Catalytic Regio- and Enantioselective Haloazidation of Allylic Alcohols Frederick J. Seidl,‡ Chang Min,‡ Jovan A. Lopez, and Noah Z. Burns

Gold(I)-Catalyzed Enantioselective Intramolecular Dehydrative Amination of Allylic Alcohols with Carbamates** Paramita Mukherjee and Ross A. Widenhoefer*
The transition-metal-catalyzed enantioselective amination of allylic esters and carbonates represents one of the most wellestablishedroutes tochiral, nonracemicallylic amines.[1] With the potential to condense synthetic sequences and reduce wastestreams,thedehydrativeaminationofallylicalcoholsas aroutetoenantiomericallyenrichedallylicamineshasgained considerable interest. However, while the stereospecific amination of chiral secondary allylic alcohols has been demonstrated,[2–4] the enantioselective amination of allylic alcohols remains problematic.[5] Carreira et al. have reported the IrI-catalyzed enantioselective amination of 1-cyclohexylprop-2-enol with sulfamic acid in 70% ee.[6] Hartwig et al. have reported the IrI/BPh3-catalyzed enantioselective intermolecularaminationofprimaryallylicalcoholswitharomatic amines with up to 94% ee, but this method was restricted to cinnamyl alcohols in the absence of a stoichiometric Lewis acid promoter.[7] The groups of Yamamoto[8] and Kitamura[9] have independently reported the enantioselective intramolecular amination of allylic alcohols catalyzed by HgII and RuII complexes, respectively. However, these methods were restricted to sulfonamide nucleophiles and high enantioselectivity was realized only for the formation of arene-fused nitrogen heterocycles. Herein we report a gold-catalyzed protocol for the intramolecular enantioselective amination of allylic alcohols with carbamates to form five- and sixmembered aliphatic nitrogen heterocycles with up to 95% ee. We recently reported the intramolecular dehydrative amination of allylic alcohols with alkylamines catalyzed by an achiral gold(I) phosphine complex.[4,10] Encouraged by the high efficiency and stereospecificity of this transformation and guided by both our previous work in the area of gold(I)catalyzed enantioselective allene hydroamination[11,12] and Bandinis recent demonstration of gold(I)-catalyzed enantioselective arylation[13] and alkoxylation[14] of allylic alcohols,[15] we targeted axially chiral bis(gold) complexes as catalysts for the intramolecular enantioselective amination of the ebenzylamino allylic alcohol (E)-1a(Table 1). Unfortunately, optimization within this framework[16] proved largely unsuccessful: treatment of (E)-1a with a catalytic 1:2 mixture of [(S)-2](AuCl)2 and AgSbF6 in dioxane at 258C for 5 h led to
quantitative conversion to 2-vinylpyrrolidine 3a, but with only 29% ee (Table 1, entry 1).[17] We then focused our attention on the manipulation of the nitrogen nucleophile as a means to amplify stereoinduction (Table 1). These experiments proved fruitful and gold(I)-catalyzed cyclization of Fmoc-protected e-amino allylic alcohol (E)-1gemploying an optimized catalyst system comprised of [(S)-2](AuCl)2 (2.5 mol%) and AgClO4 (5 mol%) in dioxane at room temperature for 48 h led to the isolation of (S)-3g in 95% yield with 91% ee (Table 1, entry 7).[16,18] The scope of this gold(I)-catalyzed enantioselective intramolecular amination was evaluated as a function of alkene configuration, substitution, and ring size (Table 2). The enantioselectivity of the amination was sensitive to the alkene configuration: (Z)-1gwas converted into 3gin 99% yield with 5%ee (Table 2, entry 1). Although e-amino allylic alcohols that possessed gem-dialkyl substitution at the homoallylic position cyclized with higher enantioselectivity than did an unsubstituted e-amino allylic alcohol (Table 2, entries 2–4), homoallylic gem-disubstitution was not required for high enantioselectivity (Table 2, entries 5 and 6). For example, gold(I)-catalyzed cyclization of4, which possessed a single phenyl group at the homoallylic position, led to isolation of pyrrolidine 5 in 87% yield as a 1:1 mixture of
Table 1: Effect of the nucleophile on the gold(I)-catalyzed intramolecular amination of allylic alcohols (E)-1 under optimized conditions.[16,18]
Entry 1+3,R[a] X Time [h] Yield [%][b] ee [%][c] 1 a, Bn SbF6 5 100[d] 29 2 b, Cbz ClO4 48 99 79 3 c, Boc ClO4 48 97 80 4[e] d, Troc ClO4 48 62 84 5 e, CO 2Me ClO4 48 97 75 6 f, Ts ClO4 48 98 76 7 g, Fmoc ClO4 48 95 91 [a] Bn=benzyl, Cbz=benzyloxycarbonyl, Boc=tert-butyloxycarbonyl, Troc=2,2,2-trichloroethoxycarbonyl, Ts=4-toluenesulfonyl, Fmoc= fluorenylmethyloxycarbonyl. [b] Yield of isolated product. [c] Determined by HPLC analysis on chiral support. [d] Conversion. [e] Reaction run at 408C.
