Ketene-imine addition

Cyclization of halogenoaryl-substituted /3-lactams can be mediated by palladium(n) derivatives. The formation of the lactam from a ketene-imine addition and subsequent cyclization of the product can be carried out as a one-pot process. As an example, in situ generation of the ketene from the acid chloride and formation of the /3-lactam followed by addition of palladium(ll) acetate, triphenylphosphine, and thalium carbonate gave 495 in 54% yield (Equation 79) <1995TL9053>. 

Nelson and co-workers reported cinchona alkaloid-catalyzed [4-1-2] cycloaddition of ketenes and N-thioacyl imine, affording the 4,5-cw-disubstituted l,3-thiazin-6-one derivatives 146 with high enantioselectivities (>95% ee) and diastereoselectivities (>95 5 cis. trans). Scheme 3.47 [63], Ketene, in situ generated from acyl halide 143 and base, followed by addition to imine which was generated in situ via basic elimination of a-amido sulfone 144, providing the ketene-imine addition pathway toward the cycloadducts. 

CBz-protected benzimidazole gave primarily oxazinone [31], while 3/f-indoles incorporated two equivalents of imine (Eq. 4) [32]. In these cases it appears that the initially formed zwitterionic ketene-imine adduct could not close, and reacted with additional photo activated carbene or substrate. 

Addition of ketenes to imines addition of enamines to isocyanates... 

Base-catalyzed addition of glycosyl oxides for anomeric O-activation has been extended meanwhile to trifluoroacetonitrile (see Scheme 9), to dichlor-oacetonitrile, to l-aryl-l,l-dichloroacetonitriles, and to ketene imines (46,51,52). Also 2-(glycosyloxy)-pyridine and -pyrimidine derivatives were readily prepared from the corresponding 2-halo precursors (78). However,... 

In an analogous late-stage arylation approach, terminal alkyne 31 was envisioned as a versatile intermediate. Slow addition of 4-pentynoyl chloride to imine 3 and (n-Bu)3N at reflux (efficient condenser, 100°C, 12 h, 1 1 toluene heptane) afforded only trace amounts of 31. Reaction of 4-pentynoyl chloride with triethylamine in methylene chloride under preformed ketene conditions ( 78°C, 1 h), followed by addition of 3 and warming to — 10°C over 4 h, afforded a complex mixture of products. Since high-yield preparation of 31 remained elusive, access to internal alkynyl analogs (type 33) was accomplished by preassembly of the appropriate arylalkynyl acid substrate for the ketene-imine cycloaddition reaction (Scheme 13.9). 

Addition of ketenes to imines addition of enamines to isocyanates 8-17 Reaction between cyclic ketones and hydrazoic acid (Schmidt)... 

For 5-alkylidenetetrazolines (33) three reaction paths have to be considered. They afford either N-methyl ketene imines and methyl azide, or, in addition to molecular nitrogen, a 3-alkylidenediaziridine (least-motion path) or a methyliminoaziridine (non-least-motion path). As was shown by... 

In conclusion, the CAI activity of spiro-(3-lactams, their antiviral and antibacterial properties, their potential as efficient (3-tum nucleators and (3-tum mimetics, and their application as synthons for a,a-disubstituted (3-amino acids motivated synthetic and medicinal chemists to design novel spirocyclic (3-lactams. Several approaches to the stereoselective synthesis of spiro-(3-lactams have been described in this review. However, ketene-imine cycloaddition (Staudinger Reaction) shows much versatility for the access to diversely functionalized spiro-(3-lactams. In addition, we have developed a facile route to novel spiro-(3-lactams by using... 

Compared with the single-bond construction approach of (3-lactam synthesis, the ketene-imine cycloaddition, which includes carbenoid insertion and the Staudinger reaction, have been widely used [56, 65]. Due to the ready availability of both imines and ketenes, the Staudinger reaction has provided a useful and economical approach for the synthesis of (3-lactams. In addition, the ketene-imine cycloaddition is efficient, which constructs the (3-lactam four-member ring in just one-step... 

Fu has demonstrated that acetate anion attack on the silicon center of the silyl ketene acetal, as well as formation of an acyl pyridinium salt, contribute towards the promotion of these reactions [62]. Additionally, silyl ketene imines have also been shown to participate in analogous asymmetric C-acylation reactions to yield chiral quaternary nitriles, and this method was employed as a key step in the synthesis of verapamil [65]. 

The Bose group s prolific applications of the microwave-assisted ketene-imine annelation process suggest that research laboratories everywhere should be able to justify acquisition of microwave equipment to accelerate research programs via the rapid preparation of a variety of new structures. In a process development setting, the microwave technique should find application in the rapid evaluation and optimization of process parameters, such as solvent, reaction concentration (and neat reactions), temperature, time, pressure, the structure of catalyzing bases/acids, rates of addition, and so on. 

