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MICROREVIEW

DOI: 10.1002/ejoc.201402097

Transition-Metal-Catalyzed Allylic Substitutions of Trichloroacetimidates

Jeffrey S. Arnold,[a] Qi Zhang,[a] and Hien M. Nguyen*[a]

Keywords: Synthetic methods / Asymmetric catalysis / Rearrangement / Overman rearrangement / Allylic substitution

With the development of practical methods for their prepara-tion, trichloroacetimidates have proven to be valuable sub-strates for use in carbohydrate and organic synthesis. Thebroad utility of allyl trichloroacetimidates for the constructionof carbon-heteroatom bonds is the result of the unique fea-tures of the trichloroacetimidate nitrogen functionality as a

1. Introduction

The efficient and selective incorporation of heteroatomsinto the carbon frameworks of synthetically useful targetscontinues to be of paramount importance in the field oforganic chemistry. Improvements in our understanding of

[a] Department of Chemistry, University of Iowa,Iowa City, Iowa 52245, USAE-mail: [email protected]://chem.uiowa.edu/nguyen-research-group

Jeffrey S. Arnold obtained his B.A. degree in biology and chemistry from Luther College in Decorah, Iowa. After fourteenyears in the pharmaceutical industry he returned to his home state in 2009 and pursued his Ph.D. studies under thedirection of Professor Hien M. Nguyen at the University of Iowa. His research focuses on organic synthesis and organome-tallic method development. He received his Ph.D. degree in May 2014 and currently works as a Senior Scientist and LabManager at Corden Pharmaceutical Company in Woburn, Massachusetts. During his graduate studies, he published sevenpapers as the first co-author and was the recipient of the A. Lynn Anderson Outstanding Graduate Research Award givenannually to the top graduate students in the Department of Chemistry at the University of Iowa.

Qi Zhang received his B.S. degree in Pharmacy from Fudan University, P.R. China. In 2010 he started his Ph.D. researchunder the direction of Professor Hien M. Nguyen at the University of Iowa. His research focuses on rhodium-catalyzedasymmetric amination and regioselective fluorination.

Hien M. Nguyen obtained a B.S. in chemistry from Tufts University, where he conducted research under the direction ofProfessor Marc d’Alarcao. He went on to the University of Illinois at Urbana-Champaign and joined the research groupof the late David Y. Gin. In 2003 he was awarded a Ph.D. in organic chemistry and moved to Stanford University as anNIH postdoctoral fellow under the guidance of Professor Barry M. Trost. He began his independent career in 2006 andis currently an Associate Professor of Chemistry at the University of Iowa.

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directing, nucleophilic, and leaving group. In this review wedescribe the expansion of Overman’s [3,3]-rearrangement ofallyl trichloroacetimidates to allylic substitution reactions forregio- and enantioselective C–N, C–O, and C–F bond-form-ing methodologies.

chemical reactivity and new mechanistic insights are ex-panding our capabilities and inspiring new catalytic strate-gies for these methods of bond construction. The findingsof the scientific community help drive our endeavors, withintense areas of investigation often stemming from a fewinnovative and pioneering works. The utilization of tri-chloroacetimidates in carbohydrate and organic synthesis isone particular example, largely attributable to the efforts ofOverman, with the development of a highly selective [3,3]-sigmatropic rearrangement for the efficient preparation of

J. S. Arnold, Q. Zhang, H. M. NguyenMICROREVIEW

Scheme 1. Transformations of allyl trichloroacetimidates.

allyl trichloroacetamides,[1,2] whereas Schmidt popularizedthe utilization of trichloroacetimidates as effective leavinggroups in glycosylation reactions.[3] The contributions ofOverman and Schmidt are of great importance and haveresulted in many review articles on [3,3]-sigmatropic re-arrangement of allyl acetimidates[2] and on carbohydratecoupling with glycosyl trichloroacetimidates.[3]

This review focuses on new strategies for efficient incor-poration of oxygen, nitrogen, and fluoride nucleophilesonto allyl systems with the aid of transition-metal catalysis(Scheme 1). For C–O bond-forming reactions, we discussasymmetric synthesis of allyl esters and aryl ethers fromprimary allyl trichloroacetimidates (Scheme 1, a). For C–Nand C–F bond-forming reactions, we discuss the regio- andenantioselective substitutions of secondary and tertiary allylsubstrates (Scheme 1, b).

2. Reactions of Primary AllylTrichloroacetimidates with Oxygen Nucleophiles

We begin with a brief discussion of the development of,and recent asymmetric advances in, [3,3]-sigmatropic re-arrangement of allyl trichloroacetimidates. This work pro-vided a path to the discovery of PdII-catalyzed asymmetricallylic substitutions of prochiral allyl trichloroacetimidateswith carboxylic acids and phenols, as is detailed in the fol-lowing section.

2.1 Discovery of Rearrangement of Allyl Acetimidates

The first thermal [3,3]-sigmatropic rearrangement of anallyl imidate was described by Mumm and Möller in 1937.[4]

However, this early method was of low synthetic utility, dueto poor yields in the preparation of the starting allyl imidatesubstrates and the requirement for elevated temperatures(above 200 °C) for the [3,3]-rearrangements of allyl N-phen-ylimidates.[1,2,5] In 1974, Overman reported a thermal [3,3]-sigmatropic rearrangement involving the 1,3 interchange ofthe nitrogen and oxygen functional groups in allyl trichloro-acetimidates 2 (Scheme 2).[1] This aza-Claisen rearrange-ment, now referred to as the Overman rearrangement, wassignificant because it provided access to allylamines 3 fromcommercially available or easily prepared allyl alcohols 1via the requisite acetimidates 2, synthesized with trichloro-acetonitrile and substoichiometric amounts of DBU.[6,7]

The base may vary, due to purification or reactivity issues.For example, a stronger base such as NaH, which helps

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generate alkoxides, facilitates the preparation of tertiaryallyl trichloroacetimidates 2.[74,87] Recently, NaHMDS wasfound to be more effective than NaH in promoting forma-tion of tertiary substrates 2.[87] The resulting allyl imidates2 can be used directly, or can be subjected to silica gelchromatography, although tertiary and some secondarysubstrates might require addition of an amine base to theeluent to prevent acid-catalyzed decomposition.[2,74,87]

Scheme 2. Overman rearrangement of allyl trichloroacetimidates.

Under thermal conditions, rearrangement of allyl imid-ates 2 (Scheme 2) is a powerful and operationally simplecarbon-nitrogen bond-forming transformation that is typi-cally conducted in xylenes at 140 °C for 1–12 h.[2] This reac-tion is applicable to a variety of primary, secondary, andtertiary allyl acetimidates and has been exploited in the syn-thesis of nitrogen-containing compounds.[2]

In addition to the thermal rearrangement conditions,[1]

Overman described the first metal-catalyzed [3,3]-re-arrangement of allyl acetimidates 2 in 1976 (Scheme 2).[5]

The use of catalytic loadings of mercury(II) salts increasesthe rearrangement rate relative to the thermally inducedreaction, allowing efficient transformation into the tri-chloroacetamide products 3 at ambient temperatures.

Reports soon followed in which it was demonstrated thatsoluble palladium(II) complexes [e.g., Pd(PhCN)2Cl2] weresuperior catalysts, and palladium has become the metal ofchoice.[2,8,9] The palladium-catalyzed reaction is quite selec-tive, providing high ratios of trans olefins with excellenttransfer of chirality. However, the scope of the reaction islimited to primary (E)-disubstituted alkenes because metalchelation to the basic imidate nitrogen leads to competitiveionization and elimination with less reactive substrates.[5,8]

The development of an efficient metal-catalyzed transpo-sition of the trichloroacetimidate functionality promptedinvestigations directed toward an enantioselective vari-ant.[10] Work began with the development of cationic palla-dium(II) complexes containing chiral oxazoline[11] and di-amine[12] ligands (e.g., 4, Figure 1). These first-generationcatalysts provided the rearrangement products 6 from pri-mary allyl N-phenylbenzimidates 5 with good yields and

Catalyzed Allylic Substitutions of Trichloroacetimidates

enantioselectivity. The cationic palladium-catalyzed reac-tions were limited by competing ionization of the startingsubstrates 5, resulting in elimination and [1,3]-rearrange-ment products. As a result, studies targeting neutral PdII

complexes ensued.[10] Neutral cyclopalladated amine dimersimproved reaction efficiency, but the products 6 were ob-tained with low ee values. Enantioselectivity returned to thelevels obtained with cationic PdII complexes when neutralferrocenyl palladacycles 4b (Figure 1), with increased stericbulk above and below the coordination plane were investi-gated.[13,14] Ferrocenyl palladacycle 4c (Figure 1) was mosteffective, affording high enantioselectivity when startingfrom both (E)- and (Z)-N-phenylbenzimidate substrates5.[15,16] Unfortunately, ferrocenyl palladacycles such as com-plex 4c are not applicable to allyl trichloroacetimidates,which are useful building blocks for the synthesis of com-plex targets.

Figure 1. Chiral palladium-catalyzed rearrangement of N-aryl-benzimidates.

In 2003, Overman and co-workers reported that chiralcobalt oxazoline palladacycles 7 (Scheme 3, a) efficientlycatalyzed the [3,3]-rearrangement of primary (E)-allyl tri-chloroacetimidates 8 to the corresponding trichloroacet-amides 9 with excellent yields and enantioselectivity.[17,18]

Scheme 3. COP-Cl-catalyzed asymmetric [3,3]-rearrangements of allyl trichloroacetimidates.

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The potential utility of the enantioenriched allyl acetamideproduct was illustrated in the preparation of the GABAaminotransaminase inhibitor (S)-vigabatrin (11) throughsimple hydrolysis of the ester and trichloroacetyl groups(Scheme 3, b). In contrast with early palladium catalysts,COP-Cl (7) catalyzed the enantioselective rearrangement of(Z)-allyl imidate substrates 8 (Scheme 3, a) with diminishedrates and asymmetric induction relative to the trans-config-ured olefins.[19] This feature led to the development of PdII-catalyzed asymmetric allylic substitutions of (Z)-trichloro-acetimidates with oxygen nucleophiles.

