N-H Insertions

TABLE 8.6. C-H Insertion into Cyclic Substrates of Diazoacetates Catalyzed by AgTp Complex 22 

Entry Substrate Products Yield (%) Products Yield (%) Products Yield (%) 

TABLE 8.7. C-H Insertions into Acyclic Alkanes Catalyzed by AgTp Complexes 22, 33, and 108 

Catalyst Substrate Primary Site (%) Secondary Site (%) Tertiary Site (%) 

These values have been normalized to account for C-H insertion products only. 

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To date most of the nitriles studied have been simple alkyl or aromatic derivatives with little other functionality. We recently attempted to extend the reaction to iV-protected a-aminonitriles, derived by dehydration of a-aminoacid amides (Path A, Scheme 25), but this proved unsatisfactory, and therefore we investigated an alternative diazocarbonyl based route in which the order of steps was reversed, i.e. a rhodium catalysed N-H insertion reaction on the amide followed by cyclodehydration to the oxazole (Path B, Scheme 25). 

Carbenoid N-H insertion of amines with diazoacetates provides a useful means for the synthesis of ot-amino esters. Fe(III) porphyrins [64] and Fe(III/IV) corroles [65] are efficient catalysts for N-H carbenoid insertion of various aromatic and aliphatic amines using EDA as a carbene source (Scheme 16). The insertion reactions occur at room temperature and can be completed in short reaction times and with high product yields. It is performed in a one-pot fashion without the need for slow... 

Whereas pyrrole was reported not to give N/H insertion by ketocarbenoids, such a reaction mode does occur with imidazole Copper-catalyzed decomposition of ethyl diazoacetate at 80 °C in the presence of imidazole gives ethyl imidazol- 1-ylacetate exclusively (93 %) small amounts of a C-alkylated imidazole were obtained additionally under purely thermal conditions 244). N/H insertion also takes place at benzimidazole 245 a). The reaction is thought to begin with formation of an N3-ylide, followed by N1 - C proton transfer leading to the formal N/H insertion product. Diazomalonic raters behave analogously however, they suffer complete or partial dealkoxycarbonylation under the reaction conditions 244) (Scheme 34). N-alkylation of imidazole and benzimidazole by the carbenoids derived from co-diazoacetophenone and 2-(diazoacetyl)naphthalene has also been reported 245 b>. 

The outcome of the copper-catalyzed decomposition of a diazo compound in the presence of a 1,1-diarylmethanimine depends on the nature of the diazo compound. With diazodiphenylmethane, the N/H insertion product 281 and the isomeric imine... 

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). 

For intramolecular N/H insertion involving a (3-lactam, Rh2(OAc)4 was found to be superior to other catalysts and to the photochemical route 300). Therefore, this procedure has been appraised to be the most efficient one for constructing a bicyclic P-lactam and, consequently, has become a standard method for synthesizing... 

Failure to obtain the desired azacarbacephem 331 had to be accepted with the diazetidinone 330. Instead of the hoped-for N/H insertion, the ketocarbenoid derived from 330 attacked the more nucleophilic N-l atom to give an intermediate ammonium ylide which then went on to the products 332 and 334 as suggested... 

Contrary to P-lactams, N/H insertion is only a minor process in the copper-catalyzed reaction between 2-pyrrolidinone and methyl diazoacetate. With pyrro-lidine-2-thione, this process does not take place at all. For 2-piperidinone, N/H insertion seems to be easier, but once again, the corresponding thione fails to produce such an insertion product (Scheme 35) 322),... 

Two type la syntheses of (3-hydroxypyrroles have appeared. An aza-Nazarov cyclization of l-azapenta-l,4-dien-3-ones produced (3-hydroxypyrroles including 2,2 -bipyrroles <06EJO5339>. A second approach to a (3-hydroxypyrrole involved an intramolecular N-H insertion into a rhodium carbene derived from the decomposition of a diazoketone <06JOC5560>. On the other hand, the photochemical decomposition of the diazoketone led to pyrrolidin-2-ones. 

Ylides other than acceptor-substituted diazomethanes have only occasionally been used as carbene-complex precursors. lodonium ylides (PhI=CZ Z ) [1017,1050-1056], sulfonium ylides [673], sulfoxonium ylides [1057] and thiophenium ylides [1058,1059] react with electrophilic transition metal complexes to yield intermediates capable of undergoing C-H or N-H insertions and olefin cyclopropanations. 