[*] P. Mukherjee, Prof. R. A. Widenhoefer French Family Science Center, Duke University Durham, NC 27708–0346 (USA) E-mail: [e-mail] [**] We thank the NIH (GM-080422) for support of this research. P.M. thanksDukeUniversityforsupportprovidedthroughtheBurroughs Welcome and C.R. Hauser Fellowships. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201107877.
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cis and trans diastereomers, both of which were formed with 90% ee, indicative of overriding catalyst control of stereoinduction. The gold-catalyzed enantioselective amination also tolerated gem-dialkyl substitution at the hydroxybound carbon atom (Table 2, entry 7) and was applicable to thesynthesisofsix-memberednitrogenheterocycles(Table 2, entries 8–11), proving particularly effective for the synthesis ofdifferentlyprotected2-vinylpiperazines(Table 2,entries 9– 11). The effect of a chiral secondary allylic alcohol moiety on the efficiency and stereoselectivity of this gold-catalyzed allylic amination was evaluated employing e-amino allylic alcohol 6. In one experiment (Scheme 1), cyclization of rac-6 catalyzed by [(S)-2](AuCl)2/AgClO4 led to isolation of a 1:1 mixture of (E)-7 and (Z)-7 in 91% combined yield. Hydrogenationofthismixtureformed2-propylpyrrolidine8in92% yield with 93% ee, which established that (E)-7 and (Z)-7
possessed the same absolute configuration (S by analogy),[18] and HPLC analysis of the conversion of rac-6 to 7 revealed that both enantiomers of 6 reacted at similar rates (kS/kR= 1.06). In two additional experiments (Scheme 2), cyclization of enantiomerically enriched (R)-6 catalyzed by [(S)-2](AuCl)2/AgClO4 led to isolation of a 40:1 mixture of (S,E)-7 and(R,Z)-7in93% combinedyieldwhile cyclizationof (R)-6 catalyzed by [(R)-2](AuCl)2/AgClO4 led to isolation of a 25:1
mixture of (R,Z)-7 and (S,E)-7 in 95% combined yield. Together, these results established that asymmetric induction is determined solely by the catalyst configuration (S!S; R! R) and that E/Z selectivity is determined by the stereochemical relationship between the incipient N-bound stereocenter and the extant O-bound stereocenter (S/R!E; R/R!Z), consistentwiththenetsyndisplacementofthehydroxygroup by the attacking carbamate nucleophile. The net syn displacement of the hydroxy group by the nitrogen nucleophile, which was also documented for the amination of allylic alcohols catalyzed by achiral mono(gold) complexes,[3,4] is consistent with a mechanism involving pcomplexation of gold to the C=C bond followed by antiaddition of the nucleophile and anti-elimination of the hydroxy group, perhaps facilitated by an intramolecular N HO hydrogen bond (Scheme 3).[19] Alternatively, syn-sub
Scheme 1. Cyclization of rac-6 catalyzed by [(S)-2](AuCl)2/AgClO4. R=Fmoc.
Scheme 2. Cyclization of enantiomerically enriched (R)-6 (97% ee) catalyzed by [(S)-2](AuCl)2/AgClO4 (top pathway) and [(R)-2](AuCl)2/ AgClO4 (bottom pathway). R=Fmoc.
