SHORT COMMUNICATION

DOI: 10.1002/ejoc.201101312

An Efficient One-Step Synthesis of Piperidin-2-yl and Pyrrolidin-2-ylFlavonoid Alkaloids through Phenolic Mannich Reactions

Thanh Binh Nguyen,[a] Qian Wang,*[a,b] and Françoise Guéritte[a]

Keywords: Alkaloids / Mannich reaction / Imines / Natural products / Regioselectivity

An efficient one-step synthesis of piperidin-2-yl and pyrrol-idin-2-yl flavonoid alkaloids was achieved in good to excel-lent yields by a highly regioselective phenolic Mannich reac-tion of chrysin with cyclic imines or iminium salts. Performingthe reaction in a mixture of H2O/THF in the absence of an

Introduction

Flavonoid alkaloids, in which the nitrogeneous ring is at-tached to the flavonoid moiety, display potent biologicalactivities.[1a–1c] Representative natural 2-azacycloalkyl-sub-stituted flavonoid alkaloids 1–6 are shown in Scheme 1. Al-though no biosynthetic studies have been carried out, it isproposed that the N-methyl-Δ1-pyrrolidinium ion, which isin turn derived from ornithine, is the common precursor ofthe N-methylpyrrolidine moiety of isoficine (3), ficine (5),and phylospadine (6).[2] The phloroglucinol motif is embed-ded in most natural flavonoid alkaloids, as exemplified bythe structures of 1–6.[1]

In connection with our ongoing research program deal-ing with the synthesis of a flavonoid alkaloid library, weneeded rapid and practical access to a large collection of 2-azacycloalkyl-substituted flavones. Taking advantage of thehigh nucleophilicity of phloroglucinol derivatives, wethought that Mannich reaction of a flavone, such as chrysin(7a), with cyclic imines 8 should provide a direct, conver-gent, and versatile method for the construction of this classof natural product and analogues thereof. Although thephenolic Mannich reaction is known,[3] most of the re-ported methods use naphthols or activated phenols as nu-cleophiles; cyclic imines have been rarely used as the electro-philic partner.[4,5] The Mannich reaction between naphtholsand 3,4-dihydroisoquinoline under solvent-free or micro-

[a] Centre de Recherche de Gif,Institut de Chimie des Substances Naturelles, CNRS,91198 Gif-sur-Yvette Cedex, FranceFax: +33-1-69077247

[b] Institute of Chemical Sciences and Engineering,Ecole Polytechnique Fédérale de Lausanne (EPFL),EPFL-SB-ISIC-LSPN,1015 Lausanne, SwitzerlandFax: +41-21-6939740E-mail: q.wang@epfl.chSupporting information for this article is available on theWWW under http://dx.doi.org/10.1002/ejoc.201101312.

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external reagent afforded the C-6 alkylated product exclu-sively. The same reaction in water in the presence of NaOHprovided the C-8 alkylated flavonoid as a major product. Thereaction has been successfully extended to simple phenols.

Scheme 1. Flavonoid alkaloids and retrosynthetic analysis.

wave-assisted conditions has been reported.[4] Very recently,Cimarelli and co-workers reported the Mannich reaction ofnaphthols or activated phenols with cyclic imines.[5] To thebest of our knowledge, there are only two reports dealingwith the reaction of a flavonoid with cyclic imines. In bothcases, no systematic studies were carried out, and the de-sired products were obtained in low yields (�10 and 30%)and low regioselectivities (about 1:1).[6,7] In spite of the re-ported low efficiency, its potential in the synthesis of fla-vonoid alkaloids prompted us to reinvestigate this reaction.Herein we report that the phenolic Mannich reaction offlavones with cyclic imines or in situ generated iminiumsalts can provide either C-6- or C-8-alkylated flavonoids inhigh yields under appropriate conditions. This led to ahighly efficient one-step synthesis of piperidin-2-yl and pyr-rolidin-2-yl flavones, as exemplified by the synthesis of thenatural products N-demethylcapitavine (1), capitavine (2),

Synthesis of Piperidin-2-yl and Pyrrolidin-2-yl Flavonoid Alkaloids

isoficine (3), N,O-didemethylbuchenavianine (9a), and theiranalogues. The expansion of this reaction to simple phenolswill also be documented.

