5-aminopenta-2,4-dienals: Synthesis, activation towards nucleophiles, molecular modeling and biosynthetic implications in relation to the manzamine alkaloids

Article abstract of DOI:10.1002/ejoc.201402331

Substituted 5-aminopentadienals and glutaconaldehydes are key elements postulated in the biosynthesis of the diverse class of manzamine-type alkaloids. The activation of 5-aminopentadienals into electrophilic iminium salts and their subsequent reactivity

Full text of DOI:10.1002/ejoc.201402331

FULL PAPER
DOI: 10.1002/ejoc.201402331
5-Aminopenta-2,4-dienals: Synthesis, Activation towards Nucleophiles,
Molecular Modeling and Biosynthetic Implications in Relation to the
Manzamine Alkaloids
Lok-Hang Yan,[a] Adam Skiredj,[a] Yves Dory,[b] Bernard Delpech,[c] and Erwan Poupon*[a]
Keywords: Alkaloids / Nucleophilic addition / Natural products / Aminopentadienal / Manzamine
Substituted 5-aminopentadienals and glutaconaldehydes are
key elements postulated in the biosynthesis of the diverse
class of manzamine-type alkaloids. The activation of 5-
aminopentadienals into electrophilic iminium salts and their
calculations of HOMO/LUMO was in agreement with the ex-
perimental results indicating that strong electrophilic agents,
such as POCl3 are required to turn 5-aminopentadienals into
electrophiles. New examples of glutaconaldehyde reactivity,
subsequent reactivity towards various nucleophiles has per- especially towards pyridinium salts, are presented and bio-
mitted the synthesis of a series of unsaturated compounds
sometimes accompanied by cascades of rearrangements.
Molecular modeling of these systems carried out using DFT
synthetic considerations are kept in mind throughout this
study.
Introduction
Highly complex and intriguing alkaloids (as represented
by 1–5 in Figure 1) belonging to the “manzamine family”
have stimulated an impressive amount of scientific research
over the last 25 years following the isolation and structure
determination of manzamine A (1) from Haliclona sp.
sponges by Higa in 1986 (Figure 1).[1]
Although little is known about their true biosynthetic
pathway[2] and, in fact, their real origin (symbiotic bacteria
within the sponges),[3] manzamine alkaloids have been the
focal point of state of the art efforts directed toward their
total synthesis especially when biosynthetically inspired. In-
deed, two complementary biosynthetic models were put for-
ward in the 1990s, following the Baldwin and Whitehead
acrolein and dihydropyridinium hypothesis.[4] The Maraz-
ano malonaldehyde and pyridinium hypothesis[5] further
enriched a fruitful debate. Both models enabled great
achievements in biomimetic synthesis and were finalized in
late 2000 by way of a unified model.[6]
[a] Université Paris-Sud, Laboratoire de Pharmacognosie associé
au CNRS, UMR 8076 (BioCIS), LabEx LERMIT, Faculté de
Pharmacie,
5, rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France
E-mail: erwan.poupon@u-psud.fr
http://www.biocis.u-psud.fr
Figure 1. Representative examples of manzamine alkaloids.
[b] Laboratoire de Synthèse Supramoléculaire, Département de
Chimie, Institut de Pharmacologie, Université de Sherbrooke,
3001, 12è avenue Nord, Sherbrooke, Québec, J1H 5N4, Canada
E-mail: Yves.Dory@USherbrooke.ca
Biosynthetically speaking, the key formation of pyridin-
ium salts could be explained by a three-component reaction
between a long-chain fatty primary amine, a similar alde-
hyde and a C3 unit such as malonaldehyde 6.[5a] Three types
of acyclic C5 reactive intermediates may be involved in the
process: two different types of aminopentadienals (7Ј) and
[c] Institut de Chimie des Substances Naturelles, Centre de
Recherche de Gif, CNRS,
Avenue de la Terrasse, 91198 Gif-sur-Yvette CEDEX, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402331.
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a glutaconaldehyde entity (8Ј) as represented in Scheme 1.
Thus, the reactivity of such intermediates constitutes a cen-
tral question when dealing with the intimate mechanisms
governing the formation of manzamine-type alkaloids.
Scheme 2. Preparation of aminopentadienal
aldehyde potassium enolate 8.
7 and glutacon-
Activation to Iminium Salts
Aminopentadienal 7 was first treated with different acti-
vation agents and converted into the corresponding imin-
ium salts or masked forms. Compounds 10–13 were quanti-
tatively formed (as the major diastereomers Ͼ90%) upon
reaction of 7 with trimethylsilyl cyanide (TMSCN), tri-
methylsilyl trifluoromethanesulfonate (TMSOTf), tert-
butyldimethylsilyl trifluoromethanesulfonate (TBDMSOTf)
and methyl trifluoromethanesulfonate (MeOTf), respec-
tively. These iminium species (or their equivalents) could be
observed by 1H NMR spectroscopy when reactions were
conducted in NMR tubes (Scheme 3). Nevertheless, reac-
tions of 10–13 with nucleophiles appeared to be disappoint-
ing as they led mainly to the recovery of 7 or the formation
of inconclusive complex mixtures thereby making recourse
to other activating agents indispensable.
Scheme 1. Key C5 intermediates involved in the possible biosynthe-
sis of pyridinium rings, and their biomimetic equivalents.
In the present work, 5-aminopentadienal 7 and glutacon-
aldehyde salt 8, relevant to the above-mentioned intermedi-
ates postulated in the biosynthesis of manzamine alkaloids
(they both display a lateral methyl group in place of the
long fatty unsaturated side chains), have been prepared and
their reactivity studied primarily following activation
towards nucleophiles.[7] Biosynthetic considerations are also
put forward.
To be more specific, 5-(dimethylamino)penta-2,4-dienals
(7Ј), also called “Zincke aldehydes”, are the focus of this
work. These species readily result from ring opening of
pyridinium salts such as “Zincke salts”. 5-(Dialkylamino)-
penta-2,4-dienals (7Ј) are more stable than the N-alkyl
counterparts since they cannot cyclize to pyridinium salts.
Scheme 3. Structure of iminium salts (or masked forms) 10–13
quantitatively obtained from compound 7 with different activating
agents in CDCl3.
Results and Discussion
Synthesis of Substrates
Aminopentadienal 7 was prepared in a one-step pro-
cedure by ring-opening of Zincke salt 9 by dimethylamine
in a mixture of ethanol and water at reflux.[8] Removal of
dinitroaniline by filtration afforded aminopentadienal 7,
which could be used without further purification. An alka-
Activation with Phosphorus Oxychloride and Reaction with
Various Nucleophiles
Reaction of 7 with phosphorus oxychloride (POCl3)
line hydrolysis of 7 in THF at reflux then allowed the prepa- (Scheme 4) was then investigated and found to generate
ration of glutaconaldehyde salt 8, as detailed in Scheme 2. chloropentadiene iminium compound 14 as the reactive
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5-Aminopenta-2,4-dienals: Role in Accessing Manzamine Alkaloids
electrophilic entity that can, in fact, be considered as a dicarboxylate (Table 1, Entry 4) in the presence of 1,8-di-
double vinylogous Vilsmeier reagent.[9]
azabicyclo[5.4.0]undec-7-ene (DBU) and finally, Meldrum’s
acid (Table 1, Entry 5), which led respectively to com-
pounds 15–19.
Appearing as pivotal functionalities in alkaloid biosyn-
thesis, enamines were also tested as nucleophiles, as detailed
in Scheme 5. An endocyclic enamine, masked as its amino-
nitrile form 20 was used. Reaction of 20 with iminium com-
pound 14, in the presence of AgBF4, led to isolation of
Scheme 4. Structure of chloropentadiene iminium compound 14
obtained by reaction of aminopentadienal 7 with phosphorus
oxychloride in CDCl3.
The reactivity of various nucleophiles towards 14 was
then evaluated. The ensuing reactions led to isolation of
mainly 1,2-addition compounds in moderate yields as
summarized in Table 1. This was the case with isopropyl-
magnesium chloride (Table 1, Entry 1), methyl acetoacetate
(Table 1, Entry 2), 2,4-pentanedione (Table 1, Entry 3) both
in the presence of sodium methoxide, dimethyl 1,3-acetone-
Table 1. Reactivity studies of aminopentadienal 7 activated by phos-
phorus oxychloride.
