Ring annulation

A more recent ring annulation strategy for the total synthesis of steroids from the Stork group is shown in the following equation (210 — 211 — ... 

Table 1 lists some of the common binucleophiles utilized in heterocyclic synthesis, the numerical prefixes referring to the relative positions of the nucleophilic centers to each other. Higher order binucleophiles, e.g. 1,5-systems, come readily to mind and the above illustrative examples rapidly increase in scope when the incorporation of these structural elements into heterocyclic systems is considered. This last group offers many opportunities for ring annulations. 

Formation of ring-fused systems by reactions of this type can be achieved in two ways in one the heterocycle to which ring annulation is to occur acts as the dipolarophile the alternative mode utilizes incorporation of the 1,3-dipole into the heterocyclic ring for reaction with the dipolarophile. Both approaches have been investigated intensively. 

Just as in the Diels-Alder reaction, 1,4-dipolar cycloadditions lead to six-membered rings. Their principal use in five-membered heterocycles is for ring annulations giving [5,6] ring-fused systems. 

An interesting application of a phosphorus ylide in heterocyclic synthesis is in a ring annulation. The diazopyrazole (592) when treated with various phosphorus ylides gave the 3//-pyrazolo[5,l-c][l,2,4]triazole derivatives (593) with elimination of triphenylphosphine (79TL1567). 

Sulfimides have been utilized extensively for the synthesis of monocyclic ring systems as well as ring annulations. 

Tlie constrLiction of carbocydic cotnpoutidi by ring-annulation procedures frequently plays a prominent role in total syntliesis. Tlie tolerance of various functional groups in tlie zinc reagents employed in copper-catalyzed asymmetric 1,4-additions fornis tlie basis for tliree novd catalytic enantioselective annulation metliods discussed bete. 

The copper and nickel nitroporphyrins 6 (M = Cu, Ni) undergo pyrrole ring annulation with isocyanoacetates according to the Barton-Zard condensation originally designed for the preparation of simple monopyrroles112 (cf. Houben-Weyl, Vol.E6a, p650). 

Stereoselective Ring Annulations by Intramolecular 1,6-Addition of an Allylsilane Function... 

Dienones, such as 4-[4-(trimethylsilyl)-2-butenyl]-3-vinyl-2-cyclohexenone, are useful precursors for these particular transformations the allylsilane side chain is too short for effective 1,4-addition, but just right for 1,6-addition, resulting in six-ring annulation. Three different Lewis acids can be used titanium(IV) chloride, boron trifluoride diethyl ether complex, and ethylaluminum dichloride. The best chemical yields and complete asymmetric inductions were obtained with ethylaluminum dichloride. 

Optically Active Ring-Annulated Cyclopentadienyl Ligands. . . . 135... 

Optically Active Ring-Annulated Cyclopentadienyl Ligands... 

Helquist and coworkers60 have developed a six-membered ring annulation via a conjugate addition of aryllithium generated by metal-halogen exchange and subsequent intramolecular alkylation. This is illustrated in equation 71. 

Bicyclic System Case Small-Ring-Annulated Bicyclo[2.2.1]heptanones... 

Nair and co-workers have extended the use of enals for homoenolate generation to allow ring annulation with enones [13], Cyclopentene formation is achieved via... 

Watt and Drummond, were considered to be inert for C-C bond forming reactions. However, by the expedient of transmetallation to Cu, Ni, Zn, Li, and Al, methodologies for the stereoselective synthesis of olefins and dienes, as well as unusual heterocycles, aromatics and their ring-annulated products are now available which are beginning to make impact on material science, e. g. synthesis of pentacenes and polyphenylenes. Takahashi and Li provide evidence that, with further developments in transmetallation and handling the zirconacycles outside of the Schlenk tube techniques, synthetic utility will increase and new catalytic reactions will be developed. 

The cycloaddition reaction of the allenyl chloromethyl sulfone 130c was successfully applied to an iterative ring-annulation procedure [115]. 

Bicyclo[4.3.0]nonenes, thanks to their frequent appearance in natural products, are other important targets for novel annulation methodology. A six-membered ring-annulation to cyclopentenones has yet to be developed, the main reason for this being that, until very recently, the levels of enantioselectivity in catalytic 1,4-additions to 2-cyclopentenone were too low for a synthetically useful procedure. However, a highly enantioselective annulation of a five-membered ring to 2-cyclo-hexenone has been developed (Scheme 7.26) [80]. 

SCHEME 16. Ring annulation of cycloalkanones due to Uthiated 3,3-dichloropropene... 

Carboxy substituted diazepines 226 and 229 react with phenyl isocyanate to afford pyrimido diones 227 and 230, correspondingly (Scheme 48, Section 3.1.1.3 (1993JHC897)). N-Hydroxymethylation on an indole ring annulated to benzaze-pinone, as well as formation of the corresponding carbamate and urea, has been described (2004MI1076). 

While ring annulation is not uncommon, the formation of a five-membered ring onto an existing pytazine is somewhat unique. Thus, 25 reacts with malononitrile and then with an amine to form the tricyclic product 26 (Equation 9) <2001MC152>. Thiophene and pyrrole analogs of 25 react similarly. Note that 26 is suitably substituted to add yet another ring. 

Table 9. Cleavage of Four-Membered-Ring-Annulated Pinene Derivatives.165...

A notable eight-membered ring annulation was reported by Echavarren et al. in their study of indoles as substrates for the intramolecular reaction [134]. 

Huisgen and coworkers have also described the cycloaddition behavior of the munchnones , unstable mesoionic A2-oxazolium 5-oxides with azomethine ylide character.166 Their reactions closely parallel those of the related sydnones. These mesoionic dipoles are readily prepared by cyclodehydration of N-acyl amino acids (216) with reagents such as acetic anhydride. The reaction of munchnones with alkynic dipolarophiles constitutes a pyrrole synthesis of broad scope.158-160 1,3-Dipolar cycloaddition of alkynes to the A2-oxazolium 5-oxide (217), followed by cycloreversion of carbon dioxide from the initially formed adduct (218), gives pyrrole derivative (219 Scheme 51) in good yield. Cycloaddition studies of munchnones with other dipolarophiles have resulted in practical, unique syntheses of numerous functionalized monocyclic and ring-annulated heterocycles.167-169... 

Thermal instability arises from thiepine-benzene sulfide valence isomerization and subsequent irreversible loss of sulfur. There are two main approaches for stabilization. First, thiepines can be stabilized by electronic effects such as aromatic ring annulations, and, second, thiepines can also be stabilized by steric effects. These stabilization effects were discussed in CHEC-II <1996CHEC-II(9)67>. Some new results on thermal stability have been reported. 

Several reviews are available on the synthesis and properties of selenophene, its derivatives, and compounds having a selenophene ring annulated to benzene or a heterocyclic ring [1, 14, 117-120], The methods are based on the formation of one, two or three bonds, or on ring transformations. 

Nucleophilic Aromatic Substitution of Hydrogen as a Tool for Heterocyclic Ring Annulation... 

The number of similar cyclizations, including tandem and cascade sequences where an SnH reaction is a key step, has been considerably increased. As a rule, they are easily performed allowing at times the synthesis of complex polynuclear heterocycles in one step. The present paper, which summarizes about 130 articles on this topic, shows SnH cyclizations to be a very promising strategy for heterocyclic ring annulations. 

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