Transition Metal‐Free N‐Arylation of Amino Acid Esters with Diaryliodonium Salts

Abstract A transition metal‐free approach for the N‐arylation of amino acid derivatives has been developed. Key to this method is the use of unsymmetric diaryliodonium salts with anisyl ligands, which proved important to obtain high chemoselectivity and yields. The scope includes the transfer of both electron deficient, electron rich and sterically hindered aryl groups with a variety of different functional groups. Furthermore, a cyclic diaryliodonium salt was successfully employed in the arylation. The N‐arylated products were obtained with retained enantiomeric excess.


Introduction
Amino acids are important building blocks in organic synthesis as they are as ubstantial parto ft he chiral pool. Functionalization of such speciesi sa ttractive in drug discovery as am ean of obtaining novel compoundst hat can act as an affinity probe for enzyme studies [1] or exhibit bioactivity. [2] N-Arylated amino acids are found as ac ore structure in biologically active compounds such as the protein kinase C( PKC) activatori ndolactam-V [3] and itsa nalogue benzolactam-V8, [4] fibrinogen receptor antagonistS B2 14857, [5] and NMDA receptor antagonist L689560. [6] Existing methods to reach N-aryl amino acids are mostly based on transition metal catalysis. [7] Cu-catalyzedU llman cross couplings have ag ood scope, although high Cu loading and extended reactiont imes at high temperatures or excessr eagents are often needed. [1c, 2a, 8] Jain and co-workersr ecently reported an N-arylation under milder conditions with the use of ad iketone ligand in DMF( Scheme1a). [9] After adjustmento f the reactionc onditions, also heterocyclesc ouldb et ransferred. [10] Alternatively,C u-catalyzed couplings with excessa rylboronic acidc an be performed at room temperature with a limited scope. [11] Pd-catalyzedB uchwald-Hartwig arylations have been less explored,a nd early methods suffered from limiteds cope or partial racemization. [12] Recent reports partly circumvent that problem through the use of advanced catalytic systems. [13] The development transition metal-free coupling reactions has received increasing attention to overcome drawbacks with transition metals, such as toxicity,c ost, need for substrate-dependentd esigner ligands, reactions ensitivitya nd the risk of product contamination in the pharmaceutical industry. [14] Transition metal-free syntheses of N-aryl amino acidsa nd their derivatives are, however,m uch lesse xplored. Reporteds yntheses of specific targets include reactions with anilines and suitable electrophilic species through S N 2d isplacementorS N Ar. [15] Reactions with enantiomerically enriched trichloromethyl alcohols provided N-aryl amino amides throughaJ ocic-type reaction. [16] Alternatively,a mino acid derivatives can be N-arylated with the biobased reagent methyl-3-dehydroshikimate as aryl precursor. [17] Triphenylsulfonium triflate can be employed in the N-arylation of racemic amino acid derivatives in ar eaction proceeding through arynes. [18] Ac ommon feature with the methods above is that their scope is very limited.
Poelarends and co-workersr ecently published an elegant biocatalytic approacht oN-arylated aspartic acids through enzymaticr eactions of anilines with fumarate. [19] Moderate to good yields with excellent ee were obtained, although sterical-ly hindered or strongly electron deficienta nilinesw ere not tolerated.
Hypervalenti odine compounds have become efficient reagents for aw ide variety of transition metal-free reactions. [20] Diaryliodonium salts have severala ttractive features including easy availability,h igh stability,a nd low toxicity.T hey are highly reactive electrophilicarylation reagents, and have been applied successfully in av ariety of transition metal-free C-, O-, N-a nd S-arylations. [21] Iodoniums alts have been utilized to functionalize amino acid derivatives through fluoroalkylation, [22] and as malls et of diaryliodonium bromides were employed in aC u-catalyzed Narylation of amino acid esters, which required excesss ubstrate and as tochiometric amount of AgNO 3 (Scheme 1b). [23] We have recently reported am etal-free N-arylation of aliphatic amines with diaryliodonium salts under mild conditions (Scheme1c). [24] The methodology has ab road amine scope, butp roved inefficientf or arylation of aminoa cids.T of acilitate thea ccesst oe nantiomericallye nriched N-arylateda mino acid derivatives, we seto ut to developatransition metal-free N-arylationo fa mino acidsd erivatives,a nd herein presento ur results.

