Tandem cyclization/phenylation

The protocol for this tandem cyclization involves deprotonation of allylic phenyl thioethers such as 218136. The authors observed that transmetalation with LiBr was required to obtain high yields of the cyclization product. Conversion of the resulting allyllithium 219 to the monocyclic intermediate 220 followed by intramolecular displacement of the thiophenoxide ion efficiently afforded the fused vinylcyclopropane 221 (Scheme 66). Formation of the five-membered ring was quantitative, starting from a substrate in which both alkene functions were monosubstituted126. 

We recently reported a convenient and efficient synthetic route to new 3-substituted 2,3-dihydrobenzo[h]furans 278 based on the tandem cyclization-y-alkylation of 2-bromophenyl ( )-3-phenyl-2-propenyl ether 276 whose operational simplicity could find favor in many applications161. Previous attempts using 2-bromophenyl (E)-2-propenyl ether failed because the cyclic intermediate underwent a y -elimination. We thought that a likely strategy to overcome the y-elimination in the cyclic (2,3-dihydrobenzo[h]furanyl)methyllithium intermediate could be substitution by a phenyl moiety that could provide increased resonance stabilization to the cyclic lithium intermediate 277 (Scheme 85). 

Representative procedure for the gold-catalyzed tandem cyclization/pinacol rarrangement of 3-silyloxy-l,5-enynes. 3a,4,5.6,7,7a-Hexahydro-l-phenyl-3H-indene-3a-carbaldehyde ° ... 

In their attempts to build a host system that will recognize and sense anions in solution, Curiel and co-workers used a tandem cyclization between phenyl hydrazine derivatives and 1,2-cyclohaxanedione to provide pentacyclic carbazoles in one step and moderate yields. It is important to note that even with substitution at the or//zo-position Curiel did not experience any significant drop in the percent yield of entry 4 as compared to entry 1 or 3. 

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

The pyrirnido[ 1,6-/z [3,l [benzoxazin-1 -thionc 230 was formed in a tandem [5+1, 6+0 (/ )] cyclization as depicted in Scheme 38. The first step is the nucleophilic attack of the aniline nitrogen of 228 (X = O) onto the isothiocyanate and then onto the aldehyde carbon to form l-(2-hydroxymethyl)phenyl-6-hydroxy-tetrahydropyrimidine-2-thione, which cyclizes to 230 <2005BMC3185>. 

Tandem mass spectrometry has been used to demonstrate that M+ as well as MH+ of substituted A-(ort/zo-cyclopropylphenyl)benzamides isomerizes before the fragmentation, with formation of 3-aryl-1-ethyl-lH-benzoxazines and 5-ethyl-2-oxodi-benzoazepines (Scheme 5.14). The methyl group in /V-[ortho-( 1 -methylcvclopropyl )-phenyl]benzamides quenches the latter process, leaving the formation of benzoxazines as the only cyclization reaction. A subsequent chemical experiment in solution confirmed the mass spectral predictions [24]. A similar study confirmed the analogy of cyclization of substituted A-(ort/zo-cyclopropylphenyl)-A -aryl ureas and N- ortho-cyclopropylphenyl)-A -aiyl thioureas in the ion source of mass a spectrometer and in solution [25]. 

Scheme 28 explains the stereochemical outcome from the tandem radical cyclization in the presence of the [Yb(Ph-pybox)(OTf)3] (pybox = 2,6-bis(2-oxazolin-2-yl)pyridine). The ytterbium complex 107 is shown in an octahedral geometry (with one triflate still bound to the metal) where re-face cyclization is favored due to the steric interactions of the substrate and the ligand s phenyl groups. The 6-endo cyclization takes place via a chair-like transition state to yield a tertiary radical 108 followed by a ring flip and... 

There are very few examples of photolysis being used for preparation of a carbonyl ylide. The Dittami protocol follows work completed from his lab with aryl vinyl sulfides. Photolysis, followed by cycloaddition, led to the cycloadduct 305 in excellent yield and stereoselectivity. If the aryl vinyl ether 304 was subjected to irradiation in a mixed solution of toluene-methanol at 366 nm rather than a single solvent of toluene, cyclized product was obtained, but no cycloadduct was formed. If a simple phenyl aryl ether was subjected to the same tandem conditions, the cyclized product was generated, but no cycloadduct was detected. 

Nitrones can be generated by Michael reaction of oximes with appropriate conjugated substrates.25 If a generated nitrone has a built-in dipolarophile, cyclization can ensue (Scheme 15). There are three synthetic variations on this theme.25a,b First, the oxime may contain the dipolarophile as in (56). Reaction of (56) with phenyl vinyl sulfone provided a quantitative yield of the tandem product as one stereoisomer. Alternatively, die dipolarophile can reside in the Michael substrate as in (57). Reaction of (57) with cyclohexanone oxime produced two isoxazolidines from competitive cyclization of the intermediate nitrone through six- and seven-membered carbocyclic transition states. It is also possible to carry out an intramolecular Michael addition followed by an intramolecular nitrone cyclization as in thermolysis of (58) to produce a tricyclic isoxazolidine. Very recently several examples of a tandem Diels-Alder, Michael addition, nitrone cyclization sequence have been reported.250... 