2.2 Palladium-Catalyzed Asymmetric Substitutions ofLinear (Z)-Allyl Trichloroacetimidates with CarboxylicAcids

In 2005, the Overman group expanded the scope ofCOP-OAc-catalyzed reactions (Scheme 4) by subjecting(Z)-allyl acetimidate 13a to intramolecular aminopallad-ation.[20] A 1:1 mixture of the desired 4-vinyloxazoline 15and diacetate 14a was obtained in the reaction.[21] This ex-periment suggests that SN2� displacement of (Z)-allylic sub-

Scheme 4. Discovery of asymmetric allylic esterification of imid-ates.

J. S. Arnold, Q. Zhang, H. M. NguyenMICROREVIEWstrate 13a with acetic acid to form allyl diacetate 14a wascompeting with intramolecular attack of the acetimidate ni-trogen to afford the desired oxazoline product 15. To sup-press the amino-cyclization pathway, the Overman groupemployed 3 equiv. of acetic acid in the process, and com-plete conversion to the diacetate product 14a was then ob-served (Scheme 4).

Recently, Jirgensons and co-workers have reported a ver-satile approach to racemic unsaturated α- and β-amino ac-ids (Scheme 5) through Lewis-acid-catalyzed intramolecularallylic substitution of bis(trichloroacetimidates) 16. The 4-vinyloxazolines 16a and 4-vinyloxazines 16b were thentransformed into the corresponding unsaturated amino ac-ids 17a and 17b, respectively, in excellent yields.[21b,21c]

Scheme 5. Lewis-acid-catalyzed intramolecular allylic substitutionof bis(trichloroacetimidates).

These findings initiated development of the first catalyticasymmetric allylic esterification of (Z)-allyl trichloroacet-imidates with carboxylic acid nucleophiles.[22]

In light of the initial results shown in Scheme 4, the reac-tion behavior of linear (Z)-allyl trichloroacetimidate 13b inthe presence of acetic acid and of a number of chiral palla-dium(II) catalysts was explored. Although COP-OAc (12)was not effective in the Overman rearrangement, it turnedout to be the most effective catalyst in the enantioselectiveallylic esterification, providing chiral allyl ester 14b(Scheme 6) in 88% yield and 94 % ee along with tri-chloroacetamide byproduct (identified by GC analy-sis).[22,23] Solvents were found to play an important role inthe reaction efficiency. The following order was observedwhen allyl trichloroacetimidate 13b reacted with 3 equiv. ofacetic acid in the presence of 1 mol-% COP-OAc (12) atambient temperature: CH3CN (8 %, 17 h)� benzene (43%,16 h)�THF (69 %, 16 h)� CH2Cl2 (88%, 17 h). Except inacetonitrile, (R)-allyl ester product 14b was obtained withexcellent levels of asymmetric induction (91–94% ee). Low-ering the reaction temperature to 0 °C dramatically de-creased the yield of the desired ester 14b (88% �17%), al-beit with slightly improved enantioselectivity (96 % ee). Todetermine the role of acetic acid in the transformation, con-trol experiments were performed with sodium or ammo-nium acetate as the nucleophile; this resulted in no productformation. These results suggest that protonation of theacetimidate nitrogen is required to generate a competenttrichloroacetamide leaving group.


Scheme 6. Asymmetric esterification of (Z)-allyl acetimidate 13b.

Table 1 summarizes Overman’s investigations into theallyl trichloroacetimidate scope of this transformation.Branched allyl esters 14c–h are obtained in moderate tohigh yields with excellent enantiomeric purity. Allyl imidate13e (Entry 3), containing a free hydroxy group, was com-patible with the reaction conditions, and the correspondingallyl ester 14e was obtained in 92% yield and with 97 % ee.Allyl substrates bearing ester, ether, and silyl ether func-tional groups were also well tolerated (Entries 4–6). Due tothe steric nature of cyclohexyl-containing imidate 13d, thereaction was quite sluggish and produced only a 45% yieldof 14d (Entry 2).

Table 1. Scope of allyl trichloroacetimidate substrates.

In addition to acetic acid, a number of aromatic carbox-ylic acids were evaluated with allyl imidate 13i (Table 2).Both electron-donating and electron-deficient benzoic acidsare tolerated, and the corresponding allyl esters 14i–n (En-tries 1–6) were isolated in 65–95% yields and with excellentenantioselectivities (87–97% ee). Only sterically encum-bered 2-chlorobenzoic acid (Entry 7) was not a suitable sub-strate, affording 14o in 24 % yield and with 53% ee. Withthe exception of benzoic acid and 4-methylbenzoic acid(Entries 1 and 2), other aromatic carboxylic acid nucleo-philes were used at 38 °C to improve their solubility inCH2Cl2.[23]

A number of aliphatic carboxylic acids were also success-fully utilized as nucleophiles in [COP-OAc]2-catalyzed reac-tions with (Z)-allyl imidate substrates 13b and 13i (Table 3).Accordingly, the reactions of phenylacetic acid and iso-butyric acid (Entries 1 and 2) with 13b proceeded smoothlyat room temperature to provide the corresponding allyl es-ters 14p and 14q, respectively, in high yields and with goodenantioselectivities.[23] Sterically encumbered carboxylic ac-ids (Entries 3 and 4) and less soluble carboxylic acids (En-


Table 2. Scope of aromatic carboxylic acid nucleophiles.

tries 5 and 6) reacted well at 38 °C, giving the allyl esterproducts 14r–u in good yields (65–95%) and with excellentlevels of asymmetric induction (86–96 % ee).

Table 3. Scope of aliphatic carboxylic acid nucleophiles.

Taken together, the results shown in Tables 1, 2, and 3demonstrate the broad scope of this COP-OAc-catalyzedasymmetric substitution with a variety of (Z)-allyl tri-chloroacetimidates and carboxylic acids. This catalyticmethodology is, however, not suitable with (E)-allyl acet-imidate 18 (Scheme 7, a), producing allyl ester 19 in 82 %yield and 66% ee along with a 10 % yield of the competingrearrangement product 20.[23] This result is consistent withearlier reports that the E stereoisomer of an allyl acetimid-ate undergoes [3,3]-sigmatropic rearrangement at a fasterrate than its Z isomer counterpart.[2,22] Allyl acetimidate 21,containing an additional C(3)-methyl group, does not reactin the desired manner under the COP-OAc conditions, but


gives a mixture of linear and branched allyl esters 22 and 23(Scheme 7, b). On the other hand, application of stericallyhindered C(2)-methyl-substituted allyl imidate 24 resultedin no reaction (Scheme 7, c).[23]

Scheme 7. Reactions with challenging primary allyl trichloroacet-imidates.

Kinetic and computational studies support the mecha-nism shown in Scheme 8 for the [COP-OAc]2-catalyzedSN2� displacement of (Z)-allyl trichloroacetimidates withcarboxylic acids. In this mechanism, chelation of the basicimidate nitrogen to palladium(II) is a critical step for theselective C–O-forming transformation.[24] Reversible bind-

Scheme 8. Catalytic cycle for PdII-catalyzed allylic esterification.

J. S. Arnold, Q. Zhang, H. M. NguyenMICROREVIEWing of the trichloroacetimidate nitrogen in substrate 28forms monomeric chiral palladium complex 29, which di-rects the metal center to the alkene unit to form bidentatepalladium-olefin complex 30. Experimental studies indicatethat although a variety of bridged palladium complexes 25–27 (Scheme 8) are present, it is monomeric palladium(II)complexes that are involved in the catalytic cycle.[24] Thepath from imidate-nitrogen-coordinated complex 29 to thecorresponding activated complex 30 (Scheme 8) is reversibleand enantiodetermining, setting the stage for an oxypallad-ation/deoxypalladation sequence. Deuterium-labeling stud-ies provided support for the view that the reaction is likelyto proceed in an antarafacial fashion. DFT calculationsgave support for the presence of bidentate substrate-boundintermediates and indicated that the antarafacial selectivityis the result of an anti-oxypalladation/syn-deoxypalladationpathway. N-Aryl allyl acetimidates and allyl esters are noteffective substrates in the reaction; this provides further evi-dence for participation of the imidate nitrogen in the cata-lytic cycle. Substituent effects at C1 and C2, combined withvery high regioselectivity in the reaction, support the pres-ence of cyclization product 31 (Scheme 8) rather than theformation of an η3-allylpalladium intermediate.

Enantioenriched branched allyl esters are versatile pre-cursors of branched allyl alcohols, which are valuable build-ing blocks for the preparation of a wide range of biolo-gically relevant organic molecules.[25,26] There are a few re-ports that describe the catalytic asymmetric synthesis ofallyl esters by utilization of sodium carboxylates with allylcarbonates/halides mediated by Pd-BINAP catalysts[27a] orplanar-chiral cyclopentadienyl ruthenium catalysts.[27b]

Thus, the [COP-OAc]2-catalyzed enantioselective substitu-tion of (Z)-allyl imidates with carboxylic acids is a practicalmethod for preparation of enantioenriched allyl esters.[22,23]

2.3 Synthetic Applications

The efficacy of the [COP-OAc]2-catalyzed enantioselec-tive formation of allyl esters has been applied by Haug andKirsch as the key step in the total synthesis of (+)-chloriol-ide (43, Scheme 9).[28] The 12-membered polyketide-derivedfungal macrolide 43 was obtained from solid-substrate cul-tures of Chloridium virescens var. chamydosporium in 2006by Gloer and co-workers.[29] The closest known analoguesof 43 – cladospolides and patulolides – have been reportedto exhibit antifungal and antibacterial activity.[30,31] Thus,43 was an attractive target for total synthesis that wouldallow further evaluation of its biological activity. The prep-aration of 43 commenced with the reaction between allylacetimidate 34 (Scheme 9) and benzoic acid in the presenceof 1 mol-% of (+)-COP-OAc (12)[22,23] to yield the allyl esterintermediate (95%, 96% ee), which was converted into thedesired primary alcohol 35. Oxidation of 35 with IBX, fol-lowed by Wittig olefination and HF-mediated removal ofthe TIPS group, gave rise to allyl alcohol 36. Coupling offragment 36 with acetate-containing compound 39 (alsoprepared with COP-OAc-catalyzed allylic esterification as


the key step)[22,23] afforded the corresponding disiloxane 40in 77% yield (Scheme 9). Subsequent functional group ex-change, followed by Yamaguchi macrolactonization, gavethe corresponding 12-membered ring chloriolide (43).[28]

