Intermolecular cyclopropenation

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... 

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. 

Metal Carbene TVansformations. The effectiveness of Rh2(55 -MEPY)4 and its 5R-form, Rh2 5R-MEPY)4, is exceptional for highly enantioselective intramolecular cyclopropanation and carbon-hydrogen insertion reactions. Intermolecular cyclopropanation occurs with lower enantiomeric excesses than with alternative chiral copper salicylaldimine or C2-symmetric semicorrin or bis-oxazoline copper catalysts, but intermolecular cyclopropenation exhibits higher enantio-control with Rh2(MEPY)4 catalysts. The methyl carboxylate attachment of Rh2(55-MEPY)4 is far more effective than steri-cally similar benzyl or isopropyl attachments for enantioselective metal carbene transformations. The significant enhancement in enantiocontrol is believed to be due to carboxylate carbonyl stabilization of the intermediate metal carbene and/or to dipolar influences on substrate approach to the carbene center. 

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). ... 

Dirhodium(II) catalysts that possess chiral 2-pyrrolidone-5-carboxylate ester ligands (mepy) are the most effective among those of dirhodium or copper for highly diastereoselective and enantioselective intermolecular cyclopropenation reactions between l-alkynes and diazoesters (eq. (9)). Product yields are moderate, and enantiomeric excesses range from 40 to 98 %. Interestingly, the (R) or (5) catalyst produces the cyclopropene-l-carboxylate respectively with the (/ ) or (5) configuration [26]. 

The same dichotomy was observed with hexafluorodimethylcarbene (228), formed by thermolysis of diazirine (227) at 150 °C. The carbene (228) can stabilize itself either intramolecularly to perfluoropropene (229), or intermolecularly by addition to multiple bonds. Oxirane (230) is formed with hexafluoroacetone, cyclopropene (231) with 2-butyne (66MI50800). 

Alkinyloxy)diazoacetic esters 11 give rise to product mixtures that could be separated only partially. The isolated products result from a tandem intramolecular cyclopropenation/cyclopropene —> vinylcarbene isomerization (12, 14) and from a twofold intermolecular (3+2)-cycloaddition of the intact diazo compound (13). 

The intermolecular reaction of alkynes with acylcarbene complexes normally yields cyclopropenes [587,1022,1060-1062]. Because of the high reactivity of cyclopropenes, however, in some of these reactions unexpected products can result. In particular intramolecular cyclopropanations of alkynes, which would lead to highly strained bicyclic cyclopropenes, often yield rearrangement products of the latter. In many instances these products result from a transient vinylcarbene complex, which can be formed by two different mechanisms (Figure 4.3). 

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 contrast to considerations of 50 years ago, today carbene and nitrene chemistries are integral to synthetic design and applications. Always a unique methodology for the synthesis of cyclopropane and cyclopropene compounds, applications of carbene chemistry have been extended with notable success to insertion reactions, aromatic cycloaddition and substitution, and ylide generation and reactions. And metathesis is in the lexicon of everyone planning the synthesis of an organic compound. Intramolecular reactions now extend to ring sizes well beyond 20, and insertion reactions can be effectively and selectively implemented even for intermolecular processes. 

Although thermal [2 + 2] cycloadditions are forbidden as concerted reactions by the orbital symmetry conservation rules the same structural features which promote intermolecular cy-cioadditions will also promote intramolecular reactions. In addition, the proximity between two alkene moieties dictated by the tether length and rigidity would make these processes entropically favorable. A few reports have documented thermal intramolecular cycloadditions to cyclopropenes and activated alkenes. The thermal Cope rearrangement of allylcyclopropenes apparently proceeds by a two-step mechanism in which intramolecular [2 + 2] adducts have been observed.72-73... 

Intermolecular free-radical addition of iodoalkyl sulfones to vinylsilanes yields regios-electively the adduct 146 which can be further transformed to cyclopropene derivatives (equation 122)214. 

Cazes et al. reported the Pd-catalyzed intermolecular hydroamination of substituted allenes using aliphatic amines in the presence of triethylammonium iodide leading to allylic amines [19]. In a way similar to the Pd-catalyzed hydrocarbona-tion reactions we reported that the hydroamination of allenes [20], enynes [21], methylenecyclopropanes [22], and cyclopropene [10] proceeds most probably via oxidative addition of an N-H bond under neutral or acidic conditions to give allylic amines. The presence of benzoic acid as an additive promotes the Pd-medi-ated inter- and intramolecular hydroamination of internal alkynes [23]. Intramolecular hydroamination has attracted more attention in recent years, because of its importance in the synthesis of a variety of nitrogen-containing heterocycles found in many biologically important compounds. The metal-catalyzed intramolecular hydroamination/cyclization of aminoalkenes, aminodienes, aminoallenes, and aminoalkynes has been abundantly documented [23]. 

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. 

Cyclopropene can also be used as the aUcene component and affords bicyclo[3.1.0]hexen-2-ones upon reaction with alkyne dicobalt octacarbonyl complexes in the presence of NMO (Scheme 250). Vinyl ethers and vinyl esters serve as ethene equivalents in Pauson-Khand reactions. For example, reaction of vinyl benzoate with complex (169) furnished cyclopentenone (170) (Scheme 251). This reaction was used in a synthesis of (-l-)-taylorine and nortaylorine. Allenes participate in intermolecular Pauson-Khand reactions affording alkylidene-substituted cyclopentenones (Scheme 252). ... 

The intermolecular addition of a carbene to a cyclopropene to give a bicyclo-[l.l.OJbutane is not a viable synthetic method since products of ring cleavage are usually observed However, diazoalkane addition to a cyclopropene (or bis-addition to an alkyne) is known to occur and subsequent deazetation generally leads to bicyclobutane and diene by separate pathways. 

In contrast to the preceding intramolecular reactions, only a few intermolecular examples leading to bicyclo[l. 1. OJbutanes by carbene addition to cyclopropanes have been reported. Copper-catalyzed procedures generally require relatively high temperatures and yield mixtures of exo,exo-, endo.exo- and endo,endo- somtr% when 3-substituted cyclopropenes are used as reactants. Methyl 2,3-dipropylcycloprop-2-ene-l-carboxylate (8) provides the isomeric dimethyl l,3-dipropylbicyclo[1.1.0]butane-2,4-dicarboxylates (9) as a mixture (bp 90 100°C/0.5 Torr) that can be separated by preparative GC. The ejico,exo-isomer 9A is the major product. No yield is given. 

These reactions are summarized in more detail in Section 1.2.1., as topologically they constitute syntheses from C, + Cj building blocks. Some special intra- and intermolecular cases in which cyclopropenes serve as alkenes are discussed in Section 1.1.6.3.1.2. 

The intermolecular addition of azides to cyclopropenes gives triazines, apparently through the formation and rearrangement of a triazabicyclo[3.1.0]hexene, e.g. formation of I. ... 

Scheme 7.33 NHC-catalyzed asymmetric intermolecular Stetter reaction of aromatic aldehydes and cyclopropenes reported by Glorius.

Later, the group used cyclopropenes 49 as acceptors for the intermolecular Stetter reaction. In the presence of electron-rich triazolium salt H4, a variety of aldehydes and cyclopropenes worked well and afforded the acyl-cyclpropanes 50 in up to 98% yield with up to 96% enantiomeric excess (Scheme 20.24). 

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