Table 2: Substrate scope of the intramolecular amination of allylic alcohols (0.6m) catalyzed by a 1:2 mixture of [(S)-2](AuCl)2 (2.5 mol%) and AgClO4 (5 mol%) in dioxane at 258C for 48 h.[18] Entry Substrate Heterocycle Yield [%][a] ee [%][b]
1 99 5
2R =Me 94 90 3R _ R=(CH2)5 95 94
4 89 62
5R =Ph[c] 87[d] 90/92 6R =iPr 98[d] 85/91
7 87[d] 88/90
8R
_
R=(CH2)5 69 77
9[c] R1=Fmoc, R2=Boc 86 94 10[c] R1=Fmoc, R2=Ts 99 92 11[e] R1=Boc, R2=Fmoc 99 91 [a] Yield of isolated product. [b] Determined by HPLC analysis on chiral support. [c] Compounds 4 and 5:R=Ph (entry 5). [d] Diastereomeric ratio1:1. [e] Reaction run at 508C.
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stitution is also consistent with a mechanism involving sactivation of the hydroxy group followed by concerted SN2’ displacement[20] and Toste et al. have recently demonstrated that bis(gold) phosphine complexes are sufficiently Lewis acidic to acidify the hydroxy proton of an alcohol.[21] However, the failure of either triflic acid or BF3·OEt2 (10 mol%, 258C, 48 h) to catalyze the cyclization of (E)-1g argues against a s-activation pathway for this allylic amination. In summary, we have developed a gold(I)-catalyzed protocol for the intramolecular enantioselective amination of allylic alcohols with carbamates to form five- and sixmembered nitrogen heterocycles with up to 95% ee. Cyclization of chiral e-amino allylic alcohols that possessed a stereogenic homoallylic or hydroxy-bound carbon atom occurred with overriding catalyst control of asymmetric induction. Stereochemical analysis of the cyclization of (R)6, which possessed a secondary allylic alcohol moiety, established the net syn-displacement of the hydroxy group by the carbamate nucleophile.
Received: November 9, 2011 Published online: January 3, 2012 . Keywords: alcohols · amination · asymmetric synthesis · gold · nitrogen heterocycles
[1] a) B. M. Trost, T. Zhang, J. D. Sieber, Chem. Sci. 2010, 1, 427– 440; b) Z. Lu, S. Ma, Angew. Chem.2008, 120, 264–303; Angew. Chem. Int. Ed. 2008, 47, 258–297; c) B. M. Trost, D. L. Van Vranken, Chem. Rev. 1996, 96, 395–422; d) B. M. Trost, M. L. Crawley, Chem. Rev. 2003, 103, 2921–2943. [2] a) M. Roggen, E. M. Carreira, J. Am. Chem. Soc. 2010, 132, 11917–11919; b) S. M. Hande, N. Kawai, J. Uenishi, J. Org. Chem. 2009, 74, 244–253; c) N. Kawai, R. Abe, J. Uenishi, Tetrahedron Lett. 2009, 50, 6580–6583; d) H. Yokoyama, Y. Hirai, Heterocycles 2008, 75, 2133–2153; e) F. Ozawa, H. Okamoto, S. Kawagishi, S. Yamamoto, T. Minami, M. Yoshifuji, J. Am. Chem. Soc. 2002, 124, 10968–10969.
[3] P. Mukherjee, R. A. Widenhoefer, Org. Lett. 2010, 12, 1184– 1187. [4] P. Mukherjee, R. A. Widenhoefer, Org. Lett. 2011, 13, 1334– 1337. [5] For a recent Highlight of the enantioselective dehydrative functionalization of allylic alcohols, see: M. Bandini, Angew. Chem. 2011, 123, 1026–1027; Angew. Chem. Int. Ed. 2011, 50, 994–995. [6] C. Defieber, M. A. Ariger, P. Moriel, E. M. Carreira, Angew. Chem. 2007, 119, 3200–3204; Angew. Chem. Int. Ed. 2007, 46, 3139–3143. [7] Y. Yamashita, A. Gopalarathnam, J. F. Hartwig, J. Am. Chem. Soc. 2007, 129, 7508–7509. [8] H. Yamamoto, E. Ho, K. Namba, H. Imagawa, M. Nishizawa, Chem. Eur. J. 2010, 16, 11271–11274. [9] K. Miyata, H. Kutsuna, S. Kawakami, M. Kitamura, Angew. Chem. 2011, 123, 4745–4749; Angew. Chem. Int. Ed. 2011, 50, 4649–4653. [10] For a recent review of the gold-catalyzed dehydrative functionalization of allylic alcohols, see: B. Biannic, A. Aponick, Eur. J. Org. Chem. 2011, 6605–6617. [11] a) Z. Zhang, C. F. Bender, R. A. Widenhoefer, J. Am. Chem. Soc. 2007, 129, 14148–14149; b) Z. Zhang, C. F. Bender, R. A. Widenhoefer, Org. Lett. 2007, 9, 2887–2889. [12] For a recent review of the enantioselective gold(I) catalysis, see: A. Pradal, P. Y. Toullec, V. Michelet, Synthesis 2011, 