Scheme 5. Reaction of masked enamine 20 with iminium com-
pound 14 and aminopentadienal 7 in the presence of AgBF4.
[a] Isolated yield. [b] A mixture of nucleophile and sodium meth-
oxide (1.5 equiv.) was added to the iminium compound 14; 22 h later,
a mixture of nucleophile (2 equiv.) and 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) (2 equiv.) was added to the reaction mixture. [c] Di-
methyl 1,3-acetonedicarboxylate (1.2 equiv.) was added. After 23 h,
additional nucleophile (1.2 equiv.) with DBU (1.2 equiv.) was added. 22.
Scheme 6. Hypothesized mechanism for formation of compound
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1,2-addition adduct 21 along with aminopentadiene imin- Activation with Acetyl Chloride and Reaction as a Diene
ium salt 22.[10] The formation of 22 may involve the hydrol-
The O-acetylation of 7 by acetyl chloride in dichloro-
methane was achieved leading to iminium compound 27
(see selected NMR spectroscopic data in Scheme 8).[12]
Whereas the addition of some nucleophiles evaluated above
(such as 2,4-pentanedione, methyl acetoacetate) failed to
provide new compounds and led to the recovery of starting
ysis of chloro iminium compound 14. As silver tetrafluoro-
borate is highly hygroscopic, the hydrolysis of 14 might lead
to the release of dimethylamine, which could undergo a 1,6-
addition to afford compound 22.[11] (Scheme 6). When 20
reacted directly with unactivated aminopentadienal 7, in the
presence of AgBF4, aminopentadiene iminium salt 22 could
be isolated together with minor product 23. The latter may
result from an impressive cascade of reactions and re-
arrangements leading to, among other processes, formation
of a disubstituted benzaldehyde aromatic ring as proposed
in Scheme 7. Indeed, awaited compound 25 underwent hy-
drolysis providing a secondary amine and free aldehyde 26.
Compound 26 reacted with another molecule of 7 and with
cyclization of the newly formed aminoheptatrienal (a vin-
ylogous analogue of aminopentadienals evoked so far in
this paper).
Scheme 8. Formation of compounds 29 and 30 by reaction of
Scheme 7. Hypothesized mechanism for formation of compound 23. acetoxy iminium compound 27 with N-phenylmaleimide (28).
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5-Aminopenta-2,4-dienals: Role in Accessing Manzamine Alkaloids
7, acetoxy iminium compound 27 could be involved as a
diene in a Diels–Alder reaction with N-phenylmaleimide
(28). Two rearranged compounds 29 and 30 were isolated,
resulting from one and two cycloaddition reactions in 18
and 24% yields, respectively, according to the proposed
mechanism (Scheme 8). In fact, a first cycloaddition reac-
tion with N-phenylmaleimide (28), followed by in situ elimi-
nation of acetic acid, could generate intermediate 32 which,
in turn, may aromatize to 29 or undergo a second cycload-
dition affording compound 30.
Molecular Modeling
As observed experimentally, aminopentadienal 7 does
not appear to be aggressive enough to react efficiently with
mild nucleophiles. This species needs to be activated by
means of the strong electrophilic agent POCl3. The re-
sulting chloro iminium compound 14 is then able to act as
an electrophile with a plethora of nucleophiles (Table 1).
The addition reactions predominantly afforded 1,2 adducts
with C-nucleophiles (Table 1, Entries 1–5). Alternatively,
acetoxy iminium compound 27, equivalent of 14, seems to
react at its carbonyl carbon atom with anionic nucleophiles.
However, 27 also behaves as a good diene partner in the
Diels–Alder reaction with N-phenylmaleimide (28) as the
dienophile (Scheme 8).
Figure 3. LUMO orbitals of 7, 14 and 27 (from top to bottom).
Mulliken charges are shown in bold/italics. Calculations were carried
out with dichloromethane as a solvent. (Number 1 has been given
to the nitrogen atom for compounds 7, 14 and 27).
To shed light on our experimental results, we carried out
a modeling study of these systems on the B98 DFT level
of theory[13] as implemented within GAMESS.[14] The 6-
31++G(dp) criterion was selected as the basis set through-
out all the modeling experiments to give a fair representa-
tion of glutaconaldehyde as its enolate form 8 (Figure 2).[15]
The Cs symmetry was imposed on the four studied mol-
ecules 7, 8, 14 and 27 with all-trans configurations to ease
the reading of orbital coefficients, particularly those of the
LUMO and HOMO Pz orbitals.[16]
Accordingly, 7 is not a good electrophile. These figures
obtained from calculations with dichloromethane as a sol-
vent, are very similar to those resulting from gas-phase
computations.[17] To account for the selectivity of addition,
the shapes of LUMO orbitals were examined. In all cases,
the empty orbital is highly delocalized mainly over three
carbon atoms (C-2, C-4 and C-6). The Pz orbitals are de-
composed into three constituents, describing internal, inter-
mediate and external contributions. The delocalization is so
well dispatched that it is difficult to pinpoint precisely
which carbon centre constitutes the preferred electrophilic
site. It is then necessary to consider another important fea-
ture of these molecules, their electronic distribution. Being
electrophiles, they are destined to react with electron-rich
molecules, like anions (Table 1). Consequently, electron-
deficient regions will be preferentially attacked by nucleo-
philes. By considering both orbital coefficients as well as
charges over the carbon atoms of interest (C-2, C-4 and C-
6), we could ascertain the following trends. First, chloro
iminium compound 14 definitely reacts through its C-2 po-
sition. Additionally, acetoxy iminium compound 27 could
undergo addition at the C-4 position. However, the ester
Figure 2. HOMO orbital of glutaconaldehyde as its enolate form 8.
Mulliken charges are shown in bold/italics. Calculations were carried
out with ethanol as a solvent.
In good agreement with the experimental data, chloro carbonyl carbon atom (C-8) is so positively charged (0.66)
iminium compound 14 was found to be the most reactive that this property could overwhelm the impact of all other
since its LUMO energy was as low as –3.54 eV (Figure 3). parameters. Attack at this position would induce cleavage
Then came acetoxy iminium compound 27 at –3.35 eV and of the enol acetate. This is indeed confirmed experimentally,
finally, aminopentadienal 7, whose LUMO energy was since 27 consistently reverts back to its aldehyde precursor
found to be only –1.52 eV.
7 when treated with various nucleophiles.
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On the other hand, 27 reacts with N-phenylmaleimide glutaconaldehyde 8ЈЈ did not yield any characterizable
(28) to give the Diels–Alder adduct 31. The pathway of this cross-coupling-derived compounds. Instead, substituted
transformation was entirely reconstructed by means of an benzaldehyde 34 corresponding per se to dimerization of
intrinsic reaction coordinate (IRC) protocol using dichloro- 8ЈЈ according to the proposed mechanism (Scheme 9) was
methane as a solvent (Figure 4)[18] Its activation energy is isolated.[20] Compound 35, a 1,6-addition adduct (see frame
rather low at 20.5 kcalmol–1 (from the s-cis conformer of in Scheme 9) of 8ЈЈ with iminium compound 14 was also
27Ј). Accordingly, the reaction is rather facile since it re- isolated from the reaction mixture. However, a crucial C–C
quires only a temperature as low as that of boiling dichloro- bond formation was also observed when one of the C5 units
methane. Only the endo trajectory was considered as it usu- was replaced by Zincke salt 9. After standing at room tem-
ally leads to the primary experimental adduct.[19] The exo perature, compound 36 was isolated with some difficulty[21]
adduct, normally less favoured, is formed following a very and was characterized as the adduct of two molecules of 9
similar path. The main goal of the study was predominantly and one molecule of 8. Furthermore, generation of 36 was
to estimate the energy profile of the reaction and its mecha- accompanied by compound 37,[22] resulting from ring open-
nism. Thus, the mechanism is concerted and asynchronous. ing of pyridinium salt 9 after the addition of a hydroxide
At the transition state, the shortest bond located at the acet- ion at C-2. Compound 36 may be formed and explained
ate end of the diene is 2.16 Å long, whereas the length of according to the mechanism presented in Scheme 10. Usu-
the longest bond undergoing formation is 2.29 Å.
ally, the pyridinium ring of the Zincke salt is attacked at
the C-2 or C-6 positions by nucleophiles with concomitant
expulsion of 2,4-dinitroaniline. However, in our case, glut-
aconaldehyde salt 8, as a soft nucleophile, reacted at the C-
4 position of the pyridinium ring. We then envision that
the enol oxygen atom of intermediate 38 attacked a second
molecule of 9 since its two nucleophilic carbon atoms were
substituted.[23] This type of nucleophilic substitution of the
pyridinium ring of the Zincke salt is uncommon with the
release of picoline instead of the 2,4-dinitroaniline. In itself
and as represented in the frame of Scheme 10, compound
36 displays the key C–C bond found in most complex man-
zamine alkaloids. However, its low rate of formation also
casts doubt on the implication of pyridinium salts acting
as electrophiles during the biosynthesis of manzamine-type
alkaloids.
