silver-catalyzed transformation of propargylic amine n -oxides to enones and acyloxy ketones via...

DOI: 10.1002/adsc.201400395

Silver-Catalyzed Transformation of Propargylic Amine N-Oxidesto Enones and Acyloxy Ketones via Isoxazolinium Intermediates

Jian-Fang Cui,a Karen Ka-Yan Kung,a Hok-Ming Ko,a Tsz-Wai Hui,a

and Man-Kin Wonga,*a State Key Laboratory of Chirosciences, Department of Applied Biology and Chemical Technology, The Hong Kong

Polytechnic University, Hung Hom, Hong Kong, People�s Republic of ChinaFax: (+852)-2364-9932; e-mail: [email protected]

Received: April 22, 2014; Published online: && &&, 0000

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400395.

Abstract: A novel silver-catalyzed transformationof propargylic amine N-oxides with switchableproduct profiles has been developed. A diversity ofenones with excellent E/Z ratios (up to >20:1)were obtained when the reactions were conductedin aprotic solvents. In contrast, 3-chlorobenzoxy-methyl ketones and a-(3-chloro)-benzoxy enoneswere obtained by using protic solvents. Mechanisticstudies suggested that in situ generated isoxazolini-um ions are the key intermediates involved in thesenovel silver-catalyzed reaction pathways. Applica-tions on the chemoselective modification of cys-teine-containing peptides in aqueous medium havealso been achieved.

Keywords: isoxazolinium salts; N-oxides; peptidemodification; propargylic amines; silver catalysis

Advances in silver catalysis have led to new organictransformation reactions with high selectivity undermild reaction conditions.[1,2] Although silver catalysishas not been extensively studied as compared withcopper and gold catalysis in the past decades,[3] distin-guished reactivity modes are generally observed insilver catalysis. It is envisioned that exploration onthe unique properties of silver catalysis would providenovel and efficient synthetic methodologies for organ-ic synthesis.[1–3]

Propargylic amine N-oxides, easily accessed fromtheir corresponding propargylic amines through oxi-dation,[4,5] have been reported to undergo thermalMeisenheimer-type [2,3]-sigmatropic rearrangement[6]

and [1,5]-hydrogen shift to give propenal in an aproticmedium or go through prototropic rearrangement toafford acrylamides and enamino aldehydes in a proticmedium (Scheme 1, A).[4] However, only limited ex-

amples were reported and elevated temperature wasrequired for the reactions.[4] Transformation studies ofthe propargylic amine N-oxides using transition metalcatalysis remain unexplored.

Silver catalysis is able to activate alkynes towardsnucleophilic attack through p coordination to thecarbon-carbon multiple bonds.[1,2] Given the closeproximity of N-oxide and alkyne moieties in the skel-eton of propargylic amine N-oxides, it is envisagedthat investigation of silver catalysis on the transforma-tion of propargylic amine N-oxides would lead tonovel reaction pathways that would not be observedunder thermal heating conditions.

Over the years, we have been developing gold andsilver catalysis for organic synthesis[7] and bioconju-gation.[8] Efficient methods for the synthesis of struc-turally diverse propargylic amines via a three-compo-nent coupling reaction[7a,c,f,g,8a,9] and enantioselectivesyntheses of allenes from propargylic amines via [1,5]-hydride shift[7b,d,10] have been developed (Scheme 1,B).

Herein, we disclose a novel silver-catalyzed trans-formation of propargylic amine N-oxides via isoxazo-linium intermediates under mild conditions(Scheme 1, C). Treatment of propargylic amines1 with m-chloroperoxybenzoic acid (m-CPBA) fol-lowed by silver salts afforded enones 3 in an aproticmedium, while 3-chlorobenzoxymethyl ketones 4 to-gether with a-(3-chloro)-benzoxy enones 5 were ob-tained in a protic medium. In addition, the chemose-lective modification of cysteine-containing peptideswas achieved.

