Carbenes, from diazoketones

A key observation by Wenkert proved vital in the subsequent popularity of rhodium as a highly effective catalyst for the generation of carbenes from diazoketones and their engagement in C-H insertion reactions (Equation 27) [15, 16, 88], In this experiment, treatment of diazoketone 153 with Rh2(OAc)4 led to a stereoselective C-H insertion reaction to generate ketone 154 in 59% yield [88], Importantly, no cyclization was observed in the presence of CuSO,. 

Photoelimination of nitrogen from diazoketones is complicated by Wolff rearrangement of the intermediate carbene, as shown below for diazoaceto-phenone<35) ... 

Ketocarbenes generated from diazoketones give two main type of reactions. The first one is the conventional carbene reaction, i.e. intramolecular insertion into a C—H or C—C bond, as applied in the synthesis of a... 

Carbenes have divalent carbon with a lone pair and hence only six electrons in the outer shell of the carbon atom. They are normally electrophilic and can form two bonds at once with a re-system.7 One way to make carbenes is by loss of nitrogen from diazocompounds such as diazoketones 33. The formation of very stable nitrogen is initiated by heat or light and compensates for the formation of the unstable carbene 30. Diazoketones are easily made by acylation of diazomethane with an acid chloride 31. Loss of a very acidic proton from the diazonium salt 32 gives 33. Normally the diazoketone and the alkene are combined and treated with heat or light.8... 

The ambident nucleophilic character of enaminones is again demonstrated by the reaction with keto carbenes, produced in situ from diazoketones. Acyclic enaminones react via the -position to directly yield pyrroles (equation 11). Cyclic enaminones are shown to react at the nitrogen to give adducts which can be cyclized with KOH to... 

The ease of insertion of an acylmethylene group (derived as the carbene from a diazoketone) is dependent on the nature of the bonding at tetracoordinate quinquevalent phosphorus. Thus, insertion is accompanied by rearrangement during reactions with... 

Dihydro-l,3-thiazin-5-ones (e.g., (321)) are uncommon, but they can be synthesized from diazoketones (322), which in the presence of an acid eliminate nitrogen and form the heterocycles, presumably via intermediate carbenes (Equation (37)) <80KGS1327>. 

The Wolff-rearrangeinent of oxocarbenes derived from diazoketones is probably the most widely known carbene rearrangement D. 

Reactions of enaminones 138 with keto carbenes 139, generated from diazoketones in the presence of Cu(acac)2, afforded the corresponding tetrasubstituted pyrroles 140 (88JOC2084). Cyclic enaminones underwent the same reaction to give tetrahydroindoles (Section V,D,4). 

Carbenes from a-diazoketones have the special property that they rearrange faster than they are trapped. For example, rearrangement gives a ketene, which can be trapped by an alkene, and this forms the basis of a method for synthesizing four-membered rings (Scheme 5.59). A variant of this reaction is the ring contraction of carbenes from cychc a-diazoketones (Scheme 5.60). 

Taber has reported as series of C-H insertion reactions giving rise to a variety of useful cyclic building blocks. A notable example involves treatment of diazoketone 155 with Rh2(OAc)4 to afford the tricyclic product 156 in 91 % yield (Scheme 15.16) [89]. This transformation formed a key step in the synthesis of pentalenolactone E methyl ester (157) [90]. In another meritorious example, Rh-catalyzed generation of the carbene from 158 and stereo-specific insertion into the benzylic C-H afforded 159 in 67 % yield (Scheme 15.17) [91]. This transformation provided rapid access to the key ring system that was subsequently used to complete the synthesis of the sesquiterpene (-i-)-a-cuparenone (160). 

Products of a so-called vinylogous Wolff rearrangement (see Sect. 9) rather than products of intramolecular cyclopropanation are generally obtained from P,y-unsaturated diazoketones I93), the formation of tricyclo[2,1.0.02 5]pentan-3-ones from 2-diazo-l-(cyclopropene-3-yl)-l-ethanones being a notable exception (see Table 10 and reference 12)). The use of Cu(OTf), does not change this situation for diazoketone 185 in the presence of an alcoholl93). With Cu(OTf)2 in nitromethane, on the other hand, A3-hydrinden-2-one 186 is formed 160). As 186 also results from the BF3 Et20-catalyzed reaction in similar yield, proton catalysis in the Cu(OTf)2-catalyzed reaction cannot be excluded, but electrophilic attack of the metal carbene on the double bond (Scheme 26) is also possible. That Rh2(OAc)4 is less efficient for the production of 186, would support the latter explanation, as the rhodium carbenes rank as less electrophilic than copper carbenes. 

