Aminocarbene

Based on these assumptions many different heteroatom-substituted carbenes have been synthesized. They are not limited to unsaturated cyclic di-aminocarbenes (imidazolin-2-ylidenes Scheme 3, A) [17-22] with stericbulk to avoid dimerization like 1 l,2,4-triazolin-5-ylidenes (Scheme 3, B), saturated... 

Alkylideneaminocarbene complexes 76, which are aza analogs of alkenyl-carbene complexes, upon reaction with alkynes primarily give formal [3+2] cycloadducts analogous to the 1-aminocarbene complexes (Scheme 16) [74,75]. Aumann et al. proposed that this should be considered as a formal 1,3-dipo-... 

Non-heteroatom-stabilised Fischer carbene complexes also react with alkenes to give mixtures of olefin metathesis products and cyclopropane derivatives which are frequently the minor reaction products [19]. Furthermore, non-heteroatom-stabilised vinylcarbene complexes, generated in situ by reaction of an alkoxy- or aminocarbene complex with an alkyne, are able to react with different types of alkenes in an intramolecular or intermolecular process to produce bicyclic compounds containing a cyclopropane ring [20]. 

The insertion reaction between alkenylcarbene complexes and electron-rich alkynes such as 1-alkynylamines (ynamines) leads to mixtures of two regioi-someric cyclopentyl derivatives [78]. Thus, if the insertion occurs on the carbon-metal bond a new aminocarbene complex is produced which evolves to a cyclopentenylmetal derivative. On the other hand, if the insertion reaction occurs on the carbon=carbon double bond of the alkenyl complex, the reaction gives a l-metala-4-amino-l,3,5-triene complex which finally generates a different regioisomer of the cyclopentenylmetal derivative (Scheme 31). 

The superior donor properties of amino groups over alkoxy substituents causes a higher electron density at the metal centre resulting in an increased M-CO bond strength in aminocarbene complexes. Therefore, the primary decarbo-nylation step requires harsher conditions moreover, the CO insertion generating the ketene intermediate cannot compete successfully with a direct electro-cyclisation of the alkyne insertion product, as shown in Scheme 9 for the formation of indenes. Due to that experience amino(aryl)carbene complexes are prone to undergo cyclopentannulation. If, however, the donor capacity of the aminocarbene ligand is reduced by N-acylation, benzannulation becomes feasible [22]. 

Wulff et al. examined the necessary reaction conditions for a,fi-unsaturated aminocarbene complexes to react in a benzannulation reaction [23]. The reaction of dimethylamino(alkenyl)carbene complexes 18 with terminal alkynes in non-coordinating and non-polar solvents afforded phenol products in acceptable yields (Scheme 12). 

Merlic et al. were the first to predict that exposing a dienylcarbene complex 126 to photolysis would lead to an ort/zo-substituted phenolic product 129 [74a]. This photochemical benzannulation reaction, which provides products complementary to the classical para-substituted phenol as benzannulation product, can be applied to (alkoxy- and aminocarbene)pentacarbonyl complexes [74]. A mechanism proposed for this photochemical reaction is shown in Scheme 54. Photo activation promotes CO insertion resulting in the chromium ketene in-... 

Chromium aminocarbenes [39] are readily available from the reaction of K2Cr(CO)5 with iminium chlorides [40] or amides and trimethylsilyl chloride [41]. Those from formamides (H on carbene carbon) readily underwent photoreaction with a variety of imines to produce /J-lactams, while those having R-groups (e.g.,Me) on the carbene carbon produced little or no /J-lactam products [13]. The dibenzylaminocarbene complex underwent reaction with high diastereoselectivity (Table 4). As previously observed, cyclic, optically active imines produced /J-lactams with high enantioselectivity, while acyclic, optically active imines induced little asymmetry. An intramolecular version produced an unusual anti-Bredt lactam rather than the expected /J-lactam (Eq. 8) [44]. 

With optically active formamide-derived aminocarbene complexes high enantioselectivity was observed in most cases (Table 5). This chemistry was used in the synthesis of 1-carbacephalathin and 3-ANA precursors (Eq. 9) [48], as well as the synthesis of a,a -disubstituted amino acids (Scheme 1) [49]. 

Table 4 Reaction of chromium aminocarbenes with imines ...

In contrast to alkoxycarbene complexes, most aminocarbene complexes appear too electron-rich to undergo photodriven reaction with olefins. By replacing aliphatic amino groups with the substantially less basic aryl amino groups, modest yields of cyclobutanones were achieved (Table 10) [63], (Table 11) [64]. Both reacted with dihydropyran to give modest yields of cyclobutanone. Thio-carbene complexes appeared to enjoy reactivity similar to that of alkoxycar-benes (Eq. 15) [59]. 

Photodriven reactions of Fischer carbenes with alcohols produces esters, the expected product from nucleophilic addition to ketenes. Hydroxycarbene complexes, generated in situ by protonation of the corresponding ate complex, produced a-hydroxyesters in modest yield (Table 15) [103]. Ketals,presumably formed by thermal decomposition of the carbenes, were major by-products. The discovery that amides were readily converted to aminocarbene complexes [104] resulted in an efficient approach to a-amino acids by photodriven reaction of these aminocarbenes with alcohols (Table 16) [105,106]. a-Alkylation of the (methyl)(dibenzylamino)carbene complex followed by photolysis produced a range of racemic alanine derivatives (Eq. 26). With chiral oxazolidine carbene complexes optically active amino acid derivatives were available (Eq. 27). Since both enantiomers of the optically active chromium aminocarbene are equally available, both the natural S and unnatural R amino acid derivatives are equally... 