We commenced our studies with propargylic amine1a[11] as the substrate (Table 1). Treatment of 1a withm-CPBA, (1.0 equiv.) in CDCl3 at 0 8C for 15 min insitu generated the corresponding propargylic amineN-oxide 2a. Then, AgNO3 (5 mol%) was added, andthe reaction mixture was stirred at room temperaturefor 3 h. Enone 3a was obtained in 73% yield with an

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E/Z ratio of 10:1 (Table 1, entry 1). Control experi-ments indicated that both AgNO3 and m-CPBA areessential for this reaction (Table 1, entries 2 and 3).Besides, other silver salts were found to effectivelycatalyze the reaction (Table 1, entries 4–10). But noenone product was observed (with propargylic aminepresumably being converted into the correspondingN-oxide) when other metal salts/complexes were usedas catalysts (Table 1, entries 11–20). Moreover, noenone was afforded and propargylic amine was recov-ered when other oxidants instead of m-CPBA wereused (see the Supporting Information, Table S1).Aprotic solvent screening experiments suggested thatTHF provided the best yield and E/Z ratio (up to>20:1) (Table 1, entries 21–24). These findings re-vealed that the reaction was exclusively catalyzed bysilver salts, and the oxidant m-CPBA is crucial.

Using the optimized reaction conditions, the reac-tion scope was studied by using propargylic amines1a–1w with different combinations of R1 (aryl/alkyl)and R2 (aryl/alkyl) groups (Table 2). A diversity ofenones 3a–3w with good to high isolated yields (up to

94%) and excellent E/Z ratios (up to >20:1) were ob-tained. In addition, oxidation sensitive functionalgroups (i.e., hydroxy, cyclohexenyl and ethynyl)remain intact after the reaction. Propargylic amines1 with different amine components (azepane, pyrroli-dine, l-prolinol and diethylamine) smoothly affordedenones 3 in good isolated yields (up to 79%) but withpoor E/Z ratios (see the Supporting Information,Table S2).

According to aforementioned literature reports,[4,5]

propargylic amine N-oxides were converted to differ-ent products depending on the solvent systems used(propenal in aprotic medium or acrylamides togetherwith enamino aldehydes in protic medium). Thesefindings promoted us to examine the effect of solventsystems on the present silver-catalyzed reaction. Sur-prisingly, when propargylic amine 1a was treated withm-CPBA (1.0 equiv.) followed by AgNO3 (10 mol%)in CH3CN/H2O (1:1), two unexpected products [3-chlorobenzoxymethyl ketone 4a (42%) and a-(3-chloro)-benzoxy enone 5a (45%)] instead of enone 3awere isolated (Table 3, entry 1). Propargylic amine 1b

Scheme 1. Organic transformations of propargylic amine N-oxides and propargylic amines.

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(R1 =cyclohexyl) and 1c (R1 = isopropyl) gave compa-rable product profiles under the same reaction condi-tions (Table 3, entries 2 and 3). These findings sug-gested that the choice of solvent systems exhibiteda significant effect on the product distribution.

With CH3CN as the solvent, enone 3c (65%) wasformed as the major product, while 4a (28%) and 5c(36%) were the major products with H2O as the sol-vent (Table 3, entries 4 and 5). Notably, using the sol-vent system of CH3OH/H2O (19:1), 3-chlorobenzoxy-methyl ketones 4 were obtained as the major producttogether with a trace amount of 5. But no enone 3was observed (Table 3, entries 6–14).

Gold- and silver-catalyzed transformations of prop-argylic esters (or alcohols) into enones and a-substi-

tuted enones are known.[12] However, the novel prod-uct formation observed in the present silver-catalyzedtransformations of propargylic amine N-oxides to giveenone 3 in an aprotic solvent or 3-chlorobenzoxy-methyl ketone 4 together with a-(3-chloro)-benzoxyenone 5 in a protic solvent have not been reported.Recently, Hashmi and co-workers reported a gold-cat-alyzed reaction of keto aldehydes and terminal al-kynes in the presence of piperidine to give enones inwhich a propargylic amine was considered as the in-termediate.[13] In contrast, the substitution pattern(R1/R2) in the enone products of Hashmi�s work is op-posite to that observed by us in the present silver-cat-alyzed reaction.

