Diazoacetates cyclopropenation with

Table 17. Cyclopropenation with alkyl diazoacetates according to R C = CR2 + N2CHCOOR3 - 224 + 225... 

Ethyl diazopyruvate, under copper catalysis, reacts with alkynes to give furane-2-carboxylates rather than cyclopropenes u3) (Scheme 30). What looks like a [3 + 2] cycloaddition product of a ketocarbenoid, may actually have arisen from a primarily formed cyclopropene by subsequent copper-catalyzed ring enlargement. Such a sequence has been established for the reaction of diazoacetic esters with acetylenes in the presence of certain copper catalysts, but metallic copper, in these cases, was not able to bring about the ring enlargement14). Conversely, no cyclopropene derivative was detected in the diazopyruvate reaction. 

Over the last few years it has become clear that rhodium(II) acetate is more effective than the copper catalysts in generating cyclopropenes.12 126 As shown in Scheme 28,12S a range of functionality, including terminal alkynes, can be tolerated in the reaction with methyl diazoacetate. Reactions with phenyl-acetylene and ethoxyacetylene were unsuccessful, however, because the alkyne polymerized under the reaction conditions. 

The mechanism of cyclopropenations of alkynes with ethyl diazoacetate, catalysed by (AcO)4Rh2 and (DPTI)3Rh2(OAc), has been studied by a combination of kinetic isotope effects and theoretical calculations. With each catalyst, a significant normal 13C KIE was observed for the terminal acetylenic carbon, while a very small 13C KIE was detected at the internal acetylenic carbon. These isotope effects are consistent with the canonical variational transition structures for cyclopropenations with intact tetrabridged rhodium carbenoids but not with a 2 + 2-cycloaddition on a tribridged rhodium carbenoid structure.99... 

One of the products isolated by treatment of cyclopropene with methyl diazoacetate is dihydropyridazine 48,101 apparently formed via an unstable adduct (47) [Eq. (7)]. 

Ethyl diazoacetate reacts with acetylenes in the presence of Cu to give ethyl cyclopropene-3-carboxylates. In the examples shown in Scheme 13,... 

The above two consecutive transformations provide straightforward access from propargyl alcohols to cyclopropene derivatives with an a- or /1-hydroxy group. This simple method is complementary to the access to 3-hydroxymethylcyclopropenes, via Rh2(OAc)4 catalyzed addition of diazoacetate to alkynes followed by reduction of the ester group, a route that is restricted to the access of primary cyclopropenyl alcohols [57], and is an alternative to the use of 2,2-dibromo-l-chlorocyclopropane via cyclopropenyl Uthium. 

Transition-metal catalyzed decomposition of alkyl diazoacetates in the presence of acetylenes offers direct access to cyclopropene carboxylates 224 in some cases, the bicyclobutane derivatives 225 were isolated as minor by-products. It seems justified to state that the traditional copper catalysts have been superseded meanwhile by Rh2(OAc)4, because of higher yields and milder reaction conditions217,218) (Table 17). [(n3-C3H5)PdCl]2 has been shown to promote cyclopropenation of 2-butyne with ethyl diazoacetate under very mild conditions, too 2l9), but obviously, this variant did not achieve general usage. Moreover, Rh2(OAc)4 proved to be the much more efficient catalyst in this special case (see Table 17). 

Reaction of propargylic alcohols 229 with alkyl diazoacetates entails competition between O/H insertion and cyclopropenation. 

Under the catalytic action of Rh2(OAc)4, formation of a propargylic ether from a terminal alkyne (229, R1=H) is preferred as long as no steric hindrance by the adjacent group is felt162,218>. Otherwise, cyclopropenation may become the dominant reaction path [e.g. 229 (R1 = H, R2 = R3 = Me) and methyl diazoacetate 56% of cyclopropene, 36% of propargylic ether162)], in contrast to the situation with allylic alcohols, where O/H insertion is rather insensitive to steric influences. 

Cyclopropanation and Cyclopropenation. At this time, intermolecu-lar cyclopropanation with alkyl diazoacetates is best accomplished with cobalt cat-... 

The addition to a carbon-carbon triple bond results in the formation of cyclo-propene products, and with diazoacetates the catalyst of choice for intermolecular addition is the dirhodium(II) carboxamidate 13 (e.g., Eq. 26). The reactions are general, except for phenylacetylene whose cyclopropene product undergoes [2 + 2]-cycloaddition, and selectivities are high. However, high selectivities have not been reported for reactions with allenes. 

In the presence of catalytic amounts of Rh2(5/ -MEPY)4, reaction between ethyl diazoacetate and representative alkynes results in the formation of ethyl cyclopropene-3-carboxylates (Eq. 5.21) with enantiopurities ranging from 54% ee to 98% ee in good yields (70-85%) [108]. 

TABLE 5.10. Knantioseleclive Cyclopropenation of Alkynes with Diazoacetates (Eq. 5.21) [108]... 