Scheme 9. Total synthesis of chloriolide (43). Reagents and condi-tions: (a) PhCO2H (3 equiv.), (+)-COP-OAc (1 mol-%), 23 °C,CH2Cl2, 95%, 96% ee; (b) K2CO3, 0 °C, MeOH, 89%; (c) TIPSCl,imidazole, DMF, 96%; (d) DDQ, pH 7 buffer/CH2Cl2, 99%;(e) 1. IBX, 80 °C, EtOAc; 2. Ph3P=CHCO2Me, CH2Cl2, 23 °C,78% (two steps); (f) HF, MeCN/H2O, 23 °C, 88%; (g) PMBO-(CH2)3CO2H, (+)-COP-OAc (5 mol-%), 23 °C, CH2Cl2, 83%,dr� 99:1; (h) HF, MeCN/H2O, 23 °C, 79%; (i) Ac2O, pyridine,83%; (j) 1. DDQ, pH 7 buffer/CH2Cl2; 2. KOtBu (15 mol-%), THF,87% (two steps); (k) iPr2SiCl2, pyridine, 23 °C then 36, 77%; (l) sec-ond-generation Grubbs catalyst (5 mol-%), 38 °C, toluene, 86%;(m) HF, MeCN/H2O, 23 °C, 85%; (n) TBSCl, imidazole, DMF,80%; (o) DIBAL-H, –78 °C, CH2Cl2, quant.; (p) 1. MnO2, CH2Cl2;2. NaClO2, 2-methylbut-2-ene, NaH2PO4, tBuOH/H2O, 87% (twosteps); (q) 1. 2,4,6-trichlorobenzoyl chloride, Et3N; 2. DMAP,benzene, 23 °C, 65% (two steps); (r) HF, MeCN/H2O, 23 °C, quant.

This allylic esterification reaction was further illustratedin the construction of the first and all subsequent stereo-genic centers in 1,3-polyol 46 (Scheme 10).[32,33] The 1,3-polyol is an important structural motif embedded in a widevariety of polyketide-derived natural products.[34] Conse-quently, numerous strategies have been developed for theefficient construction of 1,3-polyol-containing com-pounds.[35] These approaches are based on substrate-con-trolled asymmetric induction[36,37] or on chiral boron[38] ortitanium[39] reagents. Catalytic methodologies for sequentialconstruction of carbon-oxygen bonds through Sharplessasymmetric epoxidation,[40] proline-catalyzed α-aminoxyl-ation,[41] a Cu-catalyzed aldol reaction,[42] a triple-aldol cas-cade reaction,[43] chromium-mediated allylation,[44] andasymmetric conjugate silyl transfer[45] have also been devel-oped. Krische and co-workers recently reported the synthe-


sis of 1,3-polyols by means of an iridium-catalyzed transferhydrogenation allylation.[46] Accordingly, substitution of(Z)-allyl acetimidate 13i with benzoic acid (Scheme 10) un-der COP-OAc-catalyzed conditions provided allyl ester 14iin 93 % yield and with 96% ee. In a sequential asymmetricallylic esterification reaction, syn-diol 45 was obtained in95 % yield and with high diastereoselectivity (dr = 94:6). Athird allylic esterification with (–)-COP-OAc was also pos-sible. This modification resulted in the formation of 1,3-triol 46 (Scheme 10) with excellent diastereoselectivity(dr �95:5) and in 13% overall yield.[32,33]

Scheme 10. Catalytic asymmetric synthesis of 1,3-polyols. Reagentsand conditions: (a) PhCO2H (3 equiv.), (+)-COP-OAc (1 mol-%),23 °C, CH2Cl2; (b) 1. DIBAL, –78 °C, CH2Cl2; 2. CH2=CHCO2H,DCC, DMAP, CH2Cl2, 23 °C, 88%; (c) 1. second-generationGrubbs catalyst (1 mol-%), 38 °C, CH2Cl2; 2. DBU, CH2Cl2, 23 °C,82% (two steps); (d) NaBH4, CeCl·7 H2O, MeOH, 91%; (e) 1. TE-SOTf, lutidine, 0 °C, CH2Cl2; 2. K2CO3, MeOH, 90%; (f) Cl3CCN,DBU, CH2Cl2, 94%; (g) PhCO2H (3 equiv.), (–)-COP-OAc (1 mol-%), 23 °C, CH2Cl2.

The utility of this sequential catalytic asymmetric strat-egy for the construction of 1,3-polyols was demonstrated byKirsch and co-workers in the total syntheses of (+)-solistatin (Scheme 11)[32,47] and (+)-polyrhacitide B(Scheme 12).[50] Isolated from Penicillum solitum,[48] solista-tin (51) is an aromatic compactin analogue that inhibitscholesterol biosynthesis. In addition, 51 is structurally sim-ilar to HMG CoA reductase inhibitors.[49] To this end, the

Scheme 11. Synthesis of (+)-solistatin (51). Reagents and condi-tions: (a) PhCO2H (3 equiv.), (+)-COP-OAc (1 mol-%), 23 °C,CH2Cl2, 92%, 94% ee; (b) see Scheme 10, 40 % dr = 94:6; (c) 1. DI-BAL, –78 °C, CH2Cl2; 2. TESCl, DMF, 23 °C, 72%; (d) 1. 9-BBN,0 °C, THF; 2. NaOH, H2O2, 0 °C, 79%; (e) IBX, 23 °C, DMSO,66%; (f) 1. NaClO2, 2-methylbut-2-ene, NaH2PO4, 23 °C, tBuOH/H2O; 2. pTsOH, 23 °C, EtOH, 85%.


synthesis of 51 (Scheme 11) was accomplished in 17 stepsby use of Kirsch’s iterative asymmetric allylic esterificationsequence.[32]

Scheme 12. Synthesis of (+)-polyrhacitide B (59). Reagents andconditions: (a) PhCO2H (3 equiv.), (+)-COP-OAc (1 mol-%), 23 °C,CH2Cl2, 97 %, 96 % ee; (b) 1. K2CO3, 0 °C, MeOH; 2. TBSCl, imid-azole, DMF, 83 % (two steps); (c) 9-BBN, 0 °C then H2O2, NaOH;(d) IBX, 23 °C, DMSO, 89% (two steps); (e) NaH, (PhO)2P(O)-CH2CO2Me, THF, –20 °C, 87%; (f) 1. DIBAL, –78 °C, CH2Cl2;2. DBU, Cl3CCN, CH2Cl2, 94% (two steps); (g) DIBAL, –78 °C;(h) CH2=CHCH2CO2H, DCC, DMAP, 72% (two steps); (i) sec-ond-generation Grubbs catalyst (1 mol-%), 38 °C, CH2Cl2;(j) DBU, 23 °C, CH2Cl2, 81% (two steps); (k) 1. HF, MeCN/H2O,23 °C; 2. DBU, 23 °C, CH2Cl2, 66% (two steps).

Application of the COP-OAc-catalyzed esterification se-quence was also illustrated in the total synthesis of poly-rhacitide B (59, Scheme 12),[50] a secondary metabolite iso-lated from the Chinese ant species Polyrhachis lamellid-ens.[51,52] Because of the limited supply of 59 from naturalsources,[51] its biological activity has not been extensivelyexplored. It has, however, been used in traditional Chinesemedicine for the treatment of hepatitis and arthritis.[53] TheKirsch and Menz synthesis of polyrhacitide B (59) com-mences with repeated cycles of Overman’s asymmetric all-ylic esterification for the rapid assembly of 1,3-polyol unit56 (Scheme 12). In the first cycle, treatment of (Z)-imidate52 with benzoic acid in the presence of 1 mol-% of (+)-COP-OAc (12) afforded allyl ester 53 in 97% yield and with96% ee. Each cycle of iterative allylic esterification requiredthe use of (+)-COP-OAc (12) to install the C–O bond withcorrect configuration of the natural target. Although highlevels of diastereoselectivity were observed in each cycle,this approach to 1,3-polyol structures requires eight stepsfor each iteration. From 56, the synthesis was completedwith a six-step sequence to install the bicyclic lactone core,providing polyrhacitide B (59).

J. S. Arnold, Q. Zhang, H. M. NguyenMICROREVIEW2.4 Palladium-Catalyzed Asymmetric Substitutions ofLinear (Z)- and (E)-Allyl Trichloroacetimidates withPhenols

Enantioenriched chiral aryl ethers are present in manynatural products and are useful building blocks for asym-metric synthesis.[54] Transition-metal-catalyzed enantiose-lective substitutions of allylic electrophiles with phenols of-fer a significant opportunity for the synthesis of such com-pounds with high asymmetric induction. In recent years,many catalytic asymmetric approaches for the formation ofchiral aryl ethers from prochiral allyl substrates and phen-ols/phenoxides catalyzed by Pd,[55] Ru,[56] and Ir com-plexes[57] have been developed. The most efficient method-ology is the use of iridium-phosphoramidite complexes de-veloped by Hartwig and co-workers.[57] This reaction, how-ever, requires use of phenoxides as nucleophiles. To illus-trate the utility of [COP-OAc]2-catalyzed asymmetric allylicsubstitution further, Overman extended its scope to phenolnucleophiles,[58] including intermolecular[59] and intramo-lecular[60] aryl-ether-forming reactions from Z- and E-con-figured imidates.[61]

Under COP-OAc-catalyzed optimized conditions,[22,23]

the reactions between linear (Z)-allyl trichloroacetimidate13b and a wide range of phenol nucleophiles 60a–j wereinvestigated (Table 4). Reaction times to reach completionwith phenol nucleophiles were longer than those with carb-oxylic acids. Good to excellent yields and enantiomeric ex-cesses were obtained both with electron-donating and withelectron-withdrawing phenols. Efficient formation of allylaryl ethers 61f–h (Entries 6–8) demonstrates the compatibil-ity of this methodology with base-labile functional groups.Phenol nucleophile 60i (Entry 9), containing an aldehydefunctionality, proved to be stable, and aryl ether 61i wasobtained in 90 % yield and with 94% ee. Although 3-nitro-phenol (60j, Entry 10) reacted smoothly with (Z)-imidate13b to yield allyl aryl ether 61j in 90% yield, a lower levelof asymmetric induction (65 % ee) was observed.

