Cyclization atom-transfer

Scheme 3.25. Dioxatriquinanes by triethylborane-induced domino radical atom transfer/ cyclization of 1,5-diynes.

Iodocarbonyls are excellent substrates for atom transfer cyclization, as shown by examples from our recent work in Scheme 29.19-129 When two carbonyl (or cyano) groups are present, bromides can also serve as radical precursors. Photolysis with 10% ditin usually provides excellent yields of kinetic products at high concentration, and alkene substituents often dictate the regioselectivity. The y-iodo ester products are particularly versatile for subsequent transformations, which can often be conducted in situ. Although tertiary iodine products sometimes go on to give lactones or alkenes, primary and secondary iodides can often be isolated if desired. The last example is particularly noteworthy the kinetic product from the cyclization presented in Scheme 27 is trapped, because bromine atom transfer is much more rapid that reverse cyclization. 

Iodine atom transfer reactions between alkyl radicals and iodocarbonyls are very rapid (107 M-1 s-1 to 109 M-1 s-1).130 This means that, even when these iodides are cyclized by the tin hydride method, iodine atom transfer may supersede hydrogen transfer, and the reductively cyclized product will ultimately be derived from the reduction of a cyclic iodide. Tin hydride cyclizations of halocarbonyls also often require very low concentration to avoid reduction of the initial radical prior to cyclization. For these reasons, reductively cyclized products are best formed by atom transfer cyclization at high concentration, followed by reduction of the product in situ. In a recent full paper, we have described in detail the preparative and mechanistic features of these cyclizations,19 and Jolly and Livinghouse have reported a modification of our reaction conditions that appears to be especially useful for substrates that cyclize very slowly.131 Cyclizations of a-iodocarbonyls can also be promoted by palladium.132... 

Indium trichloride was identified as an efficient catalyst for the atom-transfer cyclization of allylic halides with an alkyne pendant [(42) (43)]. Mechanistic evidence... 

Treatment of 4-pentenyl iodoacetate (221) with bis(tributyltin) at room temperature under irradiation with a sun lamp generates 7-iodoheptanolactone (222a), which is an atom-transfer cyclization product (eq. 3.87) [234]. 

Chiral Lewis acid-catalyzed atom-transfer cyclization is performed by the reaction of a-bromo-a-methyl-(3-keto esters (46) in the presence of Mg(C104)2 and a chiral ligand such as Z fsoxazoline, initiated by Et3B, as shown in eq. 10.22. The Lewis acid promotes not only the atom-transfer radical cyclization, but also high stereoselectivity through the chelation onto Mg2+. Intermediate [X] is a plausible chelated radical intermediate. 

Fe(II)-Fe(III) Catalysis Kharasch Additions and Atom Transfer Cyclizations 210... 

Fig. 39 Pd-catalyzed iodine atom transfer cyclization reactions...

Intramolecular 1,5-hydrogen atom transfer cyclizations.3 In reactions with low concentrations of the tin hydride (14,313), an original vinyl radical can undergo a 1,5-hydrogen shift to produce a new radical from a C—H bond, which then undergoes cyclization (equation I). 

A key intermediate in the synthesis of pretazettine (Eq. 8), an alkaloid that contains a ds-3a-arylhydroindole ring system and shows antiviral and anticancer properties, has been synthesized by chlorine-atom transfer cyclization of a chloroacetamide in a highly stereocontrolled manner [25]. 

Both complexes 12 and 13 are active toward atom-transfer cyclization of N-allyltrichloracetamides [40]. Of particular interest is the synthesis of a pyrrozi-lidine alkaloid skeleton. Much milder conditions are needed when using ruthenium-based catalysts instead of copper derivatives, although a high catalyst loading (30 mol %) is still required. Thus, an N-functionalized vinyl pyrrolidine is smoothly converted at room temperature into a bicyclic lactam, in 90% and 85% yield with complexes 12 and 13, respectively. The product is a precursor of the pyrrozilidine alkaloids trachelantamidine and pseudohehotridane (Eq. 10). 