Figure 4. Summary of IRC calculations of the Diels–Alder reaction
with 27Ј as diene and 28 as dienophile (endo approach). Calculations
were carried out using dichloromethane as a solvent.
Combining Aminopentadienal 7 and Glutaconaldehyde
Salt 8 and Beyond
The self- and cross-condensations of substituted C5 units
such as aminopentadienals and glutaconaldehydes are,
among others, crucial points in biomimetic approaches to
the manzamine alkaloid group.[6] Whereas both types of
units may react with electrophilic dihydropyridinium salts
(corresponding to a cyclized and partially reduced form of
aminopentadienals), the condensation of such units remains
a challenge. In our hands, reaction of chloro iminium com-
Scheme 9. Reactivity of glutaconaldehyde 8ЈЈ with chloro iminium
pound 14 (prepared with phosphorus oxychloride) with compound 14.
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5-Aminopenta-2,4-dienals: Role in Accessing Manzamine Alkaloids
Scheme 11. Reactive tool box.
turn the latter into electrophiles as demonstrated in the
present work. Dihydropyridinium salts may also act as
dienophiles and aminopentadienals (or their activated
form) may serve as dienes.
(iii) Self-condensation of glutaconaldehyde-type entities
is possible in the laboratory (see formation of compound
34) but has no obvious biosynthetic consequences to the
best of our knowledge.
The extensive tool box of reactivities generated over the
years should now be applied to in vivo studies to help illu-
minate the biosynthetic pathways responsible for such com-
plex alkaloids.
Scheme 10. Reactivity of glutaconaldehyde potassium enolate 8 with
Zincke salt 9.
Experimental Section
Conclusions
General: Reactions were monitored by thin-layer chromatography
carried out on silica gel plates (Merck TLC Silicagel 60F254) using
UV light as visualizing agent and sulfuric vanillin and heat and
Draggendorff reagent and heat as developing agents. Merck Sil-
icagel Geduran® Si 60 (particle size 40–63 μm) was used for flash
chromatography. NMR spectra were recorded in deuterated chloro-
form on AM-300 (300 MHz) or AM-400 (400 MHz) Bruker spec-
trometers and calibrated using undeuterated chloroform as an in-
ternal reference. The following abbreviations are used to explain
the multiplicities: s = singlet; d = doublet, t = triplet; q = quartet;
quint = quintet; m = multiplet; br. = broad. IR spectra were re-
corded with a Vector 22 Bruker spectrometer, and values are re-
ported in cm–1 units. Mass spectra were recorded at the Service
d’Analyse des Médicaments et des Métabolites (Université Paris-
Sud).
From the numerous and informative biomimetic stud-
ies[4–6] and from the present results of our work, it is pos-
sible to distinguish several reactive entities plausibly impli-
cated in the biosynthesis of manzamine-type alkaloids. A
selection of key elements allows us to highlight the follow-
ing points (Scheme 11) and more generally to demonstrate
the usefulness of biomimetic strategies in comprehending
potential mechanistic steps at play during the biosynthesis
of natural substances.
(i) The entities acting predominantly as strong electro-
philes in biosynthetic pathways should be dihydropyridin-
ium salts: general reactivity constraints should allow easy
functionalization in vivo.
(ii) Glutaconaldehydes and aminopentadienals appear to
(2E,4E)-5-(Dimethylamino)-2-methylpenta-2,4-dienal (7): Adapted
serve as good nucleophiles. Strong activation is needed to from Michel et al.[8] To a stirred solution of Zincke salt 9 (10.0 g,
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33.8 mmol) in a mixture of EtOH/H2O (1:1) (100 mL) at reflux,
N-Methyl-N-[(2E)-4-methyl-5-(trimethylsilyloxy)penta-2,4-dienyl-
dimethylamine (9.30 mL, 40% in H2O, 73.8 mmol) was added idene]methanaminium Trifluoromethanesulfonate (11): To a solution
dropwise. After 1 h of stirring at reflux, the mixture was concen-
trated under reduced pressure, and water (150 mL) was added. The
precipitated brown 2,4-dinitroaniline was then removed by fil-
tration through a pad of Celite®. The filtrate was extracted with
CH2Cl2 (4ϫ 60 mL), and the combined organic layers were dried
with MgSO4 and concentrated in vacuo to give aminopentadienal 7
of aminopentadienal 7 in CDCl3 (previously filtered through
K2CO3) was added one drop of TMSOTf in an NMR tube. Two
isomers A and B were observed (ratio 60:40). Isomer A (major):
3
1H NMR (300 MHz, CDCl3): δ = 8.42 (d, JH,H = 11.1 Hz,
3
1 H, CH=N), 7.78 (d, JH,H = 13.8 Hz, 1 H, CH), 7.29 (s, 1 H,
3
CHOSiMe3), 6.14 (dd, JH,H = 13.8, 11.1 Hz, 1 H, CH), 3.59 (s, 3
(4.24 g, 90%) as an orange solid. M.p. 56 °C. 1H NMR (400 MHz,
H, CH3N), 3.38 (s, 3 H, CH3N), 1.79 (s, 3 H, CH3), 0.05 (s, 9 H,
3
1
CDCl3): δ = 9.17 (s, 1 H, CHO), 6.84 (d, JH,H = 11.6 Hz, 1 H, SiMe3) ppm. Isomer B: H NMR (300 MHz, CDCl3): δ = 8.22 (d,
3
3
CH), 6.77 (d, JH,H = 12.4 Hz, 1 H, =CHN), 5.25 (dd, JH,H
=
3JH,H = 11.1 Hz, 1 H, CH=N), 7.61 (d, 3JH,H = 13.8 Hz, 1 H, CH),
7.54 (s, 1 H, CHO), 6.03 (dd, 3JH,H = 13.8, 11.1 Hz, 1 H, CH), 3.53
(s, 3 H, CH3N), 3.33 (s, 3 H, CH3N), 1.78 (s, 3 H, CH3), 0.31 (s, 9
H, SiMe3) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.7 (CH),
167.6 (CH), 167.5 (CH), 166.6 (CH), 165.0 (CH), 161.7 (CH), 121.0
(CIV), 116.9 (CIV), 109.6 (CH, A), 107.7 (CH, B), 48.1 (CH3N, A),
47.7 (CH3N, B), 39.9 (CH3N, A), 39.5 (CH3N, B), 8.6 (CH3, A),
8.3 (CH3, B), 1.9 (CH3Si, A), –0.6 (CH3Si, B) ppm. IR (film,
12.4, 12.0 Hz, 1 H, CH), 2.96 (s, 6 H, 2 CH3), 1.76 (s, 3 H, CH3)
ppm. 13C NMR (100 MHz, CDCl3): δ = 192.7 (CHO), 153.4 (CH),
151.2 (=CHN), 126.2 (CIV), 95.0 (CH), 9.1 (CH3) ppm. IR (film,
CH Cl ): ν
= 1543 (ν C=O) cm–1. MS (APCI): m/z = 140 [M +
˜
max
2
2
H]+. HRMS (ESI): calcd. for C8H14NO 140.1075 [M + H]+; found
140.1078. Rf = 0.62 (CH2Cl2/MeOH, 9:1).
(2E,4E)-5-Hydroxy-2-methylpenta-2,4-dienal Potassium Salt (8):[8]
Potassium hydroxide (2.01 g, 30 mmol) was dissolved in a minimum
of MeOH under N2; then dry THF (75 mL) and aminopentadienal
7 (4.24 g, 30 mmol) were added. The mixture was stirred at reflux
for 6 h, then cooled in an ice bath (–5 °C), and Et2O (130 mL) was
added. After 30 min of stirring, the brown precipitate was filtered
and rinsed with CH2Cl2. The solid was dissolved in absolute EtOH
(200 mL), cooled to –10 °C for 30 min and filtered through a pad
of Celite®. The filtrate was concentrated in vacuo to give the potas-
sium salt of glutaconaldehyde 8 (3.20 g, 70%) as a beige powder.