The functional-group tolerance of the COP-OAc systemwas evaluated with five other additional imidate substratesand various phenols (Table 5). Allyl aryl ethers 67–78 (En-tries 1–12) were obtained in high yields (70–97%) and withexcellent enantioselectivity (90–97 % ee).[58] A currentlimitation of the reactions in Table 5 is that low yields areattained with allyl imidates in which the γ-substituent isbranched. For instance, use of substrate 66 (Entry 13) pro-vided aryl ether 79 in 30 % yield after 96 h.

Furthermore, [COP-OAc]2 (12) is not suitable with linear(E)-trichloroacetimidates. For instance, the reaction be-tween 80 (Scheme 13) and phenol 60a in the presence of1 mol-% of 12 provided aryl ether 61a in 32% yield andwith 90% ee [for comparison, its Z isomer counterpart 16awas obtained in 86% yield and with 92% ee (Table 4, En-try 1)].[58] The E isomer 80 undergoes a competitive [3,3]-sigmatropic rearrangement to provide trichloroacetamide82 as the major product (Scheme 13).[58] To optimize thereaction conditions, a number of COP (cobalt oxazolinepalladacycle) catalysts were investigated by Overman and


Table 4. Asymmetric synthesis of allyl aryl ethers from (Z)-imidate13b.

Table 5. Substrate scope of COP-OAc-catalyzed formation of arylethers.

co-workers.[59] The [COP-NHCOCCl3]2 complex (81,Scheme 13) was found to be the most effective catalyst inpromoting the reaction between (E)-imidate 80 and phenol60a to yield the desired allyl aryl ether 61a in 82% yieldand with 91 % ee.


Scheme 13. Reaction of E isomer 80a in the presence of COP cata-lysts.

The COP-NHCOCCl3 complex (81) having been estab-lished as the optimal catalyst, the effects of the steric andelectronic nature of the substituents on the phenyl ring inphenol nucleophiles were examined in reactions with (E)-allyl trichloroacetimidate 80 (Scheme 14, a).[59] Allyl arylethers 83b–j were obtained in moderate to good yields (45–83%) and with high enantioselectivities (86–94% ee). Al-though the positions and electronic natures of the substitu-ents have profound influences on reaction times, allyl arylethers 83b–j (Scheme 14, a) were obtained with excellentbranched-to-linear selectivity in all cases. In general, longerreaction times and lower yields were observed with use ofphenols bearing electron-donating groups or featuring or-tho-substitution. The scope of the reaction was further ex-amined with (E)-imidates 80a–d (Scheme 14, b), bearingvarious aliphatic groups and functionalities. The reactionswere performed in either CH2Cl2 or CHCl3, with allyl arylethers 84–87 being obtained in 59–88% yields and with 78–93 % ee values.[59] Only a moderate yield (59%) of allylphenyl ether product resulted on use of an allyl trichloro-acetimidate containing a carbonyl functionality, but theenantioselectivity was high (90 % ee).[59]

Scheme 14. Scope of [COP-NHCOCCl3]2-catalyzed reactions.

In an effort to expand the capabilities of this enantiose-lective method, the development of the intramolecular vari-


ant was pursued (Table 6).[60,62,63] The cyclization of phen-olic (E)-allyl imidate 88a in the presence of the two COP-derived catalysts 12 and 81 (Entries 1 and 2) was examinedunder previously optimized conditions.[59] Use of 12 af-forded 2-vinylchromane (89a, Entry 1) in 86% yield andwith 89% ee.[60] Although use of the [COP-NHCOCCl3]2complex 81 (Entry 2) provided the desired product 89a ingood yield and with high levels of enantioselectivity, thecompetiting formation of the rearranged trichloroacet-amide, in 13 % yield, was also observed.[60] Lowering thecatalyst loading to 0.5 mol-% (Entry 3) did not diminish theyield and enantiomeric purity (91% and 94% ee). The 4-bromo- and 4-methoxyphenol acetimidate precursors (En-tries 4 and 5) also smoothly underwent cyclization, yieldingthe corresponding six-membered-ring heterocycles 89b and89c in excellent yields (92–94 %) and enantioselectivity (90–91% ee).

Table 6. Catalytic asymmetric cyclization of phenolic (E)-allyl imid-ates.

This intramolecular variant is also suitable for the enan-tioselective synthesis of both 2-vinyl-1,4-benzodioxane(89d) and 2,3-dihydro-2-vinyl-2H-1,4-benzoxazine 89e(Scheme 15) in excellent yields and with 94% and 98 % ee,respectively.[60] Unfortunately, the [COP-OAc]2-catalyzedintramolecular reaction is not applicable for preparation of2,3-dihydro-2-vinyl-2H-1,4-benzothiapyran (89f). This islikely due to binding of the palladium complex 12 to thesulfur group of allyl trichloroacetimidate 92, shutting downthe reaction.

Scheme 15. Enantioselective synthesis of six-membered-ring het-erocycles.

In summary, efficient catalytic asymmetric esterificationand etherification processes, developed by Overman and co-workers, utilize the COP catalyst family to promote reac-tions of linear (Z)- and (E)-allyl trichloroacetimidates withcarboxylic acid and phenol nucleophiles. The corresponding

J. S. Arnold, Q. Zhang, H. M. NguyenMICROREVIEWallyl esters and aryl ethers were formed in good yields andwith excellent levels of enantioselectivity and branched-to-linear ratios. The methodology is compatible with a widerange of functional groups incorporated both on primaryallyl imidate precursors and on oxygen nucleophiles.

3. Reactions of Branched Allyl Acetimidates withNitrogen Nucleophiles

The Pd-catalyzed asymmetric [3,3]-sigmatropic re-arrangement of trans-disubstituted allyl trichloroacetimid-ates, developed by the Overman group, is an efficient meth-odology for the preparation of enantioenriched α-substi-tuted allylamines (nitrogen-containing tertiary centers).[2,18]

However, this reaction is of limited utility for the enantiose-lective synthesis of sterically encumbered nitrogen-contain-ing quaternary centers (α,α-substituted allylamines).[63] All-ylic substitutions catalyzed by palladium,[64] rhodium,[65]

and iridium[66] have also been successfully applied to asym-metric amination reactions to provide the correspondingenantioenriched α-substituted amines. In general, thesemethodologies utilize linear allyl acetate and carbonateelectrophiles to afford the amination products in goodyields and with excellent levels of regioselectivity and asym-metric induction.[67] Alternatively, chiral allylamines havebeen accessed through transition-metal-catalyzed kineticresolutions[68] or dynamic kinetic asymmetric transforma-tions (DYKATs)[69] of branched allylic electrophiles. Asidefrom utility in resolution-type methods, branched racemicallylic substrates are advantageous because they are easilyprepared from allyl alcohols derived from vinyl additionsto a variety of aldehydes and ketones, and react at a fasterrate than their linear counterparts, due to less steric conges-tion at the olefin.[70] Collectively, transition-metal-catalyzedsubstitutions of allyl acetates and carbonates are powerfultransformations for the synthesis of various α-substitutedallylamines. However, these substrates are not suitable forthe asymmetric preparation of the challenging α,α-disubsti-tuted allylarylamines. In 2012, Nguyen’s group reported thefirst rhodium-catalyzed aminations of racemic allyl tri-chloroacetimidates with aniline nucleophiles for the asym-metric synthesis of these quaternary arylamine-bearing cen-ters.[71] Our review of this method begins with the develop-ment of the regioselective amination of secondary and terti-ary allyl trichloroacetimidates and follows with theDYKAT reaction of a tertiary electrophile and an anilinenucleophile for the synthesis of enantioenriched α,α-disub-stituted allylarylamines.

3.1 Rhodium-Catalyzed Regioselective Substitutions ofRacemic Secondary Allyl Trichloroacetimidates withAnilines

In 2010, Nguyen and co-workers reported a process forhighly regioselective Rh-catalyzed amination of secondaryallyl trichloroacetimidates with a variety of aniline nucleo-philes.[72] In contrast with previous stereospecific amina-


tions catalyzed by rhodium,[65] these substitutions utilizeunactivated anilines, avoiding the need to pretreat the nu-cleophile or to add base to the reaction mixture.

This work began with catalyst optimization studies withTBS-protected acetimidate 93 and 3 equiv. of aniline (94a)in THF at 40 °C (Table 7). To evaluate the ability of a tri-chloroacetimidate as an electrophile under previously re-ported amination conditions,[65] a combination of 10 mol-% Wilkinson’s catalyst and 20 mol-% P(OMe)3 ligand wasfirst investigated; it provided a 13% yield and a 5:1 ratio ofbranched product 95a and linear product 95b (Entry 1).Next, a number of readily available rhodium diene dimerswere evaluated (Entries 2–4) with 5 mol-% [RhCl(ethyl-ene)2]2 (Entry 4) and 20 mol-% of P(OMe)3; this providedan 84% yield of allylarylamine with branched/linear = 65:1in favor of the branched product 95a. Triphenylphosphiteligand (Entry 6) proved optimal, with the highest yield andregioselectivity (95 %, branched/linear �99:1). Lowering therhodium catalyst loading to 1 mol-% still maintained theyield and regioselectivity (Entry 8). Additionally, the Over-man product was not observed in the reaction, suggestingthat the ionization of allyl acetimidate 93 is faster than its[3,3]-sigmatropic rearrangement to the corresponding tri-chloroacetamide.

Table 7. Studies of Rh-catalyzed amination of secondary allyl imid-ate 93.