Results and Discussion
Phenylalanine methyl ester (1a)w as chosen as the model substrate, and was obtained by deprotonation of the corresponding hydrochloride salt 1a-HCl.T he free amine 1a provedt ob e unstableu pon storage, [23a, 25] and was therefore prepared within 5days of use.
An extensive optimization was performed, [26] with initial screening of the arylation conditions using 4-nitrophenyl(phenyl)iodonium triflate (2aa-OTf). The conditions used in our arylationo fa liphatic amines [24a] gave poor conversion into product 3a with substantial amountso fr ecovered 1a (Table 1, entry 1). The conversion was improved by increasing the temperature (entries 2,3), and the combinationw ith excessi odonium salt resulted in 59 %y ield of 3a (entry 4). Arylations with iodonium salt 2aa-OTf generally give complete chemoselectivity, [27] with transfer of only the nitroaryl group, butw eo bserved small amountso fp henylated side-product 3-Ar 2 and a deterioration of the overall mass balance when the reaction was performed at 150 8C.
The reactivity of 4-nitrophenyl(phenyl)iodoniums alts with other anions( 2aa-X)w as next examined, and salts with tetrafluoroborate, tosylate or bromide anions provedt og ive inferior results( entries 5-7). In fact, iodonium salts 2aa-OTs and 2aa-Br suffered from ac ompeting pathway where the anion acted as nucleophile to deliver the corresponding 4-nitrophenyl tosylate (4-OTs)a nd bromide (4-Br), respectively.S uch sideproducts have previously been reported with diaryliodonium bromides, [28] whereas reactions with diaryliodonium tosylates are often efficient also at elevated temperatures. [24a, 28b, 29] Unsymmetric diaryliodoniums alts are known to react with high chemoselectivity when they have sufficiently different electronic properties. [30] Then on-transferable aryl group is called a" dummyg roup", and the phenyl group is generally a sufficient dummyg roup in transfer of strongly electron-defi-cient aryl groups. [27] Since the phenylated side-product was observedi nt his reaction, we investigated iodonium salts with other dummyg roupst oi mprovet he chemoselectivity and simplify the isolation of product 3a.R eactions with mesityls alt 2ab-OTf resulted in similary ield and chemoselectivity (entry 8). The anisyl moiety is often ag ood dummy group [27] and salt 2ac-OTf indeed reacted with complete chemoselectivity.M ore surprisingly,t he conversion was also improved and 3a was isolated in 79 %y ield as the only product (entry 9).
We next examined whether the deprotonation of 1a-HCl could be combined with the arylation to circumvent the handling of unstablea mine 1a.1a-HCl was thus reacted with salt 2ac-OTf (1-2 equiv) in the presenceo f2equiv sodium carbonate (Scheme2). However,o nly minor amounts of 3a were detected and the major product was instead 4-Cl,w hich formed when the released chloride anion acted as ac ompeting nucleophile. The mass balance in the first reaction shows that 1a is rather stable at elevated temperatures once 2ac-OTf is consumed, but partly decomposesi nt he presence of excess 2ac-OTf,l ikely due to the higho xidation potentialo fthe diaryliodonium salt. [26] The arylation scope of amino ester 1a with various aryl(anisyl)iodonium triflates 2-OTf was subsequently examined. Aryl groups with electron-withdrawing groups (EWG) wereefficiently transferred using the optimized conditions (Scheme3A), as exemplified by the synthesis of p-CN substituted products 3b and 3c.A ryl groups with CF 3 substituentsw erea lso well tolerated (3d-3f), where even the sterically encumbered product 3f was formed in high yield. Also halogen-containing aryl moieties could be transferredt op rovide 3f-3h.I odonium salts with strongE WG reacted with similar efficiency at 130 and 150 8Cw hile the other salts showedr educed activity at 130 8C. [26] The transfer of aryls with electron-donating groups( EDG) is generally more challenging in reactions with diaryliodonium salts. [27a, 31] We were hence pleasedt os ee that such arylations were feasible by prolonging the reaction time to 24 h. In this fashion,t he phenylated product 3i