Cyclization 1,3-dipolar

Diazo, carbenoid, cyclization, dipolar-cycloaddition, carbonyl ylide, rhodium, tandem... 

Coldham, A. J. M. Burrell, H. D. S. Guerrand, N. Oram, Cascade cyclization, dipolar cycloaddition to bridged tricyclic amines related to the Daphniphyllum alkaloids, Org. Lett. 13 (2011) 1267-1269. 

Reaction of thiazoles with DMAD illustrates the overall reaction and the rearrangements which may be encountered. Thiazole or 2-methylthiazole (411 R=H and Me, respectively) in DMF reacted with DMAD to give an initial 1,4-dipolar species (412). Reaction with a second DMAD gave the 1 2 molar adduct, presumably (413). Ring opening to (414), followed by cyclization in the alternative mode, resulted in the formation of (415), the structure of which (R = Me) was established by X-ray analysis (78AHC(23)263) (see also Chapter 4.19). 

The concept of a 1,5-dipolar cyclization gives rise to a general method for the synthesis of an appreciable number of heterocyclic systems. 1,5-Dipoles are derived from 1,3-dipoles by conjugation with different double bond systems, and it is possible to derive 98 theoretically possible 1,5-dipolar systems. The general expression for a 1,5-dipole and some possible combinations of double bond systems are shown in Scheme 14. 

Dipolar cyclizations leading to monocyclic and ring-fused systems are known. The... 

Dipolar cyclization of (421) through X leads to oxadiazoles, thiadiazoles and triazoles (70CB1918, 65CB2966) (see also Chapter 4.13). 

The thermal conversion of 1-substituted 5-aminotetrazole (423) into a 5-substituted aminotetrazole (424) can be rationalized by a similar 1,5-dipolar cyclization. 

Hart and Brewbaker have described the cyclization of l,3-bis(diazopropane) to pyrazole (Scheme 49) by a concerted, intramolecular 1,3-dipolar cycloaddition (69JA711). 

A 4,5-dihydro derivative (608) was prepared by the intramolecular 1,3-dipolar cyclization of (607) (75MI41607). 

Although cyclizations of fluonnated substrates to form five-membered rings were only rarely encountered in the literature prior to 1972, there has been an explosion of activity in this area recently, particularly with regard to 1,3-dipolar cycloadditions... 

An example of 1,3-dipolar cycloaddition involving a thiazole dioxide derivative was described (99T(55)201). A-Benzoyl-(R)-thiazolidin-4-carboxylic acid 5,5-dioxide 120 was cyclized to the bicylic mesoionic thiazolo-oxazolium 5,5-dioxide with Ac O and reacted with the imine 121 in DMF... 

Easy cyclization of 2, 6 -dinitrobiphenyl-2,6-dicarboxylic acids 290 during their heating in dipolar aprotic solvents providing high yields of tetracyclic... 

Compound 432, which can be easily prepared from trinitrochlorobenzene (76), treated with triethylamine in dipolar aprotic solvents provided good yield of the denitrocyclization product 433 (80JCS(P1)2205). Reaction of 2,3,5,6-tetra-chloronitrobenzene (434) with various 1,2-diamines under high pressure provided mixtures of the corresponding open products of the nitro group displacement, e.g. 435, and cyclized products, e.g. 436 (Scheme 69). Compound 436 was formed by denitrocyclization reaction, since compound 435 did not cyclize under the used conditions (94BCJ196, 95BCJ3227). 

In addition there are certain other methods for the preparation such compounds. Upon heating of the thionocarbonate 2 with a trivalent phosphorus compound e.g. trimethyl phosphite, a -elimination reaction takes place to yield the olefin 3. A nucleophilic addition of the phosphorus to sulfur leads to the zwitterionic species 6, which is likely to react to the phosphorus ylide 7 via cyclization and subsequent desulfurization. An alternative pathway for the formation of 7 via a 2-carbena-l,3-dioxolane 8 has been formulated. From the ylide 7 the olefin 3 is formed stereospecifically by a concerted 1,3-dipolar cycloreversion (see 1,3-dipolar cycloaddition), together with the unstable phosphorus compound 9, which decomposes into carbon dioxide and R3P. The latter is finally obtained as R3PS ... 

The cyclopentene derivatives 9 undergo both 1,5- and 1,7-dipolar electrocyclizations to yield mixtures of pyrazoles 10 and benzodiazepines 11. In addition, loss of nitrogen results in the carbenes 12, which cyclize to the tetrahydrocyclopent[fl]indenes 13.117... 

Another 1,7-dipolar cyclization leading to 1,2-benzodiazepines, but with the difference that a C-C bond is formed, is the ring closure of the nitrile imines 15 to give 17 by a [1,5]-sigmatropic shift of hydrogen in the intermediates 16. The nitrile imines are generated from the (2-vinylphenyl)hydrazonoyl chlorides 14."8 120... 

Thermolysis of the l-(2-thienyl)-3-diazoalkenes 1 gives 3//-thieno[3,2-f]-l,2-diazepines 2 by sequential 1,7-dipolar electrocyclization and [l,5]-hydrogen shifts, together with 37/-pyrazoles 3, which are produced by a competing 1,5-cyclization.140... 

Scheme 4 Access to various a,/ -unsaturated carbene complexes from alkynylcarbene complexes 23. A 1,3-Dipolar cycloaddition. B Diels-Alder reaction. C Ene reaction. D [2+2] Cycloaddition. E Michael-type addition followed by cyclization. F Michael-type additions...

Although the exact mechanism of the Tschitschibabin cyclisation has not been elucidated, it is reasonable, as shown in Scheme 4, to assume a series of reversible steps from the vinylogous ylide (or methylide) to a methine and an enol-betaine intermediate and then finally an irreversible dehydration to the indolizine nucleus. The reaction might be related to the modern electrocyclic 1,5 dipolar cyclization. 

Olefination Reactions Involving Phosphonium Ylides. The synthetic potential of phosphonium ylides was developed initially by G. Wittig and his associates at the University of Heidelberg. The reaction of a phosphonium ylide with an aldehyde or ketone introduces a carbon-carbon double bond in place of the carbonyl bond. The mechanism originally proposed involves an addition of the nucleophilic ylide carbon to the carbonyl group to form a dipolar intermediate (a betaine), followed by elimination of a phosphine oxide. The elimination is presumed to occur after formation of a four-membered oxaphosphetane intermediate. An alternative mechanism proposes direct formation of the oxaphosphetane by a cycloaddition reaction.236 There have been several computational studies that find the oxaphosphetane structure to be an intermediate.237 Oxaphosphetane intermediates have been observed by NMR studies at low temperature.238 Betaine intermediates have been observed only under special conditions that retard the cyclization and elimination steps.239... 

DipolarCycloaddition Reactions. The 1,3-dipolar cyclization of nitrile oxide with dipolarophiles generates structurally important heterocycles. As shown by Lee,139 the reaction can be carried out in an aqueous-organic biphasic system in which the nitrile oxide substrates can be generated from oximes or hydrazones in situ. The method provides a convenient one-pot procedure for generating a variety of heterocyclic products. 

Ethyl diazoacetate and ImCSIm can be cyclized by a dipolar addition to give the corresponding ethyl 5-imidazolyl-l,2,3-thiadiazole-4-carboxylate ... 

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