Synthesis of Functionalized Cyclopropanes from Carboxylic Acids by a Radical Addition–Polar Cyclization Cascade

Abstract Herein, we describe the development of a photoredox‐catalyzed decarboxylative radical addition–polar cyclization cascade approach to functionalized cyclopropanes. Reductive termination of radical–polar crossover reactions between aliphatic carboxylic acids and electron‐deficient alkenes yielded carbanion intermediates that were intercepted in intramolecular alkylations with alkyl chlorides appended to the alkene substrate. The mild conditions, which make use of a readily available organic photocatalyst and visible light, were demonstrated to be amenable to a broad range of structurally complex carboxylic acids and a wide variety of chloroalkyl alkenes, demonstrating exquisite functional group tolerance.

Over the last decade,p hotoredox catalysis has been extensively explored. [1] Them ild conditions,h igh functional group tolerance,and diversity of compatible carbon-centered radical precursors,h as resulted in numerous synthetically valuable methodologies,p articularly in the area of alkene functionalization. [2] Them echanistic pathways of such reactions are dependent on the fate of the open-shell intermediate generated upon addition of aradical to the alkene substrate, which can undergo aradical-mediated bond-forming process (Scheme 1A,p ath 1) [3] or ar adical-polar crossover (Scheme 1A,path 2). [4,5] In the latter case,asingle-electron transfer (SET) event leads to acarbocation (oxidative termination) or ac arbanion (reductive termination), which can then react with an ucleophile or electrophile,r espectively.W hilst both processes have been extensively reported, in the case of reductive termination the anion generated has invariably been protonated (Scheme 1A,p ath 2, E = H). [5] We were interested in exploring whether the anion generated could be trapped by acarbon-based electrophile as this would be much more synthetically useful but has rarely been reported. [6] We recently reported ap hotoredox-catalyzed decarboxylative radical addition of carboxylic acids to vinyl boronic esters,p roceeding through ar adical-polar crossover with reductive termination to give an a-boryl anion. [7] We queried whether the catalytically-generated carbanions could undergo intramolecular alkylations with alkyl halides,a st his would provide ad ecarboxylative radical addition-polar cyclization cascade for the synthesis of cyclic boronic esters (Scheme 1B). [8] We were particularly interested in targeting cyclopropanes,a st hese strained carbocycles are highly valuable motifs in drug development and are common components of bioactive natural products. [9] Herein, we report the successful development of aphotoredox-catalyzed radical-polar crossover cyclopropanation, in which abroad range of readily available carboxylic acids are directly converted to structurally diverse cyclopropanes through decarboxylative reactions with chloroalkyl alkenes. During the preparation of this manuscript, Molander and coworkers reported ac yclopropanation of styrene derivatives using iodomethyl silicates that proceeds through ar adicalpolar crossover with intramolecular alkylation of an inter-mediate b-iodo anion. [10] Our process represents af ragment coupling approach, which is distinct from Molanders, and other, photoredox-catalyzed cyclopropanations that use carbenoid-like radicals to introduce aone-carbon unit in aformal [2+ +1] cycloaddition. [10,11] We began our investigation by studying the reaction of (4chlorobut-1-en-2-yl)boronicacid pinacol ester 1a(Scheme 2).
We were delighted to discover that irradiation of amixture of 1a,Boc-Pro-OH (2), and cesium carbonate in the presence of the iridium photocatalyst Ir(ppy) 2 (dtbbpy)PF 6 (3)l ed to the formation of cyclopropyl boronic ester 4a in 90 %y ield. Analysis of the crude reaction mixture confirmed that no hydrofunctionalization product 5 was formed, which highlights the high rate of intramolecular alkylation of the carbanion intermediate.R emarkably,i tw as found that 1mol %ofthe more economical cyanobenzene-based organic photocatalyst 4CzIPN (6)c ould promote the reaction with even higher efficiency than 3,p roviding cyclopropane 4a in quantitative yield. [12,13] Having identified optimal conditions,w eb egan to investigate the scope of the transformation with respect to other homoallyl chlorides 1 (Table 1). Thereaction was found to be amenable to adiverse range of electron-withdrawing groups, including carboxylate esters (4b), nitriles (4c), primary amides (4d), sulfones (4e), and phosphonate esters (4f), providing the cyclopropane products in excellent yields.T he methodology could also be applied to the preparation of vicinally disubstituted cyclopropanes 7 by using allyl chlorides 8.Boronic ester 7a was formed in moderate yield, which was attributed to the formation of allyl ester side-products by S N 2 displacement of the chloride of 8aby the carboxylate of 2.For allyl chloride substrates 8,the enhanced reactivity of the alkyl chloride towards O-alkylation resulted in ester formation becoming competitive with SET and decarboxylation. Switching solvents from DMF to CH 2 Cl 2 greatly reduced the amount of O-alkylation in the case of carboxylate ester and thioester substrates 8b and 8c,e nabling products 7b and 7c to be generated in high yields.Cyclopropanes 7a-c were formed in high diastereoselectivity with respect to the vicinal cyclopropyl substituents but with low stereocontrol at the pyrrolidine stereocenter,w hich is in keeping with ar adical-polar crossover process.T he reaction was not limited to the use of homoallyl chlorides bearing electron-withdrawing groups,a s styrene derivatives 1g-j were also capable substrates,with the stabilized benzylic radical intermediate undergoing efficient single-electron reduction prior to cyclization. Fore xample, cyclopropanes containing phenyl (4g)a nd naphthyl (4h) groups were accessed in high yields.F urthermore,t he reaction proved to be relatively insensitive to the electronics of the aromatic ring, with homoallyl chlorides functionalized with electron-deficient pyridines or electron-rich benzofurans yielding the corresponding heteroaromatic-substituted cyclopropanes 4i and 4j in 70 %and 68 %yield, respectively.
