Tri-n-butyltin Hydride-Mediated Radical Reactions of ortho-and meta-Iodobenzamides to Synthesize Benzomacrolactams . Surprising Formation of Biphenyl Compounds from meta-Regioisomers

Reações de 4-O-alil-2,3-di-O-benzil-6-desoxi-6-(3-iodobenzoilamino)-α-D-galactopiranosídeo de metila, seu epímero glico, 2,3-di-O-benzil-6-desoxi-6-(3-iodobenzoilamino)-4-O-(1-pentenil)α-D-glicopiranosídeo de metila e seu regioisômero orto-iodobenzamida com hidreto de trin-butilestanho foram realizadas em diferentes condições. Dependendo das condições, os três precursores que contêm o átomo de iodo em posição meta conduziram a uma surpreendente quantidade de compostos bifenílicos, nos quais o átomo de iodo foi substituído por um grupo fenila. O substrato 2-iodobenzamida levou apenas ao produto de hidrogenólise. Nenhum produto ciclizado foi isolado de nenhuma das reações. As estruturas dos compostos bifenílicos inéditos foram elucidadas utilizando-se as espectrometrias de massa, de RMN H e C e experimentos DEPT, COSY, HMQC e HMBC. Foram propostos mecanismos de formação dos compostos bifenílicos e hipóteses para explicar os diferentes comportamentos dos isômeros ortoe metaiodobenzamidas na reação radicalar.