A convenient synthesis of thiazolo-fused 2-pyridones 41 has been developed <07JOC4917>. Thus, A2-thiazolines 39 undergo acyl ketene imine cyclocondensation with Meldrum s acid derivatives 38 to give the dihydro thiazolo-fused 2-pyridones 40, which transform to 41 via bromination-elimination process. Pyridones 41 are converted to the 2-substituted analogs 43 and the saturated products 42 by Heck coupling and conjugate addition, respectively. 

For example, photocyclization61,78 of compound 49, derived from the phenyl complex la by addition of cyclopentadiene, was shown to afford the 1,2-dioxy naphthalene 50 (Scheme 18).79 Thus, the regiochemistry of this type of ring annulation is complementary to that of the Dotz reaction, which yields 1,4-dioxy compounds. Photocyclization of aminocarbene complex 5180 involves insertion of carbon monoxide and leads to production of an 2-amino-l-oxy naphthalene derivative 52. Regio isomers, e.g., l-amino-2-oxy compounds 54, can be generated thermally by intermediate formation of a ketene imine 53 by addition of an isocyanide to compound 49 79,81,82 (Amino)alkynylcarbene complexes also give [4+2] cycloadducts, but they prove to be much less reactive than the corresponding alkoxycar-bene compounds (Scheme 18).42,83... 

For a review of reactions of ketene imines, generated from carbene complexes by addition of isocyanides, see Ref. 3q and Aumann, R. In Organometallics in Organic Synthesis Aspects of a Modern Interdisciplinary Field de Meijere, A. tom Dieck, H., Eds. Springer-Verlag Berlin, Heidelberg, 1987, pp. 69-83. 

Azirines can be transformed to imino esters (259) and (260) (Scheme 37) by addition of alcohols or alkoxy carbenes respectively. By sodium methoxide catalyzed addition of methanol to the ketene imine (261 Scheme 38) the imino ester (262) is obtainable. Keteneimines undergo photoinduced addi-... 

The Mannich reaction has been reviewed comprehensively by Blicke (1942), Reichert (1959), Hell-mann and Opitz (1960), and Tramontini (1973). These reviews also include synthetic applications of Mannich bases. Mechanistic studies of the Mannich reaction have been reviewed by Thompson (1968). Some variants of the Mannich reaction have been covered as subtopics in other reviews for example. Layer (1963) and Harada (1970) have reviewed general additions of stabilized carbanions to imines, while Bdhme and Haake (1976) have reviewed similar additions to methyleneiminium salts. In more specific reviews, Pai and coworkers (1984) have summarized stabilized carbanion additions to 3,4-dihy-droisoquinolines and 3,4-dihydroisoquinolinium salts in connection with the total synthesis of protober-berines and phthalide isoquinolines, and Evans et al. (1982) " have analyzed the stereochemical aspects of ester enolate and silyl ketene acetal additions to imines. 

Guanti and coworkers have reported that catalytic amounts (0.1 equiv.) of TMS-OTf can be used in place of stoichiometric amounts of TiCU in silyl ketene acetal-imine additions.When conducted at the optimal temperature of -65 C, 3-amino esters enriched in the anti diastereomer are obtained in 45-85% yields. Use so far has been limited to nonenolizable imines. Interestingly, the observed anti stereoselectivity is independent of the geometry of the silyl ketene acetal, further evidence that a nonpericyclic mechanism is involved in the Lewis acid catalyzed addition of silyl ketene acetals to imines. An applies-... 

Das N-phosphorylierte Keten-imin laBt sich nicht isolieren, da es unter den Reduktionsbedingungen mit nu-cleophilen Reagenzien (Wasser, Alkohole. Amine, Carbanionen) unter Abspaltungdcs Phosphors und Addition des Nucleophilen zum Carbonsaure-Derivat weiterreagiert. 

This investigation opened the way to further two-step cycloadditions of the thiocarbonyl ylide 6.23 with other electrophilic alkenes, e.g., with l,2-dicyano-l,2-bis(trifluoromethyl)ethene (Huisgen et al., 1989). Both the latter dipolarophile and tetracyanoethene demonstrated that, besides the 1,3-dipolar addition product 6.28, the cyclic ketene imine 6.29 is formed in a reversible 1,7-ring closure (6-18, Huisgen et al., 1986b, 1989). 

The mechanism of the Staudinger ketene imine cycloaddition reaction has been the subject of much debate and has recently been reviewed. The mechanism has been studied both computationally and experimentally. Experimental evidence gathered on solution phase reactions supports a two-step mechanism, in which addition of the imine nitrogen to the ketene carbonyl group occurs to generate an intermediate zwitterion. Subsequent cyclization of the zwitterion results in formation of the key C3-C4 a-bond. 

Ketene-imine cy do addition forming p-lactams was one of the first and perhaps the most important reaction of ketenes to be discovered, and with the finding of the medicinal utility of penicillin has assumed a major role in ketene studies, which has continued for more than 70 years. The importance of these reactions contributed to the theoretical understanding of cycloaddition reactions, and thus these have played a significant role in the development and continued growth of physical organic chemistry. 

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