Some free-radical cyclization reactions require only a catalytic amount of BusSnH or Bu3SnSnBu3. Such a reaction, instead of replacing a C-X bond with a OH bond, simply relocates the X atom. These atom transfer cyclizations differ from more conventional free-radical cyclizations in that the last step in the propagation involves abstraction of X- from a C-X bond not by -SnBu3 but by the cyclized starting material. The last step is kinetically viable only when a stronger bond is made from a weaker one. In the following example, a Si-1 bond is made at the expense of a OI bond. 

Using supported ditin compounds, it is possible to promote free radical addition of organic iodides to ttiple bonds and atom transfer cyclization of e-unsaturated iodoacetates or iodoamides using UV irradiation. In this latter case, tin contamination was found to be 5-34 ppm using 0.1 eq. of ditin reagent, and recycling of the tin reagent was also possible. 

Scheme 5.8.13 Catalytic atom transfer cyclization with resin-bound reagent...

Atom-transfer cyclization proceeded smoothly (Scheme 11.62) [87] as did radical cyclization of acylgermanes [88]. 

The atom-transfer cyclizations of 2-iodo-6-heptyne amides substituted with a chiral sultam derivative yield E Z mixtures of vinyl iodides38. The reductive dehalogcnation with tributyltin hydride and subsequent desilylation gives two diastereomeric methylenecyclopentanes in a ratio of 90 10. 

A synthetic pathway to trachelanthamidine. the C-7 epimer of isoretronecanol, is the radical cyclization of a chiral 2-vinylpyrrolidine derivative72. The atom-transfer cyclization affords the fAot.v-pyrrolidizinone, hence, introducing the opposite relative configuration when compared to the cyclization of the bridgehead a-acylamino radicals. 

Phenyl selenide transfer radical addition reactions can be limited by the lack of reactivity observed in some precursors. Simple alkyl phenyl selenides do not undergo inter- or intramolecular radical additions to olefins. Phenylselenotrichloromethane will add to olefins upon photolysis, and the products formed can be elaborated into a, ff-unsaturated carboxylic acids (Scheme 20) [57], Benzyl phenylselenides have been observed to undergo atom transfer cyclization (Scheme 20) [58]. 

In a similar process, the a-chloro-a-thioacetamide 37 leads to the pyrrolizidines 38 and 39 upon chlorine atom-transfer cyclization initiated by catalytic ruthenium chloride (Eq. 2). The high efficiency of this method, which was applied to alkaloid synthesis, was attributed to the captodative effect [30],... 

Our own efforts began with failure. Inspired by the radical addition-atom transfer-cyclization-fragmentation sequence reported by Heiba (Eq. 1) [5], we attempted the... 

Scheme 51), Weavers utilized direct formation of the a-iodomethylene-y-butyrolactone 148 from the propiolate 147 via atom transfer cyclization. Alke-noyloxymethyl iodides and selenides were converted into lactones upon treatment with tributylstannane or tributylgermane [101], In the (—)-zearalenone (152) synthesis reported by Pattenden [102] (Scheme 52), the ester tether is a bystander in the radical macrocyclization. 

In contrast to the parent hydrocarbon, cyclopenta-TMMs of general structure 8 (Fig. 2) have proven very useful in a number of contexts that call for their use in organic synthesis. There exist five fundamentally different reactivity patterns that characterize their chemistry (Scheme 1). With the exception of dimerization [9], each is discussed in the sections that follow. The other reactions include eyclo-addition (19 + 20—>21) [10], atom transfer-cyclization (9 to 11) [11], fragmenta-tion-cyclization (12 15 and/or 16) [12], and interception of a dipolar diyl 17 with water and/or alcohols [13]. 

Figure 6. Schematic representation of atom transfer cyclization...

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