The scope of the amination was then evaluated with anumber of secondary allyl trichloroacetimidates – 93, 96,and 97 – and aniline nucleophiles 94a–f (Table 8). Aniline94a, electron-poor aniline 94b, containing a 4-fluoro sub-stituent, and electron-rich anisidine 94c all worked well withthis imidate class, providing amine products 98–110 withexcellent yields (72–99 %) and regioselectivities (�99:1).Even more impressive are the reactions of allyl imidateswith sterically demanding anilines 94d–f, which would beexpected to react sluggishly and with low regioselectivity.On the contrary, 2-methyl-substituted toluidine 94d (En-


tries 9–11) was an effective amine nucleophile, providing theamination products 106–108 in high yields (80–94%) andwith �99:1 branched-to-linear ratios. Both 2,4,6-trimeth-ylaniline (94e) and N-methylaniline (94f), nucleophiles thatprovided poor regioselectivity (1:1 to 4:1) in a previous re-port,[66a] yielded the allylamine products 109 and 110 (En-tries 12 and 13) in 85–86% yields and with 60:1 to 70:1branched selectivity.

Table 8. γ-Substituted trichloroacetimidates and aniline nucleo-philes in rhodium-catalyzed regioselective allylic amination.

The scope of the amination was further investigated withallyl trichloroacetimidates 111–113 (Scheme 16), in whichsubstituents on the alkyl chain are one carbon closer tothe newly formed nitrogen center than in the substrates inTable 7. Amination reactions were high-yielding (91–99 %)and regioselective (�99:1) with aniline (94a) and 4-fluoro-aniline (94b). However, use of 4-methoxyaniline (94c) re-sulted in low yields of the amination products (20–47%)with β-oxygen-containing allyl imidates 111 and 112,whereas substrate 113, lacking this moiety, provided the all-ylarylamine in 80% yield and with �99:1 regioselectivity.[72]

Scheme 16. β-Substituted trichloroacetimidates and aniline nucleo-philes in rhodium-catalyzed allylic amination.

In view of the encouraging results illustrated in Table 8and Scheme 16, allyl trichloroacetimidate electrophiles 122–124 (Table 9), which possess cyclohexyl, isopropyl, orphenyl substituents at the α-position with respect to the ap-


proach of aniline nucleophile, were then subjected to therhodium-catalyzed amination reaction conditions. It has re-cently been reported that α-substituted allyl carbonates arepoor substrates in amination reactions in the presence ofWilkinson’s catalyst,[65b] providing the linear allylaryl-amines as the major products. Accordingly, treatment oftrichloroacetimidates 122–124 (Table 9) with anilines 94a–din the presence of 10 mol-% rhodium-phosphite complex atambient temperature afforded the amination products 125–135 with good regioselectivities. Anilines 94a–c of varyingbasicity were all viable nucleophiles in the substitution(Table 9, Entries 1–9), resulting in α-substituted arylamines125–133 in good yields (75–96%) and with excellent regio-selectivities (19:1 to 90:1). Outstanding results were ob-tained (Entries 10 and 11) with sterically encumbered allylimidate substrates 122–123 and 2-methyl-substituted anil-ine, which resulted in high yields (70–73%) and selectivities(12:1 to 14:1 branched-to-linear) of amine products 134 and135 (Table 9). This showcases the utility of branched allyltrichloroacetimidate substrates in rhodium-catalyzed sub-stitution reactions with aniline nucleophiles.

Table 9. α-Substituted trichloroacetimidates and aniline nucleo-philes in rhodium-catalyzed allylic amination.

Recently, iridium-catalyzed regioselective amination ofbis-allyl trichloroacetimidates for diastereoselective synthe-sis of bridged bicyclic heterocycles 145–147 was reportedby Braun and co-workers (Scheme 17).[73] Bis-allyl imidates139–141 were prepared in a three-step sequence by one-potoxidative cleavage of syn-diols 136–138, followed by vinylGrignard addition and derivatization of the resulting diolswith trichloroacetonitrile and DBU. Conditions optimizedfor maximum yield of the “cis” diastereomers[73] in the bis-amination reaction included 5 mol-% of [IrCl(COD)]2 cata-lyst and cumylamine nucleophile in DCE at 0 °C� roomtemperature for 18 h, providing 142–144 in 67–84 % yieldsand with moderate to good levels of diastereoselectivity (dr

J. S. Arnold, Q. Zhang, H. M. NguyenMICROREVIEW= 3.5:1–12:1). In these studies, the aminations of bis-allylacetates and carbonates with anilines provided the desiredamine products with poor diastereoselectivity, highlightingthe efficacy of allyl trichloroacetimidates. Finally, heterocy-cles 145–147 were formed by ring-closing metathesis.

Scheme 17. Diastereoselective synthesis of bridged bicyclic hetero-cycles 145–147. Reagents and conditions: (a) PhI(OAc)2, CH2Cl2,0 °C, 1 h; (b) CH2CHMgBr, –78 °C to room temp., 16 h;(c) Cl3CCN, 50 mol-% DBU, CH2Cl2, 0 °C to room temp., 18 h;(d) 5 mol-% [IrCl(COD)]2, 1.2 equiv. cumylamine, 0 °C to roomtemp., 18 h; (e) second-generation Grubbs catalyst, toluene, 120 °C,20 h.

3.2 Rhodium-Catalyzed Regioselective Substitutions ofRacemic Tertiary Allyl Trichloroacetimidates with Anilines

In 2011, the scope of allylic amination was expanded totertiary imidate substrates for the regioselective preparationof α,α-disubstituted allylarylamines.[74] At that time, fewtransition-metal-catalyzed substitution methods were avail-able for the preparation of nitrogen-containing quaternarycenters, and the range of arylamines that had been used wasquite narrow.[64d,64e,66e,75] At the start of the investigation,an optimal rhodium catalyst was identified by evaluatingcommercially available rhodium complexes (Table 10). Ini-tial investigations were conducted with acetimidate 148 andoptimized conditions utilized for secondary allylic sub-strates,[72] providing α,α-disubstituted arylamine 149a in45% yield and with branched/linear = 14:1 (Entry 1). In-creasing the catalyst loading (Entries 2 and 3) and use of amore strongly electron-withdrawing phosphite ligand (En-try 4) increased both the yield of 149a (45 �86%) and theregioselectivity (14:1�31:1 branched-to-linear). Cyclooc-tadiene (COD) and norbornadiene (NBD) dimers were ef-fective catalysts that increased the yield, regioselectivity,and rate of the reaction (Entries 5–6), relative to rhodium-phosphite complexes. Further, lowering the reaction tem-perature of the [RhCl(NBD)]2-catalyzed amination in-creased the regioselectivity from 50:1 to 62:1 (Entry 7).Decreasing the catalyst loading to 1 mol-% had little impacton the reaction results (Entry 9).


Table 10. Studies of Rh-catalyzed amination of tertiary allyl imid-ates.

The amination of tertiary imidates 148–153 in the pres-ence of 1–5 mol-% of [RhCl(NBD)]2 in THF at ambienttemperature was amenable to a range of sterically and elec-tronically diverse anilines 94a–i (Table 11). A trend that ismarkedly evident in the amination reactions of tertiary allyltrichloroacetimidates is that regioselectivity is generallyhigh for a substrate possessing a β-oxygen substituent (i.e.,150 and 151) and moderate for a substrate lacking thisfunctionality (152 and 153). For example, treatment of theTBS-protected imidate 150 with aniline (94a) provided 154in 95 % yield and with �99:1 branched regioselectivity (En-try 1). In contrast, use of the same aniline (94a) and phenyl-

Table 11. Scope of tertiary acetimidates and aniline nucleophiles.


Scheme 18. Synthesis of N-isoprenylated indoles.

ethyl substrate 152 resulted in an 84 % yield and an 11:1branched-to-linear regioselectivity for allylarylamine 155(Entry 2). In another example, benzyloxy-substituted imid-ate 151 provided arylamine product 158 in 87% yield andwith �99:1 branched-to-linear ratio, whereas monoter-penoid substrate 153 provided 159 in 85 % yield and with18:1 regioselectivity, when paired with 4-fluoroaniline (94b)as nucleophile (Entries 5 and 6). It is hypothesized that thepresence of an oxygen substituent in the allylic electrophileintroduces a point of chelation, providing additional con-trol during C–N bond formation. Table 11 highlights high-yielding and regioselective amination reactions with a widevariety of para-, meta-, and ortho-substituted aniline nu-cleophiles; these make this method the most versatile routeto α,α-disubstituted allylarylamines of synthetic utility. Forexample, 4-boronic acid ester, 3-ester, and 2-bromo deriva-tives 166, 167, and 168 possess useful substituents for subse-quent functionalization. In addition, quaternary centersbearing monomethylated nitrogen are readily accessible,with the rhodium-catalyzed substitution of imidate 150with N-methylaniline (94f) providing allylic N-methylamine165 in 78% yield and with an impressive 62:1 branched-to-linear ratio. Throughout the course of these investigations,no Overman rearrangement of tertiary allyl trichloroaceti-midates was observed in the reactions.

The efficacy of the rhodium-catalyzed regioselectiveamination of tertiary allyl trichloroacetimidates has beenillustrated in the synthesis of reverse prenylated indoles172–174 (Scheme 18).[74] The N-(1,1-dimethylprop-2-enyl)-indoles and their derivatives are structural motifs found inbiologically relevant natural products and pharmaceuti-cals.[76] These alkaloid compounds are commonly preparedby a multistep sequence involving N-propargylation ofindoline, oxidation to indole, and final partial hydrogen-ation of alkyne to afford the alkene.[76] A direct reverse iso-prenylation of indole has recently been described.[77] Ac-cordingly, tertiary imidates 148, 150, and 151 (Scheme 18)were subjected to optimized amination conditions with 2-(trimethylsilyl)ethynyl-aniline (94j), resulting in allylaryl-amines 169–171, respectively, in good yields (69–85%) andwith excellent regioselectivity (branched/linear = 54:1 to90:1). The resulting branched arylamine products sub-sequently cyclized to the corresponding reverse-prenylatedindoles 172–174 (Scheme 18) in high yields on treatmentwith CuI at 80 °C for 15 h.