Intramolecular carbonyl ylide formation was also invoked to explain the formation of the AH-1,3-oxazin-5(6//)-ones 291a, b upon copper-catalyzed decomposition of diazoketones 290a, b 270 >. Oxapenam 292, obtained from 290b as a minor product, originates from an intermediary attack of the carbenic carbon at the sulfur atom. In fact, this pathway is followed exclusively if the C(Me, COOMe) group in 290b is replaced by a CH2 function (see Sect. 7.2). 

The reaction, formally speaking a [3 + 2] cycloaddition between the aldehyde and a ketocarbene, resembles the dihydrofuran formation from 57 a or similar a-diazoketones and alkenes (see Sect. 2.3.1). For that reaction type, 2-diazo-l,3-dicarbonyl compounds and ethyl diazopyruvate 56 were found to be suited equally well. This similarity pertains also to the reactivity towards carbonyl functions 1,3-dioxole-4-carboxylates are also obtained by copper chelate catalyzed decomposition of 56 in the presence of aliphatic and aromatic aldehydes as well as enolizable ketones 276). No such products were reported for the catalyzed decomposition of ethyl diazoacetate in the presence of the same ketones 271,272). The reasons for the different reactivity of ethoxycarbonylcarbene and a-ketocarbenes (or the respective metal carbenes) have only been speculated upon so far 276). 

The reaction of ADC compounds with carbenes and their precursors has already been discussed in Section IV,A- In general, the heterocyclic products are not the result of 1,2-addition but of 1,4-addition of the carbene to the —N=N—C=0 system.1 Thus the ADC compound reacts as a 4n unit in a cheletropic reaction leading to the formation of 1,3,4-oxadiazolines. Recent applications include the preparation of spiro-1,3,4-oxadiazolines from cyclic diazoketones and DEAZD as shown in Eq. (14),133 and the synthesis of the acyl derivatives 85 from the pyridinium salts 86.134 The acyl derivatives 85 are readily converted into a-hydroxyketones by a sequence of hydrolysis and reduction reactions. 

Two type la syntheses of (3-hydroxypyrroles have appeared. An aza-Nazarov cyclization of l-azapenta-l,4-dien-3-ones produced (3-hydroxypyrroles including 2,2 -bipyrroles <06EJO5339>. A second approach to a (3-hydroxypyrrole involved an intramolecular N-H insertion into a rhodium carbene derived from the decomposition of a diazoketone <06JOC5560>. On the other hand, the photochemical decomposition of the diazoketone led to pyrrolidin-2-ones. 

A density functional study has been made of the competition between Wolff rearrangement and [1,2]-H shift in /S-oxy-a-diazocarbonyl compounds. Silver-catalysed decomposition of a-diazoketones (88 n = 0), derived from A-tosyl a-amino acids in methanol, gave rise to mixtures of products of Wolff rearrangement (89) and direct insertion of the carbene into the NH bond (90). The -amino acid derived species (88 n = 1) gave rise to products of Wolff rearrangement. 

There are several reports in the literature dealing with the bimolecular [3 + 2] cycloaddition reactions of alkynyl-substituted diazo compounds. Propargyl diazoacetate 212, when stored for 2 weeks at 0 °C, was transformed into an oligomer to which the constitution 213 was assigned (273) (Scheme 8.50). The alkynyl-diazoketone 214 requires a much higher temperature and is transformed into pyrazole 215, which probably arises from intermolecular cycloaddition, pyrazole tautomerization, and carbenic N/H insertion (274). The inter-intramolecular... 

The diverse chemistry of carbenes is beyond the scope of this account, but a few typical reactions are shown here to illustrate the usefulness of the photochemical generation of these reactive species. A carbene can insert into a C—H bond, and this finds application in the reaction of an a-diazoamide to produce a P-lactam (5.29). Carbenes derived from o-diazoketones can rearrange to ketenes, and thus a route is opened up to ring-contraction for making more highly strained systems <5.301. Carbenes also react with alkenes, often by cycloaddition to yield cyclopropanes in a process that can be very efficient (5.31) and highly stereoselective (5.321. 

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