Insertion cyclization

In 1980, a Merck group disclosed the results of a model study which amply demonstrated the efficiency with which the strained bicyclic ring system of thienamycin can be constructed by the carbene insertion cyclization strategy.12 Armed with this important precedent, Merck s process division developed and reported, in the same year, an alternative route to carbene precursor 4.13 Although this alternative approach suffers from the fact that it provides key intermediate 4, and ultimately thienamycin, in racemic form, it is very practical and is amenable to commercial scale production. The details of this interesting route are presented in Schemes 4-6. 

The anti addition of amines to the double bond of cationic (alkene)(cyclopentadienyl)di-carbonyliron complexes and to the analogous molybdenum and tungsten complexes has been reported31 33. The adducts underwent carbonyl insertion-cyclization to give chelate complexes, which were then oxidized to /8-lactams. For example, from the Fp complexes of ( )- and (Z)-2-butene the corresponding /8-lactams were obtained diastereoselectively in 10-15% yield by the direct oxidation of the benzylamine adducts with chlorine at low temperature33. The stereochemistry was determined by H-NMR spectroscopy. 

If a group, such as (C(0)0CH2CH2CH2CH=CH2), was used, the olefin was conforma-tionally constrained to bind perpendicular to the Pd—C bond and insertion-cyclization did not occur. Alkene insertion reactions into metal-acyl bonds usually occur more rapidly than insertions into metal-alkyl bonds. 

Intramolecular insertion-cyclization has been examined systematically ... 

The key to clarifying the catalytic cycle is to determine whether or not hydride-palladium (H-Pd) is the active species. Taking advantage of hydride exchange between D2O and H-Pd to generate D-Pd species [69,70], the reactions under excess D2O (600 mol%) conditions were examined (Scheme 16). Consequently, the deuterated product at the vinylic position was obtained without diminution of catalytic activity under either polar or less polar conditions. These results indicate that the hydride(deuteride)-palladium is the active species. The possible catalytic cycle would be completed as shown in Scheme 17 the initially formed D-Pd coordinates to acetylene (B ), followed by D-Pd addition (H), insertion (cyclization) (E), and P-H elimination to give the product (9) and regenerate the H-Pd species. 

The conversion of l,3-hexadien-5-yne to benzene can occur by another mechanism, namely, an acetylene to vinylidene rearrangement followed by insertion - cyclization into a vinyl C-H bond (Scheme 7.23). 

The syntheses of palladium 7 -allylic complexes from these substrates usually involve the sequential insertion of several of the same or different unsaturated molecules into Pd-R bonds in an often mechanistically complicated process. Some examples have been reported recently. The insertion of two alkyne molecules and subsequent intramolecular insertion (cyclization) leads to a spirocyclic derivative coordinated to Pd in an 77 -allylic form Disubstituted alkynes... 

Transition metal-catalysed methods for carbenoid insertion into C-H bonds remain well documented. The asymmetric intramolecular Cu(II)-catalysed C-H insertion reactions of (i) a-diazo-/ -keto esters and phosphonates and (ii) a-diazo sulfones have been described. One can note that the optimal reaction conditions have been found to be quite similar regardless of the nature of the carbenoid precursor the best conditions featured CUCI2 as Cu(II)-source, bis(oxazoline) (68) as chiral ligand and sodium tetrakis[3,5-bis(trifluoromethyl)phenyl] borate (i.e., NaBARF) as additive. Under the so-optimized reaction conditions, each of these carbenoid sources have been eonverted into five-membered cyclopentanone-based derivatives (69), whereas a-sulfonyl diazo esters (70) have led to six-membered cyclic compounds (71), thus featuring a distinct but well-known selectivity. In a related work, the asymmetric C-H insertion cyclization of (70) to (71) has also been achieved under Rh(II)-catalysis, using a combination of Rh2(5-pttl)4 (72) as chiral catalyst and menthyl ester as chiral auxiliary. As already mentioned in the previous section, allene-containing substrates (49) have been shown to undergo an intramolecular C-H insertion process under Rh(II)-catalysis. ... 

Double Carbon Monoxide Insertions. Cyclization forming a four-membered ring was likely to be slower than carbonylation under 1 atm. A series of substrates was designed to take advantage of this rate differential and permit incorporation of two carbon monoxide molecules into the product (eq 88). In the above case (eq 88), the first CO insertion occurs faster than slow 4- aco-trig carbopalladation allowing a facile 5-exo-trig acylpalladation. The... 

Scheme 22 Pd-catalyzed domino insertion/cyclization sequence for 8-fluoroisoquinoline synthesis...

Diazocarbonyl compounds are often the only starting materials for transformations into products that could not be achieved by other means. Sengupta et al reported that InCl3 is a mild catalyst for SH insertions, cyclization and addition to aldehydes and ketones [293] (Figure 8.135). Muthusamy et al reported that ln(OTf)3 (10mol%) catalyzes the OF insertion to give good to excellent yields of a-alkoxy ketones at room temperature in mostly less than 10 minutes [294]. Yadav... 

An intramolecular diazocarbonyl insertion procedure that generated cyclic urethanes was reported by Avery et al. to be best catalyzed by In(OTf)3 [296]. The diazocarbonyl compound is generated in situ with resin supported morpholine and diazomethane, with the In(III) influencing the final insertion-cyclization of the intermediate (Figure 8.136). 

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