1501–1514. [13] M.Bandini,A.Eichholzer,Angew.Chem.2009,121,9697–9701; Angew. Chem. Int. Ed. 2009, 48, 9533–9537. [14] M.Bandini,M.Monari,A.Romaniello,M.Tragni,Chem.Eur.J. 2010, 16, 14272–14277. [15] For additional examples of the catalytic enantioselective addition of carbon and oxygen nucleophiles to underivatized allylic alcohols, see ref. [9] and also: a) M. Roggen, E. M. Carreira, Angew. Chem. 2011, 123, 5683–5686; Angew. Chem. Int. Ed. 2011,50,5568–5571;b) S.Tanaka,T.Seki,M.Kitamura,Angew. Chem. 2009, 121, 9110–9113; Angew. Chem. Int. Ed. 2009, 48, 8948–8951; c) M. Rueping, B. J. Nachtsheim, S. A. Moreth, M. Bolte,Angew.Chem.2008,120,603–606;Angew.Chem.Int.Ed. 2008, 47, 593–596; d) B. M. Trost, J. Quancard, J. Am. Chem. Soc. 2006, 128, 6314–6315. [16] A full description of the optimization studies is provided in the Supporting Information. [17] Using a 1:1 mixture of [(S)-2](AuCl)2 and AgSbF6 led to significant decrease in both rate and enantioselectivity.[16] [18] The absolute configuration of (S)-3b was determined by comparisontotheHPLCtraceof(R)-3b .[11a] The Sconfiguration of the heterocycles depicted in Table 2, entries 4 and 10 was establishedbychemicalcorrelation. Theabsoluteconfigurations of all other heterocycles were assigned by analogy. [19] R. S. Paton, F. Maseras, Org. Lett. 2009, 11, 2237–2240. [20] a) R. M. Magid, Tetrahedron 1980, 36, 1901–1930; b) L. A. Paquette, C. J. M. Stirling, Tetrahedron 1992, 48, 7383–7423. [21] C. H.Cheon,O.Kanno,F. D.Toste,J.Am.Chem.Soc.2011,133, 13248–13251.
Scheme 3. Proposed mechanism of the gold-catalyzed allylic amination of (R)-6.R _ R=(CH2)5,R ’=Fmoc.
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EnantioselectiveDearomatizationofNaphtholDerivativeswithAllylic Alcohols by Cooperative Iridium and Brønsted Acid Catalysis Dan Shen, Qiliang Chen, Peipei Yan, Xiaofei Zeng,* and Guofu Zhong*

Dedicated to Professor Dieter Enders on the occasion of his 71st birthday
Abstract: The combination of a transition-metal catalyst and organocatalyst was designed to achieve a highly enantioselective system for the allylic dearomatization reaction of naphthols with racemic secondary allylic alcohols. The desired bnaphthalenones, bearing an all-carbon quaternary center, were obtained in good yields with high chemo- and enantioselectivities. The cooperative catalytic system, involving a chiral iridium complex and phosphoric acid, provided measurable improvements in yields, and chemo- and enantioselectivities relative to single-catalyst systems. Control experiments indicated that the chiral iridium complex functions as a key species in the control of the absolute configuration, thus enabling the formation of both b-naphthalenone enantiomers by simply employing opposite enantiomeric ligands. Catalytic asymmetric dearomatization (CADA) of readily available phenols and naphthols is a very important and efficient tool for construction of chiral multifunctionalized cyclic enones, which are frequently found in many natural products and pharmaceuticals.[1,2] Thus, much attention has been paid. To date, a series of successful examples of enantioselective dearomatizations of phenols and naphthols have been realized by using oxidative[3] and non-oxidative[4–8] strategies. Remarkably, the non-oxidative dearomatization reactionshavebeendevelopedfortheasymmetricinstallation of various functionalities adjacent to a carbonyl group by using different electrophiles such as nitroethylenes,[4] azodicarboxylates,[5] aziridines,[6] halogenationreagents,[7] activated propargylic compounds,[8] etc. Despite these impressive advances, a rejuvenation of the CADA reaction by exploring new types of electrophiles, to enrich the application scope of thesetransformations,isstillchallengingandhighlydesirable. The asymmetric allylic alkylation (AAA) reactions constitute one of the most facile and straightforward routes for the formation of carbon–carbon bondsin organic chemistry.[9] A variety of highly regio- and enantioselective allylic substitution reactions have been realized with various activated precursors of p-allyl fragments (allyl halides, esters, and carbonates, etc.) and nucleophiles. However, examples of successful utilization of naphthols in allylic substitution reactions are limited.[10,11] Very recently, the groups of You and Hamada independently reported the inter- and intra