3.3 Studies of Unique Features of AllylTrichloroacetimidates in Rhodium-Catalyzed RegioselectiveAmination

During the course of the development of rhodium-cata-lyzed regioselective amination of branched allyl trichloro-acetimidates, Nguyen and co-workers conducted a numberof control studies to gain mechanistic insight and to providevalidation of hypotheses that eventually led to these investi-gations.[72,74] Much was drawn from Overman’s mechanisticstudies.[22–24] Nguyen and co-workers realized the impor-tance of the strong chelating and directing functions of thebasic acetimidate nitrogen and the dependence of the reac-tion outcome on the geometry of the olefin moiety.[8,19,24]

On the basis of these precedents, Nguyen and co-workersproposed that branched allyl trichloroacetimidates of lesssterically encumbered terminal olefins would ionize morerapidly than their linear isomer counterparts. Thus, theOverman [3,3]-sigmatropic rearrangement products wouldnot be observed in the reaction.

To confirm that the ionization of the branched imidatesis faster than that of their linear isomers, the reaction be-havior of primary (E)- and (Z)-allyl trichloroacetimidates175 and 176 was investigated under standard rhodium con-ditions (Scheme 19, a). It required 21 h for the reaction toreach completion, and the amine products 95a and 95bwere obtained in 65–79% yields in favor of the linear isomer(95a/95b = 1:14 to 1:17).[76] In another study, imidate 93and aniline 94a were subjected to 2 mol-% BF3·OEt2 at40 °C (Scheme 19, b).[72] Although complete conversion wasobserved after 15 h, a 1:1 mixture of branched and linearisomers (95a/95b) was obtained. This result provides theevidence that the rhodium catalyst is unlikely to act as aLewis acid. To validate the efficacy of the trichloroacetimid-ate in acting both as a leaving group and as a directinggroup in the amination reaction, branched allyl carbonate177 and acetate 178 were examined and found to be unreac-tive under the rhodium conditions (Scheme 19, c).[72] Onthe other hand, N-aryl imidate 179 (Scheme 19, d) provideda low yield (22 %) of amine 149a and a 32% yield of theOverman rearrangement product 180.[74] A control experi-ment was also investigated with allyl trichloroacetamide 181(Scheme 19, d), which results from the Overman rearrange-ment. No amination product was observed after 12 h.[74]

Overall, substrates that lack the basic and strongly coordi-


Scheme 19. Rhodium-catalyzed amination control studies.

nating trichloroacetimidate nitrogen are not effective for therhodium-catalyzed regioselective allylic amination.

In a pivotal study, the allylic amination of enantio-enriched trichloroacetimidate (S)-182 did not progressenantiospecifically, instead resulting in nearly racemic prod-uct 183 (Scheme 20).[72] This result conflicts with othertransition-metal-catalyzed allylic substitution methodolo-gies, which have been reported to provide the products withnet retention of stereochemistry.[65]

Scheme 20. Rhodium-catalyzed amination of enantioenrichedimidate (S)-182.

The outcome of the experiment illustrated in Scheme 20could be explained by comparing the relative rates of equili-bration of organorhodium complexes 185 and ent-185 and


nucleophilic attack by aniline nucleophile (Figure 2). Therhodium catalyst coordinates to both the imidate nitrogenand the alkene functionality of 182 to afford Rh-olefincomplex 184, which subsequently undergoes ionization togenerate π-allylrhodium complex 185.[78] Nucleophilic at-tack of the aniline nucleophile at the internal position of

Figure 2. Proposed mechanism for formation of racemic amine183.


organorhodium intermediate 185 provides the desiredamination product 183. The authors hypothesize that therate of aniline substitution (k1 and k2) is much slower thanthat of π-σ-π interconversion, resulting in racemization inthe amine product 183.

3.4 Rhodium-Catalyzed Enantioselective Substitutions ofRacemic Tertiary Allyl Trichloroacetimidates with Anilines

Having developed a highly regioselective method for rho-dium-catalyzed amination of racemic trichloroacetimidatesand armed with new ideas relating to the mechanistic as-pects of this transformation, Nguyen and Arnold initiatedstudies directed towards making this method enantioselec-tive. They proposed that if the rate of isomerization of π-allylrhodium complexes 185 (Figure 2) were faster than at-tack by aniline, dynamic kinetic asymmetric transforma-tions (DYKATs) of racemic allyl trichloroacetimidatescould be feasible.[79] Through the use of a chiral ligand, amore sterically congested environment is established, whichslows down the rate of nucleophilic substitution by anilineand increases the time available for the equilibration be-tween the two diastereomeric π-allylrhodium complexessuch as 185 and ent-185 (Figure 2). An unfavorable interac-tion between one of the two organorhodium species woulddetermine which enantiomer of the amination product 183(k1 ��k2) is preferentially formed in the reaction.

DYKAT studies commenced with tertiary allyl imid-ates,[71] bulky electrophiles that would potentially slowdown the rate of nucleophilic attack by aniline (Table 12).To mimic the optimized regioselective conditions with thenorbornadiene (NBD) rhodium catalyst,[74] a number ofreadily available chiral diene ligands were tested in combi-nation with [RhCl(ethylene)2]2. In addition, because chiraldiene ligands are good π-acids,[80] they increase the cationiccharacter of the π-allylrhodium complex through back-bonding. The increased cationic character is more stable atthe substituted allyl position and directs addition of anilineto the more stabilized allyl carbon. Hayashi’s bicyclo[2.2.2]-octadiene[77] L1 (Table 12) was the most effective, providingthe highest yield and level of asymmetric induction of theamination product 186. Studies using L1 ensued, investiga-ting the effects of temperature, solvents, and equivalents ofaniline (94a, Table 12, Entries 1–10) and providing optimalresults with use of 1.5 equiv. of aniline at ambient tempera-ture for 1 h in methyl tert-butyl ether (Entry 10). Optimiza-tion was continued through variation of the electronic andsteric properties of the aryl ring on the chiral diene ligand(L2–L6, Entries 11–13), with 4-fluorophenyl Hayashi deriv-ative L4 resulting in an 85 % yield of the α,α-disubstitutedarylamine 186 with 94% ee (Table 12, Entry 13).

To explain the improved enantioselectivity with an elec-tron-withdrawing chiral diene ligand (L4 vs. L1, Table 12),the ligation of the chiral diene ligands to rhodium was mon-itored by 13C NMR spectroscopy (Table 13). It was deter-mined that the electronic density of the diene ligand signifi-cantly influences the coordination shift (Δδ = δcomplex –


Table 12. Studies of rhodium-catalyzed DYKAT amination of terti-ary allyl trichloroacetimidate 151.

δfree ligand) due to increasing back-donation from the metalcenter.[81] For example, electron-withdrawing diene ligandL4 has a larger coordination shift than electron-donatingdiene ligand L2. This result suggests that the presence ofthe electron-withdrawing group on the chiral diene ligandL4 shifts the hybridization of the coordinated alkene carbonfrom sp2 towards a more sp3 character and thus makes thisdiene ligand bind more strongly to rhodium than electron-donating ligand L2 (Table 13).[81] In addition, the magni-tude of the 103Rh-13C coupling constant, of 10.6–12 Hz,suggests that there is considerable s-character in the rho-dium-chiral diene complexes (Table 13).[82]

Table 13. Studies of the stabilities of rhodium-diene complexes.

The reactions between racemic allyl trichloroacetimidate151 and various aniline nucleophiles 94b–n were then exam-ined. Overall, moderate to good yields of amination prod-ucts 187–195 (Table 14) were obtained with high asymmet-ric induction and maintenance of excellent levels of regio-

J. S. Arnold, Q. Zhang, H. M. NguyenMICROREVIEWselectivities for branched products. para-Substituted elec-tron-withdrawing anilines 94b, 94k, and 94l (Entries 1, 6,and 7), electron-donating aniline 94c (Entry 2), and N-methylaniline 94n (Entry 9) provided α,α-disubstituted all-ylarylamines in good yields (51–86 %) and with high selec-tivities (branched/linear = 30:1 to 99:1 and 85–96% ee).meta- and ortho-substitutions were amenable to the DY-KAT reaction as well, and are highlighted in the aminationwith ethyl 3-aminobenzoate 94h (Entry 5), toluidine 94d(Entry 3), and sterically hindered 2-isopropylaniline (94m,Entry 8). To establish the absolute stereochemistry of theallylarylamine products, compound 193 was converted intothe corresponding TFA salt and determined to be S-config-ured by X-ray crystallographic analysis.[71] By applying tri-chloroacetimidate as the leaving group to allylic substitu-tion methodology, the authors provided the first exampleof DYKAT with a wide range of aniline nucleophiles for thesynthesis of enantioenriched α,α-disubstituted arylamines.

Table 14. Rhodium-catalyzed DYKAT of tertiary allyl acetimidate151 with anilines 94b–n.

Investigation of the DYKAT process continued with anumber of tertiary allyl trichloroacetimidates – 150, 152,and 196–202 – and 4-fluoroaniline (94b, Table 15). On thebasis of previous studies of tertiary allyl imidates in regiose-lective amination,[74] substrates were chosen with the aim ofevaluating reaction outcomes in terms of the accessibilityof a β-ether substituent. Table 15 demonstrates that any orall of the amination reaction parameters, including yield,regioselectivity, and enantiomeric excess, are affected by thelocation of the oxygen functionality and by its charge den-sity. Aminations of imidate substrates 196–200 (Entries 1–5) possessing β-ether functional groups provided allylaryl-amines 203–207, respectively, in good yields (57–84%) withhigh asymmetric induction (80–93% ee) and excellent regio-selectivities (�99:1). The inductive effect of β-benzoyl ester192, however, provided amine product 208 in 53% yield andwith 59% ee (Entry 6). In comparison, β-benzyloxy imidate


151 provided amine product 187 (Table 14, Entry 1) in 82 %yield and with high selectivity (�99:1 branched-to-linear,96% ee). Substrate 202, with the benzyl-protected etherfunctionality at the position γ to the trichloroacetimidateleaving group, provided 210 in 70% yield and with 5:1branched-to-linear ratio and 56% ee (Entry 8).

