Spiro substitution

Wehle, D. Fitjer, L. Tetrahedron Lett., 1986, 27, 5843, have succeeded in producing two conformers that are indefinitely stable in solution at room temperature. However, the other five positions of the cyclohexane ring in this case are all spiro substituted with cyclobutane rings, greatly increasing the barrier to chair-chair interconversion. 

The cycloaddition of alkynes and alkenes to nitrile oxides has been used in the synthesis of functionalised azepine systems <96JHC259>, <96T5739>. The concomitantly formed isoxazole (dihydroisoxazole) ring is cleaved by reduction in the usual way. Other routes to 1-benzazepines include intramolecular amidoalkylation <96SC2241> and intramolecular palladium-catalysed aryl amination and aryl amidation <96T7525>. Spiro-substituted 2-benzazepines have been prepared by phenolic oxidation (Scheme 5) <96JOC5857> and the same method has been applied to the synthesis of dibenzazepines <96CC1481>. 

Recently, [2+3] cycloaddition reaction of 2-acetyl-[l,2,3]diazaphosphole (6) with 9-diazofluorenes (96) has been reported [105, 106], From the reaction in cyclohexane at rt, bicyclic phosphirane 97 was obtained as a result of the loss of nitrogen from the initial cycloadduct (Scheme 30). The cycloadduct, 3-spiro substituted 3H-[l,2,4]diazaphospholo-fused [l,2,3]diazaphosphole (98) could be isolated in good yield at room temperature in one case (R=/Bu) its stability was assigned to the presence of bulky fert-butyl group at 7-position. Use of polar solvent like dichloromethane led to the cyclic trimeric compound 99 (Scheme 30). 

Miyamoto and Yamazaki elaborated a general synthetic method to spiro-substituted [l,2,4]triazolo[l,5-c]pyrimi-dines bearing alicyclic rings of different sizes and bearing different (amino and sulfano) substituents in position 5 <1997JHC871>. 13C NMR chemical shifts of the ring carbon atoms of some selected derivatives are compiled in Table 4. 

The condensation reaction of the spiro-substituted partially saturated thiazolo[3,2-3][l,2,4]triazine compound 149 was published by Abdel-Rahman et al. <1994PHA729>, as shown in Scheme 22. The transformation was carried out in glacial acetic acid under heating to yield the ethenyl derivative 150 in acceptable yields (55-60%). 

An enormous number of different 1,3-dioxane structures have been reported since 1996 in Figure 3, mono-, bicyclic and spiro variants are presented, while Figure 4 contains examples of tricyclic structures with the 1,3-dioxane moiety. The conformations, bond lengths, bond and dihedral angles of the 1,3-dioxane rings are determined by the ring fusion, the attached substituents, and the presence of exocyclic double bonds. Thus, published structures are classified as either monocyclic (mono), spiro-substituted (spiro), bicyclic (bi), or tricyclic (tri). The well-known Meldrum s acid derivatives (M) have been most intensively studied. 

The effects of substituents and solvent polarity on the luminescence properties also have been evaluated for of a series of bichromophoric anthronyl-substituted anthracenes 98 and 99. It can be concluded from the quantum yield data summarized in Table 20 for spiro-substituted compounds 98a e that, dependent on solvent polarity, two different modes of intramolecular interactions between the electronically excited anthracene chromophore and the ground state ketone typically are operative, and both types of interaction result in fluorescence quenching. In nonpolar solvents, fluorescence quenching apparently involves endothermic intramolecular... 

TABLE 21 Solvent Dependence of Quantum Yields of Emission from the Locally Excited State of Spiro-Substituted Benzanthracenes 99a and 99b 109 ... 

The synthesis of bicyclo[3.2.2]non-6-en-3-one (192) and the spiro-substituted derivatives (195) can be achieved via similar methodology. Thus, thermolysis of the enol silyl ether (190), which is readily derived from the ketone (189), gives the bicyclic substance (191). Mild acid hydrolysis of (191) affords (192 Scheme 27). In a similar fashion the exo-ketones (193) have been converted, via the enol silyl ethers (194), into the tricyclic keto alkenes (195). ... 

Diisopropyl phosphonodithioformates 597 were also found to be efficient C=S dipolarophiles in reaction with thiocarbonyl ly-methylides, affording spiro-substituted 1,3-dithiolanes 598-601 with the phosphonate moiety at the 1,3-dithiolane ring (Scheme 85) <2005EJ01604>. 

New cyclolinear phosphazene poly(ether ketones) (224a, b) have been synthesized by the condensation of the new spiro-substituted cyclophosphazene (223) with 4,4 -difluorobenzophenone and a bisphenol. ... 