Table 16 Photo-driven reactions of aminocarbenes to produce a amino acids...

Activated esters for use in peptide-coupling reactions were produced by photolysis of optically active chromium aminocarbenes with alcohols which are good leaving groups, such as phenol, pentafluorophenol, 2,4,5-trichlorophenol, and N-hydroxysuccinimide (Table 17) [ 109]. Since arylcarbenes bearing the op-... 

Table 20 Synthesis of dipeptides from aminocarbenes and a-aminoesters...

For reviews on chromium aminocarbenes see Schwindt MA, Miller JR, Hegedus LS (1991) J Organometal Chem 413 143 Grotjahn DB, Dotz KH (1991) Synlett 381... 

Other reactions leading to azetidines include the dialkylation of chromium or tungsten complexes of aminocarbenes with 1,3-diiodopropane under phase-transfer conditions <96CL827> and the regio- and stereo-specific reaction of dimethylsulfoniumethoxy-carbonylmethylide with 2-substituted or 2,3-disubstituted N-arylsulfonylaziridines to afford S (R 7 H, = H) or 5 (R and R H) respectively, generally in useful yields <95JCS(P1)2605>. 

The second Had synthesis provided a route to 2,3,4-trisubstituted pyrroles <06CC2271>. Mixing cinnamaldehyde 27 with aminocarbene complex 28 in the presence of molecular sieves (MS) gave pyrrole 29. The authors proposed a mechanism that included a cyclopropane intermediate and subsequent fragmentation and intramolecular condensation. 

Generally phenol formation is the major reaction path however, relatively minor modifications to the structure of the carbene complex, the alkyne, or the reaction conditions can dramatically alter the outcome of the reaction [7]. Depending on reaction conditions and starting reactants roughly a dozen different products have been so far isolated, in addition to phenol derivatives [7-12], In particular, there is an important difference between the products of alkyne insertion into amino or alkoxycarbene complexes. The electron richer aminocarbene complexes give indanones 8 as the major product due to failure to incorporate a carbon monoxide ligand from the metal, while the latter tend to favor phenol products 7 (see Figure 2). 

Fig. 2.6. Preparation of aminocarbene complexes from isonitrile complexes (Z electron withdrawing group X=Y dipolarophile).

Multicomponent condensations have also been described in these an isonitrile, a carbonyl compound and a suitable transition metal complex are combined in one step to afford heterocycloalkylidene complexes. Examples of the use of isolated or intermediate isonitrile complexes for the preparation of aminocarbene complexes are given in Table 2.4. 

Fig. 2.7. Conversion of a-haloiminium salts into aminocarbene complexes [120].

Fig, 2.8. Generation of aminocarbene complexes from metallates and carboxamides. 

Depending on the types of substituents and the precise reaction conditions (l,3-butadien-l-yl)carbene complexes can undergo direct cyclization to yield cyclo-pentadienes [337,350]. As mentioned in Section 2.2.5.1, cyclopentadiene formation occurs particularly easily with aminocarbene complexes [351]. Alternatively, in particular at higher reaction temperatures, CO-insertion can lead to the formation of a vinylketene complex, which, again depending on the electronic properties of the substituents and the reaction conditions, can cyclize to yield cyclobutenones, furans [91,352], cyclopentenones, furanones [91], or phenols (Dotz benzannulation) [207,251,353]. 

In the a-donating (zwitterionic) resonance form of the latter heteroatom-cumu-lated free ligands, all the atoms satisfy the octet rule. Two kinds of all-carbon versions can be distinguished those that are 71-conjugated to a remote heteroatom and those that are not [14—19]. The former are largely exemplified by aminoalle-nylidenes, in which the a-donating resonance form of the free ligand is also stabilized by the octet rule (they are functional carbo-m cs of the Fischer-type aminocarbenes). The second kind is represented by C-substituted allenylidenes. 

Recent research on aminocarbenes has led to the development of a very fruitful field. The synthesis of relevant complexes (Scheme 19) such as aminobis(yhde) carbene species (69) [147], cyclic C-amino P-ylides (70) (easily transformed into carbenes) [148] and their corresponding complexes (71) [149], and special ylides (72), which also transform very easily into carbenes by loss of pyridinium group, has been reported. Emphasis has been made on the transformation between ylides and carbenes and on the donor properties of the ylides. From the results obtained the ylides have shown a stronger a-donor behavior compared with the carbenes. 

Other substituent, which does not participate in the stabilization, can be considered as a spectator substituent (Scheme 3) [34]. This stabilization system is particularly efficient with an amino group which is not only a 71-donating substituent but also a a-electron withdrawing group. This stabilization mode provides a large choice of substituents allowing an easy functionalization of the corresponding stable mono-aminocarbenes. In fact, several types of acyclic and cyclic amino carbenes have been already synthesized [8, 9]. 

The cyclic version of alkylaminocarbenes, the cyclic alkyl aminocarbenes 10c (CAACs), have also been reported [36]. The rigid cyclic structure with very bulky substituents at the nitrogen atom increases the S/T energy gap (45.1 kcal/mol) [37]. Due to this electronic effect as well as to the more resistant substituent pattern, CAACs are much more resistant than the acyclic ones. 

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