Results and Discussion

Chrysin (7a) and Δ1-piperideine (3,4,5,6-tetrahydropyr-idine, 8a)[8] were used as representative substrates in ourinitial survey of reaction conditions (Table 1). In DMF, adipolar aprotic solvent, at 80 °C, the conversion was lowand the reaction gave an equimolar mixture of separable C-6/C-8 regioisomers (Table 1, Entry 1). Good conversion wasobtained in toluene to give the C-6/C-8 coupling productsin a ratio of 1.7:1 (Table 1, Entry 2), whereas almost noreaction took place in THF (Table 1, Entry 3). In protic sol-vents (ethanol, ethylene glycol, ethanolamine, and H2O),the reaction proceeded much faster with higher C-6 regiose-lectivity (not all data shown). Finally, a mixture of H2O/THF turned out to be optimum. Heating a H2O/THF (2:1)solution of 7a and 8a at 40 °C afforded 1 in 75 % isolatedyield as a single C-6 regioisomer (Table 1, Entry 7). The re-action proceeded much faster at 80 °C, but with reducedregioselectivity (Table 1, Entry 8).

Table 1. Survey of Mannich reaction conditions.[a]

Entry Solvent Conditions Conversion [%][b] 1/9a[b]

1 DMF 80 °C, 72 h 30 1:12 PhMe 80 °C, 40 h 80 1.7:13 THF 80 °C, 16 h �5 nd4 CHCl3 80 °C, 48 h 55 1.5:15 EtOH 80 °C, 16 h 75 4:16 (CH2OH)2 40 °C, 48 h �95[c] 99:17 H2O/THF[e] 40 °C, 48 h �95 99:18 H2O/THF[e] 80 °C, 40 min �95[d] 12:1

[a] Reaction conditions: chrysin (7a) (1.0 mmol), imine 8a(1.0 mmol), in solvent (2 mL). [b] Determined by 1H NMR spectro-scopic analysis of the crude product. [c] 75% isolated yield byrecrystallization. [d] 85% isolated yield by recrystallization.[e] H2O/THF = 2:1.

With the optimized conditions in hand (H2O/THF = 2:1,40 °C), we next investigated the scope of the reaction witha range of five- and six-membered cyclic imines and imin-ium salts (Figure 1, see the Supporting Information fortheir synthesis). As shown in Figure 2, imines 8a–d and im-inium salt precursors 8e–g were all accepted as electrophilesin the present phenolic Mannich reaction, leading to thecorresponding C-6-alkylated products in good to excellent

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yields as a single regioisomer. This allowed us to develop aone-step synthesis of the natural products N-demethylcapi-tavine (1), capitavine (2), isoficine (3), and their analogues10b–e. Reaction of 7a with 8c afforded 10c as a single transdiastereoisomer. Assuming that conformer B, wherein themethyl substituent was in a pseudoequatorial position, wasmore stable than conformer A, then nucleophilic additionof phenol from the α-face of the imine would afford theobserved 2,4-trans stereoisomer (Scheme 2).[9]

Figure 1. Cyclic imines and iminium salt precursors.

Figure 2. Flavonoid alkaloids by phenolic Mannich reaction ofchrysin and cyclic imines or iminium salts.

Scheme 2. Preferred formation of 2,3-trans isomer 9c.

It is worthy noting that the reaction proceeded smoothlywithout any added catalyst. We hypothesized that the hy-droxy group of chrysin may form an H-bond with the iminesuch that the phenolic Mannich reaction proceeded throughan entropically favored pseudointramolecular process to af-ford the observed product. Indeed, when acetic acid, whichis able to protonate the imine, was used as solvent, only atrace amount of product was formed.

Having established conditions for the selective C-6-ami-noalkylation of chrysin, we turned our attention to the syn-thesis of the C-8 regioisomer. We were pleased to find thatreaction of chrysin (7a) with 8b in water in the presence ofNaOH (1.0 equiv.) at 40 °C for 1 week afforded exclusivelyC-8 regioisomer 9b in over 90% isolated yield (Scheme 3).The reaction mixture is homogeneous at the begin-

T. B. Nguyen, Q. Wang, F. GuéritteSHORT COMMUNICATIONning of the reaction and the 1H NMR spectrum of an ali-quot showed that both regioisomers were formed (C-6/C-8= 1:3). We thus speculated that the presence of NaOH ren-dered the reaction reversible. Because C-8 adduct 9b pre-cipitated out from the solution, the equilibrium was derivedtowards the exclusive formation of 9b. The same conditionsapplied to piperidine (8a), resulting in the formation of tworegioisomers 1/9a in a ratio of 1:3 in favor of the C-8 iso-mer. However, this ratio did not evolve during the courseof the reaction, probably due to the high solubility of bothadducts.

