Intermolecular addition

Mn(OAc)3 in AcOH at 60 °C oxidizes aldehydes RCH2CHO to RCH-CHO. These radicals add to alkenes to give radicals that abstract a hydrogen, or are oxidized to acetates or alkenes affording mixtures of limited synthetic utility [11a]. Similarly, Mn(OAc)3 in AcOH at 40-80 °C oxidizes acetophenone, acetone, cyclo-pentanone, cyclohexanone or other simple symmetrical ketones to a-keto radicals that add to alkenes leading to modest yields of coupled products [11a]. 

More complex products are obtained from cyclizations in which the oxidizable functionality and the alkene are present in the same molecule. y9-Keto esters have been used extensively for Mn(III)-based oxidative cyclizations and react with Mn(OAc)3 at room temperature or slightly above [4, 10, 11, 15], They may be cyclic or acyclic and may be a-unsubstituted or may contain an a-alkyl or chloro substituent. Cycloalkanones are formed if the unsaturated chain is attached to the ketone. y-Lactones are formed from allylic acetoacetates [10, 11]. Less acidic /3-keto amides have recently been used for the formation of lactams or cycloalkanones [37]. Malonic esters have also been widely used and form radicals at 60-80 °C. Cycloalkanes are formed if an unsaturated chain is attached to the a-position. y-Lactones are formed from allylic malonates [10, 11]. yff-Diketones have been used with some success for cyclizations to both alkenes and aromatic rings [10, 11]. Other acidic carbonyl compounds such as fi-keto acids, /3-keto sulfoxides, j8-keto sulfones, and P-nitro ketones have seen limited use [10, 11]. We have recently found that oxidative cyclizations of unsaturated ketones can be carried out in high yield in acetic acid at 80 °C if the ketone selectively enolizes to one side and the product cannot enolize 

High levels of asymmetric induction can be achieved in this and other cyclizations if the ethyl ester is replaced with a phenylmenthyl ester or dimethylpyrrolidine amide [41], The level of asymmetric induction can sometimes be improved by carrying these reactions out with Mn(OAc)3 and 0.2-1 equivalent of a lanthanide tri-flate in trifluoroethanol at 0°C [18]. Complete asymmetric induction can be achieved in modest yield by cyclization of enantiomerically pure /i-keto sulfoxides [42]. 

The utility of tandem oxidative cyclizations is clearly demonstrated in substrates in which both additions are to double bonds [10, 11, 46, 47]. Oxidative cyclization 

Application to natural product synthesis. The application of Mn(III)-mediated radical reactions to natural product total synthesis provides an excellent demonstration of the scope and utility of these reactions since the method must be versatile enough to deal with complex skeletons and diverse functionality. Many examples of the use of Mn(III)-mediated radical reactions have already been presented above. Some other notable examples are described below. 

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The selective intermolecular addition of two different ketones or aldehydes can sometimes be achieved without protection of the enol, because different carbonyl compounds behave differently. For example, attempts to condense acetaldehyde with benzophenone fail. Only self-condensation of acetaldehyde is observed, because the carbonyl group of benzophenone is not sufficiently electrophilic. With acetone instead of benzophenone only fi-hydroxyketones are formed in good yield, if the aldehyde is slowly added to the basic ketone solution. Aldols are not produced. This result can be generalized in the following way aldehydes have more reactive carbonyl groups than ketones, but enolates from ketones have a more nucleophilic carbon atom than enolates from aldehydes (G. Wittig, 1968). 

The hexabutyldistannane used in this reaction is not involved in the propagation sequence but may be involved in initiation or scavenging of potential chain-termination radicals. Intermolecular additions of alkyl radicals to alkynes have also been observed. 

A polyfluorinated P,y-unsaturated ketone is formed m situ from tributylamine and 3,4-bis(tnfluoromethyl)-3-(pentafluoroethyl)-5,5,6,6,6-pentafluoro-2-hex-anone. The enol form of the unsaturated ketone cyclizes via an intermolecular addition-elimination reaction that involves exclusive attack by oxygen rather than by carbon. This reaction demonstrates the hardness of a F-C= site toward... 

Although the enantioselective intermolecular addition of aliphatic alcohols to meso-epoxides with (salen)metal systems has not been reported, intramolecular asymmetric ring-opening of meso-epoxy alcohols has been demonstrated. By use of monomeric cobalt acetate catalyst 8, several complex cyclic and bicydic products can be accessed in highly enantioenriched form from the readily available meso-epoxy alcohols (Scheme 7.17) [32]. 