The first reports of N-H insertion reactions of electrophilic carbene complexes date back to 1952 [497], when it was found that aniline can be N-alkylated by diazoacetophenone upon treatment of both reactants with copper. A further early report is the attempt of Nicoud and Kagan [1178] to prepare enantiomerically pure a-amino acids by copper(I) cyanide-catalyzed decomposition of a-diazoesters in the presence of chiral benzylamines. Low enantiomeric excesses (< 26% ee) were obtained, however. 

Because of partial deactivation of many catalysts by aliphatic amines, less nucleophilic derivatives such as carboxamides or carbamates are usually used as substrates for carbene N-H insertion. 

The usefulness of this reaction for the preparation of heterocycles under mild conditions became apparent in 1978, when chemists from Merck, Sharp Dohme reported the synthesis of bicyclic 3-lactams by intramolecular carbene N-H insertion [1179]. Intramolecular N-alkylation of P-lactams by carbene complexes is one of the best methods for preparation of this important class of antibiotic and many P-lactam derivatives have been prepared using this methodology [1180 -1186] (Table 4.11). Intramolecular N-H insertion can also be used to alkylate amines [1187-1189], y-lactams [1190], and carbamates [1191-1193] (Table 4.11). 

Intermolecular N-H insertion of electrophilic carbene complexes has occasionally been used for the preparation of amino acid derivatives and other types of intermediates (Table 4.12) [956,1043,1194-1201]. 

Table 4.11. Preparation of nitrogen-containing heterocycles by intramolecular N-H insertion of electrophilic carbene complexes.

Table 4.12. Intermolecular N-H insertions of electrophilic carbene complexes.

There are several reports in the literature dealing with the bimolecular [3 + 2] cycloaddition reactions of alkynyl-substituted diazo compounds. Propargyl diazoacetate 212, when stored for 2 weeks at 0 °C, was transformed into an oligomer to which the constitution 213 was assigned (273) (Scheme 8.50). The alkynyl-diazoketone 214 requires a much higher temperature and is transformed into pyrazole 215, which probably arises from intermolecular cycloaddition, pyrazole tautomerization, and carbenic N/H insertion (274). The inter-intramolecular... 

In addition, a proline- or phenylalanine-based Rh(II) can catalyze intramolecular asymmetric carbene reactions such as aromatic ring expansion and C—H insertion with moderate selectivity (Scheme 95) (229). Rh(II) carboxamides are also effective catalysts for asymmetric C—H or N—H insertion (228c). 

Scheme 11 Synthesis of a Peptide-Based Oxazole via Rhodium-Catalyzed N—H Insertion of an a-Diazo- 3-oxo Ester into /V -(Benzyloxycarbonyl)alaninamide Followed by Cyclodehydrationt )...

Aviv and Gross developed an interesting insertion reaction of diazo compounds into a secondary amine-hydrogen bond in the presence of Fe-corrole complexes (Scheme 7.8) [12], Competition experiments performed in the presence of an amine and an alkene revealed the N—H-insertion reaction to be much faster than the cyclopropanation of the C=C bond. Apart from this chemoselectivity issue, the reactions are characterized by their very short reaction times most insertion reactions were completed within 1 min at room temperature. Most recently, Woo s group reported on a similar process using commercially available iron tetraphenyl-porphyrin [Fe(TPP)] dichloride [13]. 

Dihydropyrazines (62) have been accessed via double Rh(II)-catalysed N-H insertion of 2-diazocycloalkanedione (63) on anilines (64).51 Low yields are obtained as a consequence of inefficient double N-H insertion. 

Intramolecular C-H insertion reactions, N-H insertion reactions, and intermolecular C-H insertion reactions of aminocyanocarbenes (NCC NX2, X = H, CH3, CF3) have been studied using restricted and unrestricted CCD, CCSD, QCISD, B3LYP, and MP2 methods with the 6-31G(d), 6-311+G(d,p), cc-pVDZ, and cc-pVTZ basis sets. 66 HC NH2, NCC NH2, NCC N(CH3)2, and NCC N(CF3)2 have singlet ground states. 

Dirhodium(II)-catalysed reaction of a 3-indolyl a-diazo-/5-keto ester in the presence of hexanamide results in competing metal carbene N-H insertion and Wolff rearrangement (Scheme 85).128... 

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