6,6-spirocyclic products

The reactions of the six-membered chlorocyclophosphazene were studied with a number of aliphatic diamines (169 175), aromatic diamines (176), aliphatic diols (177-179), aromatic diols (180,181) and compounds containing amino and hydroxyl functional groups (169,170,182). This subject has been reviewed (11,16,20). There are at least five different reaction products that are possible (Fig. 19). Replacement of two chlorine atoms from the same phosphorus atom produces a spirocyclic product. Replacement of two chlorine atoms from two different phosphorus atoms in the same molecule produces an ansa product. Reaction of only one end of the difunctional reagent, resulting in the substitution of only one chlorine atom, leads to an open-chain compound. Intermolecular bridged compounds are formed when the difunc-... 

Most aromatic difunctional reagents react with N3P3Cl6 to afford spirocyclic products (20,176,180,181,189,190). With catechol, the trispiro product is observed (190). This product was shown to function as a host in the formation of several inclusion adducts, including polymers (191). Ring degradation of the cyclophosphazene ring occurs in the reaction with o-amino phenol as well as in the reaction with catechol in the presence of a triethylamine (192). 

As part of a study on the synthesis of the anticancer natural product camptothecin, alcohol 96, was synthesized (Scheme 11) <1997T10953>. Conversion of the hydroxyl group under standard conditions resulted in 97 which subsequently underwent intramolecular cyclization due to the better leaving ability of the halide. The quaternary spirocyclic product 2 was formed on standing. 

Alternatively, phenyl rings have been introduced to give the spirocyclic products 117 in isolated yields of 80-85% yields (Equation 25 and Table 7) <2004KGS29>. 

Upon oxidation, a cyclization reaction using a 4-methoxyphenyl ring-derived substrate did not form any of the fused bicyclic product. Instead, a spirocyclic product was formed in direct analogy to the chemistry of Yamamura and Swenton (Scheme 37). In general, cyclization reactions having... 

Although cyclic azoalkanes are well known as biradical precursors [159] they have been used as 1,2- and 1,3-radical cation precursors only recently [160-164]. Apart from the rearrangement products bicyclopentane 161 and cyclopentene 163, the PET-oxidation of bicyclic azoalkane 158 yields mostly unsaturated spirocyclic products [165]. Common sensitizers are triphenyl-pyrylium tetrafluoroborate and 9,10-dicyanoanthracene with biphenyl as a cosensitizer. The ethers 164 and 165 represent trapping products of the proposed 1,2-radical cation 162. Comparison of the PET chemistry of the azoalkane 158 and the corresponding bicyclopentane 161 additionally supports the notion that the non-rearranged diazenyl radical cation 159 is involved (Scheme 31). 

Spirocyclic product is formed as a result of replacement of both the chlorines on the same phosphorus atom, while the ansa product is formed as a result of the replacement of chlorines from two distinct phosphorus atoms within the same molecule. In open chain product only one end of the difunctional reagent is involved in reaction with the chlorocyclophosphazene. Finally, intermolecular bridged products result from the reaction of two chlorocyclophosphazene molecules with a difunctional reagent. This last reaction also is a model reaction for condensation polymerization involving phosphazenes. 

Heating of the benzocyclobutene derivative 1 in degassed o-dichlorobenzene at 180°C for 2 hours gives the spirocyclic product 2 in 88% yield. 

Interaction of compounds 40 with dmpe (Ph2PCH2CH2PPh2) afforded the spirocyclic product 41 in 61% yield (Equation 4) <19950M4040>. 

Kende and co-workers have reported the formation of a nitrile ylide intermediate from carbenes and methyl acrylonitrile. Thermolysis of p-diazooxide 256 in methyl acrylonitrile as solvent gave spirocyclic product 259 in 48% yield.140 The formation of 259 was interpreted in terms of the generation of nitrile ylide 258 followed by 1,3-dipolar cycloaddition across the C=C bond of a second molecule of methylacry-lonitrile. The regiochemistry of the cycloaddition is consistent with FMO theory. 

In all the following examples, the targeted double bonds were activated by suitable substituents to increase the efficacy of the desired cyclization mode. For the total synthesis of acutumine (26), an activated a,p-unsaturated ketone 27 was chosen as precursor (Scheme 10) [74, 75], Aryl radical additions to this type of alkenes are known to proceed about ten times faster than to comparable allylic alcohols. In a radical-polar crossover reaction, the spirocyclic product 28 was obtained in the presence of triethylaluminum as promoter and an oxaziridine as hydroxylating agent. The fact that even the efficient hydrogen donor tetrahydrofuran could be used as solvent nicely demonstrates the high efficacy of the cyclization step. 