molecular asymmetric allylic dearomatization (AADA) of naphthols with allyl carbonates, and the desired b-naphthalenones were obtained in good yields with excellent chemoand enantioselectivities (Scheme 1a).[12] However, the elec
trophiles involved in all cases were allyl carbonates. Because of the high synthetic step economy and positive environmental impact (water as the only stoichiometric by-product), the use of synthetically reliable alcohols instead of allyl carbonates in AAA reactions have become more and more popular.[13] It is well known that the application of allylic alcohols in AAA reactions has been limited by the poorer leaving ability of the hydroxy group. To overcome this problem, several strategies, such as using high reaction temperature, or Lewis or Brønsted acids, have been explored.[13a–e,14] Inthiscontext,somesuccessfulexampleshavebeen reported. Recently, Carreira and co-workers disclosed that theeasilyaccessibleracemicsecondaryalcoholscouldbeused as versatile and useful substrates in a series of asymmetric allylic substitution reactions by chiral iridium catalysis, and it greatly broadens the substrate scope (Scheme 1b).[15] Thus, we envisaged that highly stereoselective allylic dearomatization of naphthols might be achieved through allylic substitution reactions using alcohols (Scheme 1c). Herein, we report a cooperative iridium/Brønsted acid catalyzed AADA reac
Scheme 1. The asymmetric allylation reactions of naphthols and racemic secondary alcohols.
[*] D.Shen,Q.-L.Chen,P.-P.Yan,Prof. Dr.X.-F.Zeng,Prof. Dr.G.Zhong College of Materials, Chemistry and Chemical Engineering Hangzhou Normal University, Hangzhou 310036 (China) E-mail: [e-mail] [e-mail]
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tion of naphthols with racemic secondary alcohols in good yields and excellent enantioselectivities. To test our hypothesis, we started to investigate the AADA reaction of phenyl vinyl carbinol (1a) and 1,3dimethylnaphthalen-2-ol (2a) in the presence of chiral iridium complexes, as described in Table 1. Unfortunately,
the AADA reaction did not occur (entry 1). We realized that the addition of either a Lewis or Brønsted acid could lower the reaction barrier through activation of the allyl alcohols, and facilitate the AADA reaction. Thus, when either the ligand (R)-L1 or (R)-L2 combined with a Lewis acid, Sc(OTf)3 for instance, the reaction proceeded smoothly and the
linear alkylation product 3a, with an all-carbon quaternary center, was obtained as the major product in moderate yield (42%), but the ee value was very low (4%). It was worth noting that (R)-L1 was slightly better than (R)-L2 in the reaction (entries 2 and 3). To our delight, the O-alkylation product was formed as a minor product and no branched product was observed. To further improve the enantioselectivity, we turned to investigate a series of hydroxy group activators for allylic alcohols in the reaction. We previously demonstrated that chiral phosphoric acids exhibit excellent catalytic activity and chiral induction for aminoxylation of 1,3-dicarbonyl compounds and enecarbamates.