Cyclizations of Acyl Radicals

This methodology has been extended to the synthesis of the C-16 to C-26 fragment of the natural product mucocin in 81% yield and 15 1 diastereoselectivity as shown in Eq. (13.3). This cyclization can also be carried out sequentially. The methodology was extended towards the synthesis of polycyclic natural products [9]. Both cyclization steps proceeded in greater than 90% yield with diastereomer ratios of 6 1 for the formation of 11 and 19 1 for the formation of 13. 

The acyl radical cyclizations have been cleverly applied to the synthesis of complex natural and unnatural products (Eq. (13.4)). In one example, tandem radical cyclization of 14 provides access to the steroidal skeleton. The reaction proceeds through a 6-endo-trig cyclization to form the A/B ring and a macrocycliza-tion/transannulation to establish the C/D ring [12]. More recently, a cascade cyclization initiated by an acyl radical has allowed for the establishment of fourteen chiral centers in a single step [13]. Once again the formation of the polycyclic compound 17 involves sequential 6-endo-trig reactions. 

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Scheme 7.4 Propagation steps involving the cyclization of acyl radicals...

Acyl radical has a nucleophilic character and cyclizes via SOMO-LUMO interaction. Eq. 3.22 shows the cyclization of acyl radicals formed from the reaction of selenol esters (67) with Bu3SnH/AIBN or Bu3SnH/Et3B, to give the cyclic ketones (68) via 5-exo-trig or 6-exo-trig manner through the transition state [II] [84-90]. 

Cyclization of acyl radicals can be carried out in high yields from acyl selenide precursors 991 without using high pressures of CO (Scheme 190) <2001TL7887>. 

Ryu developed a nitrogen-philic cyclization of acyl radicals onto N=C bond [74]. In this reaction, a polar component favors the selective reaction at the A -atom. This fully regioselective reaction led to an efficient synthesis of 2-pyrrolidinones (4+1 annulation, Scheme 26, Eq. 26.1) and piperidinones (5+1 annulation, Eq. 26.2). 

Boger and Mathvink [36] explored the 1-exo trig cyclization of acyl radicals using selenoesters as precursors. Reaction of the selenoesters 126 and 128 with BusSnH and AIBN furnished exclusively the benzocycloheptanones 127 and 129, respectively. 

This concept turned out to be useful for a variety of transformations, including reductions, epimerizations [14], hydrosilylations of alkenes, hydrostannations of al-kynes [15] and carbon-carbon bond formation [13]. As an example, thiols catalyze the cyclization of acyl radicals [16a] and masked acyl radicals [16b] these reactions have no preparative value in the absence of thiols because the nucleophilic radicals resulting from the cyclization step are not able to abstract efficiently a hydrogen atom from the starting material, whereas thiyl radicals can (Scheme 2). 

A search in the literature gave us a mechanistic picture for the cyclization of acyl radicals that is reported in Scheme 6 [37]. This disconcerting picture is derived from the contribution of several groups, some of whom are leaders in the field of free radical chemistry, in the last thirty years. However, the total absence of quantitative measurements together with a careful evaluation of the data that do exist, persuaded us to study in some detail the elementary steps of our polymer modification. 

The unexpected formation of cyclopenta[b]indole 3-339 and cyclohepta[b]indole derivatives has been observed by Bennasar and coworkers when a mixture of 2-in-dolylselenoester 3-333 and different alkene acceptors (e. g., 3-335) was subjected to nonreductive radical conditions (hexabutylditin, benzene, irradiation or TTMSS, AIBN) [132]. The process can be explained by considering the initial formation of acyl radical 3-334, which carries out an intermolecular radical addition onto the alkene 3-335, generating intermediate 3-336 (Scheme 3.81). Subsequent 5-erafo-trig cyclization leads to the formation of indoline radical 3-337, which finally is oxidized via an unknown mechanism (the involvement of AIBN with 3-338 as intermediate is proposed) to give the indole derivative 3-339. 

Acyl, carbonyloxy and related radical cyclizations are rapidly gaining prominence and appear to have excellent scope. Examples of 5-exo (bridged and fused), 6-endo (possibly through equilibration as in Scheme 21) and 6-exo cyclization106 have appeared. It is not presently clear whether the favorable ratios of cyclic to reduced products obtained with acyl radicals are due to inherendy high reactivity of acyl radicals towards cyclization or to low reactivity towards tin hydride (due to the relative weakness of the forming C—H bond). 

Among the oxidants that have been used to generate radicals, manganese (HI) acetate has emerged as a powerful reagent to mediate radical cyclizations.147 The manganese(III) acetate-mediated oxidation of enolizable carbonyl compounds is one of the best methods available for the cyclization of electrophilic radicals. The substrates are vety easily prepared by standard alkylation and acylation reactions. Radicals are formed with high selectivity by oxidation of acidic C—H bonds, and, because the reaction is an oxi-... 

Radical cyclization of acyl selenides 52 (Equation 19) leads to oxepanones 53, the main product (>95% in the mixture) being f-isomer and the best yields being obtained with (TMS)3SiH <1996JOC2252>. 