CHCl ): νmax = 1616, 1576 (C=N), 1280, 1164 cm–1. MS (ESI): m/z
˜
3
= 154 [M – OTf – OSiMe3 + OMe]+.
N-[(2E)-5-(tert-Butyldimethylsilyloxy)-4-methylpenta-2,4-dienyl-
idene]-N-methylmethanaminium Trifluoromethanesulfonate (12): To
a solution of aminopentadienal 7 in CDCl3 (previously filtered
through K2CO3) was added one drop of TBDMSOTf in an NMR
tube. Two isomers A and B were observed (ratio 67:33). Isomer A:
3
1H NMR (300 MHz, CDCl3): δ = 8.51 (d, JH,H = 11.1 Hz, 1 H,
3
CH=N), 7.83 (d, JH,H = 13.8 Hz, 1 H, CH), 7.32 (s, 1 H, CH),
M.p. Ͼ400 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 8.65 (d,
6.13 (dd, JH,H = 13.8, 11.1 Hz, 1 H, CH), 3.61 (s, 3 H, CH3N),
3
3
3JH,H = 9.2 Hz, 1 H, =CHO), 8.55 (s, 1 H, CHO), 6.90 (d, JH,H
=
3.39 (s, 3 H, CH3N), 1.81 (s, 3 H, CH3), 0.95 [s, 9 H, C(CH3)3], 0.28
3
1
13.0 Hz, 1 H, CH), 5.07 (dd, JH,H = 13.0, 9.2 Hz, 1 H, CH), 1.48 [s, 6 H, Si(CH3)2] ppm. Isomer B: H NMR (300 MHz, CDCl3): δ
(s, 3 H, CH3) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 183.3 = 8.26 (d, 3JH,H = 10.8 Hz, 1 H, CH=N), 7.65 (d, 3JH,H = 13.8 Hz,
3
(CHO), 183.2 (CHO), 158.6 (CH), 110.8 (CIV), 103.6 (CH), 9.5 1 H, CH), 7.59 (s, 1 H, CH), 6.01 (dd, JH,H = 13.8, 10.8 Hz, 1 H,
(CH ) ppm. IR (solid): ν
= 1504 (ν C=O) cm–1. HRMS (ESI): CH), 3.54 (s, 3 H, CH3N), 3.33 (s, 3 H, CH3N), 1.79 (s, 3 H, CH3),
˜
3
max
calcd. for C6H7O2 111.0446 [M – K]; found 111.0437.
0.86 [s, 9 H, C(CH3)3], 0.01 [s, 6 H, Si(CH3)2] ppm. Isomers A and
B: 13C NMR (75 MHz, CDCl3): δ = 168.8 (CH), 167.0 (CH), 162.2
(CH), 122.6 (CIV, A or B), 120.8 (CIV, A or B), 109.6 (CH), 48.1
(CH3N), 39.9 (CH3N), 25.7 and 25.2 [(CH3)3C-Si], 18.0 [C(CH3)3],
1-(2,4-dinitrophenyl)-3-methylpyridinium Chloride (Zincke Salt
9):[24] To
a solution of 1-chloro-2,4-dinitrobenzene (21.7 g,
107 mmol) in acetone (100 mL), 3-picoline (10.5 mL, 107 mmol)
was added, and the reaction mixture was stirred at reflux for 12 h.
After cooling at room temperature, filtration and rinsing with acet-
one gave the expected compound (27.8 g, 87%) as a purple powder.
8.6 (CH ), –3.0 (CH Si), –5.4 (CH Si) ppm. IR (film, CHCl ): ν
˜
max
3
3
3
3
= 1615, 1582 (C=N), 1193, 1163 cm–1. MS (ESI): m/z = 154 [M –
OTf – OTBDMS + OMe]+.
1
4
M.p. 206–207 °C. H NMR (400 MHz, D2O): δ = 9.40 (d, JH,H
=
N-[(2E,4E)-5-Methoxy-4-methylpenta-2,4-dienylidene]-N-methyl-
3
2.4 Hz, 1 H, CH), 9.03 (s, 1 H, CH), 8.98 (d, JH,H = 6.6 Hz, 1 H, methanaminium Trifluoromethanesulfonate (13): To a solution of
3
4
CH), 8.94 (dd, JH,H = 8.8, JH,H = 2.4 Hz, 1 H, CH), 8.76 (d,
aminopentadienal 7 in CDCl3 (previously treated with K2CO3) was
3JH,H = 8.0 Hz, 1 H, CH), 8.25 (dd, 3JH,H = 8.0, 6.6 Hz, 1 H, CH), added one drop of MeOTf in an NMR tube. H NMR (300 MHz,
1
8.22 (d, JH,H = 8.8 Hz, 1 H, CH), 2.67 (s, 3 H, CH3) ppm. 13C
CDCl3): δ = 8.34 (d, JH,H = 10.8 Hz, 1 H, CH=N), 7.74 (d, JH,H
3
3
3
3
NMR (75 MHz, D2O): δ = 149.6 (CH), 149.5 (CNO2), 144.5 (CH),
= 14.0 Hz, 1 H, CH), 7.17 (s, 1 H, CHOCH3), 6.11 (dd, JH,H
=
142.9 (CNO2), 142.5 (CH), 140.5 (CMe), 138.7 (CIV), 131.1 (CH),
14.0, 10.8 Hz, 1 H, CH), 3.79 (s, 3 H, OCH3), 3.56 (s, 3 H, CH3N),
130.5 (CH), 127.6 (CH), 122.7 (CH), 17.8 (CH3) ppm. IR (film, 3.37 (s, 3 H, CH3N), 1.77 (s, 3 H, CH3) ppm. 13C NMR (75 MHz,
CHCl ): ν
= 1531 (NO2), 1345 (NO2) cm–1. MS (ESI): m/z = CDCl3): δ = 168.4 (CH), 168.0 (CHOCH3), 166.2 (CH), 117.1
˜
3
max
259 [M]+.
(CIV), 109.3 (CH), 62.7 (OCH3), 48.0 (CH3N), 39.8 (CH3N), 8.7
(CH ) ppm. IR (film, CHCl ): ν = 1605, 1572 (C=N), 1193,
˜
max
3
3
(3E,5E)-2-(Dimethylamino)-5-methyl-6-(trimethylsilyloxy)hexa-3,5-
dienenitrile (10): To a solution of aminopentadienal 7 in CDCl3
1142 (C=C–OCH3) cm–1. MS (APCI): m/z = 154 [M – OTf]+.