Next, we turned our attention to determining the generality of the reaction with respect to the carboxylic acid substrate (Table 2). Initially,w ef ocussed on the reaction of a-amino acids with 1a because of the potential for rapid access to cyclopropanated g-amino boronic acid derivatives.Further to boronic acid derivatives being highly valuable synthetic handles in organic synthesis, [14] they are also finding increased application as novel drug candidates. [15] We also applied the reactions to 1b to access cyclopropanated analogues of gamino butyric acid (GABA), the main inhibitory neurotransmitter in the mammalian nervous system. [16] Structurally diverse a-amino acids reacted efficiently with 1a to yield the corresponding cyclopropyl boronic esters,i ncluding those possessing various carbamoyl protecting groups (9a), as well as cyclic (10 a)a nd acyclic (11 a)a mino acids.B yu sing an increased catalyst loading of 2mol %, a-amino acids with ac arbamate NÀHg roup also reacted efficiently (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Increasing the size of the a-substituent from methyl to iso-Scheme 2. Optimized conditions. propyl to tert-butyl resulted in ag radual decrease in yield (products 12 a, 13 a and 14 a); however, N-Boc-protected tertleucine still reacted to give 14 a in synthetically useful yield. Primary and tertiary a-amino acids,B oc-Gly-OH and Boc-Aib-OH, also gave the desired products in reasonable yields (15 a and 16 a). Reaction of these lower yielding substrates with 1b led to substantially improved yields of methyl ester cyclopropanes 15 b and 16 b.T he higher yields obtained with carboxylate ester 1b compared to boronic ester 1a are in keeping with Carbonisobservations that acrylates react more rapidly with alkyl radicals than vinyl boronic esters. [17] Diversely functionalized amino acid substrates were tolerated, including those with aromatic and heteroaromatic rings, sulfides,e sters,a nd primary amides (products 17 a-21 a, 18 b  and 19 b). Dipeptides Z-Gly-Phe-OH and Z-Phe-Leu-OH were also viable substrates (products 22 a, 22 b and 23 a), demonstrating the success of this methodology in peptide modification.
We then proceeded to investigate aw ider range of carboxylic acids.T etrahydrofuran-2-carboxylic acid reacted efficiently with both homoallyl chlorides 1a and 1b,d emonstrating that a-oxy acids also function well under the optimized conditions (products 24 a and 24 b). This was also the case for simple secondary alkyl carboxylic acids,w ith 2methylheptanoic acid yielding cyclopropanes 25 a and 25 b in good yields.B is-cyclopropane product 26 b could also be prepared upon reaction of acyclopropylcarboxylic acid with 1b.T he poor yield of product 26 b reflects the challenges associated with the generation and subsequent addition reactions of cyclopropyl radicals. [18] Indeed, attempted reaction of the same cyclopropyl carboxylic acid with the less reactive alkenyl boronic ester 1a [17] only resulted in recovery of unreacted starting materials.S imilarly,p rimary alkyl carboxylic acids,i ncluding benzylic and non-benzylic,w ere found to be unreactive with 1a but reacted efficiently with 1b to give good yields of cyclopropanes 27 b and 28 b.
We then targeted more complex carboxylic acids as substrates for our reaction, with the aim of demonstrating its potential as avaluable method for late-stage diversification of bioactive natural products and drug molecules.T othis end, dehydroabietic acid underwent efficient reaction with both 1a and 1b to give the 29 a and 29 b in high yields and good levels of diastereocontrol. Similarly,o ther tertiary alkyl carboxylic acids,i ncluding the phenol-containing vitamin Ea nalogue Tr olox and the fibrate drug gemfibrozil, provided the cyclopropane products 30 a, 30 b, 31 a and 31 b in good to excellent yields.F urthermore,t he densely functionalized naturallyoccurring primary alkyl carboxylic acids cholic acid and biotin reacted with 1bto give the structurally complex cyclopropane products 32 b and 33 b,respectively.
