Alkenes, radical addition stereoselectivity

The stereoselectivity of the radical addition can be explained in terms of a bridged structure similar to that involved in discussion of ionic bromination of alkenes ... 

From a synthetic point of view, the regioselectivity and stereoselectivity of the cyclization are of paramount importance. As discussed in Section 11.2.3.3 of Part A, the order of preference for cyclization of alkyl radicals is 5-exo > 6-endo 6-exo > 7-endo S-endo > 1-exo because of stereoelectronic preferences. For relatively rigid cyclic structures, proximity and alignment factors determined by the specific geometry of the ring system are of major importance. Theoretical analysis of radical addition indicates that the major interaction of the attacking radical is with the alkene LUMO.321 The preferred direction of attack is not perpendicular to the it system, but rather at an angle of about 110°. 

In any consideration of stereoselectivity in radical addition to acylic substrates, interpretation of the results is complicated by the knowledge that alkenes may be converted, at least in part, into their geometrical isomerides by traces of bromine (or of HBr, i.e. by Br, cf. p. 315). This may, however, be minimised by working at low temperatures, and by using a high concentration of HBr. Thus addition of liquid HBr at -80° to cis 2-bromobut-2-ene (67) was found to proceed with high TRANS stereoselectivity, and to yield (68) almost exclusively ... 

Tandem radical addition/cydization reactions have been performed using unsaturated tertiary amines (Scheme 9.11) [14,15]. Radical attack is highly stereoselective anti with respect to the 5-alkoxy substituent of 2-(5f-J)-furanones, which act as the electron-deficient alkenes. However, the configuration of the a position of the nitrogen cannot be controlled. Likewise, tandem addition cyclization reactions occur with aromatic tertiary amines (Scheme 9.12) in this case, acetone (mild oxidant) must be added to prevent the partial reduction of the unsaturated ketone [14]. 

Bertrand, S., Hoffmann, N., and Pete, J.P. (2000) Highly efficient and stereoselective radical addition of tertiary amines to electron-deficient alkenes-application to the enantioselective synthesis of necine bases. European Journal of Organic Chemistry, 82, 2227—2238. 

Recently examples of ring closure by addition of nitrogen centered radicals to alkenes have been explored thus anodic oxidation of the Li salt of substituted 5-alkeny-lamines in THF/HMPA (30 1) gave stereoselectively cw-2,5-substituted-l-methylpyrroli-dines by aminyl radical addition to the double bond [81]. A somewhat similar ring closure with addition of a nitrogen-centered radical is observed in the anodic oxidation in aqueous THF of a methoxyamine-substituted dibenzo[a,fiTjcycloheptene (XXVI) to (XXVII) the... 

Few examples exist in the literature concerning the stereoselective addition of acyl radicals to a radical acceptor in an acyclic manner. Equation (13.1) shows the efficient 1,2-asymmetric induction in the addition of aliphatic or aromatic acyl radicals to chiral acyclic alkenes 1 [7]. The corresponding a-hydroxy ketones 3 were produced with high syn selectivity (Table 13-1). This acyl radical addition is very exothermic, and it is hypothesized that Hammond s postulate can be invoked to predict a transition state that is very close in energy to the starting alkene 1. The X-ray structure of 1 was then used to rationalize the stereochemical outcome of this radical addition by determination of the least sterically hindered path for the approaching radical. 

Stereoselective P additions have also been controlled by the introduction of chiral sulfinyl auxiliaries at the a position of alkenes. Several advantages of sul-finyl auxiliaries are pointed out. The use of bulky substituents on the chiral sulfoxide functions to shield one face of the P position of the alkene, allowing for control of radical addition. The dipole of the sulfoxide can be used to control ro-tamer populations with and without Lewis acids. In the absence of a chelating Lewis acid, dipole-dipole repulsion orients the sulfoxide and carbonyl groups in an anti conformation. On the other hand, bidentate Lewis acids can chelate these two Lewis basic functionalities and keep them oriented in a syn conformation. Finally, the sulfinyl group is easily removed or chemically transformed into other functionality. 