Not departing too far from fluorenones, Iiu et al. have done an elegant study on the photodegradation of fluorene oligomers [220]. The structures they use vary from that of compound 51 to compound 72, shown in Fig. 19, by varying the amount of alkyl versus spiro-substitution. These compounds are carefully characterized and found to contain no detectable fluorenone as synthesized. Also shown are a number of defect sites they propose and subsequently detect after photoirradiating the samples. Figure 20 shows the matrix-assisted laser... 

These results contributed to the design of spiroindan-substituted opiates with a 5 address moiety that is restricted to a conformation that is perpendicular to that of NTI or OMI. This restriction is due to the spiro substitution which prevents torsion of the indan benzene moiety. 

According to the X-ray data, dinitro compound 163 exists in a CB conformation (117). In contrast, the 1,3,7-triaza system 164 adopts a CC conformation in the solid state (118). A CC conformation was also found for the 9-spiro-substituted compound 165 (X-ray study) (119). 

Tu and coworkers reported a new and highly stereoselective four-component protocol for the domino reaction of 2,6-diaminopyrimidine-4-one 153 with structurally diverse aryl aldehydes 69 and various barbituric acids 156, resulting in 6-spiro-substituted pyrido[2,3-d]pyrimidines 157 and 158 with high diastereoselectivity (up to 99 1), in which the major diastereomer bears a cis relationship between the substituents at the 5- and 7-positions (Scheme 12.63) [87]. 

Moreover, Tu, li, and coworkers [89] presented a regioselective [4-I-2-I-1] domino cychzation for the synthesis of spiro-substituted benzo[fc]furo[3,4-e][l,4]diazepine... 

Scheme 12.63 Diastereoselective synthesis of 6-spiro-substituted pyrido[2,3- /]pyrimidines.

Scheme 12.65 Divergent synthesis of spiro-substituted benzo[b]furo[3,4-e][l,4]diazepines.

Cheng C, Jiang B, Tu SJ, Li G (2011) [4 + 2+1] Domino cyelization in water for chemo- and regioselective synthesis of spiro-substituted benzo[6]furo[3,4-e][l,4]diazepine derivatives. 

Nucleophilic addition of a primary amine to the dienyl complex 10.114 proceeded regioselectively with initial attack para to the methoxy group, despite the additional substituent at that position. Cyclization in situ gave a spiro-substituted complex 10.116 that was converted to enone 10.117 on decomplexation and hydrolysis (Scheme 10.29). °... 

Spiro substitution is common in both natural products and in molecules so far encountered only in the laboratory. Note in Figure 5.48 how poorly a two-dimensional picture represents the real shape of such molecules. Even the simplest spirocyclic compound, spiropentane, is badly served by the flat page. The central carbon is approximately tetrahedral, and we really must use wedges to give a three-dimensional feel to this kind of molecule. 

Dave, P.R., Forohar, F., Axenrod, T., Bedford, C.D., Chaykovsky, M., Rho, M.-K., Gilardi, R., George, C. Novel spiro substituted cyclotriphosphazenes incorporating ethylenedinitramine units. Phosphorus Sulfur Silicon 90, 175-184 (1994)... 

Two papers have appeared describing the cycloaddition reactions of ketens which, ultimately, lead to jS-lactams. In the first diphenyl keten is generated in situ, and by reaction with Schiff s bases affords fair yields of N-alkylazetidinones (69). In the second example,[2 + 2]cycloaddition of iminothiadiazoles (70) with ketenes gave spiro-substituted /3-lactams (71), which were readily desulphurized with Raney nickel or by reflux with DMF. 

The photocyclization of a series of suitably substituted enamides [e.g. (197)] has been used to create spiro-substituted isoquinolin-l-ones (198) a ring system present in a range of natural products. Although a great variety of products is available by this route, compounds lacking CHjPh do not cyclize. 

Chromanols are prepared in good yields by cyclization of hydroquinone, resorcinol, and catechol with phytyl chloride in the presence of cation-exchange resin complexes of metal ions. ° The reaction of dihydrocoumarins with readily available 0 ,Grignard reagents has led to chromans which are spiro-substituted at the 2-position (125). The initially formed O-hydroxyphenylethyl cycloalkanols (124) were converted to chromans in high yield by simple acid treatment. ... 

A [4 + 2 +1] domino cyclization in water involving condensation of 2,2-dihydroxy-indene-l,3-dione (149), tetronic acid 150 and OPD catalyzed by acetic acid has been developed for the synthesis of spiro-substituted benzofurodiaz-epine derivatives 152 and 153 (Scheme 32) in a one-pot manner xmder MW proceeding within few minutes [102]. The authors observed that the outcome of tiie process was dependent on the ratio of reactants as well as on the electronic effects of the substituent in the aromatic ring of the diamine. 

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