We have conducted mechanistic studies to providesupport for a proposed reaction mechanism(Scheme 2). Initially, the in situ generated N-oxide 2is activated by a silver cation through p coordination,leading to an Ag intermediate I’ which then under-goes protolysis to give an isoxazolinium intermediateI. Subsequent fragmentation of I gives enone 3 andimine 7 in an aprotic solvent (Scheme 2, path A).[14] Incontrast, in a protic solvent, nucleophilic attack of Iby 3-chlorobenzoxy anion gives an a-acyloxy-b-aminocarbonyl compound[15a] 8 which affords 3-chloroben-zoxymethyl ketone 4 together with iminium ion 9 viaC�C bond cleavage and a-(3-chloro)-benzoxy enone5 together with amine 10 via elimination (Scheme 2,path B).[15b]

The proposed reaction mechanism was supportedby the following experiments (Scheme 3). An isoxazo-linium salt [D1]-A was detected (see the SupportingInformation, Figure S1 and Figure S2) and character-ized by NMR (1H, 13C and DEPT-135) and MS analy-ses when the in situ generated N-oxide of 1c (charac-terized by NMR and MS) was treated with AgNO3

(5 mol%) in CD3OD (Scheme 3, A). Silver-catalyzedreaction of 1x in THF afforded enone 3a in 71% yieldand, more importantly, imine 11 was observed in thereaction mixtures by NMR and MS (see the Support-ing Information, Figure S3) analyses (Scheme 3, B).Deuterated propargylic amine [D10]-1c gave enone 3c(67% isolated yield) with no deuterium incorporation(Scheme 3, C), which ruled out the possibility of a re-action pathway via thermal Meisenheimer-type [2,3]-sigmatropic rearrangement and [1,5]-hydrogen shift.[4]

Using CDCl3/D2O (10:1) as solvent for the reactionof 1c, 75% deuterium incorporation in the product[D1]-3c (83% isolated yield) was observed (Scheme 3,D). For the reaction of 1y in CH3OH/H2O (50:1), a-acyloxy-b-amino carbonyl compound[15a] 8a was isolat-ed (68% yield, anti:syn= 2.6:1) and characterized byNMR and MS (see the Supporting Information,Table S4) analyses. Furthermore, 4a (44% isolatedyield) together with 5c (20% isolated yield) were ob-tained from 8a upon treatment with silica gel(Scheme 3, E).[15b]

Table 1. Silver-catalyzed transformation of propargylicamine 1a to enone 3a.[a]

Entry Catalyst Solvent Yield [%][b]

1 AgNO3 CDCl3 73 (10:1)2[c] AgNO3 CDCl3 03 – CDCl3 04 AgNTf2 CDCl3 64 (10:1)5 AgOOCCF3 CDCl3 68 (9:1)6 AgOTf CDCl3 67 (8:1)7 AgF CDCl3 71 (6:1)8 AgPF6 CDCl3 68 (8:1)9 AgBF4 CDCl3 64 (4:1)10 AgSbF6 CDCl3 65 (12:1)11 KAuCl4 CDCl3 012 AuBr3 CDCl3 013 AuCl CDCl3 014 PPh3AuCl CDCl3 015 CuI CDCl3 016 CuCl CDCl3 017 Cu ACHTUNGTRENNUNG(OTf)2 CDCl3 018 Zn ACHTUNGTRENNUNG(OTf)2 CDCl3 019 PdCl2 CDCl3 020 RuCl3 CDCl3 021 AgNO3 CHCl3 65 (>20:1)22 AgNO3 CH2Cl2 60 (>20:1)23 AgNO3 toluene 58 (16:1)24 AgNO3 THF 75 (>20:1)

[a] Reactions were performed with 1a (0.30 mmol), m-CPBA (0.30 mmol) and catalyst (0.015 mmol) in solvent(3.0 mL).