(previously filtered through K2CO3) was added one drop of
N-[(2E,4E)-5-Chloro-4-methylpenta-2,4-dienylidene]-N-methylmeth-
1
TMSCN in an NMR tube. H NMR (300 MHz, CDCl3): δ = 6.49 anaminium Dichlorophosphate (14): To a solution of aminopen-
(s, 1 H, CHOSiMe3), 6.44 (d, 3JH,H = 16.0 Hz, 1 H, CH), 5.32 (dd, tadienal 7 in CDCl3 was added one drop of phosphorus oxy-
3
1
3JH,H = 16.0, 4.5 Hz, 1 H, CH), 4.31 (d, JH,H = 4.5 Hz, 1 H,
chloride (POCl3) in an NMR tube. H NMR (300 MHz, CDCl3):
3
3
CHCN), 2.31 [s, 6 H, (CH3)2N], 1.70 (s, 3 H, CH3), 0.21 (s, 9 H,
δ = 8.77 (d, JH,H = 10.5 Hz, 1 H, CH=N), 7.78 (d, JH,H =
SiMe3) ppm. 13C NMR (75 MHz, CDCl3): δ = 143.2 (CHOSiMe3),
14.4 Hz, 1 H, CH), 7.11 (s, 1 H, CHCl), 6.53 (dd, JH,H = 14.4,
3
135.5 (CH), 116.7 (CIV), 116.2 (CH), 115.1 (CN), 60.8 (CHCN), 10.5 Hz, 1 H, CH), 3.76 (s, 3 H, CH3N), 3.58 (s, 3 H, CH3N), 2.07
41.5 [(CH3)2N], 9.3 (CH3), –0.5 (SiMe3) ppm. IR (film, CHCl3):
(s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.7
(CH=N), 161.3 (CH), 138.2 (CHCl), 137.4 (CIV), 115.9 (CH), 49.5
ν
max
= 1255, 1183 cm–1. MS (APCI): m/z = 239 [M + H]+, 212
˜
[M – CN]+.
(CH N), 41.5 (CH N), 12.4 (CH ) ppm. IR (film, CHCl ): ν
=
˜
3
3
3
3
max
4980
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4973–4984

5-Aminopenta-2,4-dienals: Role in Accessing Manzamine Alkaloids
1657, 1599 (C=N), 1227, 1069 (C–Cl) cm–1. HRMS (ESI): calcd. anol (0.2 mL, 1.08 mmol) was added, and the reaction mixture was
for C8H13ClN 158.0731 [M – OPOCl2]+; found 158.0731.
stirred at room temperature for 24 h after which a mixture of 2,4-
pentanedione (0.15 mL, 1.44 mmol) and DBU (0.22 mL,
1.44 mmol) in CH2Cl2 was added. After 6 d of stirring, the reaction
mixture was concentrated in vacuo. The oily residue was then puri-
fied by flash chromatography on silica gel with a gradient solvent
system (cyclohexane/ethyl acetate, 9:1 to 7:3) to afford compound
Compound 15: To a solution of aminopentadienal 7 (100 mg,
0.719 mmol) in dry dichloromethane (5 mL) was added phos-
phorus oxychloride (0.07 mL, 0.719 mmol) at 0 °C under N2. After
stirring for 10 min, a 2 m isopropylmagnesium chloride solution in
THF (0.36 mL, 0.720 mmol) was added, and the reaction mixture
was stirred at room temperature for 24 h after which additional
isopropylmagnesium chloride (0.72 mL, 1.44 mmol) was added. Af-
ter 2 d of stirring, water (5 mL) and brine (5 mL) were slowly
added. The layers were separated, and the aqueous layer was ex-
tracted with CH2Cl2 (2ϫ 20 mL). The combined organic phases
were dried with MgSO4 and concentrated in vacuo. The oily residue
was then purified by flash chromatography on silica gel with a gra-
dient solvent system (CH2Cl2 to CH2Cl2/MeOH, 95:5 to 90:10) to
afford compound 15 (26 mg, 18 %) as an orange oil. 1H NMR
1
17 (56 mg, 37%) as an orange oil. H NMR (400 MHz, CDCl3): δ
3
3
= 7.06 (d, JH,H = 10.8 Hz, 1 H, CH), 6.69 (d, JH,H = 15.2 Hz, 1
3
H, CH), 6.61 (dd, JH,H = 15.2, 10.8 Hz, 1 H, CH), 6.43 (s, 1 H,
CCl), 2.37 (s, 3 H, MeCO), 2.36 (s, 3 H, MeCO), 1.95 (s, 3 H,
CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 202.8 (COMe), 197.0
(COMe), 144.1 (CH), 142.3 (CH), 141.8 (CIV), 137.2 (CIV), 126.3
(CHCl), 123.7 (CH), 31.7 (MeCO), 26.4 (MeCO), 12.7 (CH3) ppm.
IR (film, CHCl ): ν
= 1698, 1656, 1602, 1558, 1229 cm–1
.
˜
3
max
HRMS (ESI): calcd. for C11H13ClNaO2 235.0502 [M + Na]+;
found 235.0493. Rf = 0.27 (cyclohexane/ethyl acetate, 7:3).
3
(400 MHz, CDCl3): δ = 6.32 (d, JH,H = 15.6 Hz, 1 H, CH), 6.29
(s, 1 H, CHCl), 5.62 (dd, 3JH,H = 15.2, 9.6 Hz, 1 H, CH), 3.26 (dd,
Compound 18: To a solution of aminopentadienal 7 (100 mg,
0.719 mmol) in dry dichloromethane (5 mL) was added phos-
3JH,H = 10.0, 6.4 Hz, iPrCHCH=), 2.73 [s, 6 H, (CH3)2N], 2.20 [m,
3
1 H, CH(CH3)2], 1.94 (s, 3 H, CH3), 1.10 (d, JH,H = 6.8 Hz, 3 H, phorus oxychloride (0.067 mL, 0.719 mmol) at 0 °C under N2. Af-
3
CH3CH), 1.04 (d, JH,H = 6.8 Hz, 3 H, CH3CH) ppm. 13C NMR ter stirring for 10 min, dimethyl 1,3-acetonedicarboxylate (150 mg,
(100 MHz, CDCl3): δ = 139.6 (CH), 135.3 (CIV), 123.5 (CHCl), 0.863 mmol) was added, and the reaction mixture was stirred at
118.2 (CH), 75.1 (iPrCHCH=), 41.2 [(CH3)2N], 28.8 [CH(CH3)2], room temperature for 23 h after which a mixture of dimethyl 1,3-
20.7 (CH3CH), 18.1 (CH3CH), 12.9 (CH3) ppm. HRMS (ESI): acetonedicarboxylate (150 mg, 0.863 mmol) and DBU (0.130 mL,
calcd. for C11H21ClN 202.1363 [M + H]+; found 202.1363. Rf = 0.863 mmol) was added. After 6 d of stirring, the reaction mixture
0.45 (CH2Cl2/MeOH, 9:1).
was concentrated in vacuo. The oily residue was then purified by
flash chromatography on silica gel with a gradient solvent system
(cyclohexane/ethyl acetate, 9:1 to 8:2) to afford compound 18
(24 mg, 12%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ =
7.50 (d, 3JH,H = 11.6 Hz, 1 H, CH), 7.01 (dd, 3JH,H = 14.8, 11.6 Hz,
1 H, CH), 6.77 (d, 3JH,H = 14.8 Hz, 1 H, CH), 6.50 (s, 1 H, CHCl),
3.86 (s, 3 H, OMe), 3.81 (s, 2 H, CH2), 3.72 (s, 3 H, OMe), 1.98 (s,
3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 193.8 (CO),
167.9 (2 COOMe), 148.2 (CH), 146.8 (CH), 137.5 (CIV), 137.4
(CIV), 127.0 (CHCl), 124.2 (CH), 52.2 (MeO), 49.3 (MeO), 47.5
Compound 16: To a solution of aminopentadienal 7 (100 mg,
0.719 mmol) in dry dichloromethane (5 mL) was added phos-
phorus oxychloride (0.07 mL, 0.719 mmol) at 0 °C under N2. After
stirring for 10 min, a mixture of methyl acetoacetate (0.08 mL,
0.741 mmol) and a 30% (w/w) sodium methoxide solution in meth-
anol (0.20 mL, 1.08 mmol) was added, and the reaction mixture
was stirred at room temperature for 22 h after which a mixture
of methyl acetoacetate (0.16 mL, 1.44 mmol) and DBU (0.22 mL,
1.44 mmol) in CH2Cl2 was added. After 4 d of stirring, the reaction
mixture was concentrated in vacuo. The oily residue was then puri-
fied by flash chromatography on silica gel with a gradient solvent
system (cyclohexane/ethyl acetate, 9:1 to 7:3) to afford compound
16 (59 mg, 36%) as a yellow oil. A mixture of 2 isomers A and B
with a ratio 70:30 in favour of isomer A and for each isomer, two
forms are observed by NMR spectroscopy, leading to a mixture
(CH ), 12.7 (CH ) ppm. IR (film, CHCl ): ν = 1712 (C=O),
˜
max
2
3
3
1593 (C=O), 1548, 1237 cm– 1 . HRMS (ESI): calcd. for
C13H15O5ClNa 309.0506 [M + Na]+; found 309.0503. Rf = 0.72
(cyclohexane/AcOEt, 5:5).
