An efficient one-step synthesis of piperidin-2-yl and pyrrolidin-2-yl flavonoid alkaloids through phenolic Mannich reactions

Article abstract of DOI:10.1002/ejoc.201101312

An efficient one-step synthesis of piperidin-2-yl and pyrrolidin-2-yl flavonoid alkaloids was achieved in good to excellent yields by a highly regioselective phenolic Mannich reaction of chrysin with cyclic imines or iminium salts. Performing the reaction in a mixture of H₂O/THF in the absence of an external reagent afforded the C-6 alkylated product exclusively. The same reaction in water in the presence of NaOH provided the C-8 alkylated flavonoid as a major product. The reaction has been successfully extended to simple phenols.

Full text of DOI:10.1002/ejoc.201101312

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101312
An Efficient One-Step Synthesis of Piperidin-2-yl and Pyrrolidin-2-yl
Flavonoid 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-
external reagent afforded the C-6 alkylated product exclu-
idin-2-yl flavonoid alkaloids was achieved in good to excel- sively. The same reaction in water in the presence of NaOH
lent yields by a highly regioselective phenolic Mannich reac-
tion of chrysin with cyclic imines or iminium salts. Performing
the reaction in a mixture of H2O/THF in the absence of an
provided the C-8 alkylated flavonoid as a major product. The
reaction has been successfully extended to simple phenols.
Introduction
Flavonoid alkaloids, in which the nitrogeneous ring is at-
tached to the flavonoid moiety, display potent biological
activities.[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 is
proposed that the N-methyl-Δ1-pyrrolidinium ion, which is
in turn derived from ornithine, is the common precursor of
the 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 by
the structures of 1–6.[1]
In connection with our ongoing research program deal-
ing with the synthesis of a flavonoid alkaloid library, we
needed rapid and practical access to a large collection of 2-
azacycloalkyl-substituted flavones. Taking advantage of the
high nucleophilicity of phloroglucinol derivatives, we
thought 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 class
of natural product and analogues thereof. Although the
phenolic 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 naphthols
and 3,4-dihydroisoquinoline under solvent-free or micro-
Scheme 1. Flavonoid alkaloids and retrosynthetic analysis.
wave-assisted conditions has been reported.[4] Very recently,
Cimarelli and co-workers reported the Mannich reaction of
naphthols or activated phenols with cyclic imines.[5] To the
best of our knowledge, there are only two reports dealing
with the reaction of a flavonoid with cyclic imines. In both
cases, no systematic studies were carried out, and the de-
sired products were obtained in low yields (Ͻ10 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 of
flavones with cyclic imines or in situ generated iminium
salts can provide either C-6- or C-8-alkylated flavonoids in
high yields under appropriate conditions. This led to a
highly efficient one-step synthesis of piperidin-2-yl and pyr-
rolidin-2-yl flavones, as exemplified by the synthesis of the
natural products N-demethylcapitavine (1), capitavine (2),
[a] Centre de Recherche de Gif,
Institut de Chimie des Substances Naturelles, CNRS,
91198 Gif-sur-Yvette Cedex, France
Fax: +33-1-69077247
[b] Institute of Chemical Sciences and Engineering,
Ecole Polytechnique Fédérale de Lausanne (EPFL),
EPFL-SB-ISIC-LSPN,
1015 Lausanne, Switzerland
Fax: +41-21-6939740
E-mail: q.wang@epfl.ch
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101312.
7076
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7076–7079

