Generation, carbene

All the thermal protocols discussed above initially form singlet carbenes, as do the photolysis of diazo and diazirine compounds. For cases where the triplet is the ground state, relaxation to the triplet state can occur in competition with additions and insertions. In addition, it is possible to use a photochemical sensitizer (see Chapter 16) to produce a triplet state directly. Here, the sensitizer is a photo-excited triplet state of an additive that transfers its energy to the carbene precursor, creating the triplet carbene directly. 

The production of carbenes from haloforms (Eq. 10.54) is an interesting reaction. The reaction sequence displays second-order kinetics, first order in both base and haloform. This supports a mechanism involving an equilibrium deprotonation prior to rate-determining a-halogen departure. The loss of an equivalent of HCl from HCCI3 constitutes an elimination reaction, and is specifically called a 1,1-elimination or an a-elimination. 

Phase transfer catalysts (see Chapter 9 for a discussion) have been used to facilitate the reaction depicted in Eq. 10.54. The halomethyl anion is transported as an ion pair with a tetraalkylammonion counter cation into an organic pha.se, where reprotonation occurs at a lower rate. The a-elimination to form the carbene occurs in the organic medium where the alkene or alkyne targeted for addition resides. 

The Simmons-Smith reagent (ICH2ZnI) also acts as a carbene source. The reaction between CH2I2 and Zn does not generate a full-fledged free carbene, but instead a carbenoid (Eq. 10.55). A carbenoid is a carbene that is stabilized by complexation to a metal. Even the carbenes created by the reaction between strong bases and haloforms sometimes react as carbenoids, where the carbene is complexed to the counter cation of the strong base. We will examine more carbenoid species in Chapter 12, when alkylidenes and Fischer carbenes are discussed. 

The reactivity of most singlet carbenes with alkenes is dominated by the electrophilic character of the carbene (the empty p orbital). Thus, the more electron rich the alkene, the faster the carbene addition. Increasing alkyl group substitution on alkenes increases the rate of addition. This trend parallels the reactivity for the addition of other electrophiles with alkenes, such as acids, Xj, and borane. Dialkylcarbenes are less selective than dihalocarbenes, whereas carbenes with neighboring O or N atoms are resonance stabilized (see margin) and are highly selective. This trend tracks the reactivity-selectivity principle (see Chapter 7), where the more stable carbenes are the more selective. 

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Ring enlargement of benzene derivatives by carbenes generated from diazo compounds (better in the presence of a Rh catalyst) Conversion of aldehydes to ketones by diazo compounds (Schlotterbeck) see also Ptau Planer... 

Tnmethyl(trifluororaethyl)tin can also be prepared via in situ formation and capture of tnfluorometbide by trimethyltin chlonde [13, 14] (equation 9) This tin analogue has been used as a precursor for difluorocarbene either by thermal decomposition or by reaction with sodium iodide m 1,2-dimethoxyethane This carbene generation procedure has been used to study difluorocarbene selectivity with steroidal olefins [75] (equation 10). 

These precursors have received considerable attention as nonbasic precursors to halofluorocarbenes [167] (equation 124), and several reviews describe the scope of this mode of carbene generation [166, 167, 168]... 

The Ciamician-Dennstedt reaction involves the reaction of a pyrrole (1) with the carbene generated from chloroform and a base to provide a 3-chloropyridine (2, Scheme 8.3.1). 

Due to the commercial availability of EMME in good purity, there has not been a need to develop new methods to prepare 3-anilino-acrylates therefore, only a few alternatives have been reported. One approach described thermal carbene generation from 37, and rearrangement to form 38. Cyclization in refluxing 1,2-dichlorobenzene (1,2-DCB) provided the 2, 3, 4-trisubstituted quinolines. An electron-withdrawing group (EWG) on the carbene carbon was required for this reaction, and therefore led to the EWG substitution in the 2-position of the quinoline. 

The imidazoline denvative cibeiuoline (64) is a class I antiarrhythmic agent which has undergone clinical trials in the United States with apparently satisfactory results It is synthesized by diphenylcyclopropananon of acrylonitrile by thermal carbene generation from diphenyldiazo methane (62) to give 1 cyano 2,2 diphenylc>clopropane (63) Reaction of this with ethylenedia mine tosylate completes the synthesis of ciben/oline (64) [221... 

