Dimethoxycarbene, nucleophilicity

Carbene reactivity is strongly affected by substituents.117 Various singlet carbenes have been characterized as nucleophilic, ambiphilic, and electrophilic as shown in Table 10.2 This classification is based on relative reactivity toward a series of both nucleophilic alkenes, such as tetramethylethylene, and electrophilic ones, such as acrylonitrile. The principal structural feature that determines the reactivity of the carbene is the ability of the substituent to act as an electron donor. For example, dimethoxycarbene is devoid of electrophilicity toward alkenes because of electron donation by the methoxy groups.118... 

Indeed, such donation is calculated to stabilize singlet dimethoxycarbene by 76 kcal/mol relative to the corresponding triplet.93 The electron donation also modulates carbenic reactivity 78 a strong electron donor on Q raises both the carbene s HOMO and LUMO energies, thereby increasing the carbene s nucle-ophilicity while rendering its LUMO less accessible to nucleophiles (decreasing its electrophilicity).94 These consequences are illustrated by 69 and the related structures in Scheme 6. 

There is no published example of a cyclopropanation of the double bond in chlorocyclopropylideneacetate 1-Me with retention of the chlorine atom. Thus, attempted cyclopropanations under Simmons-Smith [37] or Corey [38] conditions failed [25]. The treatment of the highly reactive methylenecyclopropane derivative 1-Me with dimethoxycarbene generated by thermal decomposition of 2,2-dimethoxy-A -l,3,4-oxadiazoline 26 (1.5 equiv. of 26,PhH, 100 °C,24 h),gave a complex mixture of products (Scheme 7) [39], yet the normal cycloadduct 28 was not detected. The formation of compounds 29 - 33 was rationalized via the initially formed zwitterion 27, resulting from the Michael addition of the highly nucleophilic dimethoxycarbene to the C,C-double bond of 1-Me. The ring closure of 27 to the normal product 28 is probably reversible, and 27 can rearrange or add a second dimethoxycarbene moiety and a molecule of acetone to form 33. 

Catalyst-mediated decomposition of diazo compounds in the presence of C=S compounds has found application for the preparation of thiiranes in homogeneous systems (68,110,111). Recently, a convenient procedure for the preparation of geminal dichlorothiiranes from nonenolizable thioketones and chloroform under Makosza conditions was reported (112). Another approach to 2,2-dihalogenated thiiranes (e.g., 2,2-difluoro derivatives) involves the thermolysis of Seyferth reagents in the presence of thioketones (113,114a). Nucleophilic dimethoxycarbene was shown to add smoothly to adamantanethione to provide a unique approach to a thiiranone (5, 5 )-dimethylacetal (114b). 

The computed values of Aee and Aen also predict that dimethoxycarbene should be a nucleophilic carbene. Experimentally, dimethoxycarbene does not add at all to electron-rich alkenes (preferring to dimerize instead), but does add readily to electron-poor methyl acrylate and acrylonitrile." Many other nucleophilic reactions of (CH30)2C and related dialkoxycarbenes have been investigated and reviewed by Warkentin." ... 

At the opposite end of the philicity spectrum, nucleophilic carbenes have proven useful in synthesis. Warkentin" pioneered the thermolysis of oxadiazolines as precursors for (CH30)2C and related dioxacarbenes (Scheme 7.3). Dimethoxycarbene generated from an oxadiazoline undergoes a variety of intermolecular reactions." One example is the ring enlargement of strained cyclic ketones, for example, cyclo-butanone. In this reaction, the nucleophilic carbene initiates the ring expansion by... 

The synthetic reactions of nucleophilic carbenes have been reviewed.11 Isonitriles, dimethoxycarbene, and NHCs are covered. The review focuses on the 1,3-dipolar cycloaddition reactions made possible when the nucleophilic carbene reacts with electrophiles such as dimethylacetylene dicarboxylate. Such reactions were also the subject of research papers during 2005 (see the section on nucleophilic and basic carbenes). 