Scheme 3. Regioselective C-8 alkylation of chrysin.

Although naphthols have been used in the phenolic Man-nich reaction,[3–5] simple phenols have been considered tobe not reactive enough. We were thus pleased to find thatnot only naphthols (Table 2, Entries 1–9) but also electron-rich phenols (Table 2, Entries 10–22) and simple phenols(Table 2, Entries 23–26) participated in this reaction to af-ford the corresponding adduct in good to excellent yields.For less-reactive phenols 1k–m, forcing conditions (130 °C,3 equiv. of NaOH; Table 2, Entries 23–26) were needed todrive the reaction to completion. Notably, this reaction ishighly regioselective and furnishes one single regioisomer ineach case.

A high trans-selectivity was observed for the reaction ofphenol 7h with 4-methylpiperideine (8c), as in the case ofchrysin (Table 2, Entry 20). However, with naphthols 7band 7c, the thermodynamically more stable 1,3-cis-isomerswere formed as major products (Table 2, Entries 3 and 7).Assuming that the 1,3-trans adduct was the kinetic product,the isomerization could be accounted for by a retro-Michaeladdition/Michael addition sequence proceeding via an or-tho-quinone methide intermediate.[10] Naphthol derivativesare more prone to trans–cis isomerization than are phenolderivatives, which is in accord with their lower aromaticity,and hence the easy formation of the ortho-quinone methideintermediate.

The stereochemistries of the trans- and cis-isomers wereunambiguously determined by NOESY experiments, as ex-emplified by 11cc (Figure 3).[11]

Because pyrroline (8b) can be obtained easily by silvernitrate catalyzed oxidation of pyrrolidine by peroxodisulfatein aqueous basic media,[12] a one-pot synthesis of N-de-methylisoficine (10b) was subsequently developed(Scheme 4). Thus, oxidation of pyrrolidine (12) (Na2S2O8,AgNO3, NaOH, H2O) followed by addition of chrysin (7a)afforded 10b in 96% yield as a single regioisomer.

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Table 2. Mannich reaction of phenols and imines.

[a] Reaction conditions: see the Supporting Information for details.[b] The regioselectivity is shown by the arrow. [c] Isolated yield.[d] The ratio 1,3-cis/1,3-trans = 97:3 was determined by 1H NMRspectroscopic analysis. [e] The ratio 1,3-cis/1,3-trans = 1.6:1 was de-termined by 1H NMR spectroscopic analysis. [f] The ratio 1,3-cis/1,3-trans = 1:1 was determined by 1H NMR spectroscopic analysis.[g] The ration 1,3-cis/1,3-trans = 4:96 was determined by 1H NMRspectroscopic analysis.

Synthesis of Piperidin-2-yl and Pyrrolidin-2-yl Flavonoid Alkaloids

Figure 3. NOESY correlation for 1,3-cis and 1,3-trans of 11cc.

Scheme 4. One-pot synthesis of N-demethylisoficine.

Conclusions

In summary, an efficient phenolic Mannich reaction in-volving the use of cyclic imines or iminium salts as electro-philes has been developed. When chrysin was used as thenucleophile, both C-6 and C-8 regioisomers were accessibleby changing the reaction conditions. The power of this reac-tion is illustrated in the one-pot synthesis of N-demethylca-pitavine (1), capitavine (2), isoficine (3), N,O-didemeth-ylbuchenavianine (9a), and their analogues. The conditionswere successfully extended to a variety of phenols. Themethod should find application in the diversity-orientedsynthesis of a library of 2-flavonoid alkaloids for the studyof structure–activity relationships of this class of naturalproducts. Work towards this direction is ongoing in our lab-oratory.

Supporting Information (see footnote on the first page of this arti-cle): Experimental procedures, product characterization, and copiesof the 1H and 13C NMR spectra.

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Acknowledgments

Financial support from the Centre National de la Recherche Sci-entifique (CNRS) is gratefully acknowledged. T. B. N. thanks theInstitut de Chimie des Substances Naturelles (ICSN) for a postdoc-toral fellowship.

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Chem. 2008, 51, 2216.Received: September 8, 2011

Published Online: October 31, 2011