N-H bonds, insertion

Carbon-heteroatom bond-forming reactions 4.4.1 Cu-catalyzed N—H bond insertion reactions... 

The strained bicyclic carbapenem framework of thienamycin is the host of three contiguous stereocenters and several heteroatoms (Scheme 1). Removal of the cysteamine side chain affixed to C-2 furnishes /J-keto ester 2 as a possible precursor. The intermolecular attack upon the keto function in 2 by a suitable thiol nucleophile could result in the formation of the natural product after dehydration of the initial tetrahedral adduct. In a most interesting and productive retrosynthetic maneuver, intermediate 2 could be traced in one step to a-diazo keto ester 4. It is important to recognize that diazo compounds, such as 4, are viable precursors to electron-deficient carbenes. In the synthetic direction, transition metal catalyzed decomposition of diazo keto ester 4 could conceivably furnish electron-deficient carbene 3 the intermediacy of 3 is expected to be brief, for it should readily insert into the proximal N-H bond to... 

The diazo function in compound 4 can be regarded as a latent carbene. Transition metal catalyzed decomposition of a diazo keto ester, such as 4, could conceivably lead to the formation of an electron-deficient carbene (see intermediate 3) which could then insert into the proximal N-H bond. If successful, this attractive transition metal induced ring closure would accomplish the formation of the targeted carbapenem bicyclic nucleus. Support for this idea came from a model study12 in which the Merck group found that rhodi-um(n) acetate is particularly well suited as a catalyst for the carbe-noid-mediated cyclization of a diazo azetidinone closely related to 4. Indeed, when a solution of intermediate 4 in either benzene or toluene is heated to 80 °C in the presence of a catalytic amount of rhodium(n) acetate (substrate catalyst, ca. 1000 1), the processes... 

Intermediate 37 can be transformed into ( )-thienamycin [( )-1)] through a sequence of reactions nearly identical to that presented in Scheme 3 (see 22— 1). Thus, exposure of /(-keto ester 37 to tosyl azide and triethylamine results in the facile formation of pure, crystalline diazo keto ester 4 in 65 % yield from 36 (see Scheme 5). Rhodium(n) acetate catalyzed decomposition of 4, followed by intramolecular insertion of the resultant carbene 3 into the proximal N-H bond, affords [3.2.0] bicyclic keto ester 2. Without purification, 2 is converted into enol phosphate 42 and thence into vinyl sulfide 23 (76% yield from 4).18 Finally, catalytic hydrogenation of 23 proceeds smoothly (90%) to afford ( )-thienamycin... 

Insertion of a carbene unit into the N—H bond of primary or secondary amines by copper salt catalyzed decomposition of diazo compounds has been known for a number of years14). The copper chelate promoted reaction of diazodiphenyl-methane 291) or 2-diazo-1,2-diphenyl-1-ethanone 292) with primary benzylamines or... 

Formal insertion reactions into the N—H bond of imidazoles (Sect. 4.2) and imines (Sect. 5.1) have already been discussed. 

Rh2(OAc)4 has become the catalyst of choice for insertion of carbene moieties into the N—H bond of (3-lactams. Two cases of intermolecular reaction have been reported. The carbene unit derived from alkyl aryldiazoacetates 322 seems to be inserted only into the ring N—H bond of 323 246). Similarly, N-malonyl- 3-lactams 327 are available from diazomalonic esters 325 and (3-lactams 326 297). If, however, the acetate function in 326 is replaced by an alkylthio or arylthio group, C/S insertion rather than N/H insertion takes place (see Sect. 7.2). Reaction of ethyl diazoacetoacetate 57b with 328 also yields an N/H insertion product (329) 298>, rather than ethyl l-aza-4-oxa-3-methyl-7-oxabicyclo[3.2.0]hex-2-ene-2-earboxylate, as had been claimed before 299). 

Table 21. Rh2(OAc)4-catalyzed intramolecular carbenoid insertion into the N—H bond of JJ-lactams.

Figure 5.30 PNP-DTP can modify amine-containing molecules through its p-nitrophenyl ester group to form amide bonds. Exposure of its photosensitive diazo group with UV light generates a highly reactive carbene that can insert into active C—H or N—H bonds.

Figure 5.33 Benzophenone-4-iodoacetamide reacts with sulfhydryl-containing compounds to give thioether linkages. Subsequent photoactivation of the benzophenone residue gives a highly reactive triplet-state ketone intermediate. The energized electron can insert in active C—H or N—H bonds to give covalent crosslinks.

Figure 5.34 Benzophenone-4-maleimide can couple to thiol-containing molecules to form stable thioether bonds. Exposure of the benzophenone group to UV light causes transition to a triplet-state ketone of high reactivity for insertion into C—H or N—H bonds.