wasi solated in 67 %y ield, and a tert-butyl-substituted aryl moiety could also be transferred to provide 3j.The methoddemonstrated good compatibility with the sterically demanding mesityl group (3k)a nd a highly functionalized aryl moiety could be transferred( 3l). A heteroaryliodonium salt was employed to give pyridyl product 3m in modest yield. Additionally,t he 6-membred cyclic diaryliodonium salt 2n could be used to generate the iodosubstituted product 3n in 59 %y ield. Reactions with cyclic diaryliodonium salts generally requiret ransition metal catalysis due to decreased reactivity, [32] and this result is conceptually important as reactions with such saltsh aveh igher atom efficiency and deliver productsw ithac onvenient iodine handle for further transformations. [32d] The substrate scope of primary amino esters 1 was next examined. Arylation of benzyl ester 1b was first investigated and provided the arylated products 3o and 3p in equallyh igh yields as the corresponding methyle ster 1a (cf. products 3a, 3b). Having demonstrated the compatibility of the benzylp rotecting group,i tw as used to protect alanine( 1c)a nd valine (1d), as their corresponding methyle sters (1e, 1f)p roved to be volatile and easily evaporated under vacuum or high temperatures. Arylation of the alaninea nd valine benzyl esters was successful providing 3q and 3r in moderate to good yields. Substrates 1c and 1d could also be arylated with less activated diaryliodonium salts, providing the phenylateda nd tertbutyl-substituted products 3s-3v.T he reactions with valine ester 1d gave consistently higher yields than the corresponding reactions with 1c,atrend that has also been reported in previous N-arylations. [2a, 12a, 13b] Scheme2.Attempted arylationo fa mino acid ester salt 1a-HCl ( 1 HNMR yields with TMB as internalstandard). We next explored the compatibilityw ith more challenging substrates, such as unprotected,h eteroatom-substituted amino acid esters. Heteroatom substituents are usually well toleratedi nm etal-free arylationsw ith diaryliodonium salts, [21] but such substrates proved difficult to arylate under the current conditions. For example, reactions with tryptophan methyl ester (1g)g ave only 15 %p roduct with 2ac-OTf, [26] which could be due to competing coordination of the indole nitrogen to the iodine(III) reagent. To the contrary,a rylation of tyrosine methyl ester (1h)d elivered the diarylated product 3w' in high yield and retained ee,without detection of the corresponding monoarylated product 3w (Scheme 4).

Scheme3.Arylations
To investigate the performance of the unsymmetrica nisyl salts, af ew products in the scope were also synthesized using the corresponding aryl(phenyl) salts or symmetric diaryliodonium salts. Reagents with the anisyl dummyg enerally performed best, as chemoselectivity problems were avoided and better arylation yields were obtained. [26] SFC and HPLC analyses werep erformed to determine the ee of the products,s ince previously reported methods for N-arylation of amino esters showed partial racemization [7c, 12a, 13, 25c] or had insufficient data to judge the enantiomeric purity. [1c, 9-10, 12b] As expected, the current methodology generally left the existing stereocenter intact and the majority of the products were isolated with 95 to > 98 % ee. Even when prolonged reaction time was applied in reactions with EDG salts, very little racemization occurred.
Secondary amino esters were evaluated next,a nd proline methyl ester (5a)p roved to be as uitable substrate (Scheme 5). Arylation with electron-withdrawing aryl moieties provided products 6a--6c in high yields.U pon prolonged reactiont ime, also phenylation( 6d)a nd mesitylation (6e)w as feasible,t hese transformations proved better with the symmetric iodonium salts than with the anisyl salts. N-arylation of the N-methylated a-phenylalanine ester 5b resulted in 58 %y ield of 6f with high enantiomeric excess, and b-phenylalanine ester (5c)g ave the nitrophenylated product 6g in good yield. The SFC analysis of products 6 showedasmall decrease of the enantiomeric purity (90-94 % ee).