The radical reactions were performed in the usual way 20,30 with slow addition (1.5 to 5 h) of a solution mixture of Bu 3 SnH (1.5 molar equivalents) and catalytic amount of AIBN to a solution of 5, 6, 9 and 10 at concentrations ranging from 0.003 to 0.012 mol L -1 (Table 1).The products formed (16, 17, 18, 19, 20 and 21) and recovered (6) (Scheme 1) were isolated after solvent elimination and column chromatography.
As shown in table 1, different reaction conditions with variable dilution, addition time and solvent were attempted for the synthesis of the macrocycles.Using benzene as solvent, lower dilution (substrate concentration: 0.08 and 0.012) and faster addition of the Bu 3 SnH/AIBN mixture (1.5 h) only the uncyclized reduced products (16 and 18 )  were isolated in the reactions of 5, 9 and 10 (entries 1, 6 and 10, Table 1).Since higher dilution and longer addition time are recommended to improve the formation of cyclized products and to decrease the rate of hydrogen atom transfer to uncyclized radicals, 20,30 using benzene as solvent, the addition of Bu 3 SnH/AIBN solution was made over a longer period (3 to 5 h) and a higher dilution (0.003 mol L -1 in 5; 0.004 mol L -1 in 6, 9 and 10) (entries 2, 5, 7 and 11, Table 1).Surprisingly, in these conditions, the biphenyl compounds 19, 20 and 21, yielded by intermolecular reaction of the aryl radical with bezene, were the only products formed at a sufficient amount for isolation from the three metaiodobenzamides 5, 6 and 9. On the other hand, at the same reaction conditions the ortho-iodobenzamide 10 only led to the hydrogenolysis product 18.In an attempt to avoid the formation of the biphenyl products and to favour the desired cyclization, the reactions of 5 and 9 were carried out in cyclohexane 30,31 (entries 3 and 8, Table 1) and the reaction of 9 was also developed in acetonitrile 32 (entry 9, Table 1).When it was necessary for dissolution of the substrates and Bu 3 SnH/AIBN, a small amount of benzene was added and the dilution was made with cyclohexane or acetonitrile to give a reaction mixture of 0.003 and 0.004 mol L -1 in meta-iodobenzamides 5 and 9 respectively.Only the hydrogenolysis product 16 (71%) and 18 (97% and 55%) were isolated after column chromatography.In contrast with the other substrates, the 3-iodobenzamide 6 also produced the biphenyl product 20 in the reaction carried out in substrate concentration of 0.008 mol L -1 and addition time of 2 h (entry 4, Table 1).No cyclized product was isolated in any reaction.
The biphenyl compounds 19, 20 and 21 are products of homolytic intermolecular aromatic substitution reactions between the radicals of benzamides 5, 6 and 9 (generated by tri-n-butyltin radicals) and benzene, the solvent.The mechanisms of Bu 3 SnH-mediated homolytic aromatic substitution presented in the literature 31,33 can be applied to explain the formation of the unexpected biphenyl products.These mechanisms are shown in scheme 2. The first step proceeds by addition of the initial radical of the benzamides 5, 6 and 9 to the benzene (solvent) to yield the π radical A. 31,33 Disproportionation of A or hydrogen-atom transfer from Bu 3 SnH leads to the intermediate B and its isomers, which can undergo oxidation by oxygen on workup (path a). 31 Whilst oxidation during workup may be plausible, dihydro-type systems, such B, are not oxidized rapidly in air 31 and the yield of the biphenyl compound 21 was higher than 50% (67%), as occur frequently in this kind of reaction. 31These facts ruled out the path a as the main mechanism.Hydrogen-atom transfer of π radical A to other radicals present in the reaction mixture, 31,33 mainly 2-cyanoprop-2-yl radical furnished by the radical initiator AIBN, 31 appears to be the predominant reaction to yield biphenyl compounds (path b). 31,33Addition of reactive aryl radical to the solvent may compete effectively with the desired chain-transfer processes for reactions involving very low concentrations of substrate. 30,31,34However, to the best of our knowledge, in the literature there are no biphenyl compounds obtained as main product by the Bu 3 SnH method, as described here.
Initially, we were surprised by the total lack of cyclization of benzamides 5 and 6 because there are a number of reports in the literature of successful 12-endo cyclization 12,20 and no obvious reason was apparent for the difference between these results and those previously published for their orthoisomers 1 and 2. 6,7 However, two hypotheses can be presented to explain the difference between the Bu 3 SnH-mediated reaction of the ortho-iodobenzamides (1 and 2) and the meta-iodobenzamides (5 and 6).
The importance of conformational pre-organization in successful macrocyclization reactions is well known. 1 It is also recognized the role of intramolecular weak forces and structural elements in the pre-organization that facilitates macrocyclization reactions. 5,13In our previous papers we considered that the cyclization reactions were favoured by the conformational restriction present in the precursors due to the amide bond, the sugar moiety and the presence of a hydrogen bond formed between the hydrogen atom of the amide group and the oxygen atom of the allyloxy group. 6,7,9,35The lack of cyclization products from radical reactions of 5 and 6 can indicate that the restricted rotation around the aryl-carbonyl bond present in 1 and 2 due to the iodine atom ortho to the amide group 36,37 also contributes to give a pre-organization to favour the ring closure.Despite this conformational restriction being absent in the aryl radicals, it is assumed that the relative amounts of Scheme 2. Mechanisms proposed for the formation of biphenyl compounds.
the aryl radical rotamers is determined by the equilibrium concentrations of the starting rotamers due to the short lifetime of the radicals. 37Probably, in the benzamides 5 and 6, and consequently in the aryl radicals formed, there would be a great number of rotamers due to the absence of conformational restriction around the aryl-carbonyl bond.The absence of conformational restriction for pre-organized structure in compounds 5 and 6 could therefore explain the observed results.
Another possible explanation for the absence of cyclization products from 5 and 6, in contrast with the radical reaction of 1 and 2, can be attributed to insufficient proximity of the terminal carbon of allyloxy group to the attacking aryl radical.This hypothesis is supported by the fact that no report to date of Bu 3 SnH-mediated aryl radical cyclization from meta-haloarenes to give products in which the formed rings have smaller than fourteen members.We found only two meta-haloarenes as precursors of 14-and 17-membered macrocycles. 13n order to verify if this second hypothesis is consistent and considering that a 14-membered lactam was obtained from a meta-bromobenzene derivative, 13 we decided to apply the Bu 3 SnH-mediated radical reaction to the methyl (9).The meta-iodo derivative 9, which presents a longer alkenylic chain than 6, could give the 14-membered benzomacrolactam 11, formed by endo cyclization mode.Aiming at completing the observations in comparing ciclizations of ortho-and meta-iodo isomers, the ortho-iodobenzamide 10 was also synthesized and submitted to the reaction with Bu 3 SnH to give the 13-membered lactam 12 (Figure 2).
The reactions with 9 were carried out in four different conditions (entries 6-9, Table 1) but cyclization also failed.Only the uncyclized reduced product 18 and the new biphenyl compound 21 were isolated (Scheme 1).The ortho-isomer 10, with a pentenyl group replacing the allyl group of 1, was submitted to the reaction with Bu 3 SnH in two different conditions (entries 10 and 11, Table 1) and gave only the hydrogenolysis compound 18 (Scheme 1).
The absence of biphenyl compound from 10 can be easily explained taking into account the steric hindrance effect caused by the large substituent in ortho position to the aryl radical.The lack of cyclized product in the reactions of 9 can be attributed to the greater conformational freedom of the pentenyl group, which has larger alkyl chain than allyl group present in the C-4 of 1. Bearing in mind that the ortho-iodobenzamide 10 didn't provide the expected macrolactam, we can not judge whether the distance between the aryl radical and the terminal carbon of the allyl group bounded to C-4 of 5 and 6 was the factor that prevented the formation of cyclized products.
The hydrogenolysis products 16, 17 and 18 were readily identified from their 1 H and 13 C NMR data.The structural elucidation of 19, 20 and 21 required a detailed analysis of the NMR spectra ( 1 H, 13 C and DEPT) and connectivity studies by COSY, HMQC and HMBC experiments.For instance, the 1 H NMR spectrum of 19 indicates the presence of five aromatic hydrogen atoms more deshielded than the other fourteen aromatic hydrogen atoms.These five hydrogen atoms are assigned as the hydrogens ortho to the both carbonyl and phenyl groups (d 7.97, t, 1H), para to the carbonyl group (d 7.71, dt, 1H), ortho to the carbonyl group (d 7.67, dt, 1H) and ortho to the benzamide group (d 7.58, d, 2H).The 13 C NMR and DEPT spectra demonstrate the presence of five ipso carbons.Two of these ipso carbon atoms show chemical shifts compatibles with biphenyl group (d 141.7 and 140.1).Signals of allyloxy and benzyloxy groups, methyl galactopyranoside moiety and benzamide were also observed.Similar pattern is observed in the spectra of 20 and 21.
The electrospray ionization mass and tandem mass spectra in the positive ion mode [ESI-MS(/MS)] were also found to be compatible with the formation of 19, 20 and 21.For instance, the ESI-MS of 19 shows major ions due to protonated and cationized molecule (Figure 3A 3B) is also consistent with the proposed structure 19 since it shows dissociation that can be easily rationalized for the proposed structure (Scheme 3) and occur mainly by the consecutive losses of CH 3 OH (m/z 562) and PhCH 2 OH (m/z 454).