[b] Determined by 1H NMR using 1,3,5-trimethoxybenzeneas the internal reference and E/Z ratio indicated in pa-renthesis.

[c] Without m-CPBA.

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These findings suggested that in situ generated iso-xazolinium ions are the key intermediates involved inthese reaction pathways. Isoxazolinium intermediatesare unstable in an aprotic solvent and easily decom-pose[14] to give enones 3. In contrast, the isoxazolini-um intermediates are stable in a protic solvent whichis attributed to hydrogen bonding interactions[4d,e] and

are susceptible to nucleophilic attack by 3-chlorobenz ACHTUNGTRENNUNGoxy anion to give adducts 8.

Selective cysteine modification is a particularlyuseful bioconjugation reaction owing to the high reac-tivity of the cysteine sulfhydryl group and the rela-tively sparse occurrence of the cysteine unit in pep-tides and proteins.[16] Along with our ongoing interest

Table 2. Scope of catalytic transformation of propargylic amines 1 into enones 3.[a]

[a] Reactions were performed with 1 (0.30 mmol), m-CPBA (0.30 mmol) and AgNO3

(0.015 mmol) in THF (3.0 mL). Yield of the isolated product. E/Z ratio was determinedby 1H NMR.





in the development of bioconjugation reactions.[8,17]

we envision that the in situ generated isoxazoliniumintermediates in the present silver-catalyzed reactionwould be a useful handle for bioconjugation of cys-teine-containing peptides.

Treatment of a cysteine-containing peptideSTSSSCNLSK with propargylic amine 1a (or 1v)(5.0 equiv.), m-CPBA (1.0 equiv.) and a solution ofAgNO3 (5 mol%) in PBS buffer (pH 7.4) at roomtemperature for 1 h afforded a cysteine-modified pep-

Table 3. Catalytic transformation of propargylic amines 1 in a protic medium.[a]

Entry 1 R1 R2 Solvent Yield [%][b]

3 4 5

1 1a n-Hex Ph CH3CN/H2O (1:1) 0 (3a) 42 (4a) 45 (5a)2 1b c-Hex Ph CH3CN/H2O (1:1) 0 (3b) 43 (4a) 39 (5b)3 1c i-Pr Ph CH3CN/H2O (1:1) 0 (3c) 38 (4a) 42 (5c)4 1c i-Pr Ph CH3CN 65 (3c) 3 (4a) 5 (5c)5 1c i-Pr Ph H2O trace[c] 28 (4a) 36 (5c)6 1c i-Pr Ph CH3OH/H2O (19:1) 0 68 (4a) trace[c]

7[d] 1c i-Pr Ph CH3OH/H2O (19:1) 0 65 (4a) trace[c]

8[e] 1c i-Pr Ph CH3OH/H2O (19:1) 0 65 (4a) trace[c]

9[f] 1c i-Pr Ph CH3OH/H2O (19:1) 0 66 (4a) trace[c]

10 1ca i-Pr (4-methoxy)phenyl CH3OH/H2O (19:1) 0 62 (4aa) trace[c]

11 1cb i-Pr ACHTUNGTRENNUNG(4-fluoro)phenyl CH3OH/H2O (19:1) 0 58 (4ab) trace[c]

12 1cc i-Pr (6-methoxy)2-naphthyl CH3OH/H2O (19:1) 0 56 (4ac) trace[c]

13 1cd i-Pr (4-hydroxymethyl)phenyl CH3OH/H2O (19:1) 0 57 (4ad) trace[c]

14 1v i-Pr (4-ethynyl)phenyl CH3OH/H2O (19:1) 0 58 (4ae) trace[c]

[a] Reactions were performed with 1 (0.30 mmol), m-CPBA (0.30 mmol) and AgNO3 (0.03 mmol) in different solvents(3.0 mL).