N-Protected derivatives of 1a,b remained largely untouched under the reactionc onditions, which is useful in arylation of more complexs ubstates. To this end, acetyl-and tosyl-protected derivatives of 1a gave no arylation,w hereas aB oc-protected derivativeo f1b gave 9% of 3o with 82 %r ecovered substrate, meaning that the Boc-group had been partially fragmented under the reaction conditions. [26] As eries of control experimentsw ere performed to indicate ap ossible mechanism of the arylation. [26] Running the reaction without argon atmosphere gave as ignificantly lower yield. Addition of DPE as radical trap did not affect the outcomeo ft he reaction, indicating that ar adical pathway is unlikely. [33] Furthermore, reactions in the presenceo ff uran (5 equiv) as aryne trap didn ot result in formation of Diels-Alder adducts. Based on that experiment and the formationo fo nly one regioisomeric product in reactions with substituted diaryliodonium salts, an aryne pathway can be excluded. [33] Additionally,a na ttempted arylation of 1a with iodobenzeneo r1 -iodo-4-nitrobenzene at 150 8Cr esulted in quantitative recovery of the startingm aterials, and an S N Ar pathway with the iodoarene formed from 2aa-OTf can therefore be ruled out.
Finally,t he product stability was investigated by subjecting 3a to the reactionc onditions (Scheme 6). No diarylated product was formed and 3a could be recovered in 68 %y ield. The ee of 3a remained intact,d emonstrating that the arylated product is stable to racemization under the reaction conditions. However,p artial decomposition of 3a had occurred, which explains the mass balance problems observed in some reactions. As tability test of 2ac-OTf in the absence of any amino acid ester also showedp artial decomposition at 150 8C. [26] Based on the experiments described above, we suggest that the reactionf ollows at raditionall igand coupling pathway, where the amine does al igand exchange with the triflate to give intermediate I,f ollowed by deprotonation to II and ligand coupling to yield product 3 (Scheme 7).

Conclusions
At ransition metal-free N-arylation of amino acid derivatives with diaryliodonium salts has been presented. The moderate reactivity of the substrates was overcome by increasingt he reaction temperature, which initially resulted in ac hemoselectivity problem. The methodh as ab road arylation scope and is compatible with transfer of both electron deficient and electron rich aryl groups in good to high yields. ortho-Substituents and various functional groups are well tolerated,i ncluding a cyclic diaryliodonium salt. The amino acid ester scope includes primary and secondary a-aminoe sters, as well as b-amino esters, and the products were generally obtained with excellent enantiomeric excess. The use of aryl(anisyl)iodonium triflates provedt ob ek ey to increase both the reactivity and chemoselectivity of the process. Thisi nteresting observation will be further studied in reactions with relatedn ucleophiles.

Experimental Section
Arylation of amino acid esters 1a nd 5:A mino acid ester 1 (0.2 mmol), salt 2 (0.4 mmol, 2.0 equiv) and Na 2 CO 3 (0.2 mmol, 1.0 equiv) were added to an oven-dried, pressure-stable microwave vial and dried under vacuum for 15 min. The vial was flushed with argon 3-4 times followed by the addition of anhydrous toluene (1 mL, degassed by bubbling with argon for 20 min). The vial was added to ap reheated oil bath at 150 8C, and stirred for 4-24 h. After completion, the reaction was cooled to rt and Celite was added. The volatiles were removed under reduced pressure, and the mixture was purified by column chromatography (SiO 2 with pentane/EtOAc as eluent system), to provide product 3 or 6.T he enantiomeric purity was analyzed by Chiral SFC, Diacel OJ-H, 25 8C, 0.3 cm 1,1 5cmc olumn, 10 %M eOH in CO 2 ,f low rate: 0.8 mL min À1 .