Ring enlargement via an insertion of a carbene generated in the a-position to the ring is an established method and has also been applied to the synthesis of oxepins. The ()3-allylpalladium chloride catalyzed decomposition of substituted ethyl diazo(4/7-pyran-4-yl)acetates in benzene at room temperature gives ethyl oxepin-4-carboxylates 1 in excellent yield.190 The ester function can be replaced by the phosphonate group and other P = 0-functions (see Houben-Weyl,... 

The related [1,2]-H shift in the isomeric triplet 1-phenylethylidene (53) was also investigated. The triplet carbene, generated from irradiation of the corresponding diazo compound, was characterized in low temperature inert matrices by EPR, IR, and UV/VIS spectroscopy. In this case, the carbene was stable in Ar up to the temperature limits of the matrix (36 K). Irradiation, however, readily converted the carbene to styrene. 

Carbenes from Halides by a-Elimination. The a-elimination of hydrogen halide induced by strong base (Scheme 10.8, Entry 4) is restricted to reactants that do not have (3-hydrogens, because dehydrohalogenation by (3-elimination dominates when it can occur. The classic example of this method of carbene generation is the generation of dichlorocarbene by base-catalyzed decomposition of chloroform.152... 

Hindered lithium dialkylamides can generate aryl-substituted carbenes from benzyl halides.162 Reaction of a,a-dichlorotoluene or a,a-dibromotoluene with potassium r-butoxide in the presence of 18-crown-6 generates the corresponding a-halophenylcarbene.163 The relative reactivity data for carbenes generated under these latter conditions suggest that they are free. The potassium cation would be expected to be strongly solvated by the crown ether and it is evidently not involved in the carbene-generating step. 

Reactions involving free carbenes are very exothermic since two new theoretical treatment of the addition of singlet methylene to ethylene suggests that there is no activation barrier.168 The addition of carbenes to alkenes is an important method for synthesis of many types of cyclopropanes and several of the methods for carbene generation listed in Scheme 10.8 have been adapted for use in synthesis. Scheme 10.9, at the end of this section, gives a number of specific examples. 

The addition of dichlorocarbene, generated from chloroform, to alkenes gives dichlorocyclopropanes. The procedures based on lithiated halogen compounds have been less generally used in synthesis. Section D of Scheme 10.9 gives a few examples of addition reactions of carbenes generated by a-elimination. 

The most common rearrangement reaction of alkyl carbenes is the shift of hydrogen, generating an alkene. This mode of stabilization predominates to the exclusion of most intermolecular reactions of aliphatic carbenes and often competes with intramolecular insertion reactions. For example, the carbene generated by decomposition of the tosylhydrazone of 2-methylcyclohexanone gives mainly 1- and 3-methylcyclohexene rather than the intramolecular insertion product. 

In the presence of an imidazolium salt and a base, oxidative cyclization of a Ni(0) species upon the diene and an aldehyde takes place first and forms an oxanickellacycle 25, which equilibrates with a seven-membered oxanickella-cycle 26, naturally possessing a cis double bond. cr-Bond metathesis through 26 with hydrosilane affords (Z)-allylsilane (Z)-23. The role of NHC ligand (AT-heterocyclic carbene, generated by H+ elimination from imidazolium C2H by a base) is not clear at present a Ni(0)-NHC complex is believed to effectively produce 26. 

The group of Nakatani introduced photochemically induced cyclization that takes advantage of a system in which a carbene generator and a carbene trap are combined in the same molecule [37]. Thus, irradiation of compound 5-105 induced a cyclization to give an intermediate carbene 5-106, which underwent an intramolecular trapping by a pericyclic 6jt electrocyclization to afford 5-107 in a very good yield of 95% (Scheme 5.21). 

Me3Sn02CCX3 (CX3 = CF3, CC13, CBr3 or CF2C1) were heated in cy-clooctene where any carbenes generated would add to the double bond... 