Regioselective N-difluoromethylation of 3-phenyl 1,2,4-triazole 39 has been achieved using chlorodifluoromethane in the presence of a base. The reaction yielded a mixture of the three possible products 40-42 and proceeds by the insertion of a difluorocarbene into an N-H bond (Equation 10) <1998JFC(92)141>. 

FIGURE 23.3 (See color insert following page 302. ) Profiles of (a) energy and FF for nucleophilic attack and (b) electrophilic attack for distortion in the H-N-H bond angle of ammonia. 

Electrophilic carbene complexes can react with amines, alcohols or thiols to yield the products of a formal X-H bond insertion (X N, O, S). Unlike the insertion of carbene complexes into aliphatic C-H bonds, insertion into X-H bonds can proceed via intermediate formation of ylides (Figure 4.7). 

Among the CH oxidations, a most impressive case, for example, concerns the quantitative TFD oxidation of cyclohexane to cyclohexanone at —22° C in only 18 min (equation 26) There exists no other chemical oxidant, even metal-catalyzed systems, that may compete with this astounding oxidative reactivity of TFD. Whether the oxidation of an amine to a hydroxylamine involves the direct insertion of an oxygen atom into the N—H bond is mechanistically still uncertain, since alternatively (more probably the case on... 

The lifetime of 56 in hydrocarbon solvents at 25 °C is only several nanoseconds, so that its intermolecular chemistry should be difficult to observe. Indeed, intermol-ecular C H insertion reactions of 56 are inefficient, although the carbene can be captured (competitively with 1,2-H shift) by insertions into O H or N H bonds or by addition to isobutene. ... 

One of the key steps in building the fused ring involves the reaction of the activated acetoacetate methylene group in that compound with toluenesulfonyl azide to give the diazo intemediate (12-1). Treatment of that product with rhodium acetate leads to a loss of nitrogen with the consequent formation of carbene (12-2) this inserts into the adjacent amide N—H bond to form a five-membered ring and thus the carbapenem (12-3) [15]. The first step in the incorporation of the thioenol function consists in the conversion of the ketone to the enol phosphate derivative... 

NH3 to the iridium centre could have occurred by interaction with an Ir—H moiety derived from insertion of Ir(I) into a CH bond of the Bu groups or the methanide centre of the pincer ligand was eliminated by labelling studies All the available experimental data point to the simple insertion of the lr(l) centre into an N—H bond of ammonia. 

Alkylation of P-lactams." Alkylation of the base- and acid-sensitive /5-lactam 1 can be effected efficiently hy carbenoid insertion into the N H bond using... 

The presence of other hexane isomers and a typical hexane isomer distribution of 26% 2,3-dimethylbutane, 28% 2-methylpentane, 14% 3-methylpentane, 32% n-hexane, far from equilibrium, indicate that the 1-propyl cation (although significantly delocalized with protonated cyclopropane nature) is also involved in alkylation. It yields n-hexane and 2-methylpentane through primary or secondary C—H bond insertion, respectively (Scheme 5.3). 

Phenyl azides (azidoarenes), introduced by Knowles and co-workers,[8 9] are the most abundantly used class of photophores. Examples include 4-azidophenylalanine (1) and 4-azido-3-nitrophenylalanine (4) (Scheme 1). Irradiation (<300 nm) of phenyl azide (13) generates nitrene 14, electrophilic in nature, which prefers insertion into O—H and N—H bonds over C—H bonds. Nitrenes are considerably less reactive and, therefore, more selective than carbenes. Nevertheless, due to their short life span (0.1-1 ms) they react indiscriminately with virtually any amino add residue in the target protein.1101 Intramolecular rearrangements do not compete effectively with intermolecular proton abstraction and insertion reactions (Scheme 4). 

Peptide-Based Oxazoles by Rhodium-Mediated Carbenoid Insertion of Diazocarbonyl Compounds into an Amide N-H Bond Followed by... 

Insertions into O—H bonds, N—H bonds and C—H bonds adjacent to oxygen and nitrogen have found use in the synthesis of a number of heterocycles (see Section 4.7.3.9).187-189 The reaction of alcohol (25) with methyllithium in ether, leading to the ketone (26), has been interpreted190 as involving the insertion of an intermediate carbenoid into a P-C—H bond followed by ring opening (equation 64). 

Carbene generation from photolysis of diazirine compounds leads to efficient insertion into C—H or N—H bonds and also causes addition reactions with points of unsaturation within target molecules. Diazirine-containing photoaffinity probes have... 

The corresponding ESR signal has also been assigned to the nitroxide derivative of phenothiazine (10) which is thought to be generated by insertion of singlet oxygen (IO2) (Equation 4) into the N-H- bond (Equation 5) and subsequent homolysis of the hydroperoxide (Equation 6). 

Scheme 7.8 Fe-corrole-catalyzed insertion of diazo compounds into N —H bonds.

---