Cyclization reactions, ineffective

Baylis-Hillman Reaction. Intramolecular cyclization of MeC0(CH2)2CH=CHC02Et using (-P)-CAMP produced the cy-clopentene in 40% isolated yield. A 3 1 equilibrium mixture which favored the product cyclopentene was formed after 10 days at 25 °C. CAMP was found to be superior to other phosphines, such as PBU3. DABCO and other nitrogen bases were ineffective for the cyclization reaction. However, the enantioselectivity of the product using CAMP was only 14%. 

In contrast to the large number of studies concerned with porphyrins and phthalocyanines, other macrocyclic ligand compounds of Mn have received somewhat less attention. - In part, this appears to reflect the fact that many compounds of this type tend to be of only moderate thermodynamic stability and in some instances are air and/or moisture sensitive. In addition, Mn has been shown to be ineffective as a template metal for certain cyclization reactions which occur in the presence of other ions. - This effect may be a consequence of the relatively large size of the Mn" ion not enabling it to fit in the cavity of the target macrocycle. Alternatively, the often low affinity of Mn" for the macrocycle precursors may contribute to the absence of a template effect for particular systems. 

The benzofuran skeleton is common in natural products. A direct synthesis from o-arylmethoxybenzaldehyde by base promoted condensation reaction was reported by Kraus et al. [6] The reaction of o-arylmethoxybenzaldehyde 29 with 1.1 equiv. of phosphazene 9 in benzene or pivalonitrile at 90-100 °C gave 30 in moderate yield (Scheme 7.4). Strong ionic bases, such as LDA, LiTMP and KH, were ineffective for this cyclization reaction. 

The relation between the inter- and intramolecular acts is controlled by the reaction conditions such as type and concentration of the reagents, nature of the solvent, temperature, order in which the reagent are mixed, etc. This problem is discussed in much detail elsewhere 3). In this sub-section, we shall be only concerned with some of the experimental and theoretical studies aimed at revealing a relationship between the reagent structure and ineffective cyclization in the course of curing the epoxyamine compositions. 

Ruhland et al. used PdCl2(dppf)-NEt3 Heck conditions to add to a resin-bound aryl iodide, thereby generating supported 4-styryl (3-lactams, as shown in Scheme 17.45 This catalyst system, also found to be effective for the Suzuki reaction (see Section 2.4), is unusual for the Heck reaction and had only previously been used for an intramolecular cyclization.46 The more usual conditions of Pd(OAc)2/phosphine/NEt3 or K2C03 were found to be ineffective. 

Scheme 35.252 Although this process is promoted by EtAlCl2, B(C6F5)3 itself is ineffective probably due to a lack of labile groups. However, addition of Et3SiH to the reaction results in rapid cyclization to the cyclohexenyl product shown via a silane activation mechanism.

Lactonization. Cyclization of the thioester 1 cannot be effected with mercuric trlfluoroacetate or copper(I) trifluroacetate. The usual reagents used for this reaction (6, 582 7, 444) are ineffective, but cyclization is effected with CuOTf complexed with benzene. Two isomeric lactones (2 and 3) are obtained in 62% yield. One of thcNC is the acetate of the pyrrolizidine alkaloid crobarbatine. Unfortunately dcucctylation of these products is accompanied by further hydrolysis to the pyrrolizidine unit (retronecine). 

Reaction of 1,3-diones with propargylic alcohols leads to 3-acylfurans. Using other Lewis acids such as FeCU the reaction stops short of cyclization. Alkylation by alkenes (styrene, norbornene, cyclopentadiene, dihydropyran,. ..) affords moderate yields of the adducts.Again, InCU appears to show a special catalytic activity, as AICI3, TiCU, MnCl2, Bids are ineffective. 

R2 = NH2 R8 = R4 = H). The hydrolysis of the latter affords 39 (Rl = R2 = H). Hydrogen iodide can also be used for the reaction however, hydrogen chloride is ineffective.20-22-38 The diamide (47) was pyrolytically cyclized at 295° into 39 (Rl = R2 = H) in good yield but in a high-boiling solvent only a poor yield was obtained.89... 

Indoles. o-Alkynylanilines undergo cyclization (5-endo-dig process) on treatment with KH in NMP. Sodium hydride is largely ineffective (<5% yield) in bringing about the reaction. 

With increasing use of Fmoc SPS, a number of base-mediated side reactions have been identified and reported that require careful awareness [61]. Some of these are described elsewhere in this volume (Chapters 2 and 4). The principal base-mediated side reactions are diketopiperazine formatioii caused by cyclization, particularly during A -deprotection of the residue adjacent to C-terminal resin-linked proline [62], and aspartimide formation, particularly at Asp-X residues [63,64]. The former can now be prevented by use of the substantially sterically hindered 2-chlorotrityl linker [65]. The latter side reaction is more difficult to control and appears to be largely sequence dependent. Asp-Gly, -Ser, -Thr, -Asn, and -Gin pairs are most at risk of potential imide formation, although several other Asp-X combinations have also been observed to cyclize [66,67]. For one sensitive peptide sequence, use of piperazine for A -deprotection eliminated this side reaction [68]. However, for another peptide, this base was ineffective (J Wade, unpublished). Reduction of the basicity of the piperidine solution by addition of... 

Ruthenium In one of the earliest examples of a transition metal-catalyzed hydroalkoxylation reaction from 1998, the cyclization of 2-allylphenols to benzo-dihydrofurans was catalyzed by a cocktail of ruthenium chloride, silver- and copper triflates, and a phosphane ligand (Scheme 8a) [44]. A control experiment implied that triflic acid alone was ineffective as catalyst, but this experiment is at variance with a later report where 2-allylphenol was cyclized using only 5 mol% of triflic acid as catalyst (CH2CI2, 40°C, 3 h) [45]. 

Reaction conditions amenable to nickel-catalyzed reductive cyclization of alkynyl enones were ineffective in the intermolecular variant In the course of developing catalytic [3 -l- 2] cycloadditions of alkynes and enals [24], it was discovered that by simply using an enone instead of an enal electrophile, catalytic intermolecular reductive coupling could be achieved in a Ni(COD)2/Bu3P catalyst system using EtsB as a reducing agent in a MeOH/THF (8 1) solvent system (Scheme 8.5) [25). 

When the R on resin 29 was hydrogen or ethyl, the reaction of intermediate resins 29 under the optimal conditions failed to produce precursors of the respective target compounds and only noncyclized products were isolated. This problem is probably due to the lower acidity of the C3 a-protons in resins 29 (R =H or Et). In cases where the R substituent was an electron-withdrawing benzyl (4-N02-Bn), the sequence also failed to produce the desired target. It appeared that the acidic proton present in 29 (R = 4-NO -Bn) renders ineffective the cyclization to produce 30. ... 

Cyclic and A(-alkylated enamides proved ineffective as coupling partners in the Heck reaction forming the pyridyl olefins only to a limited extent. In contrast, olefins containing free alcohols performed well as illustrated by glycol vinyl ether obtaining the cyclized ketal 53 after acetic acid treatment of the resulting a-arylated n-butyl vinyl ether in a 58 % overall yield (Scheme 5.2). 

Macrosphelides A (75) and B (76), isolated from Mucrosphueropsis sp. FO-5050 and Periconia byssoides, have antitumoral properties. For their synthesis, several RCM conditions were used, but 1 equiv. of [Ru]-II catalyst and long reaction time were necessary to obtain the cyclized product in reasonable yields (60-65%, Scheme 5.17). The authors pointed out that the addition of a Lewis acid under catalytic conditions was ineffective [41]. 

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