An interesting variation appears when furan reacts with the allenic carbene generated by the action of potassium ter-butoxide upon l-bromo-3,3-dimethylallene. Though the yield is only 9%, one product is reasonably assigned a structure (Scheme 52) that could hardly be approached by way of a cyclopropane intermediate. The authors comment that in an allenic carbene in the singlet state two electrons will be accommodated in the sp... 

Apart from the widely studied silver(i) A-heterocyclic carbenes, Stoltz and Beauchamp made the first report on the gas-phase synthesis of silver(i) Fischer carbenes from the loss of N2 in various diazo malonates upon electrospray ionization and subsequent collisional activation.118 The carbenes generated were capable of undergoing multiple Wolff rearrangements and loss of CO (Scheme 18). 

An alternate route to carbene generation has been proposed for the RAlCl2/Re(CO)5Cl and RAlCl2/Mo(CO)5Py systems (44-46). The key step in this route is insertion of a CO ligand in the R—A1C12 followed by a sequence of steps that produce the initial carbene. Equation (16) demonstrates this proposal. 

Carbene generation is envisioned as being a reversible sequence as depicted in Eq. (24). 

Additional evidence for the contention that metathesis carbenes are nucleophilic was offered by Gassman in an interesting series of trapping experiments utilizing Michael acceptors as carbene traps (15, 17). Thus, an ethylidene carbene generated from 2-butene was trapped by ethyl acrylate to yield the expected ethylcyclopropyl ester, although yields were quite low. 

The pyridine ylide method depends on the effective trapping of the carbene by pyridine. At high pyridine concentrations every carbene produced by the laser pulse will be trapped as ylide, and the ylide s absorbance (Ay) will saturate or reach a plateau (A °). The magnitude of A ° will vary with carbene structure it will decrease with both the increasing ease of carbene rearrangement and the intervention of RIES during carbene generation.3... 

As shown in Table 1, however, the product distribution depends on the method of carbene generation. Whereas thermolysis of either tosylhydrazone salt (7) or methylethyldiazirine (8) affords essentially the same product distribution (in which 95% of the products are the 2-butenes), photolysis of diazirine 8 is quite different. 

It is suggested that the real carbene, generated by thermolysis of the diazo or diazirine precursors or photolysis of 40, gives mostly 1,3-insertion, whereas photolysis of either the diazoalkane or diazirine yields much 1,2-Me migration directly from precursor excited states.15 1 An analogous intervention of 1,2-Me migration via RIES was also observed in the photolytic decomposition of f-butylchlorodiazirine (24) to f-butylchlorocarbene (18) cf. Eq. 14.27... 

The difference in reactivity between isoprenol and isoprenyloxide, methal-lyl methyl ether and methallyloxide were investigated in the reaction with (phenylthio)carbene generated under phase-transfer conditions. With isoprenol, (phenylthio)methyl ether (41%) was the major product, whereas with methyl ether cyclopropanation (36%) was the sole reaction.1519 With alkoxides, in contrast, the major product was the C-H insertion product (45%) and (phenyl-... 

Vinylidenecarbene or allenylidene3 (R)2C=C=C has a lance-shaped, unsubstituted and sp-hybridized carbene center and, therefore, will not be easily subject to steric hindrance in its insertion reactions. On this assumption, (2-methyljpropenylidenecarbene or its carbenoid was chosen as a prototype of typical vinylidenecarbenes and its insertion reaction with several different types of alkoxides was investigated by employing two methods (A and B, Scheme 10) for carbene generation.20 The insertion products 20 were obtained almost exclusively except lithium allyloxide (Table 4, entry 10).21 By-products such as propargyl ether and allenyl ether were not formed at all. To be noted here, in... 

It has been found that the catalytic activity of PKC is enhanced by a lipid component of the cell membrane, namely phosphatidylserine. This activity is further stimulated by sn-1,2-diacylglycerol. Oleic acid also activates the enzyme in the presence of 1,2-diacylglycerol, and thus it is presumed to mimic phosphatidylserine. In order to identify that modulating binding site for oleic acid on PKC, a photoaffinity analogue was devised. A carbene generating photophore, diazirine was placed in the apolar terminus of the unsaturated fatty acid ligand (30, Fig. 12). The synthesis and the photochemical activation properties were reported by Ruhmann and Wentrup [113]. 

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