Among reports related to radicals, ab initio calculations have been used to model intramolecular additions of acyl radicals to imines.83 Imines and oxazolines bearing a pendant acyl radical at carbon have been cyclized to give 2-piperidones through a selective 6-emfo-cyclization at nitrogen.84 The acyl radical is generated via CO (g) insertion into a suitable precursor. A diastereoselective example is also reported. 

The cyclization of aminyl radical 5, produced by decomposition of tetrazene 4 (Scheme 1), was investigated, and products were analyzed by GC/MS comparisons to authentic materials. The results are summarized in Table 1 (83JA7759). It is important to note that no piperidine products were detected and that a 1 1 ratio of cyclic-to-acylic disproportionation... 

An intramolecular acyl radical cyclization of acyl selenide 1024 uses a (Z)-vinylogous sulfonate to control rotamer population, affording ry -2,6-disubstituted tetrahydropyran-4-one 1025, a key intermediate during synthesis of the tetrahydropyran unit of mucocin (Equation 399) <1997TL5249>. This methodology is also applicable to the synthesis of polycyclic ethers <1996JOC4880>. 

The ipso cyclization of an ort/io-(phenylsulfonyloxy)benzoyl radical generated by hydrogen abstraction from the corresponding aldehyde <98J(P1)67>, followed by rearomatization of the spirodienyl radical intermediate by elimination of sulfur dioxide constitutes an isolated example of acyl radical cyclization upon a benzene ring, developed by Motherwell for the synthesis of 2-hydroxyaryl aryl ketones <00TL9667>. 

Intramolecular trapping studies have verified the intermediacy of acyl radicals in the conversion of carboxylic acid chlorides to samarium acyl anions by Smli. Treatment of 2-allyloxybenzoyl chlorides with Sml2 resulted in a very rapid reaction, frtrni which cyclopropanol products could be isolated in yields of up to 60% (equation 8iy Apparently, initial formation of the acyl radical was followed by rapid radical cyclization. The 3-keto radical generated by this process undergoes cyclization by a radical or anionic process, affording the observed cyclopropanols (Section 1.9.2.3.1). 

A variety of indirect and direct methods are now available for ketone synthesis by radical reactions. Due to space limitations, this section will focus on selected topics, and only a few examples are shown for cases of frequently investigated approaches by acyl radical cyclizations. A recent review article on acyl radical chemistry provides a comprehensive survey of acyl radical cyclizations [la]. 

Several acyl radical clocks have been calibrated, and these are collected in a recent excellent review of the general subject [44]. Examples of the two types of unim-olecular clock reactions, decarbonylations and cyclizations, are shown in Fig. 7, with rate constants for reactions at ambient temperature. Decarbonylations of acyl radicals, as shown for radical 16 [45], and the related decarboxylations of alkox-ycarbonyl radicals such as 17 [2] have log A terms of about 13 for cases where alkyl radical products are formed [46, 47]. The decarbonylation reactions involve a reduction in charge separation in the transition states, and the kinetics are sensitive to solvent polarity with decreases in rates as polarity increases [45]. Cyclization reactions, such as that shown for radical 18, are complicated. The 5-exo products shown are the predominant first-formed products, but they further rearrange to the thermodynamically favored 6-endo products by addition of the radical center to the carbonyl group to give a cyclopropyloxyl radical followed by ring opening [48]. 

The second example in Table 5 shows the cyclization-carbonylation-allylation sequence, in which 5-hexenyl radical cyclization precedes CO trapping. Because of the nucleophilic nature of acyl radicals, in a mixed alkene system comprised of an electron deficient alkene and allyltin, they favor the electron deficient alkene first and the resulting product radical, which have an electrophilic character, and then smoothly add to allyltributyltin. This four-component coupling reaction provides a powerful radical cascade approach leading to y -functionalized, -unsaturated ketones, which are not readily accessible by other methods [52]. 

In 1988, Boger and co-worker found that the intramolecular free-radical cyclization reactions of acyl radicals generated from selenol esters proceeded efficiently, suppressing competing reduction and decarbonylation (Eq. 47) [98]. 

Irradiation of 99 in benzene at reflux gave 100 in high yields as the products of acyl radical cyclization with ArTe group transfer, along with an elimination product 101 (Eq. 68). 

Alkyl, alkenyl, aryl and acyl radicals can all be used in cyclization reactions. Acyl radicals can be generated by addition of alkyl radicals to carbon monoxide, or more conveniently from acyl selenides, and undergo a variety of radical reactions. A synthesis of the sesquiterpene (—)-kamausallene made use of the radical cyclization from the acyl selenide 69 (4.61). Tris(trimethylsilyl)silane and triethylborane in air were used to promote the reaction, which is highly selective (32 1) in favour of the cis stereoisomer 70, as expected from a chair-tike transition state. Best yields in the cyclization reactions of acyl radicals are found with electron-deficient alkenes, indicating the nucleophilic character of acyl radicals. 

Another example of cavity-directed synthesis is related to photocleavage of a-diketones in the cavity of a [M6L4] coordination cage, which results in unexpected cyclization products [39]. Under normal conditions, various degradation products are expected from hemolytic cleavage of a-diketones and formation of acyl radicals. In confined systems, however, kinetically unfavorable pathways without hemolytic cleavage became major pathways. 

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