Bischof and Mattay have shown that radical anion cyclization leading to spirocyclic products compete effectively with intramolecular [2 -f 2]-cycloaddition on photoexcitation of olefinic enones in the presence of triethylamine [332, 333]. The [2 -f 2] cycloadducts could be converted to the corresponding spiro compounds under PET conditions (Scheme 75) [307]. 

Tetracyanoethylene adds to the exocyclic double bond of 373 to give spirocyclic product , whilst the cyclobutadiene 374 adds to the endocyclic double bond of a variety of methylenecyclopropenes to give tricyclic [2 + 2] adducts, e.g. 375, which rearrangeto heptafulvenes, e.g. 376. 

Heck reaction and other couplings. The Heck reaction has been promoted by microwave irradiation in DMF or in water at high temperature (225°). In the intramolecular reaction leading to spirocyclic products, the double bond migration can be... 

The cyclopropane ring in lumicholestenone 22 was cleaved by hydrochloric acid to give the 5a-chlorosteroid 23. " Under these conditions, no spirocyclic product was formed, as in the reaction of similar structures with hydrobromic acid (vide infra). 

Reductive cleavage of analogous cyclopropyl ketones with lithium in liquid ammonia normally gives exclusively the spirocyclic product (see Section 2.4.1.5.6.). 

The exo double bond of 4-alkylidene and 4-arylidene-5(4//)-oxazolones undergoes cycloaddition reactions with 1,3-dipolar reagents. For example, nitrile oxides add to 2-phenyl-4-ethoxymethylene-5(4//)-oxazolone (88) to give spirocyclic products that may be hydrolyzed to 4-aminoisooxazoles... 

Similar tandem reactions have been utilized to construct all-carbon spirocyclic ring systems. Initially, achiral studies were conducted by Undheim and coworkers using Rh2(OAc)4 (25a) as the catalyst [73, 74], Although they provided proof of concept, the yields were generally low, and multi-step procedures were often necessary to obtain the final products. Additionally, the methodology was not extended to asymmetric catalysis. In 2001, Hashimoto and coworkers optimized conditions by which spirocyclic product 62 could be obtained in one pot from bis-diazo compound 60 in good yield and up to 80% ee with phthalimide catalyst Rh2(5-PTTI.)4 (29a, Scheme 13) [75],... 

Cyclization and cycloreversion. Despite its adjacency to a carbonyl group a tertiary oxy substituent at C-3 of oxindoles undergoes ionization on exposure to BF3 OEt2, and that interaction with an alkenyl chain leads to spirocyclic products. ... 

Spirocyclic 4//-pyrans 69a (90ACS833) and 69b were prepared in the same way. In the case of 69b the starting a,)8-unsaturated component was generated in situ from enolacetate 70 (89CB1285). Analogous procedures with HC=COEt were used for the preparation of other spirocyclic products 71 and 72 (89CB1285). 

To probe this, model compounds were prepared and subjected to the reaction. Firstly, formation of the ABE ring system was modeled [14]. Diazotization of the amine 35 and reaction of the resulting diazonium salt afforded the spirocyclic product 36 in an acceptable 57% yield from the amine. This marked the first example where the radical-polar crossover reaction was terminated in an intramolecular manner. Modeling the ABCE tetracycle also worked well in preparing products 40 42. Importantly, the relative stereochemistry of 42, and by implication that of the other tetracycles, was verified by X-ray crystal structure analysis... 

IsoxazoUnes. Applying the conventional method that converts aldoximes to nitrile oxides to 2,2-di-(3-butenyl)malonoaldoxime leads to spirocyclic products. Development of such compounds into chiral ligands is expected. 

When the phosphaalkynes 9 a, 9 b, and 9e are allowed to react with aluminum halides in dichloromethane in a molar ratio of 3 1, the spirocyclic products 71 are obtained (yields 85-95% (Scheme 6-16) [60,61]. These compounds represent Lewis add adducts of a 1,3-diphosphete containing both X o -and X o -phosphorus atoms addition compounds of this type are known in cyclobutadiene chemistry [62]. An X-ray crystal structure analysis of 71a has substantiated this new class of compounds [61]. The P—C atomic separations (1.70 and 1.77 A, respectively) in the cationic portion of the molecule justify the formulation of the adducts as the resonance hybrids (71A <- 71B or 71C). 

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