Compound 19: To a solution of aminopentadienal 7 (100 mg,
0.719 mmol) in dry dichloromethane (5 mL) was added phos-
phorus oxychloride (0.067 mL, 0.719 mmol) at 0 °C under N2. Af-
ter stirring for 10 min, Meldrum’s acid (124 mg, 0.863 mmol) was
1
of 4 geometric isomers in a ratio of 0.35:0.35:0.15:0.15. H NMR
(400 MHz, CDCl3): δ = 7.31–7.44 (m, 0.3 H, CH, B), 7.29–7.35 (m,
0.7 H, CH, A), 7.26–7.35 (m, 0.3 H, CH, B), 6.66–6.74 (m, 0.7 H, added, and the reaction mixture was stirred at room temperature
CH, A), 6.66–6.87 (m, 1 H, CH, A and B), 6.44 (s, 0.35 H, CHCl, for 24 h after which additional Meldrum’s acid (124 mg,
A), 6.42 (s, 0.35 H, CHCl, A), 6.21 (s, 0.15 H, CHCl, B), 6.19 (s, 0.863 mmol) was added. After 6 d of stirring, the reaction mixture
0.15 H, CHCl, B), 3.88 (s, 3 H, OMe, A), 3.83 (s, 0.9 H, OMe, B),
3.82 (s, 2.1 H, OMe, B), 2.43 (s, 3 H, CH3CO, A), 2.39 (s, 0.9 H,
was concentrated in vacuo. The oily residue was then purified by
flash chromatography on silica gel with a gradient solvent system
CH3CO, B) 2.37 (s, 2.1 H, CH3CO, B), 1.97 (s, 1.05 H, CH3, A), (cyclohexane/ethyl acetate, 9:1 to 7:3) to afford compound 19
1
1.96 (s, 1.05 H, CH3, A), 1.94 (s, 0.45 H, CH3, B), 1.92 (s, 0.45 H, (115 mg, 62%) as a yellow powder. H NMR (400 MHz, CDCl3):
3
3
CH3, B) ppm. 13C NMR (100 MHz, CDCl3): δ = 200.1 (COMe),
δ = 8.04 (d, JH,H = 12.0 Hz, 1 H, CH), 7.77 (dd, JH,H = 14.8,
3
195.4 (COMe), 166.6 (COOMe), 165.7 (COOMe), 145.1 (CH), 12.0 Hz, 1 H, CH), 7.02 (d, JH,H = 15.2 Hz, 1 H, CH), 6.68 (s, 1
144.9 (CH), 137.3 (CIV), 134.0 (CIV), 132.4 (CIV), 131.7 (CIV), 126.2
H, CHCl), 2.07 (s, 3 H, CH3), 1.74 (s, 6 H, 2 CH3) ppm. 13C NMR
(CHCl), 123.8 (CH), 121.7 (CHCl) 55.2 (MeO), 31.1 (MeCO), 12.7 (100 MHz, CDCl3): δ = 162.8 (CO), 160.5 (CO), 157.3 (CH), 152.8
(CH ) ppm. IR (film, CHCl ): νmax = 1716, 1234 cm–1. MS (APCI):
(CH), 138.0 (CIV), 131.0 (CHCl), 125.0 (CH), 112.0 (CIV), 104.8
˜
3
3
m/z = 229 [M + H]+, 197 [M – OMe]+. Rf = 0.51 and 0.38 (cyclo-
(CIV), 27.7 (2 CH ), 12.8 (CH ) ppm. IR (film, CHCl ): ν
=
˜
3
3
3
max
hexane/ethyl acetate, 7:3).
1724 (C=O), 1587, 1550, 1172 cm–1. HRMS (ESI): calcd. for
C24H26Cl2NaO8 535.0902 [2M + Na]+; found 535.0908. Rf = 0.80
(cyclohexane/ethyl acetate, 9:1).
Compound 17: To a solution of aminopentadienal 7 (100 mg,
0.719 mmol) in dry dichloromethane (5 mL) was added phos-
phorus oxychloride (0.07 mL, 0.719 mmol) at 0 °C under N2. After
stirring for 10 min, a mixture of 2,4-pentanedione (0.11 mL,
1.08 mmol) and a 30% (w/w) sodium methoxide solution in meth-
Compound 21: To a solution of aminopentadienal 7 (208.5 mg,
1.5 mmol) in dry CH2Cl2 (2 mL) was added POCl3 (0.14 mL,
1.5 mmol) at 0 °C under N2. After stirring for 10 min, N-benzyl-α-
Eur. J. Org. Chem. 2014, 4973–4984
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4981

L.-H. Yan, A. Skiredj, Y. Dory, B. Delpech, E. Poupon
FULL PAPER
cyanopiperidine 20 (100 mg, 0.5 mmol) and silver tetrafluoroborate
(CH=N), 166.0 (C=O), 163.2 (CH), 148.7 (=CHO), 120.4 (CIV),
(97 mg, 0.5 mmol) were successively added. The reaction mixture 115.1 (CH), 48.8 (CH3N), 41.0 (CH3N), 20.4 (CH3CO), 9.8 (CH3)
was stirred at room temperature for 20 h without any change ob-
served by TLC. Silver tetrafluoroborate (97 mg, 0.5 mmol) was
then added again, and the reaction mixture was stirred at 80 °C for
7 h after which additional silver tetrafluoroborate (97 mg,
0.5 mmol) was added. The reaction mixture was stirred at 80 °C
for additional 17 h. After cooling to room temperature, the silver
tetrafluoroborate excess and silver nitrate were removed through a
pad of Celite®. The filtrate was concentrated under reduced pres-
sure. The oily residue was then purified by flash chromatography
on silica gel (CH2Cl2/MeOH, 99:1 to 90:10) to afford compound
ppm. IR (film, CHCl ): ν
= 1763 (C=O), 1661, 1617 (C=N),
˜
3
max
1170, 1137 (C–O) cm–1. MS (ESI): m/z = 182 [M – Cl]+. HRMS
(ESI): calcd. for C10H16NO2 182.1176 [M]+; found 182.1177.
Compounds 29 and 30: To a solution of aminopentadienal 7
(200 mg, 1.44 mmol) in dry CH2Cl2 (4 mL) was added acetyl chlor-
ide (0.11 mL, 1.58 mmol) at 0 °C under N2. After 25 min, N-phen-
ylmaleimide (28) (274 mg, 1.58 mmol) was added, and the reaction
mixture was stirred at room temperature for 24 h and then at reflux
for 26 h without any change observed on TLC. The reaction mix-
ture was then stirred at room temperature until disappearance of
the iminium compound and concentrated under reduced pressure.