The Cu(I)-catalyzed decomposition of (alkynyloxysilyl)diazoacetates 119 furnishes the silaheterocycles 120 and/or 121 (equation 30) in modest yield63. In these cases, the photochemical extrusion of nitrogen from 119 does not lead to defined products and the thermal reaction is dominated by the 1,3-dipolar cycloaddition ability of these diazo compounds. In mechanistic terms, carbene 122 or more likely a derived copper carbene complex, is transformed into cyclopropene 123 by an intramolecular [1 + 2] cycloaddition to the triple bond. The strained cyclopropene rearranges to a vinylcarbene either with an exo-cyclic (124) or an endocyclic (125) carbene center, and typical carbene reactions then lead to the observed products. Analogous carbene-to-carbene rearrangements are involved in carbenoid transformations of other alkynylcarbenes64. 

Dirhodium(II) tetrakis(carboxamides), constructed with chiral 2-pyrroli-done-5-carboxylate esters so that the two nitrogen donor atoms on each rhodium are in a cis arrangement, represent a new class of chiral catalysts with broad applicability to enantioselective metal carbene transformations. Enantiomeric excesses greater than 90% have been achieved in intramolecular cyclopropanation reactions of allyl diazoacetates. In intermolecular cyclopropanation reactions with monosubsti-tuted olefins, the cis-disubstituted cyclopropane is formed with a higher enantiomeric excess than the trans isomer, and for cyclopropenation of 1-alkynes extraordinary selectivity has been achieved. Carbon-hydro-gen insertion reactions of diazoacetate esters that result in substituted y-butyrolactones occur in high yield and with enantiomeric excess as high as 90% with the use of these catalysts. Their design affords stabilization of the intermediate metal carbene and orientation of the carbene substituents for selectivity enhancement. 

Chiral rhodium(II) carboxamides are exceptional catalysts for highly enantio-selective intermolecular cyclopropenation reactions (50). With ethyl diazoacetate and a series of alkynes, use of dirhodium(II) tetrakis[methyl 2-pyrrolidone-5-(R)-carboxylate], Rh2(5R-MEPY)4, in catalytic amounts ( 1.0 mol %) results in the formation of ethyl eyelopropene-3-earboxylates (eq 4) with enantiomeric excesses... 

Alternative rhodium(II) carboxamide catalysts derived from 4-(R)-benzyloxa-zolidinone (47 -BNOXH) and 4-(S)-isopropyloxazolidinone (4S-IPOXH) provided only a fraction of the enantioselection obtained with Rh2(MEPY)4 catalysts. Whereas cyclopropenation of 1-hexyne with ethyl diazoacetate in the presence of Rh2(5R-MEPY)4 resulted in 15 (eq 4, R = n-Bu) with 54% ee, Rh2(47 -BNOX)4 gave the same compound in 5% ee, and Rh2(4S-IPOX)4 provided only 6% ee. 

Enantioeontrol in cyclopropenation reactions is obviously highly dependent on the carboxylate substituent of the dirhodium(II) carboxamide ligand and on the carboxylate substituent of the intermediate carbene. High enantioseleetivity is achieved with the use of Rh2(MEPY)4 catalysts and menthyl diazoacetates in reactions with 1-alkynes, and further enhancement in % ee can be anticipated. 

Table 4 Experimental 13C KIEs for cyclopropenations of 1-pentyne or 1-hexyne with ethyl diazoacetate in the presence of rhodium catalyst...

In other cases cyclopropenes have been obtained by direct reaction of an alkyne with a diazo-compound in. the presence of a suitable catalyst. Typical of these is the reaction of ethyl diazoacetate with alkynes in the presence of copper, which is reported to lead to about 40-50 % conversion to cyclopropene per equivalent of diazo-compound. This has been applied to the synthesis of the important naturally occurring cyclopropene, sterculic acid, (66) 56) ... 

The addition of alkoxycarbonylcarbene derived by catalysed decomposition of methyl diazoacetate to several simple, and in particular terminal, alkynes leads to low yields S7), but the reaction with 1 -trimethylsilylalkynes proceeds reasonably efficiently subsequent removal of the silyl-group either by base or fluoride ion provides a route to l-alkyl-3-cyclopropenecarboxylic acids. In the same way 1,2-bis-trimethylsilyl-ethyne can be converted to cyclopropene-3-carboxylic acid itself58 . The use of rhodium carboxylates instead of copper catalysts also generally leads to reasonable yields of cyclopropenes, even from terminal alkynes 59). 

Although some carbenes are reported not to add to cyclopropenes207, there are several examples of inter- and intra-molecular addition leading initially to the formation of bicyclobutanes. l,2-Diphenylcyclopropene-3-carboxylates are converted to a mixture of three stereoisomeric bicyclo[1.1.0]butanes by reaction with ethoxy-carbonylcarbene generated from the thermolysis of ethyl diazoacetate an additional product is the diene (278) which is apparently formed by rearrangement of an intermediate zwitter ion208). It should be noted, however, that cyclopropenes readily undergo addition to diazo-compounds, and that subsequent transformations may then lead to bicyclobutanes (see Section 8), and that a free carbene may therefore not be involved in the above process. 