Table 15. Tertiary allyl trichloroacetimidate substrate scope.

Although excellent yields, regioselectivities, and enantio-meric excesses result with β-oxygen-containing tertiary all-ylic substrates and a variety of aniline nucleophiles, im-provements can still be made with regard to tertiary tri-chloroacetimidate substrates lacking β-oxygen functionalityand groups other than methyl at the newly formed quater-nary carbon center. Nevertheless, this is the first exampleof transition-metal-catalyzed DYKAT of racemic tertiaryallylic electrophiles with aniline nucleophiles.

3.5 Rhodium-Catalyzed DYKAT of Racemic SecondaryAllyl Trichloroacetimidates and Synthetic Applications

The enantioselective amination of allyl trichloroacetimid-ates with aniline nucleophiles is also applicable to racemicsecondary substrates for the preparation of chiral α-substi-tuted amines (Table 16). The optimal amination conditionsconsist of 2–5 mol-% of rhodium-chloride dimer ligated toHayashi’s commercially available chiral bicyclo[2.2.2]oc-tadiene ligand L1,[83] 1.5 equiv. of aniline, and 1 equiv. ofsecondary imidate in 1,4-dioxane at 40 °C.[84,85] Yields andasymmetric induction were highest with allyl imidates at el-evated temperature. Regioselectivity could be further in-creased as required by conducting the amination reactionat 25 °C.[79] In contrast with the reactions of tertiary sub-strates, secondary allyl trichloroacetimidates lacking an ad-ditional point of chelation were equally efficient in theenantioselective amination. For example, the reaction be-


Table 16. Rhodium-catalyzed DYKAT of secondary allyl acetimidates.

tween phenethyl-substituted allyl acetimidate 97 (Entry 2)and para-methoxyaniline (94c) provided amine 215 in 83 %yield and with �99:1 branched-to-linear ratio and 89% ee.For comparison, coupling of benzyloxy-substituted tri-chloroacetimidate substrate 112 (Entry 1) and aniline 94bresulted in a 90% yield, with �99:1 regioselectivity and87 % ee for amine product 214.

A powerful aspect of the rhodium-catalyzed enantiose-lective amination of allyl trichloroacetimidates is that N-methylanilines are effective nucleophiles, performing well inreactions that give low levels of regioselectivity when allylcarbonates are utilized.[65a] Under our DYKAT conditions,aminations of a wide variety of secondary allyl trichloro-acetimidates with N-methylanilines 94n–r (Table 16, En-tries 4–10), with a variety of functionality and substitutionpatterns on the phenyl ring, provided N-methylamines 217–223 in 78–92 % yields and with good regioselectivities(branched/linear = 7:1 to 88:1) and excellent asymmetricinduction (85–95% ee). Of note in Table 16 are the substitu-tion reactions of α-branched allyl trichloroacetimidates122–124, electrophiles that had provided allylamine prod-ucts with low regioselectivities when derivatized as allylcarbonates.[65b]

Nguyen and co-workers demonstrated the synthetic util-ity of the rhodium-catalyzed DYKAT methodology by pre-paring allyl N-methylanisidine 224 (Scheme 21) and trans-forming it into the corresponding N-methylhomophenylala-nine derivatives 226–228,[84] found in antillatoxin B, a po-tent activator of sodium ion channels.[86] This work illus-trates that anilines function not only as competent nucleo-philes in the amination method, but also as masking


groups, ultimately providing enantioenriched N-methyl-amine 225, a synthetically useful intermediate for bioactivetargets.

Scheme 21. Synthesis of N-methylhomophenylalanine derivatives226–228. Reagents and conditions: (a) CAN, CH3CN, H2O,15 min; (b) Boc2O, K2CO3, THF/H2O (1:1); (c) RuCl3, NaIO4;(d) Ac2O, pyridine; (e) O3, NaOH, MeOH.

3.6 Rhodium-Catalyzed Sequential Asymmetric Aminationand Intramolecular Olefin Hydroacylation Reactions

Most recently, Nguyen and co-workers have successfullyapplied the rhodium-catalyzed DYKAT process to the chal-lenging anilines 94s, each bearing an ortho-aldehyde func-tional group, to form enantioenriched allylarylamines 230(Scheme 22).[87] The amine products then participate in in-tramolecular alkene hydroacylation,[88] forming seven-mem-bered nitrogen heterocycles 231. The unique feature of thisapproach is that the asymmetric induction is controlledduring the amination step, rather than during the hydro-acylation step.[89–92]


Scheme 22. Sequential amination and intramolecular hydroacyl-ation.

The authors were aware that the aldehyde group on theaniline nucleophile could be problematic in the aminationreaction due to competitive decarbonylation, commonlyobserved in the presence of rhodium(I).[93] To date, there isonly one example of utilization of 2-aminobenzaldehydes94s in olefin hydroacylation with alkynes.[94] However, useof 5 mol-% of [RhCl(ethylene)2]2, 10 mol-% of the chiraldiene ligand L6, 1.5 equiv. of 2-aminobenzaldehyde (94t),and an equivalent of racemic secondary allyl trichloroacet-imidate 97 in MTBE provided the corresponding allylaryl-amine 232 (Scheme 23) in 64% yield and with excellent re-gioselectivity (�99:1) and 84 % ee. This result demonstratesthe successful extension of the DYKAT methodology to thechallenging 2-aminobenzaldehyde in enantioselective amin-ation. In addition, no decarbonylation of alkenal 232 wasobserved. Furthermore, no hydroacylation product (e.g.,231, Scheme 22) was formed even at elevated temperaturesor when neutral Rh-L6 complex was converted into a morereactive cationic rhodium with silver salts.

Scheme 23. Optimized studies of rhodium-catalyzed sequential all-ylic amination followed by intramolecular hydroacylation.

Nguyen and co-workers then evaluated a number of rho-dium catalysts to effect intramolecular hydroacylation of al-kenal 232 (Scheme 23). It was anticipated that coordinationof the amine group in 232 to rhodium, forming a stablefive-membered amino-acyl rhodacycle, would be importantfor promoting hydroacylation over aldehyde decarb-onylation.[90,91] The authors then investigated a number ofbisphosphine-ligated-rhodium(I) catalysts in a number ofsolvents at elevated temperatures. The efficiency of the cy-clization of 232 decreased as the bite angle of the bisphos-phine ligand became smaller. This is consistent with whathas been observed with the reported rhodium-catalyzedasymmetric hydroacylation of alkenal ketones.[90] Readilyavailable [Rh(COD)(dppb)]BF4 was ultimately found to be


the most effective catalyst, providing the desired seven-membered-ring aza-ketone 233 in 99% yield after 1 h at105 °C. In addition, the heterocycle product 233 was pro-duced without any observable racemization. This result il-lustrates that cyclization can take place efficiently in the ab-sence of additional substituents on the nitrogen atom of anallylarylamine, even though allylarylamines were unsuitablesubstrates under Bendorf’s conditions.[91]

To illustrate the scope of the sequential process, Nguyenand co-workers turned their attention to assessing the rho-dium-catalyzed asymmetric amination of racemic second-ary allyl acetimidates (Table 17, Entries 1–5) containing sev-eral functional groups and found that they were suitable toreact with 2-aminobenzaldehyde (94t). The allylamines235–239 were isolated in 41–95 % yields and with 80–93% ee and excellent branched selectivity. Notably, α-sub-stituted imidate 122 (Entry 7) reacted efficiently to affordamine 239 with high regioselectivity; it had previously beenreported to give the amine products with low regioselectivi-ty.[65b] Furthermore, the amination reaction is compatiblewith both electron-donating and electron-deficient 2-ami-noarylaldehydes (Entries 6–8), giving access to allylaryl-amines 240–242 in 61–91% yields and with high enantio-selectivity (84–94% ee). A cyclic aniline nucleophile (En-try 9) is also amendable, providing amination product 243in 83 % yield and with 88% ee. As a further demonstrationof the efficacy of the sequential catalytic events, the asym-metric amination of racemic tertiary allylic substrate 151(Table 17, Entry 10) was attempted. Gratifyingly, α,α-disub-stituted arylamine 244 was isolated in 54 % yield and withexcellent levels of enantioselectivity (96% ee). Alkenals235–244 were subsequently subjected to the intramolecularolefin hydroacylation conditions (Table 17), consisting of5 mol-% of [RhCOD(dppb)]BF4 at 105 °C for 1 h. Cycliza-tion of 235–244 proceeded smoothly to afford seven-mem-bered nitrogen-containing heterocycles 245–254, respec-tively, in moderate to excellent yields (50–99%) without anyobservable racemization (Table 17). More aggressive condi-tions (10 mol-% [RhCOD(dppb)]BF4 at 105 °C for 1 h)were required for hydroacylation of the secondary allylanil-ine 243 and quaternary-center-containing 244, providingthe corresponding azaketones 253 and 254, respectively, in66% and 94 % yields and with 84% and 95% ee values(Table 17, Entries 9 and 10).

In summary, application of the branched trichloroacet-imidate leaving groups to rhodium-catalyzed allylic substi-tution reactions has resulted in highly regio- and enantiose-lective amination. This operationally simple and efficientmethodology utilizes rhodium(I) catalysts ligated to chiralHayashi-type bicyclo[2.2.2]octadiene ligands in combina-tion with a variety of aniline nucleophiles and racemic sec-ondary and tertiary allyl trichloroacetimidates. TheDYKAT process is applicable to the asymmetric prepara-tion of a wide range of α-substituted and α,α-disubstitutedallylamines and has overcome previous limitations associ-ated with transition-metal-catalyzed intermolecular amina-tions of allyl carbonates and acetates. The amine productsmake useful building blocks for the synthesis of enantioen-


Table 17. Scope of sequential amination and hydroacylation.

riched targets, and this has been demonstrated in the prepa-ration of amino acids and nitrogen-containing heterocycles.