The crude mixture was purified by flash chromatography on silica
gel (CH2Cl2 to CH2Cl2/MeOH, 99:1 to 90:10) to afford compound
30 (151 mg, 43% relative to 28) as a beige powder and compound
29 (78 mg, 18%) as a brown residue. 30: 1H NMR (400 MHz,
CDCl3): δ = 10.1 (s, 1 H, CHO), 7.38–7.45 (m, 6 H, Ph), 7.10–7.14
(m, 4 H, Ph), 6.37 (s, 1 H, CH=C), 3.83 (m, 1 H, CH), 3.55 (d,
1
21 (51 mg, 27%) as an orange oil. H NMR (400 MHz, CDCl3): δ
3
= 8.75 (s, 1 H, CH=N), 7.46 (d, JH,H = 12.0 Hz, 1 H, CH), 7.38–
3
7.48 (m, 5 H, CH Ph), 6.88 (d, JH,H = 14.7 Hz, 1 H, CH), 6.53
3
(dd, JH,H = 14.7, 12.0 Hz, 1 H, CH), 6.53 (s, 1 H, CHCl), 4.99 (s,
3
2 H, CH2Ph), 3.59 (t, JH,H = 6.0 Hz, 2 H, CH2N), 2.55 (quint,
3JH,H = 6.0 Hz, 2 H, CH2CH2N), 1.92–1.96 (m, 2 H, CH2CIV), 1.94
(s, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 167.8
(CH=N), 155.4 (CH), 148.2 (CH), 137.3 (CIV), 131.3 (CIV Ph),
129.7 (CHCl), 129.6 (CH, Ph), 129.5 (CH, Ph), 129.4 (CH, Ph),
127.6 (CIV), 122.7 (CH), 64.0 (CH2Ph), 48.7 (CH2N), 20.2
(CH2CH2N), 19.0 (CH2CIV), 12.5 (CH3) ppm. IR (film, CHCl3):
3JH,H = 8.4 Hz, 2 H, 2 CHC=O), 3.29 (dd, JH,H = 8.4, 3.2 Hz, 2
3
H, 2 CHC=O), 1.92 (d, 3JH,H = 1.6 Hz, 3 H, CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 197.5 (CHO), 174.8 (2 NC=O), 174.0 (2
NC=O), 142.2 (=CMe), 131.1 (CIV, Ph), 129.2 (CH, Ph), 129.0
(CH, Ph), 126.1 (CH, Ph), 119.8 (=CHCH), 52.4 (CCHO), 46.1 (2
CHC=O), 43.0 (2 CHC=O), 40.2 (CH), 21.7 (CH3) ppm. IR (film,
ν
= 1584 (C=N) cm–1. HRMS (ESI): calcd. for C18H21ClN
˜
max
286.1363 [M – BF4]+; found 286.1364. Rf = 0.39 (CH2Cl2/MeOH,
9:1).
CHCl ): νmax = 1707 (C=O) cm–1. MS (ESI): m/z = 479 [M + K]+.
˜
3
Compound 23: To a solution of N-benzyl-α-cyanopiperidine (20)
(100 mg, 0.5 mmol) in CH2Cl2 (5 mL) were successively added ami-
nopentadienal 7 (208 mg, 1.5 mmol) and silver tetrafluoroborate
(195 mg, 1 mmol). The reaction mixture was stirred at 80 °C for
20 h. After filtration through a pad of Celite®, the filtrate was con-
centrated under reduced pressure and the residue purified by flash
chromatography on silica gel (CH2Cl2 to CH2Cl2/MeOH, 99:1 to
95:5) followed by a second flash chromatography (CH2Cl2/AcOEt,
95:5) to afford compound 23 (9 mg, 5%) as an orange residue and
Rf = 0.69 (CH2Cl2/MeOH, 9:1). 29: 1H NMR (400 MHz, CDCl3): δ
= 7.87 (s, 1 H, CH), 7.83 (s, 1 H, CH), 7.40–7.53 (m, 5 H, Ph),
4.71 (s, 2 H, CH2N), 2.85 [s, 6 H, (CH3)2N], 2.56 (s, 3 H, CH3)
ppm. 13C NMR (100 MHz, CDCl3): δ = 167.8 (C=O), 166.1
(C=O), 147.5 (CMe), 138.4 (CH), 132.7 (CC=O), 131.1 (CIV, Ph),
129.2 (CH, Ph), 128.4 (CH, Ph), 128.3 (CIV), 127.6 (CC=O), 126.4
(CH), 54.3 (CH2N), 42.8 [(CH3)2N], 22.1 (CH3) ppm. IR (film,
CHCl ): ν
= 1713 (ν C=O) cm–1. HRMS (ESI): calcd. for
˜
3
max
C18H19N2O2 295.1441 [M + H]+; found 295.1443. Rf = 0.49
1
aminopentadiene iuminum compound 22 (41 mg, 32%).[25] 23: H
(CH2Cl2/MeOH, 9:1).
NMR (400 MHz, CDCl3): δ = 9.94 (s, 1 H, CHO), 9.18 (s, 1 H,
(2E,2ЈE,4E,4ЈE)-5,5Ј-Oxybis(4-methylpenta-2,4-dienal) (35). Prepa-
ration of Glutaconaldehyde (8ЈЈ): To a solution of potassium gluta-
conaldehyde enolate (8) (200 mg, 1.33 mmol) in a biphasic mixture
AcOEt/H2O (1:1) (6 mL) was added dropwise, under vigorous stir-
ring, an aqueous solution of HCl (5 n) until pH was 1 reached.
After additional stirring at room temperature for 15 min, the or-
ganic phase was collected, dried with MgSO4 and concentrated in
vacuo to yield glutaconaldehyde (8ЈЈ) (135 mg, 90%) as an orange
solid. Preparation of Iminium Compound 14: To a solution of
aminopentadienal 7 (100 mg, 0.719 mmol) in dry CH2Cl2 (5 mL)
was added POCl3 (0.067 mL, 0.719 mmol) at 0 °C under N2. After
stirring for 20 min, a solution of glutaconaldehyde (8ЈЈ) (135 mg,
1.21 mmol) in dry CH2Cl2 (0.5 mL) was added, and the reaction
mixture was stirred at room temperature for 5 d. Acetic acid
(0.041 mL, 0.719 mmol) was added, and, after stirring for an ad-
ditional 26 h, a basic medium was obtained by addition of a satu-
rated aqueous K2CO3 solution followed by water (5 mL). The lay-
ers were separated, and the aqueous layer was extracted with
CH2Cl2 (2ϫ 10 mL). The combined organic phases were dried with
MgSO4 and concentrated in vacuo. The oily residue was then puri-
fied by flash chromatography on silica gel (cyclohexane/CH2Cl2,
5:5 to 3:7) then CH2Cl2 and CH2Cl2/MeOH, 98:2) to afford “di-
meric” glutaconaldehyde 35 (34 mg, 23%) as a yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 9.58 (d, 3JH,H = 7.6 Hz, 2 H, 2 CHO), 7.09
CHO), 7.53 (s, 1 H, CH Ar), 7.45 (s, 1 H, CH Ar), 7.31–7.38 (m,
3
5 H, CH Ph), 7.21 (br. s, 1 H, CH Ar), 6.88 (d, JH,H = 13.2 Hz, 1
3
3
H, =CHN), 6.84 (d, JH,H = 13.2 Hz, 1 H, CH), 5.31 (t, JH,H
=
3
13.2 Hz, 1 H, CH), 4.39 (s, 2 H, CH2Ph), 3.22 (t, JH,H = 7.2 Hz,
3
2 H, CH2N), 2.65 (t, JH,H = 7.6 Hz, 2 H, CH2Ar), 2.40 (s, 3 H,
CH3Ar), 1.92 (quint, 3JH,H = 7.6 Hz, 2 H, CH2), 1.68 (s, 3 H, CH3)
ppm. 13C NMR (100 MHz, CDCl3): δ = 192.7 (CHO), 192.4
(CHO), 153.2 (CH), 150.1 (NCH), 141.7 (CIV, Ar), 139.2 (CIV, Ar),
136.8 (CIV, Ar), 136.2 (CIV, Ph), 135.3 (CH, Ar), 128.9 (2 CH),
128.0 (CH, Ph), 127.3 (CH, Ph), 126.7 (CIV), 126.2 (CH, Ar), 95.4
(CH), 55.0 (CH2Ph), 50.0 (CH2N), 32.6 (CH2), 28.0 (CH2), 21.1
(CH ), 9.1 (CH ) ppm. IR (film, CHCl ): νmax = 1573 (C=O) cm–1.