Almost 15 years ago Sakurai and Hosomi, in pioneering work, showed that intermolecular addition of an allylsilane to a,j6-unsaturated ketones in the presence of titanium(IV) chloride as the Lewis acid gave the desired 1,4-addition products1 4. In the case of 4,4a,5,6,7,8-hexahy-dro-2(3//)-naphthalenone, reaction was shown to proceed by 1,4-addition with exclusive production of the ris-fused product in high chemical yield. 

I.5.2.4.5. Formation of Stereogenic Centers After the Michael Addition Step I.5.2.4.5.I. Intermolecular Additions... 

Intramolecular eyclization is subject to the same factors as intermolecular addition (see 2.3). However, stereoelectronic factors achieve greater significance because the relative positions of the radical and double bond are constrained by being part of the one molecule (see 2.3.4) and can lead to head addition being the preferred pathway for the intramolecular step. 

In 1997, the intermolecular addition of organolithium reagents to fluoro-alkynylsilanes was used to synthesize three novel, stable 1-silaallenes. In this... 

West et al. have recently described the synthesis and reactions of a 1-germaallene. Germaallene 76 (Eq. (7)) is analogous to silaallene 59a and is synthesized by intermolecular addition of f-butyllithium to precursor 75, followed by salt elimination at —78 C. This germaallene is not stable above 0 C in solution, but remains intact until heated above 90°C in the solid state. In either case, the... 

Choi and Sakakura et al. reported that iron(III) triflate, in situ formed from FeCls and triflic acid, efficiently catalyzes the intermolecular addition of carboxylic acids to various alkenes to yield carboxylic esters. The reaction is applicable to the synthesis of unstable esters, such as acrylates (Scheme 40) [50]. 

Scheme 40 Iron(III)-catalyzed intermolecular addition of carboxylic acids to alkenes...

Intramolecular reactions usually dominate intermolecular addition for favorable ring sizes. Semiempirical (AMI) calculations found the intramolecular TS favorable to a comparable intermolecular reaction.68 (See Figure 4.1) The intramolecular TS, which is nearly 4 kcal/mol more stable, is quite productlike with a C—O bond distance of 1.6 A, and a bond order of 0.62. The bromonium ion bridging is unsymmetrical and fairly weak. The bond parameters for the intra- and intermolecular TSs are quite similar. 

As with carbocation-initiated polyene cyclizations, radical cyclizations can proceed through several successive steps if the steric and electronic properties of the reactant provide potential reaction sites. Cyclization may be followed by a second intramolecular step or by an intermolecular addition or alkylation. Intermediate radicals can be constructed so that hydrogen atom transfer can occur as part of the overall process. For example, 2-bromohexenes having radical stabilizing substituents at C(6) can undergo cyclization after a hydrogen atom transfer step.348... 

The structure of the reagent, the mechanism of epoxide opening, deoxygenations, dimerizations and intermolecular additions will be discussed first before covering the preparatively much more important cyclization reactions [36]. 

Malacria has reported the use of epoxysilanes for intermolecular addition reactions to acrylates, acrylonitrile and vinylsulfones [56]. 

As in the case of the intermolecular additions the cycbzations are tolerant to a wide range of functional groups. The mechanism of the cycbzations and two examples of the synthesis of more complex products are shown in Scheme 11. 

Sakurai et al. have provided what is probably the most important mechanistic finding in the area of intermolecular additions of silenes in recent years, namely a detailed proposal for the mechanism of alcohol addition to the silicon-carbon double bond.68 A cyclic silene 116 was synthesized in the presence of various amounts of methanol and other alcohols, and varying proportions of methanol adducts 117 and 118 were obtained. It was concluded that the methanolysis involved two steps, the first being the association of the oxygen lone pairs with the sp 2-hybridized silicon atom of the silene. The second step, proton transfer, could occur in two ways. If the proton was transferred from the complexed methanol molecule (path a) its delivery would result in syn addition. However, if a second molecule of methanol participated (path b), it would deliver its proton... 

Although it is possible to trap the silanethione 40 by intermolecular addition reactions at —78°C (Scheme 12), the combination of Tbt and Mes groups is not efficient enough to stabilize the silathiocarbonyl unit as stable compounds at ambient temperature. 

