazoacetate affords carbon monoxide and ethyl acrylate 115 rather than the desired ketone. 2°)... 

An extension of this reaction leading to a general synthesis of N-substituted (3-lactams involves the addition of a primary amine to a freshly prepared solution of cyclopropanone, conversion of the resulting carbinol amine to the N-chloro derivative, and then decomposition of this intermediate with silver ion in acetonitrile. 87a> The method permits one to prepare N-substituted (3-lactams of great variety (Table 14), including those constructed from amino acid esters. 87b The use of valine ethyl ester (123) as a nitrogen source leading to 124 is illustrated. 

Cyclopropanone cleavage with elimination 72 can also lead to ring contraction as in the synthesis of the trans acid 74 from natural pulegone13 70. Bromination gives the unstable dibromide 71 that is immediately treated with ethoxide to initiate the Favorskii rearrangement. The product is a mixture of cis and trans isomers of the ester 73 but hydrolysis under vigorous conditions (reflux in aqueous ethanol) epimerises the ester centre and gives exclusively the trans acid 74. 

Approaches that represent a type (ii) synthesis of 277-pyran-2-ones include the self-condensation of 1,3-dicarbonyl compounds, the reaction of cyclopropanones with pyridinium enolbetaines and the reaction of activated methylene groups with acetylenic esters <1984CHEC, 1996CHEC-II>. 4-Perfluoroalkyl-6-aryl-pyran-2-ones are formed by the reaction of the phosphonium salts 631 with 2-perfluoroalkynoates (Equation 254) <1999JFC(95)135, 1998JFC(91)99>. Dimedone reacts with dimethyl acetylenedicarboxylate to afford the pyran-2-one 632 in excellent yield (Equation 255) <2003PS2627>. 

Aside from the ready preparation of some a,p-disubstituted cyclopentanones, the utility of the cyclopropanone hemiacetal approach has been illustrated by the total synthesis of the methyl ester of 11-deoxyprostaglandin E2 342 15). Towards this end, 1-trimethylsilylbutadiynylcyclopropanol 13, readily available from the cyclopropanone hemiacetal 3 (vide supra, Sect. 2.1, Eq. (6)) was successively treated with dihydro-pyran in CH2C12 in the presence of 10% mol. equiv. of PPTS 101). Desilylation by potassium fluoride in DMF 138), formation of the lithium salt with n-BuLi and condensation with hexanal gave the propargylic alcohol 339 in 64 % overall yield. The... 

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