Although there exist numerous ground state reactions, photochemically induced asymmetric radical additions can be very efficient and even highly stereoselective [125]. Furthermore, no particular functionalization of the starting material is necessary prior to the formation of a C-C bond. In this context, the photosensitized addition of alcohols, cyclic acetals, and tertiary amines to electron-deficient alkenes has been particularly studied. This will be illustrated by a few examples. 

A decade ago, radical reactions were thought to be of little use in synthesis due to lack of selectivity. Much progress has recently been made in this domain, and it has even become possible to control the stereoselectivity in many radical reactions [1469]. Curran, Giese, Porter and their coworkers initiated the study of asymmetric radical addition reactions by introducing chiral residues either on the radical precursor or on the alkene. 

Organic fluorine compounds and methods for their preparation are the central topic of the next four procedures. Much of the synthetic versatility of methyl phenyl sulfone is embodied in FLUOROMETHYL PHENYL SULFONE and the fluoro Pummerer reaction of methyl phenyl sulfoxide with DAST is a key step in its preparation. The utility of this fluoromethyl sulfone in the preparation of fluoroalkenes Is demonstrated in a companion procedure for Z-[2-(FLUOROMETHYLENE) CYCLOHEXYL]BENZENE, a procedure with several prominent stereoselective features. Geminal difluoroalkenes are featured in the following procedure. (3,3 DIFLUOROALLYL)TRIMETHYLSILANE is prepared by a method in which the radical addition of dibromodifluoromethane to alkenes and the selective reduction of a-bromoalkylsilanes are key steps. A procedure for nucleophilic introduction of the trifluoromethyl group completes this set. The key reagent, (TRIFLUOROMETHYL)-TRIMETHYLSILANE is obtained by reductive coupling of TMS chloride and bromotrifluoromethane. Liberation of a CF3- equivalent with fluoride ion in the presence of cyclohexanone affords 1-TRIFLUOROMETHYL-1-CYCLOHEXANOL. 

Stereoselective radical addition to alkynes and reduction of iodoalkynes Et jB has been used as a catalyst for the reactions with (MejSifjSiH to yield (Z)-alkenes. 

The radical addition of sulfinates to unsaturated compounds via the iodosulfonylation-dehydroiodination reaction sequence constitutes a general method for the preparation of vinyl sulfones the latter may be rearranged to aUyUc sulfones by treatment with base. The radical addition may be carried out on a, -unsaturated carbonyl compounds as well as alkenes. In the case of unsaturated carbonyl compounds the elimination process can be quite stereoselective, ( )-alkenes being normally formed. For the addition to nonconjugated alkenes, conditions have been described for the preparation of either ( )- or (. -alkenes. ... 

Das, S., Kumar, J.S.D., Shivaramayya, K., and George, M.V., Formation of lactams via photoelectron-transfer catalyzed reactions of N-aUylamines with a,P-unsaturated esters. Tetrahedron, 52,3425,1996. (a) Bertrand, S., Glapski, C, Hoffmann, N., and Pete, J-P., Highly efficient photochemical addition of tertiary amines to electron deficient alkenes. Diastereoselective addition to (5R)-5-menthyloxy-2(5ff]-furanone. Tetrahedron Lett., 40, 3169, 1999 (b) Bertrand, S., Hoflfrnann, N., and Pete, J-P., Stereoselective radical addition of tertiary amines to (5R)-5-menthyloxy-2[5H]-furanone application to the enantioselective synthesis of (-)-isoretronecanol and (-l-)-labumine. Tetrahedron Lett., 40,3173,1999 (c) Farrant, E. and Mann, J., Novel synthesis of the indoUzidine alkaloid skeleton with appropriate functionality and stereochemistry for use as a chiral scaffold, /. Chem. Soc., Perkin Trans. 1,1083,1997. 

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