[16] Recently, Gong and co-workers reported an AAA reaction of pyrazol-5-ones with allylic alcohols catalyzed by the combination of a palladium complex and a chiral phosphoric acid,[17] thus indicating that chiral phosphoric acid could act as good activator for carbonyl compounds. Inspired by these results, a series of chiral phosphoric acids were tested. As shown in Table 1, when the cocatalyst (R)PA1 was used with 4 mol% of [{Ir(cod)Cl}2] and 8 mol% of (R)-L1, the yield and ee value of 3a were both increased (entry 4). (R)-PA2,( R)-PA4, and (R)-PA7 could also promotethereaction(entries 5,7,and10),and(R)-PA7 gavethe bestresultswithregardtobothchemo-andenantioselectivity. Unfortunately,(R)-PA3,(R)-PA5,and(R)-PA6 onlyresulted in trace amounts of the desired product (entries 6, 8, and 9). Additionofmolecularsieves(M.S.)couldeffectivelyimprove the yield to greater than 60% and enantioselectivity to greaterthan87%(entries 11–13).Afterestablishmentof(R)PA7 and 4 M.S. as the optimal cocatalyst and additive, respectively, different conditions, such as solvents, reaction temperature, and substrate concentration were subsequently tested (entries 14–19: for more detailed optimization conditions, see the Supporting Information). Thus, the best result could be achieved in the presence of 4 mol% of [{Ir(cod)Cl}2], 8 mol% (R)-L1, and 8 mol% (R)-PA7 in CHCl3 at room temperature, thus affording 3a in 75% yield and 95% ee. With the optimized reaction conditions for the asymmetricAADAreactioninhand,weevaluatedtherelativerolesof the chiral complex (Ir/L1) and cocatalyst in the asymmetric transformation. It was found that the use of (R)-L1, together with either (R)-PA7 or (S)-PA7, provided the same stereoisomer of 3ain high yields with excellent ee values (Table 2, entries 1 and 2), while (S)-L1with either (R)-PA7 or (S)-PA7 gave ent-3a with similar results (entries 3 and 4). These findings revealed that the chiral L1 played a key role in the chiral induction in the reaction, and phosphoric acid assisted to lower the reaction barrier. Furthermore, the bulkiness of the phosphoric acid in the catalytic stereoselective step increased the enantioselectivity. We then carried out the reaction in the presence of either(R)-L1 or (S)-L1 with racPA7 separately, and we were happy to find that both 3aand ent-3a were obtained in good yields with excellent enantioselectivities (entries 5 and 6). Next, several achiral acids such as TFA, CCl3CO2H, (nBuO)2PO2H, and (PhO)2PO2H were used instead of the BINOL-derived phosphoric acids under the same reaction conditions (entries 7–10). For most cases, the ee values were good (76–86%) except with TFA, and this
Table 1: Optimization of the reaction conditions.[a]
Entry L Cocatalyst
Solvent T [8C]
Yield [%][b]
3a/4a[c] ee [%][d]
1( R)-L1 – DCE 20 – – – 2( R)-L1 Sc(OTf)3 DCE 20 42 66:34 4 3( R)-L2 Sc(OTf)3 DCE 20 38 59:41 4 4( R)-L1 (R)-PA1 DCE 40 60 92:8 68 5( R)-L1 (R)-PA2 DCE 40 38 80:20 47 6( R)-L1 (R)-PA3 DCE 40 trace – – 7( R)-L1 (R)-PA4 DCE 40 66 90:10 70 8( R)-L1 (R)-PA5 DCE 40 trace – – 9( R)-L1 (R)-PA6 DCE 40 trace – – 10 (R)-L1 (R)-PA7 DCE 40 67 >95:5 79 11[e] (R)-L1 (R)-PA7 DCE 20 61 >95:5 87 12[f] (R)-L1 (R)-PA7 DCE 20 66 >95:5 88 13[g] (R)-L1 (R)-PA7 DCE 20 66 >95:5 87 14[f] (R)-L1 (R)-PA7 toluene 20 50 >95:5 84 15[f] (R)-L1 (R)-PA7 DCM 20 58 >95:5 90 16[f] (R)-L1 (R)-PA7 CHCl3 20 75 >95:5 95 17[f,h] (R)-L1 (R)-PA7 CHCl3 20 40 >95:5 83 18[f,i] (R)-L1 (R)-PA7 CHCl3 20 12 >95:5 65 19[f] (R)-L1 (R)-PA7 CHCl3 0 30 >95:5 96 [a] General conditions: 1a(0.15 mmol), 2a(0.1 mmol), [{Ir(cod)Cl}2] (4 mol%),L(8 mol%),andcocatalyst(8 mol%)in2 mLsolventfor24 h under ambient atmosphere. [b] Yield of product isolated after column chromatography. [c] Determined by 1H NMR analysis of the crude reaction mixture. [d] Determined by HPLC analysis using a chiral stationary phase. [e] 3 M.S. (30 mg) was added. [f] 4 M.S. (30 mg) was added. [g] 5 M.S. (30 mg) was added. [h] 1 mL solvent was used. [i] 4 mL solvent was used. DCE=1,2-dichloroethane, DCM=dichloromethane, M.S.=molecular sieves, Tf=trifluoromethanesulfonyl.