The addition of thiyl radicals to alkenes or alkynes to initiate tandem sequences has also been explored. A highly stereo-controlled phenyl thiyl radical addition, 10-endo macrocyclization, termination process has been used to furnish the macrocycle (37) from the dimethylacrylic ester (36).48 In other work the vinyl radical (38) fonned from addition of a thiyl radical to an enyne gives a mixture of the three products (39)-(41) formed either by 6-exo cyclization (39), addition into the aromatic ring followed by trapping with AIBN (40), or rearomatization and fragmentation to give the sulfide (41) (Scheme 15).49... 

Powell, Maki, and Fu reported a Ni-catalyzed tandem radical 5-exo cyclization/ Stille coupling reaction (Fig. 19) [75]. When allylic bromo ethers 80 were subjected to a reaction with trichlorophenylstannane 81a in the presence of 10 mol% NiCl2 and 15 mol% of bipy 26, bicyclic phenyl-substituted products 82 were isolated in 57-67% yield and moderate to excellent endo-diastereoselectivity. Suzuki-Miyaura-type coupling reactions of 80 with arylboronic acids 81b worked similarly in 69-87%... 

The tandem sequence occurs between o-benzoylbenzyllithiums and furan-2-(5/7)-one168. The o-benzoyl-a-methoxybenzyllithium intermediate was generated by deprotonation of 2-methoxymethylphenyl phenyl ketone, 292, with LDA. Treatment of the a-lithiated product with furan-2-(5//)-one afforded the Michael addition/cyclization product, 293. The 9-aryl-9-hydroxy-3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-l-(3//)-one 293 thus obtained was converted into the corresponding 9-aryl-4-methoxy-3a,4-dihydronaphtho[2,3-c]furan-] -(3//(-one 294 in good yield the subsequent dehydrogenation gave the desired product 4-methoxy-9-phenylnaphtho[2,3-c]furan-l(3/7)-one 295. 

J.K. Cha et al. developed a stereocontrolled synthesis of bicyclo[5.3.0]decan-3-ones from readily available acyclic substrates. Acyclic olefin-tethered amides were first subjected to the intramolecular Kulinkovich reaction to prepare bicyclic aminocyclopropanes. This was followed by a tandem ring-expansion-cyclization sequence triggered by aerobic oxidation. The reactive intermediates in this tandem process were aminium radicals (radical cations). The p-anisidine group was chosen to lower the amine oxidation potential. This substituent was crucial for the generation of the aminium radical (if Ar = phenyl, the ring aerobic oxidation is not feasible). 

Gross and coworkers129 also studied the unimolecular dissociation of protonated acy-lanilines, viz. A-[2-(benzoyloxy)phenyl]benzamides formed via both fast-atom bombardment (FAB) and electrospray ionization (ESI). They found that cyclization occurs upon the loss of a molecule of benzoic acid, and that a similar process occurs for the molecular ion under El. This gas-phase reaction is analogous to a solution reaction leading to phenyl-benzoxazoles. The proposed cyclization process, for which concurrent mechanisms were proposed (Scheme 38 depicts only the displacement reaction route), was corroborated by accurate mass measurements, tandem mass spectrometric experiments with comparison with reference ions, isotopic labeling and theoretical calculations. 

A series of new l//-pyrazolo[3,4- /]pyrimidin-4(5/f)-ones 84a-l has been regioselectively synthesized in four steps, via a tandem aza-Wittig reaction. The iminophosphorane 81, prepared from 5-aminopyrazole 80, reacted with phenyl isocyanate to give carbodiimide 82, which by reaction with primary or secondary alkylamines, afforded intermediate guanidines 83 that cyclized to the corresponding pyrazolopyrimidinones <04JHC393>. 

The use of intramolecular nitrogen nucleophiles in such schemes holds much promise for the formation of nitrogenous heterocycles. This is especially the case when a second radical ring closure may be built in tandem-wise (Scheme 29) [53]. The stereochemistry of the two major products (35) and (36) here is best explained by transition states for the radical cyclization which put the phenyl ring on the exosurface of the developing bicyclic system. tra y-Selectivity in cyclization of benzyl radicals is standard [54] and provides the major product (35). 

Nucleophilic substitution of hydrogen Sn can also be combined with the displacement of a good leaving group as illustrated by the reaction of 3-phenyl-5-methoxy-l,2,4-triazine with resorcinol, proceeding via the intermediate o -adduct and affording benzofuro[2,3-e]-l,2,4-triazine according to the tandem Sn -Sn cyclization protocol (Scheme 57) [175]. 

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