Synthesis of Piperidin-2-yl and Pyrrolidin-2-yl Flavonoid Alkaloids
isoficine (3), N,O-didemethylbuchenavianine (9a), and their yields as a single regioisomer. This allowed us to develop a
analogues. The expansion of this reaction to simple phenols one-step synthesis of the natural products N-demethylcapi-
will also be documented.
tavine (1), capitavine (2), isoficine (3), and their analogues
10b–e. Reaction of 7a with 8c afforded 10c as a single trans
diastereoisomer. Assuming that conformer B, wherein the
methyl substituent was in a pseudoequatorial position, was
more stable than conformer A, then nucleophilic addition
of phenol from the α-face of the imine would afford the
observed 2,4-trans stereoisomer (Scheme 2).[9]
Results and Discussion
Chrysin (7a) and Δ1-piperideine (3,4,5,6-tetrahydropyr-
idine, 8a)[8] were used as representative substrates in our
initial survey of reaction conditions (Table 1). In DMF, a
dipolar aprotic solvent, at 80 °C, the conversion was low
and the reaction gave an equimolar mixture of separable C-
6/C-8 regioisomers (Table 1, Entry 1). Good conversion was
obtained in toluene to give the C-6/C-8 coupling products
in a ratio of 1.7:1 (Table 1, Entry 2), whereas almost no
reaction 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% isolated
yield as a single C-6 regioisomer (Table 1, Entry 7). The re-
action proceeded much faster at 80 °C, but with reduced
regioselectivity (Table 1, Entry 8).
Figure 1. Cyclic imines and iminium salt precursors.
Table 1. Survey of Mannich reaction conditions.[a]
Figure 2. Flavonoid alkaloids by phenolic Mannich reaction of
chrysin and cyclic imines or iminium salts.
Entry
Solvent
Conditions
Conversion [%][b] 1/9a[b]
1
2
3
4
5
6
7
8
DMF
PhMe
THF
CHCl3
EtOH
80 °C, 72 h
80 °C, 40 h
80 °C, 16 h
80 °C, 48 h
80 °C, 16 h
40 °C, 48 h
40 °C, 48 h
30
80
Ͻ5
1:1
1.7:1
nd
1.5:1
4:1
99:1
99:1
12:1
55
75
Scheme 2. Preferred formation of 2,3-trans isomer 9c.
(CH2OH)2
Ͼ95[c]
Ͼ95
Ͼ95[d]
H2O/THF[e]
H2O/THF[e] 80 °C, 40 min
It is worthy noting that the reaction proceeded smoothly
without any added catalyst. We hypothesized that the hy-
droxy group of chrysin may form an H-bond with the imine
[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 by such that the phenolic Mannich reaction proceeded through
recrystallization. [d] 85% isolated yield by recrystallization.
[e] H2O/THF = 2:1.
an entropically favored pseudointramolecular process to af-
ford the observed product. Indeed, when acetic acid, which
is able to protonate the imine, was used as solvent, only a
With the optimized conditions in hand (H2O/THF = 2:1, trace amount of product was formed.
40 °C), we next investigated the scope of the reaction with
Having established conditions for the selective C-6-ami-
a range of five- and six-membered cyclic imines and imin- noalkylation of chrysin, we turned our attention to the syn-
ium salts (Figure 1, see the Supporting Information for thesis of the C-8 regioisomer. We were pleased to find that
their synthesis). As shown in Figure 2, imines 8a–d and im- reaction of chrysin (7a) with 8b in water in the presence of
inium salt precursors 8e–g were all accepted as electrophiles NaOH (1.0 equiv.) at 40 °C for 1 week afforded exclusively
in the present phenolic Mannich reaction, leading to the C-8 regioisomer 9b in over 90% isolated yield (Scheme 3).
corresponding C-6-alkylated products in good to excellent The reaction mixture is homogeneous at the begin-
Eur. J. Org. Chem. 2011, 7076–7079
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7077

T. B. Nguyen, Q. Wang, F. Guéritte
SHORT COMMUNICATION
1
ning of the reaction and the H NMR spectrum of an ali- Table 2. Mannich reaction of phenols and imines.
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 derived
towards the exclusive formation of 9b. The same conditions
applied to piperidine (8a), resulting in the formation of two
regioisomers 1/9a in a ratio of 1:3 in favor of the C-8 iso-
mer. However, this ratio did not evolve during the course
of the reaction, probably due to the high solubility of both
adducts.
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 to
be not reactive enough. We were thus pleased to find that
not 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 to
drive the reaction to completion. Notably, this reaction is
highly regioselective and furnishes one single regioisomer in
each case.
A high trans-selectivity was observed for the reaction of
phenol 7h with 4-methylpiperideine (8c), as in the case of
chrysin (Table 2, Entry 20). However, with naphthols 7b
and 7c, the thermodynamically more stable 1,3-cis-isomers
were 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-Michael
addition/Michael addition sequence proceeding via an or-
tho-quinone methide intermediate.[10] Naphthol derivatives
are more prone to trans–cis isomerization than are phenol
derivatives, which is in accord with their lower aromaticity,
and hence the easy formation of the ortho-quinone methide
intermediate.
The stereochemistries of the trans- and cis-isomers were
unambiguously determined by NOESY experiments, as ex-
emplified by 11cc (Figure 3).[11]
Because pyrroline (8b) can be obtained easily by silver
[a] Reaction conditions: see the Supporting Information for details.
nitrate catalyzed oxidation of pyrrolidine by peroxodisulfate
[b] The regioselectivity is shown by the arrow. [c] Isolated yield.
in aqueous basic media,[12] a one-pot synthesis of N-de- [d] The ratio 1,3-cis/1,3-trans = 97:3 was determined by H NMR
1
spectroscopic analysis. [e] The ratio 1,3-cis/1,3-trans = 1.6:1 was 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.
1
termined by H NMR spectroscopic analysis. [f] The ratio 1,3-cis/
1,3-trans = 1:1 was determined by 1H NMR spectroscopic analysis.
1
[g] The ration 1,3-cis/1,3-trans = 4:96 was determined by H NMR
spectroscopic analysis.
7078
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7076–7079