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might be due to the stronger acidity and less steric hindrance of TFA. However, the yields were all lower. When the reaction was carried out without a ligand or with the achiral ligand L3 in the presence of (R)-PA7, only racemic 3a was obtained (entries 11 and 12). Moreover, when the O-alkylation product 4a was tested in the reaction, and no further reaction occurred (Scheme 2).
On the basis of the experimental observations, together withreportedliterature,[17] aplausiblemechanismisproposed in Scheme 3. The chiral iridium complex and acid promoter react with the allylic alcohol to give the intermediate Awith
the loss of one molecule of water, thus forming the conjugate base of the acid. Then the naphthol is deprotonated by the base, and further reacts with A to generate the key intermediate B, in which a hydrogen bond is formed between the phosphoric acid and naphthol. Subsequently, the AADA reaction proceeds through an intramolecular nucleophilic addition reaction. The highly sterically hindered phosphoric acid moiety, together with the chiral iridium complex, works cooperatively and increased the enantioselectivity dramatically, thus, affording 3a with a high ee value. Finally the iridium complex and phosphoric acid are regenerated for the next catalytic cycle. Havingidentifiedtheoptimizedreactionconditionsofthe enantioselective allylic dearomatization reaction, we explored the substrate scope of the reaction in the presence of the (R)-L1/IrI complex and rac-PA7, as summarized in Table 3. Firstly, various allylic alcohols (1) were reacted with
2a to afford the linear products with excellent chemo- and enantioselectivities (entries 1–15). A wide range of aromatic groups bearing electron-rich and electron-deficient substituents on either the ortho-, meta-, or para-position of the allyl alcohols 1 were all tolerated and gave rise to the products in moderate to good yields (51–87%) with good to excellent enantioselectivities (86–>99% ee). A noticeable electronic
Table 2: Ligand and cocatalyst in the AADA reaction.[a]
Entry Ligand Acid Yield [%][b] ee [%][c]
1( R)-L1 (R)-PA7 75 95 2( R)-L1 (S)-PA7 76 95 3( S)-L1 (R)-PA7 75 954( S)-L1 (S)-PA7 73 955( R)-L1 rac-PA7 76 95 6( S)-L1 rac-PA7 75 947( R)-L1 TFA 51 21 8( R)-L1 CCl3CO2H 37 76 9( R)-L1 (nBuO)2PO2H 33 80 10 (R)-L1 (PhO)2PO2H 47 86 11 – (R)-PA7 <10 0 12 L3 (R)-PA7 58 0 [a] General reaction conditions: 1a(0.15 mmol), 2a(0.1 mmol), [Ir(cod)Cl]2 (4 mol%), L (8 mol%), acid (8 mol%) and 4 M.S. (30 mg) in 2 mL CHCl3 at RT for 24 h. [b] Yield of isolated product after column chromatography. [c] Determined by HPLC analysis using a chiral stationary phase. TFA=trifluoroacetic acid.
Scheme 2. The AADA reaction of 4a.
Scheme 3. Proposed mechanism of the AADA reaction.