4. Iridium-Catalyzed Regioselective Fluorinationof Branched Allyl trichloroacetimidates

After the successful development of the rhodium(I)-cata-lyzed asymmetric amination reaction, Nguyen and co-


workers set out to discover a transition-metal-catalyzedmethod for the regioselective synthesis of secondary andtertiary allyl fluorides.[95] Transition-metal-catalyzed incor-poration of fluorine into organic compounds had becomean area of intensive investigation, due to desirable proper-ties that can be introduced into bioactive molecules.[96–98]

In addition, fluorine-18 is regarded as an ideal radionuclidefor positron emission tomography (PET) imaging, due toits low-energy positron emission (which results in higher-quality 3D images), ease of preparation from [18O]-water,and 110 min half-life.[98] There was the opportunity to ap-ply branched allyl trichloroacetimidates to the developmentof a new transition-metal-catalyzed fluorination technique.However, incorporation of fluorine into allylic systems bydirect C–F bond formation aided by transition metal catal-ysis has proven difficult, in part due to strong metal-fluor-ine bonding.[99] Additionally, the ability of allyl fluorides toact as leaving groups in palladium catalysis has been re-ported.[100] Nevertheless, several examples of transition-metal-catalyzed allylic fluorination[101] and its analogous re-actions[102–108] have been reported. Gouverneur demon-strated the feasibility of palladium-catalyzed fluorination ofprimary allyl 4-nitrobenzoates with TBAF·(tBuOH)4 to af-ford linear allyl fluorides in moderate to excellentyields.[101c] In 2010, Doyle reported the first palladium-cata-lyzed asymmetric fluorination of cyclic allyl chlorides withAgF.[101a] Doyle extended this work to transformations ofacylic linear allyl chlorides and bromides, providing enantio-enriched allyl fluorides with varying levels of enantio-selectivity.[101b] This methodology provides allyl fluorides in24–48 h,[101b] well outside the 110 min half-life of radioac-tive fluorine-18. Recently, a new strategy of Pd-catalyzedallylic C-H fluorination has been reported for the synthesisof branched allyl fluorides with moderate to excellent re-gioselectivity.[105]

With this in mind, Nguyen’s group began by evaluatinga number of rhodium catalysts and nucleophilic fluoridesources in the fluorination of allyl trichloroacetimidate 255(Table 18). Overall, neutral rhodium complexes performedpoorly (Entries 1–5), with 10 mol-% of [RhCl(COD)]2 and3 equiv. of TEA·3HF in THF providing the best conversion(20 %) and yield (7%) of allyl fluoride product 256 by 19FNMR (Entry 5). More reactive cationic rhodium complexeswere next investigated (Entries 6 and 7); these resulted incomplete conversion in 30 min, but with only 45–48 %yields of the desired fluoride 256 along with formation of30% of elimination product 257. Conducting the fluorin-ation of imidate 256 in Et2O (Entry 12) increased the yieldto 75% by 19F NMR (69% isolated yield) and resulted inminimal formation of diene product 257.[95] In addition,this solvent change resulted in biphasic conditions, whichsimplified the reaction workup because allyl fluoride 256 issoluble in the organic layer and the catalyst remains in theTEA·3 HF layer. The iridium catalyst [IrCl(COD)]2 wassubsequently found to be more efficient than cationic rho-dium catalysts (Entry 13), providing allyl fluoride 256 in93% isolated yield and with complete branched regioselec-tivity. The use of catalyst proved critical to the allylic

J. S. Arnold, Q. Zhang, H. M. NguyenMICROREVIEWfluorination (Entry 14), and the iridium-catalyzed reactionis amenable to scale-up, providing 256 in 88% isolated yieldon a 4 g scale (Entry 15).[95]

Table 18. Optimization of the regioselective fluorination of imidate255.

[a] Yields were determined by 19F NMR with PhCF3 as an internalstandard. [b] Isolated yields. [c] 5 mol-% catalyst. [d] 4 g scale,2.5 mol-% Ir catalyst.

After determining the optimal fluorination conditions,Nguyen and co-workers turned their attention to the reac-tion scope (Table 19). A number of secondary allyl tri-chloroacetimidates – 96, 97, 112, and 258–263, bearing avariety of substituents and functional groups – were theninvestigated. Overall, secondary allyl fluorides 264–272

Table 19. Iridium-catalyzed fluorination of secondary allyl imid-ates.


were obtained in good to excellent yields (64–91%) at ambi-ent temperature within 2 h. In all cases, only trace amountsof elimination products were observed in the reactions. Thisiridium-catalyzed fluorination is tolerant of a diverse set offunctionality present in the substrates. Benzoyl esters 258and 259 (Entries 1 and 2) and ethers 112 and 262 (Entries 3and 8) provided allyl fluorides in 83–91% yields. Nitrogen-containing imidates 260 and 263 afforded fluorinatedphthalimide 267 (Entry 4) and azide 272 (Entry 9) in 64%and 89 % yields, respectively. A terminal alkyne group didnot slow the rate of fluorination, with 270 (Entry 7) beingdelivered in 68% yield within 1.5 h. It is impressive that thismethod was able to provide silyl-protected allyl fluoride 269(Entry 6) in excellent yield (78 %) in the presence of nucleo-philic fluoride ion. These secondary allyl fluorides can bestored at ambient temperature for weeks without decompo-sition.

The rapid incorporation of fluorine into allylic systemswas also observed in the iridium-catalyzed regioselective re-actions of tertiary allyl acetimidates 151–153 (Table 20). Al-though tertiary allyl fluorides 273–275 were not stable toisolation, 67–73 % yields and good regioselectivity (b/l =10:1 to 25:1) were observed after 1 h by 19F NMR spec-troscopy. To illustrate the utility of tertiary allyl fluorides,crude product 274 (Entry 2) was subjected to hydrogenationover Pd/C, and the stable tertiary alkyl fluoride was ob-tained in 50% yield over two steps.

Table 20. Iridium-catalyzed fluorination of tertiary allyl imidates.

The ability to incorporate fluorine ion regioselectivelyinto allylic systems of trichloroacetimidate substrates in un-der 2 h demonstrated the promise of this iridium-catalyzedfluorination methodology for application to the preparationof [18F]-labeled allyl fluorides, which could potentially beused as radiotracers in PET imaging. Nguyen and co-workers first investigated their method with “cold” 19F-lab-eled KF-Kryptofix as the limiting reagent in accordancewith optimized procedures (Scheme 24, a), resulting in a�95% NMR yield (82 % isolated yield) of branched allylfluoride 256 in 20 min. After this encouraging result, irid-ium-catalyzed fluorination of allyl trichloroacetimidate sub-strate 258 was attempted with “hot” [18F]KF·Kryptofix(Scheme 24, b), this being the most commonly used sourceof nucleophilic 18F ion for clinically relevant labeling.[98,101e]

An excess of allyl trichloroacetimidate 258 was added to a


Scheme 24. Fluorination with KF·Kryptofix.

4 mCi solution of [18F]KF·Kryptofix, followed by[IrClCOD]2. After the system had been stirred at 25 °C for10 min, the decay-corrected radiochemical yield (RCY) of[18F]allyl fluoride 276 (Scheme 24) was determined to be38%,[108] more than suitable for PET imaging studies.

In summary, secondary and tertiary allyl acetimidates areefficiently fluorinated in high yields and with branchedselectivity with the aid of iridium catalysis. The fluorinationreactions are easy to set up by simply combining substrate,Et2O, TEA·3HF, and iridium catalyst at ambient tempera-ture under air and sufficiently stirring the resulting biphasicmixtures. This method provides branched allyl fluorides ingood yields with a wide range of acetimidate classes andfunctionality, and is applicable to the synthesis of 18[F]-lab-eled allyl fluorides for potential use in PET imaging studies.

5. Conclusion

Allyl trichloroacetimidates are versatile substrates ofbroad utility for the synthesis of carbon-heteroatom (C-O,C–N, and C–F) bonds. Overman’s pioneering work andpursuit of mechanistic understanding in rearrangements ofprimary allyl acetimidates has inspired the development ofnew methodologies for regio- and enantioselective construc-tions of C–O, C–N, and C–F connectivity in good yieldsand with excellent selectivity. In many cases the introduc-tion of the trichloroacetimidate functionality into allylicsystems has improved access to bonding arrangements orprovided access to those not previously achieved. For exam-ple, the branched regioselectivity of transition-metal-cata-lyzed aminations of α-substituted allyl trichloroacetimidatesand reactions with N-methylanilines has been greatly im-proved in comparison with substitutions with allylic carb-onates and acetates. The rhodium-catalyzed amination oftertiary allyl trichloroacetimidates has expanded the scopeof viable aniline nucleophiles that can be utilized in thesereactions and has allowed the development of the firstDYKAT for the enantioselective synthesis of arylamine-containing quaternary centers. Furthermore, the palladium-catalyzed asymmetric reactions of linear (Z)-allyl trichloro-acetimidates with oxygen nucleophiles provide allyl esters


and aryl ethers in good yields with excellent levels ofenantioselectivity. Although allyl trichloroacetimidates canbe sensitive to acidic conditions, their ease of preparationand relative stability have found application in an increasingnumber of synthetic strategies. In view of the current use ofthese substrates in difficult areas, the utilization of linearand branched trichloroacetimidates in unsaturated environ-ments will continue to expand in new ways in the futureand potentially have impact on the strategies used for thepreparation of biologically relevant natural products andpharmaceuticals.

Acknowledgments

This work was supported by the National Institutes of Health(NIH) (R01 GM098285), the National Science Foundation (NSF)(CHEM1106082), and the University of Iowa. H. M. N. is a Uni-versity of Iowa Dean’s Scholar, and J. S. A. is the recipient of theA. Lynn Anderson Outstanding Research Award.

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[108] Various acidic additives were also explored to adjust the pHto be closer to the cold 19F conditions with HF·Et3N com-plexes.[94] No additive screened (TFA·Et3N, TFA, or Am-berlyst) other than CSA (camphorsulfonic acid) was found toimprove the yield.

Received: February 18, 2014Published Online: June 3, 2014

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