One of the first enantioselective transition metal-catalyzed domino reactions in natural product synthesis leading to vitamin E (0-23) was developed by Tietze and coworkers (Scheme 0.7) [18]. This transformation is based on a Pdn-catalyzed addition of a phenolic hydroxyl group to a C-C-double bond in 0-20 in the presence of the chiral ligand 0-24, followed by an intermolecular addition of the formed Pd-spe-cies to another double bond. 

In a more recent contribution, O Shea and coworkers described a related process leading to substituted indoles 2-544 and 2-545 by an intermolecular addition of alkyllithium to a styrene double bond and reaction of the formed intermediate 2-543 with an appropriate electrophile (Scheme 2.123) [285]. Using DMF, C-2 unsub-... 

Bailey s group has elaborated a fourfold anionic domino approach leading to a N-allyl-3,4-disubstituted indoline 2-582 from 2-580 (Scheme 2.131) [300]. The central step is the formation of an aryne by treatment of 2-fluoro-N,N-diallylaniline (2-580) with nBuLi followed by a regioselechve intermolecular addition of nBuLi to give 2-581. This then cyclizes to afford a new lithiated species which is intercepted by added TMSCI. 

A rather new concept in the context of domino radical cydizations has been developed by Gansauer and coworkers utilizing titanocene-complexes for the radical opening of unsaturated epoxides. The titanocene-catalyzed reactions [61] of 3-145 primarily led to radical 3-146, which underwent a subsequent intermolecular addition to a present a,(3-unsaturated carbonyl compound to form bicyclic carbocy-cles of type 3-148 via the intermediate 3-147 after aqueous work-up (Scheme 3.38) [62]. From a kinetic point of view, the reaction is remarkable since the intermolecular addition of simple radicals to a,(3-unsaturated carbonyl compounds is not an easy task, as highlighted above. 

Recently, Narasaka and co-workers have found that 1-nitroalkyl radicals are generated by oxidation of aci-nitroanions with CAN, and they undergo the intermolecular addition to electron-rich olefins.61 For example, when oxidation is carried out in the presence of silylenol ethers, (3-nitroketones are formed in good yield. (3-Nitroketones are readily converted into enones on treatment with base (see Section 7.3), as shown in Eq. 5.43. 

Intermolecular addition of photochemically generated nitrenes and in particular acylnitrenes to alkenes provides a useful and widely applied route to aziridines.385 An analogous intramolecular photoreaction is thought to be involved in the conversion of the o-azidophenylethylfuran 461 into the pyrrolo[l,2-a]quinoline 462 as outlined in Scheme 13,386 and intramolecular addition to an azo group has been observed in the 8-azido-1-arylazonaphthalenes 463.387... 

The product of the previous reaction provides a Baylis-Hillman type product via an intermolecular addition of an allenoate to an epoxide. The first example of a true Morita-Baylis-Hillman reaction of an epoxide has recently been reported <06CC2977>. Treatment of enone 34 with Me3P provides a good yield of the epoxide-opened product 35. The reaction must be carried out at low concentrations in order to avoid the generation of a variety of side products. When the terminal end of the epoxide is substituted (e.g. 34) the exo-mode of cyclization is the only product observed. When the terminal end of the epoxide is unsubstituted (e.g. 36), the endo-mode of cyclization predominates providing 37. 

The fruitful relationship between experiment and theory has pushed carbene chemistry further toward the direction of reaction control that is, regio- and stereoselectivity in intra- and intermolecular addition and insertion reactions. The interplay between experiment and modem spectroscopy has led to the characterization of many carbenes that are crucial to both an understanding and further development of this held. 

Intermolecular addition of activated methylenes to unsaturated systems has been investigated with silver,36 silver/ gold, and palladium catalysts. Thus, C-H addition of 2,4-pentandione to 1,3-cyclohexadiene occurs in THF at 0°C with 5mol% of palladium(ll) catalyst without base. Josiphos ligand 20 is used as a chirality source to induce... 

Although intermolecular additions to a,f5-unsaturated carbonyl compounds have not been used as often, these transformations are also attractive from a synthetic point of view for the synthesis of 5-lactones or 5-hydroxy esters. An example is shown in Scheme 12.11 [5d]. 

Scheme 12.11. Intermolecular addition to a,p-unsaturated carbonyl compounds.

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