Bu 3 SnH-mediated cyclopropyl radical cyclizations onto indole-3-carbaldehyde

1-[ ω -(2-Bromocyclopropyl)alkyl]-1 H -indole-3-carbaldehydes and benzimidazole analogues were obtained in ~80% yield via the decomposition of Barton ester intermediates. The bromo-indolecarbaldehydes were precursors for Bu 3 SnH-mediated five-and seven-membered cyclopropyl radical intramolecular aromatic substitutions giving cyclopropane-fused adducts in ~55% yields. The cyclization yields are greater than via the direct decomposition of the Barton esters. X-ray crystal structures of 1-[(2-bromocyclopropyl)- trans -methyl]-1 H -benzimidazole , 1,1 a ,2,8 b -tetrahydrocyclopropa[3,4]pyrrolo[1,2-a ]indole-8-carbaldehyde and 1,1 a ,2,3,4,10 b - hexahydrocyclopropa[3,4]azepino[1,2-a ]indole-10-carbaldehyde are included


Introduction
Recently, we reported the first radical cyclizations to give cyclopropane-fused heterocycles, as shown in Scheme 1. 1 Initiator-free intramolecular aromatic substitutions of nucleophilic alkyl and cyclopropyl radicals onto the 2-position of indole-3-carbaldehyde, indole-3-carbonitrile, and benzimidazoles were accomplished.The radicals were generated via the combined thermal and photochemical decomposition of Barton ester {pyridine-2-thione-N-oxycarbonyl (PTOC) or Oacyl thiohydroxamate} 2 intermediates formed from carboxylic acids using the Garner coupling reagent, HOTT (S-(1-oxido-2-pyridinyl)-1,1,3,3-tetramethylthiouronium hexafluorophosphate). 3 All six-membered radical cyclizations were high yielding (~80%), but the more challenging five and seven-membered cyclizations were found to give lower yields (<50%), with the exception of (i) the five-membered alkyl and cyclopropyl radical cyclizations onto indole-3-carbonitrile, which occurred in 75 and 78% yields respectively, and (ii) the seven-membered alkyl radical cyclization onto indole-3-carbonitrile gave a 61% yield.The structures of the indole fivemembered cyclization adducts correspond to the skeleton of Moody's cyclopropamitosene, a hypoxic tumor cell selective cytotoxin, 4 which was previously prepared using intramolecular 1,3-dipolar [3+2] cycloaddition methodology. 5In this article, we disclose that yields for formation of five-and seven-membered rings using cyclopropyl radical cyclizations onto indole-3carbaldehyde are greater when using the conventional Bu 3 SnH and AIBN (2,2'-azobis(2methylpropionitrile)) protocol for intramolecular aromatic substitutions from bromide precursors. 6,7The synthesis of new cyclopropyl bromide radical precursors formed via the decomposition of Barton esters is detailed, as well as our initial investigations into optimizing the conversions of carboxylic acids 1 to Barton esters.The inherent light and hydrolytic sensitivity of the required Barton esters led to difficulty in the clean isolation of these intermediates.As the starting carboxylic acid can be recovered upon inefficient decarboxylation and subsequent hydrolysis of the intermediate Barton ester, it was decided to test the efficiency of the Barton ester formation and radical decarboxylation by carrying out reactions in the presence of a large excess of bromotrichloromethane (~50 equiv.).The resulting cyclopropyl bromides were then utilized as precursors for investigating the Bu 3 SnH-mediated five-and seven-membered radical cyclization reactions onto indole-3carbaldehyde and benzimidazole.Many of the established methods for forming Barton esters were surveyed including generating the acid chloride and mixed anhydride, 8 and the Bu 3 P and 2,2'-dithiopyridine N-oxide method reported for other three-membered radical cyclizations onto indole. 9However, only two methods were found to be successful in allowing reasonable conversion of the carboxylic acid into the Barton ester.The first method was the traditional DCC-mediated coupling, which allowed acid 1a to react with N-hydroxy-2-pyridinethione (in the absence of light) followed by the trapping of the generated intermediate radical with excess BrCCl 3 , as shown in Scheme 2. It should be noted that elevated temperatures (chloroform under reflux) were required to facilitate the decarboxylation to cyclopropyl radicals, in agreement with reported slow decarboxylations of Barton esters to high energy aromatic and vinyl radicals. 8eparable bromide isomers 4a and 4b were isolated in 54% overall yield, however N-acylurea 5 from the rearrangement of the intermediate O-acylisourea was also obtained in 32% yield.The attempted DCC-mediated reaction on the analogous benzimidazole carboxylic acid 1b using the same conditions (shown in Scheme 2) was unsuccessful, leading to recovery of starting material.HOTT allowed for easier conversion of carboxylic acids into the Barton esters. 3Prior to the heating (radical initiation) step, a sample of the 1a HOTT-reaction was taken as evidence for Barton ester intermediate 6 formation (Scheme 3), and shown to have NMR signals consistent with literature Barton esters (see Experimental Section and Supplementary Material). 