General methods
All melting points were determined on a Microquimica MQAPF-301 apparatus and are uncorrected.Optical rotations were determined at 25 o C with a Perkin Elmer 341 Polarimeter.The IR spectra were recorded on an ATR-IR, Spectum One, Perkin Elmer spectrometer.The NMR spectra were measured in deuteriochloroform with TMS as the internal standard with a Bruker Avance DRX-400 or a Bruker Avance-200 instruments.Chemical shifts are given in d scale and J values are given in Hz.ESI(+)-MS spectra were obtained using a Micromass QTof hybrid quadrupole time-of-flight mass spectrometer operating at 7.000 mass resolution and 5 ppm mass accuracy using typical analytical conditions as described elsewhere. 38ESI-MS and ESI-MS/MS were acquired in a QTof Waters Micromass mass spectrometer using positive ion mode from 1:1 H 2 O-MeOH solutions with addition of a few microlitres of formic acid, and using the following basic operation conditions: capillary and cone voltages were set to 3500 V and 45 V, respectively, with a de-solvation temperature of 100 o C. For the tandem MS experiments, 15 eV collisions with argon were used.The solutions were infused directly into the ESI source by means of syringe pump (Harvard Apparatus) at a flow rate of 10 μL min -1 .Column chromatography was performed with silica gel 60, 70-230 mesh (Merck).The term "standard work-up" means that the organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure.The synthesis and characterization of the known derivatives 13a, 13b, 14a, 14b, 15a and 15b from the corresponding methyl α-D-gluco(or galacto)pyranoside were described in previous publications. 6,7

Radical reaction of compounds 5, 6, 9 and 10
To a stirring and boiling solution of 0.31 mmol of benzamide (0.20 g for 5 and 6; 0,21 g for 9 and 10) in nitrogen-saturated dry solvent was slowly added a solution of Bu 3 SnH (0.13 mL, 0.14 g, 0.47 mmol) and AIBN (ca.20 mg) in nitrogen-saturated dry solvent (from 10 to 15% of the total volume) via an addition funnel.The reaction mixture was heated under reflux and nitrogen atmosphere for a further 1 h.Subsequent solvent removal and column chromatography (silica gel and 10% m/m of KF) gave the compounds 6, 16, 17, 18, 19, 20 and 21, that were eluted with a mixture of hexane:ethyl acetate.Details of each reaction are shown in the table 2.
The biphenyl compound 19 was obtained as a white solid; mp 28.1-29.

Figure 2 .
Figure 2. Structures of iodobenzamides and their expected cyclized products.

Figure 3 .Scheme 3 .
Figure 3. A: ESI-MS of product 19; B: ESI-MS/MS of the protonated molecules of 19.Ions marked by an asterisk are fragments due to CH 3 OH and PhCH 2 OH loss that arise likely from in-source collision-induced dissociation.

Table 2 .
The Bu 3 SnH-mediated reactions of compounds 5