To probe the generality of this cyclization reaction, we also explored the formation of larger rings using haloalkyl alkenes 34, 35,a nd 36 (Table 3). Of the substrates explored, only cyclopentane formation was successful and optimum results were obtained using iodide 35 c (entry 6). Reactions with haloalkyl alkenes 34 and 36 gave the protonated Giese [a] Reactionswere performed using 0.3 mmol of the carboxylic acid and 1.2-2.0 equiv of 1aor 1b.The heat generated by the LEDs resulted in reaction temperatures of ca. 50 8 8C. See Supporting Information for exact experimental procedures.Yields are of isolated products. Diastereomeric ratios were determined by 1 HNMR analysis of the purified products.
addition products 40 and 42 instead of the 4-and 6-membered rings.The failure to generate cyclobutane 37 and cyclohexane 39 reflects the significantly slower rates of 4-and 6-exo-tet cyclization compared to 3-and 5-exo-tet,w hich results in protonation to form 40 or 42 becoming the dominant pathway. [19] To gain insight into the mechanism of this radical cascade process,w ec onducted several experiments to elucidate the presence or absence of radical and carbanion intermediates (Scheme 3). Reaction of cis-pinonic acid, ac yclobutanecontaining primary alkyl carboxylic acid, generated the ringopened product 43,c onfirming the initial formation of ap rimary carbon-centered radical, which undergoes ringopening to generate the more stable tertiary radical prior to reaction with 1b (Scheme 3A). Thef ormation of carbanion intermediates was confirmed by submitting allyl acetate 44 to the standard reaction conditions,during which elimination of the acetate group occurred to give alkene 45 in excellent yield (Scheme 3B). Elimination of the acetate group will only take place after reduction of the intermediate a-carbonyl radical to the carbanion (enolate). [20] Although this result supports ar adical-polar crossover mechanism, ap ossible alternative pathway during the cyclopropanation step is ah omolytic substitution reaction (S H 2) between the intermediate acarbonyl radical and the alkyl halide,aprocess that has previously been reported for radical cyclopropanations with alkyl iodides. [11b,c] While this alternative mechanism is unlikely given that chlorine is am uch poorer radical leaving group than iodine, [21] we gained conclusive evidence for ap olar (S N 2) cyclopropanation by carrying out the reaction of 2 with homoallyl tosylates 46 a and 46 b,w hich gave cyclopropanes 4a and 4b in comparable yields to those obtained with the homoallyl chlorides (Scheme 3C). In arelated study forming 3-membered rings,M olander and co-workers compared the activation barriers of radical and anionic cyclizationsw ith different leaving groups and also concluded that the cyclization occurred through an anionic pathway,thereby supporting our observations. [10] Based on these observations,w ep ropose the mechanism outlined in Scheme 4. Initially,v isible-light irradiation of the photocatalyst (PC)l eads to generation of the excited state catalyst (PC*). SET with the carboxylate generated from in situ deprotonation of carboxylic acid 2 results in reduction of the photocatalyst, to radical anion PCC À ,and oxidation of the carboxylate to ac arboxyl radical. Extrusion of CO 2 provides carbon-centered radical 47 that undergoes addition to homoallyl chloride 1 to form the stabilized alkyl radical 48.A second SET between radical 48 and the PCC À state of the photocatalyst completes the photoredox catalytic cycle and results in reductive termination of the radical process.Finally, the resulting stabilized carbanion 49 undergoes apolar 3-exotet cyclization to give the cyclopropane product 4.M easurement of aquantum yield (F)of0.65 for the reaction of Boc-Pro-OH (2)w ith alkenyl boronic ester 1a suggests that alternative radical chain mechanisms are not operative,t hus providing further support for the closed photoredox catalytic cycle shown in Scheme 4. Ther emarkable breadth of homoallyl chloride substituents that could be employed is especially noteworthy,r anging from strong electron-with-Scheme 3. Mechanistic studies.
Scheme 4. Proposed mechanism. drawing groups (such as carboxylate esters and nitriles) all the way to electron-rich aromatics (for example benzofuran). This highlights the broad synthetic utility of 4CzIPN,a st he reduced photocatalyst PCC À (E 1/2 [4CzIPN/4CzIPNC À ] = À1.21 Vv s. SCE in MeCN) [12b] was able to undergo SET with carbon-centered radicals of vastly different reduction potentials,i ncluding a-carboxylate ester radicals (E 1/2 [RC/ R À ] %À0.6 Vvs. SCE in MeCN) [22] and electron-rich benzylic radicals (E 1/2 [RC/R À ] < À1.4 Vvs. SCE in MeCN). [23] In conclusion, we have developed aphotoredox-catalyzed cyclopropane synthesis proceeding through adecarboxylative radical addition-polar cyclization cascade.T he mild conditions,c atalyzed by an organic photocatalyst, were found to tolerate ab road range of functional groups on both the carboxylic acid and the chloroalkyl alkenes substrates. Mechanistic studies confirmed that the reaction proceeds by ar adical-polar crossover mechanism involving reductive termination and subsequent alkylation of ac arbanion intermediate.Given the abundance of carboxylic acids in sustainable chemical feedstocks,w eb elieve that this new fragment coupling-based cyclopropanation reaction provides av aluable,a tom-economical methodology for the expedient preparation of structurally diverse cyclopropanes.