In practice, donor substituents make it possible actually to isolate a range of carbenes 4.105. With somewhat less stabilisation, the carbene 4.106, although it is only found as a reactive intermediate, is exceptionally easy to form. It is the key intermediate in all the metabolic steps catalysed by thiamine coenzymes, and its reactions are characterised by its nucleophilicity. Similarly, dimethoxycarbene 4.107 reacts as a nucleophile with electrophiles like dimethyl maleate to give the intermediate 4.108, and hence the cyclopropane 4.109, but it does not insert into unactivated alkenes. 

Chloro(methoxy)- and chloro(phenoxy)carbenes, which are generated from the diazirine precursors, behave as ambiphiles in additions to alkenes, exhibiting high reactivities toward both electron-poor and electron-rich olefins. Methoxy(phenyl)- and ferrocenyl(methoxy)methylenes have been transferred in a stereospecific manner from transition metal complexes of these species to electron-deficient alkenes. Irradiation of benzocyclobutanedione with UV light induces a rearrangement of the cyclic a-diketone to 17, which has been trapped by alkenes in good yields " . Thermolysis of 18 gives rise to nucleophilic dimethoxycarbene, which has been intercepted by electron-deficient olefins or by styrene derivatives. 

Nucleophilic carbenoids (also called ylides by some authors) react with heterocumulenes, such as isocyanates and isothiocyanates, to yield hy-dantoins, 2-thiohydantoins, and 2,4-dithiohydantoins via dipolar intermediates. Thus dimethoxycarbene adds to aryl isocyanates and isothiocyanates to form 5,5-dimethoxyhydantoins and dithiohydantoins.107 Thiazolium ylides (61) (resulting from thiazolium salts and NEt3 in DMF) give dipolar 1 1 adducts (62) or l 2-cycloadducts (63) with isocyanates or isothiocyanates.108-110 Other substrates are imidazolidine111 or 2-imidazoline derivatives.112... 

Nucleophilic carbenes like dimethoxycarbene do not undergo cycloaddition reactions with simple alkenes, nor do they insert into C—H bonds. Electrophilic carbenes, on the other hand, like the bis(methoxycarbo-nyl)carbene 4.212, with a low-energy LUMO, react with molecules like alkenes that have a high-energy... 

The insertion of a carbene into an alkene is a result of the simultaneous interaction of the HOMO of the alkene with the LUMO of the carbene or the LUMO of the alkene with the HOMO of the carbene. It is the HOMO of a nucleophilic carbene that interacts predominantly with the LUMO of the alkene and, likewise, the LUMO of an electrophilic carbene that interacts predominantly with the HOMO of the alkene. In the case of the highly nucleophilic dimethoxycarbene, the interaction of HOMO of the carbene with the LUMO of the alkene is so very strong that it gives zwitterionic intermediates such as 151, which results in the loss of stereochemistry in going from a c/.v-alkene to a -cyclopropane. With the less nucleophilic carbenes, the geometrical integrity of the alkene is retained in the product. Additionally, nucleophilic carbenes do not insert Oc-h bonds. 

The kinetic isotope effect k /kj) found by Moss et al. (1988) for attack of the significantly nucleophilic dimethoxycarbene on CH30H(D) suggests a substantial OH to carbene proton transfer during this reaction. 

Nucleophilic carbenes, such as dimethoxycarbenes (Section 5.2.1) or N-heterocyclic carbenes (NHCs) (Section 5.2.2), are used as reagents in the synthesis of heterocycles, becoming part of the final molecule. These MCRs involve zwitterionic species generated by the addition of nucleophilic carbenes to multiple bonds and subsequent reactions with electrophilic compounds. 

In this section, MCRs driven by nucleophilicity of dimethoxycarbenes and NHCs where the structure of the final product contains the carbene are analyzed (Scheme 5.2). 

In contrast to the electrophilic nature of most carbenes, highly resonance-stabilized carbenes can be nucleophilic, as suggested by the right-hand resonance structure in the margin. Dimethoxycarbene is a good example of a nucleophilic carbene. Intermediate cases such as methoxychlorocarbene can be ambiphilic, showing increased reactivity to both electron rich and electron deficient olefins. 

---