10HOTT allowed the formation of isomeric bromides of indole-3-carbaldehyde 4a and 4b, and benzimidazole 7a and 7b in superior overall yields (~80%, Scheme 3).The efficiency of Barton ester formation from benzimidazole acid 1b was optimized by addition of a catalytic amount of DMAP.The trans-isomers 4b and 7b were found to be the major products, as confirmed using the X-ray crystal structure of the benzimidazole bromide 7b (Supplementary Material, Figure S1).Homolytic aromatic substitutions carried out in the presence of Bu 3 SnH and azo-initiator are now thought to proceed via a non-chain mechanism requiring excess initiator. 6Aromatic substitutions are often improved by exposure to air (oxygen), 7 although no improvements in yield were observed in this case when a non-inert atmosphere was used.After attempting several conditions, we found that cyclization conditions similar to the reported Bu 3 SnH-mediated substitution of alkyl radicals onto indole-3-carbaldehyde, 11 provided optimal yields of cyclopropapyrrolo[1,2-a]indole-3-carbaldehyde 2a of 55% along with 26% yield of Bu 3 SnHreduced adduct 3a, as shown in Scheme 4. This compares favorably to the yield of 2a derived from the protocol in Scheme 1, where 2a and 3a were obtained in 38% and 43% yields respectively, 1 although it should be noted that the Scheme 1 protocol is a direct route from the carboxylic acid 1a, requiring no prior bromide radical precursor synthesis.The Bu 3 SnHmediated radical cyclization using the benzimidazole analogue bromides 7a-7b was however unsuccessful, although cyclopropapyrrolo[1,2-a]benzimidazole 2b could be obtained via the Scheme 1 protocol in 44% yield together with 40% yield of reduced product 3b. 1 Radical reduction through hydrogen-abstraction from the reaction solvent is the most likely explanation for 3b in the absence of Bu 3 SnH.The presence of camphorsulfonic acid (CSA) is necessary to protonate the N-3 of the imidazole ring, so activating it towards constrained radical cyclizations.
The success of the five-membered cyclopropyl radical cyclization onto indole-3carbaldehyde led us to investigate the seven-membered analogue, as shown in Scheme 5. Separable bromides 8a and 8b were obtained in 83% combined yield from carboxylic acid 1c via efficient HOTT-mediated Barton ester formation.Using the cyclization conditions in Scheme 4, bromides 8a-8b were converted into novel cyclopropane-fused adduct 1,1a,2,3,4,10bhexahydrocyclopropa [3,4]azepino[1,2-a]indole-10-carbaldehyde (2c) in 53% yield with 29% reduced cyclopropane 3c obtained.This compares favorably with yields of 39% and 38% of 2c and 3c obtained from carboxylic acid 1c using the one-pot Barton ester, and radical cyclization protocol in Scheme 1. X-ray crystal structures of cyclopropane-fused adducts 2a and 2c show exo-diastereomers; the crystal structure of azepino[1,2-a]indole 2c is shown in Figure 1.The reasons for improved yields using the Bu 3 SnH-mediated protocol for radical cyclizations onto indole-3-carbaldehyde remain unclear, and the use of different solvents and temperatures for reactions with and without initiators, makes the drawing of definitive explanations difficult.It is however well-documented that the addition-step of homolytic aromatic substitution (in this case the cyclization) is slow and reversible, 12 and it is plausible that initiator-derived radicals may intercept (or oxidize) the cyclized radical intermediate leading to higher yields of the aromatic substitution product, in comparison to the non-cyclized reduced product.It is noteworthy that the initiators had to be added over a relatively short-time of 5-15 minutes, in order to give the optimized cyclized yields reported.This supports the involvement of azo-initiator derived radicals in the aromatization process due to the rapid breakdown of AIBN at this reaction temperature (AIBN, t 1/2 < 2 min in toluene at 110 °C). 13The AIBN derived 2-cyano-2-propyl radical may be involved either in hydrogen abstraction from the cyclized radical to give directly the aromatic substitution product (oxidation) and/or via thermal breakdown of cyclized non-aromatic intermediates trapped by the 2-cyano-2-propyl radical. 14he latter may account for the requirement of prolonged (3 hour) heating of the reaction mixture in toluene under reflux after the addition of most of the initiators was completed, as previously observed in our related radical cyclizations. 7

Conclusions
To conclude, this work shows that five-and seven-membered cyclopropyl radical cyclizations can be used to access the cyclopropamitosene skeleton, and the ring expanded azepino[1,2-ARKAT-USA, Inc a]indole analogue in respectable yields.The transformations are another example of "oxidative" aromatic substitutions mediated by the "reductant" Bu 3 SnH.Included is a first report of a crystal structure of the cyclopropane-fused azepino[1,2-a]indole heterocyclic system.Overall, our radical cyclization pathways via Barton esters compare favorably with alternative cycloaddition protocols to these cyclopropane-fused heterocyclic systems.
The mixture was evaporated, dissolved in CHCl 3 (50 mL), and washed with water (3 x 25 mL).The organic extract was dried (Na 2 SO 4 ), evaporated and the residue purified by column chromatography using silica gel as adsorbent with a gradient elution of hexanes and EtOAc to yield ethyl cis-2′- [3-(3-
Supporting Information available.