[b] Yield of the isolated product.[c] Observed by crude 1H NMR.[d] 5 mol% AgNO3.[e] 20 mol% AgNO3.[f] 50 mol% AgNO3. n-Hex=n-hexyl, c-Hex=cyclohexyl, i-Pr = isopropyl, Ph=phenyl.

Scheme 2. A proposed reaction mechanism.





tide 12a (or 12b) in >99% conversion with all otheramino acid residues remaining intact as confirmed byLC-MS/MS analysis. In addition, the present biocon-jugation proceeded smoothly in a range of pH values(pH 6–9). No reaction was observed for a non-cys-teine-containing peptide YTSSSKNVVR (Scheme 4).These experiments demonstrated that this propargylicamine-based bioconjugation reaction is highly chemo-selective for cysteine-containing peptides. Given thatstructurally diverse propargylic amines can be synthe-sized from transition metal-catalyzed three compo-nent coupling reactions of aldehydes, amines and al-kynes under mild reaction conditions, diverse func-tionalities including fluorescent dyes or biotin tagscould be incorporated into peptides via the presentsilver-catalyzed propargylic amine-based bioconju-gation reaction.

A model reaction was conducted by mixing propar-gylic amine 1a (0.5 mmol) and m-CPBA (1.0 equiv.)followed by AgNO3 (10 mol%) in CH3OH/H2O(19:1) at 0 8C, and then treated with a solution of N-acetyl-l-cysteine n-butyl amide 13 (1.5 equiv.) inCH3OH at room temperature for 24 h. The formationof cysteine-methyl ketone adduct 14 (77% isolatedyield) provided structural support for the cysteine-modified peptides (Scheme 5).

In conclusion, we have developed a novel silver-cat-alyzed transformation of propargylic amine N-oxidesto enones 3, 3-chlorobenzoxymethyl ketones 4 and a-(3-chloro)-benzoxy enones 5 via isoxazolinium inter-mediates. The product profiles can be controlled byuse of aprotic or protic solvent systems. Given themild reaction conditions, a highly chemoselective

Scheme 3. Experimental support for the proposed reaction mechanism.





silver-mediated bioconjugation for cysteine-containingpeptides in aqueous medium has been developed.

Experimental Section

General Procedure for Transformation of PropargylicAmine N-Oxides to Enones

Propargylic amine 1 (0.3 mmol) was dissolved in THF(3 mL) and stirred at 0 8C, and then m-CPBA (0.3 mmol)was added. The mixture was kept at 0 8C and stirred for15 min, AgNO3 (0.015 mmol, 5 mol%) was added and

stirred at room temperature for 3 h. The reaction mixturewas concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel usingCH2Cl2-hexane as eluent to afford the corresponding enones3.

General Procedure for Transformation of PropargylicAmine N-Oxides to 3-Chlorobenzoxymethyl Ketonesand a-(3-Chloro)-benzoxy Enones

Propargylic amine 1 (0.3 mmol) was dissolved in CH3CN/H2O (1:1, 3 mL) and stirred at 0 8C, and then m-CPBA(0.3 mmol) was added. The mixture was kept at 0 8C andstirred for 15 min, AgNO3 (0.03 mmol, 10 mol%) was added

Scheme 4. Chemoselective modification of cysteine-containing peptides.

Scheme 5. Model reaction using N,C-protected cysteine 13.





and stirred at room temperature for 24 h. The reaction mix-ture was concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gelusing ethyl acetate-hexane as eluent to afford the corre-sponding 3-chlorobenzoxymethyl ketones 4 and a-(3-chloro)-benzoxy enones 5. Utilizing the same procedure, thereaction conducted in CH3OH/H2O (19:1) afforded 3-chlor-obenzoxymethyl ketones 4 as major product after columnchromatography on silica gel (pre-washed by 1% triethyla-mine in hexane).

Acknowledgements

We are grateful for the financial support of Hong Kong Re-search Grants Council (PolyU 5031/11p) and The HongKong Polytechnic University (SEG PolyU01).

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