Dirhodium(ll) tetrakis[methyl 2-pyrrolidone-5(R)-oarboxylate], Rh2(5R-MEPV)4, and its enantiomer, Rh2(5S-MEPY)4, which is prepared by the same procedure, are highly enantioselective catalysts for intramolecular cyclopropanation of allylic diazoacetates (65->94% ee) and homoallylic diazoacetates (71-90% ee),7 8 intermolecular carbon-hydrogen insertion reactions of 2-alkoxyethyl diazoacetates (57-91% ee)9 and N-alkyl-N-(tert-butyl)diazoacetamides (58-73% ee),10 Intermolecular cyclopropenation ot alkynes with ethyl diazoacetate (54-69% ee) or menthyl diazoacetates (77-98% diastereomeric excess, de),11 and intermolecular cyclopropanation of alkenes with menthyl diazoacetate (60-91% de for the cis isomer, 47-65% de for the trans isomer).12 Their use in <1.0 mol % in dichloromethane solvent effects complete reaction of the diazo ester and provides the carbenoid product in 43-88% yield. The same general method used for the preparation of Rh2(5R-MEPY)4 was employed for the synthesis of their isopropyl7 and neopentyl9 ester analogs. 

In contrast to the carbene and carbenoid chemistry of simple diazoacetic esters, that of a-silyl-a-diazoacetic esters has not yet been developed systematically [1]. Irradiation of ethyl diazo(trimethylsilyl)acetate in an alcohol affords products derived from 0-H insertion of the carbene intermediate, Wolff rearrangement, and carbene- silene rearrangement [2]. In contrast, photolysis of ethyl diazo(pentamethyldisilanyl)acetate in an inert solvent yields exclusively a ketene derived from a carbene->silene->ketene rearrangement [3], Photochemically generated ethoxycarbonyltrimethyl-silylcarbene cyclopropanates alkenes and undergoes insertion into aliphatic C-H bonds [4]. Copper-catalyzed and photochemically induced cyclopropenation of an alkyne with methyl diazo(trimethylsilyl)acetate has also been reported [5]. 

Enantioselective Intermolecular Cyclopropenation Reactions. The use of Rh2(MEPY)4 catalysts for intermolecular cyclopropenation of 1-alkynes results in moderate to high selectivity. With propargyl methyl ether (or acetate), for example, reactions with (—)-menthyl [(+)-(l/ ,25,5/ )-2-isopropyT5-methyl-1-cyclohexyl] diazoacetate catalyzed by Rh2(55 -MEPY)4 produces the corresponding cyclopropene product (eq 3) with 98% diastere-omeric excess (de). ... 

Styrene cyclopropanation continues to attract much interest. Cationic complex CpFe(CO)2(THF) BF4" mediates carbene transfer from ethyl diazoacetate with high cis selectivity cis trans = 85 15) [38]. On the other hand, Tp Cu(C2H4), where Tp is hydrotris(3,5-dimethyl-l-pyrazolyl)borate, is one of the rare catalysts to promote carbene transfer from ethyl diazoacetate to alkenes and also to alkynes. While cyclopropanes are formed in high yield, cyclopropenes are obtained only in moderate yield [39]. The same complex also catalyzes nitrene transfer from PhI=NTs to alkenes to produce aziridines in high yields. 

Decarbonylation of cyclopropene acids. In a study of the synthesis of methyl sterculate (6) from methyl stearolate (1), Gensler et al.1 were unable to repeat the apparently straightforward synthesis based on addition of the Simmons-Smith reagent described in 1, 1021-1022. They were also unable to eifect addition of methylene generated by cuprous bromide decomposition of diazomethane. However, the reaction of (1) with diazoacetic ester in the presence of copper bronze, followed by hydrolysis, gives the cyclopropene diacid (2) in 70-90% yield. 

Intramolecular insertion has been observed in reactions of homoallylic diazoacetates. With acetylenes, reaction can either consist of an insertion into the C—C bond to the acetylene" or an addition reaction forming a cyclopropene, which spontaneously rear-ranges to a vinyl carbene intermediate (284). In a polyunsaturated system, this carbene can undergo further addition". ... 

Cyclopropenation. Cyclopropenes can be formed from alkynes by reaction with methyl diazoacetate using a rhodium(ll) carboxylate as catalyst. The reaction is not particularly subject to steric hindrance, but polar groups (CH2COOCH3) inhibit cyclopropenation markedly. Insertion reactions compete with cyclopropenation in the case of acetylenic alcohols. ... 

Enantioselective cyclopropenation This chiral rhodium(ll) catalyst can effect highly enantioselective cyclopropenation of 1-alkynes with alkyl diazoacetates. The enantioselectivity increases with the steric size of the ester group, and the size and polarity of the alkyne substituent also affects the enantioselectivity. The highest selectivity is observed with menthyl diazoacetates as a result of double diastereoselection. 

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