Table 3: Scope with respect to the allylic alcohols.[a]
Entry 1,R 1 2,R 2,R 3 t [h] Yield [%][b] ee [%][c] 1 1a,C 6H5 2a, Me, Me 24 3a, 75 95 2[d] 1a,C 6H5 2a, Me, Me 24 3a, 78 96 3 1b, 4-MeOC6H4 2a, Me, Me 24 3b, 78 99 4 1c, 2-MeOC6H4 2a, Me, Me 26 3c, 87 85 5 1d, 3-MeC6H4 2a, Me, Me 30 3d, 59 99 6 1e, 3-ClC6H4 2a, Me, Me 30 3e, 66 95 7 1f, 4-ClC6H4 2a, Me, Me 30 3f, 60 92 8 1g, 4-BrC6H4 2a, Me, Me 36 3g, 55 86 9 1h, 2-MeC6H4 2a, Me, Me 25 3h, 63 90 10 1i, 2-ClC6H4 2a, Me, Me 30 3i, 67 >99 11 1j, 3-FC6H4 2a, Me, Me 36 3j, 58 92 12 1k, 4-FC6H4 2a, Me, Me 36 3k, 68 88 13 1l, 2-BrC6H4 2a, Me, Me 30 3l, 51 94 14 1m, 4-EtC6H4 2a, Me, Me 28 3m, 85 88 15 1n, 3-BrC6H4 2a, Me, Me 28 3n, 75 99 16 1a,C 6H5 2b, Me, H 24 3o, 70 90 17 1a,C 6H5 2c, Me, Br 24 3p, 71 99 18 1a,C 6H5 2d, Me, 24 3q, 68 79
19 1a,C 6H5 2e, Et, Me 24 3r, 51 32 [a] General conditions: 1a(0.15 mmol), 2a(0.1 mmol), [{Ir(cod)Cl}2] (4 mol%), L (8 mol%), cocatalyst (8 mol%) and 4 MS (30 mg) in 2 mL CHCl3 at RT. [b] Yield of the product isolated after column chromatography. [c] Determined by HPLC analysis using a chiral stationary phase. [d] 1.0 g of 2awas used.
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effect of the substituents on phenyl group of allylic alcohols was not observed in the reaction. Gratifyingly, the reaction of 1aand 2aproceeded on gram scale and provided 3ain 78% yield with 96% ee (entry 2). In addition, several substituted naphthols were tested in this reaction. When 1-methyl-2-naphthol (2b) was utilized, thedesiredproduct3owasobtainedin70%yieldand90%ee (Table 3, entry 16). It is noteworthy that the AADA reaction with1-methyl-3-bromo-2-naphthol(2c)alsooccurredingood yield with excellent enantioselectivity (entry 17). The 1methyl-2-naphtol derivative with a 3-allyl group (2d) also proceededwellandprovidedtheproduct3qingoodyieldbut with lower enantioselectivity (entry 18). Unfortunately, change in the substituent, at 1-position of 2-naphthol, to a bulkier group such as ethyl group, resulted in a drop of the enantioselectivity (entry 19). In summary, we have developed an AADA reaction of bnaphthols, with easily accessible secondary allylic alcohols, catalyzed by a dual catalytic system comprising a chiral iridium complex and phosphoric acid. The reactions proceededwellandthedesired b-naphthalenones,bearingan allcarbon quaternary center, were obtained in good yields with high chemo- and enantioselectivities, and a wide range of functional groups were tolerated. Notably, both racemic and chiral phosphoric acids assist equally in the catalytic asymmetricreactiontogiveexcellentyieldsandselectivities.These findings suggest that the chiral iridium complex and phosphoric acid work cooperatively to activate the substrates, and thechiraliridiumcomplexcontrolstheabsoluteconfiguration in the enantiodetermining step, thus providing the desired products in excellent enantioselectivities.
Acknowledgments
We gratefully acknowledge the Natural Science Foundation of China (No. 21373073, 21672048), the Young National Natural Science Foundation of China (No. 21302033), the PCSIRT (IRT 1231), Public Welfare Project of Zhejiang Province (No. 2016C33088) and Hangzhou Normal University for financial support. X.Z. acknowledges a Xihu Scholar AwardfromHangzhouCityandG.Z.appreciatesaQianjiang Scholar from Zhejiang Province in China.
Conflict of interest
The authors declare no conflict of interest.
Keywords: allylic compounds · enantioselectivities · iridium · organocatalysis · synthetic methods
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Manuscript received: October 3, 2016 Revised: January 12, 2017 Final Article published: && &&, &&&&
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Zuschriften
Allylverbindungen
D. Shen, Q.-L. Chen, P.-P. Yan, X.-F. Zeng,* G. Zhong* &&&&—&&&&
Enantioselective Dearomatization of NaphtholDerivativeswithAllylicAlcohols byCooperativeIridiumandBrønstedAcid Catalysis
Ein kooperatives Katalysesystem aus einem chiralen Iridiumkomplex und einem Phosphorsurederivat ergibt hoch enantioselektive allylierende Desaromatisierungen von Naphtholen mit racemischen sekundren Allylalkoholen. Die gewnschten b-Naphthalinone mit vollstndig kohlenstoffsubstituiertem quartrem Zentrum werden in guten Ausbeuten erhalten. Durch den Einsatz der entsprechenden Ligand-Enantiomere sind beide b-Naphthalinon-Enantiomere zugnglich.
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