Synthesis of Piperidin-2-yl and Pyrrolidin-2-yl Flavonoid Alkaloids
Acknowledgments
Financial support from the Centre National de la Recherche Sci-
entifique (CNRS) is gratefully acknowledged. T. B. N. thanks the
Institut de Chimie des Substances Naturelles (ICSN) for a postdoc-
toral fellowship.
[1] a) J. A. Beutler, J. H. Cardellina II, J. B. McMahon, M. R.
Boyd, J. Nat. Prod. 1992, 55, 207; for reviews on flavonoid
alkaloids, see: b) P. J. Houghton, in Alkaloids (Ed.: A. Brossi),
Acdemic Press, San Diego, 1987, vol. 31, pp. 67–100; c) P. J.
Houghton, Stud. Nat. Prod. Chem, 2000, 21, 123; d) A. Ahond,
A. Fournet, C. Moretti, E. Philogene, C. Poupat, O. Thoison,
P. Potier, Bull. Soc. Chim. Fr. 2 1984, 41.
Figure 3. NOESY correlation for 1,3-cis and 1,3-trans of 11cc.
[2] a) T. Kisaki, S. Mizusaki, E. Tamaki, Arch. Biochem. Biophys.
1966, 117, 677; b) E. Leete, J. Am. Chem. Soc. 1967, 89, 7081;
c) E. Leete, Planta Med. 1979, 36, 97.
[3] a) J. H. Short, C. W. Ours, J. Heterocycl. Chem. 1975, 12, 869;
b) T. Huang, C.-J. Li, Tetrahedron Lett. 2000, 41, 6715; c) J.-
X. Ji, L.-Q. Qiu, C. W. Yip, A. S. C. Chan, J. Org. Chem. 2003,
68, 1589; d) C. Cimarelli, G. Palmieri, E. Volpini, Can. J. Chem.
2004, 82, 1314; e) C. Rondot, J. Zhu, Org. Lett. 2005, 7, 1641.
[4] a) P. D. MacLeod, Z. Li, J. Feng, C.-J. Li, Tetrahedron Lett.
2006, 47, 6791; b) I. Szatmari, L. Lazar, F. Fülöp, Tetrahedron
Lett. 2006, 47, 3881; c) P. D. Macleod, Z. Li, C.-J. Li, Tetrahe-
dron 2010, 66, 1045.
Scheme 4. One-pot synthesis of N-demethylisoficine.
[5] C. Cimarelli, D. Fratoni, A. Mazzanti, G. Palmieri, Eur. J. Org.
Chem. 2011, 2094.
[6] a) E. Leete, J. Nat. Prod. 1982, 45, 605; b) G. Boudouin, F.
Tillequin, M. Koch, M. Vuilhorgne, J.-Y. Lallemand, J. Nat.
Prod. 1983, 46, 681; c) the first synthesis of (Ϯ)-ficine in nine
steps, see B. Anjaneyulu, T. R. Govindachari, Tetrahedron Lett.
1969, 10, 2847.
[7] The phenolic Mannich reaction performed with the use of
highly reactive iminium salts formed in situ from secondary
amines (piperidine, pyrrolidine, morpholine) and highly elec-
trophilic aldehydes (formaldehyde, glyoxylate) has been re-
ported, see: a) S. Zhang, J. Ma, Y. Bao, P. Yang, L. Zou, K.
Li, X. Sun, Bioorg. Med. Chem. 2008, 16, 7127; b) for a cyclic
imine nitro-Mannich reaction in water, see: P. Jakubec, M. Hel-
liwell, D. J. Dixon, Org. Lett. 2008, 10, 4267; c) for condensa-
tion of Δ-piperidine and N-methyl-2-hydroxypiperidine, see:
E. E. van Tamelen, G. G. Knapp, J. Am. Chem. Soc. 1955, 77,
1860.
[8] M.-G. A. Shvekhgeimer, Russ. Chem. Rev. 1998, 67, 1031.
[9] R. V. Stevens, Acc. Chem. Res. 1984, 17, 289.
[10] For a review, see: R. W. Van de Water, T. R. R. Pettus, Tetrahe-
dron 2002, 58, 5367.
[11] See the Supporting Information for details.
[12] A. Mores, M. Matziari, P. Beau, A. Yiotakis, V. Dive, J. Med.
Chem. 2008, 51, 2216.
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 the
nucleophile, both C-6 and C-8 regioisomers were accessible
by 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 conditions
were successfully extended to a variety of phenols. The
method should find application in the diversity-oriented
synthesis of a library of 2-flavonoid alkaloids for the study
of structure–activity relationships of this class of natural
products. 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 copies
Received: September 8, 2011
Published Online: October 31, 2011
1
of the H and 13C NMR spectra.
Eur. J. Org. Chem. 2011, 7076–7079
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7079