˜
3
3
3
HRMS (ESI): calcd. for C24H28NO2 362.2120 [M + H]+; found
362.2132. Rf = 0.36 (cyclohexane/AcOEt, 5:5).
N-[(2E,4E)-5-Acetoxy-4-methylpenta-2,4-dienylidene]-N-methyl-
methanaminium Chloride (27): To a solution of aminopentadienal
7 (100 mg, 0.72 mmol) in a mixture of CH2Cl2/Et2O (0.6 mL/4 mL)
was slowly added acetyl chloride (56 μL, 0.79 mmol) at 0 °C. The
reaction mixture was stirred for 30 min and placed in a freezer over-
night. Filtration followed by rinsing with Et2O gave iminium chlor-
ide 27 (116 mg, 89%) as a yellow powder. 1H NMR (300 MHz,
3
CDCl3 basified with K2CO3): δ = 9.77 (d, JH,H = 10.2 Hz, 1 H,
3
CH=N), 8.05 (d, JH,H = 14.4 Hz, 1 H, CH), 7.95 (s, 1 H, CHO),
3
6.52 (dd, JH,H = 14.4, 10.2 Hz, 1 H, CH), 3.88 (s, 3 H, CH3N), (d, 3JH,H = 15.6 Hz, 2 H, 2 CH), 6.64 (s, 2 H, 2 = CHO), 6.21 (dd,
3.58 (s, 3 H, CH3N), 2.26 (s, 3 H, CH3CO), 1.94 (s, 3 H, CH3)
3JH,H = 15.6, 7.6 Hz, 2 H, 2 CHCHO), 1.98 (s, 6 H, 2 CH3) ppm.
13C NMR (75 MHz, CDCl3): δ = 193.2 (2 CHO), 151.2 (2 CH),
ppm. 13C NMR (75 MHz, CDCl3 basified with K2CO3): δ = 170.5
4982
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Eur. J. Org. Chem. 2014, 4973–4984

5-Aminopenta-2,4-dienals: Role in Accessing Manzamine Alkaloids
[4]
[5]
See among others: a) J. E. Baldwin, R. C. Whitehead, Tetrahe-
dron Lett. 1992, 33, 2059–2062; b) J. E. Baldwin, T. D. W. Clar-
idge, A. J. Culshaw, F. A. Heupel, V. Lee, D. R. Spring, R. C.
Whitehead, Chem. Eur. J. 1999, 5, 3154–3161.
See among others: a) A. Kaiser, X. Billot, A. Gateau-Olesker,
C. Marazano, B. C. Das, J. Am. Chem. Soc. 1998, 120, 8026–
8034; b) K. Jakubowicz, K. Ben Abdeljelil, M. Herdemann,
M.-T. Martin, A. Gateau-Olesker, A. Al Mourabit, C. Maraz-
ano, B. C. Das, J. Org. Chem. 1999, 64, 7381–7387; for alterna-
tive approaches to 3-alkylpyridinium compounds, see: R. La-
ville, O. P. Thomas, F. Berrué, F. Reyes, P. Amade, Eur. J. Org.
Chem. 2008, 121–125.
136.3 (2 CIV), 128.8 (4 CH), 12.7 (2 CH3) ppm. Rf = 0.43 (cyclohex-
ane/CH2Cl2, 3:7).
Compound 36: To a solution of Zincke salt 9 (1.2 g, 4.06 mmol) in
EtOH (20 mL) was added in one portion potassium glutacon-
aldehyde enolate (8) (610 mg, 4.06 mmol). The reaction mixture
was stirred for 24 h after which additional 8 (305 mg, 2.03 mmol)
was added. After stirring for 4 d, the solution was diluted with H2O
(20 mL) and extracted with CH2Cl2 (3ϫ 50 mL). The combined
organic layers were dried with Na2SO4 and concentrated in vacuo.
The oily residue was then purified by flash chromatography on sil-
ica gel (cyclohexane/CH2Cl2/Et2O, 7:3:5) followed by a second flash
chromatography with CH2Cl2 as eluent to afford pure compound
36 (55 mg, 5%). 1H NMR (400 MHz, CDCl3): δ = 9.69 (s, 1 H,
[6]
[7]
J.-C. Wypych, T. M. Nguyen, P. Nuhant, M. Bénéchie, C. Mar-
azano, Angew. Chem. Int. Ed. 2008, 47, 5418–5421; Angew.
Chem. 2008, 120, 5498.
4
4
CHO), 8.88 (d, JH,H = 2.8 Hz, 1 H, CH Ar), 8.77 (d, JH,H
=
The reactivity of Zincke aldehydes is well described and an
area of active study: a) J. Becher, Synthesis 1980, 589–612 and
references cited therein; b) A. C. Friedli, E. Yang, S. R. Marder,
Tetrahedron 1997, 53, 2717–2730; c) J. Raap, S. Nieuwenhuis,
A. Creemers, S. Hexspoor, U. Kragl, J. Lugtenburg, Eur. J. Org.
Chem. 1999, 2609–2621; d) T. D. Michels, J. U. Rhee, C. D.
Vanderwal, Org. Lett. 2008, 10, 4787–4790; e) D. B. C. Martin,
L. Q. Nguyen, C. D. Vanderwal, J. Org. Chem. 2012, 77, 17–46
and references cited therein; f) H. V. Pham, D. B. C. Martin,
C. D. Vanderwal, K. N. Houk, Chem. Sci. 2012, 3, 1650–1655.
T. M. Nguyen, S. Peixoto, C. Ouairy, T. D. Nguyen, M.
Bénéchie, C. Marazano, P. Michel, Synthesis 2010, 103–109.
a) The activation of “Zincke aldehyde” by POCl3 was described
previously by Jutz with the obtention of unsaturated aldehyde
by a Vilsmeier–Haack reaction as its double vinylogous form:
C. Jutz, Chem. Ber. 1958, 91, 850–861; b) for NMR spectro-
scopic data of chloropentadiene iminium compounds, see: J.
Dorie, J.-P. Gouesnard, M. L. Martin, J. Chem. Soc. Perkin
Trans. 2 1981, 6, 912–917.
P. Mäding, J. Steinbach, J. Labelled Compd. Radiopharm. 1998,
41, 647–656.
H. G. Nordmann, F. Kröhnke, Justus Liebigs Ann. Chem. 1970,
731, 80–90.
For the activation of aminopentadienal by O-acylation, see: a)
ref.[11]; b) S. Alías, R. Andreu, M. J. Blesa, M. A. Cerdán, S.
Franco, J. Garín, C. López, J. Orduna, J. Sanz, R. Alicante, B.
Villacampa, M. Allain, J. Org. Chem. 2008, 73, 5890–5898; the
activation by O,N-bis(trifluoroacetylation) of 5-(alkylamino)-
pentadienals using trifluoroacetic anhydride was recently re-
ported, see: P. Nuhant, S. B. Raikar, J.-C. Wypych, B. Delpech,
C. Marazano, J. Org. Chem. 2009, 74, 9413–9421.
3
4
2.8 Hz, 1 H, CH, Ar), 8.53 (dd, JH,H = 9.2, JH,H = 2.8 Hz, 1 H,
CH Ar), 8.37 (dd, JH,H = 9.2, JH,H = 2.8 Hz, 1 H, CH Ar), 7.44
(d, JH,H = 9.2 Hz, 1 H, CH, Ar), 7.40 (d, JH,H = 9.2 Hz, 1 H,
CH, Ar), 7.14 (s, 1 H, CH), 6.92 (s, 1 H, =CHO), 6.27 (d, JH,H
8.0 Hz, 1 H, NCH=), 6.09 (s, 1 H, NCH=), 4.92 (dd, JH,H = 8.0,
4.0 Hz, 1 H, CH=CHN), 4.67 (d, JH,H = 4.0 Hz, 1 H, CH), 2.00
3
4
3
3
3
=
3
3
(s, 3 H, CH3), 1.67 (s, 3 H, CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 194.9 (CHO), 153.7 (CIV, Ar), 143.2 (CH), 142.3 (CIV,
Ar), 142.1 (CIV, Ar), 141.6 (CIV, Ar), 139.9 (2 CIV, Ar), 139.8 (CIV),
139.2 (CHO), 129.4 (CH, Ar), 128.2 (CH, Ar), 127.7 (CH), 126.1
(CIV), 123.5 (CH), 123.2 (CH, Ar), 122.9 (CH, Ar), 122.4 (CH,
Ar), 117.0 (CH, Ar), 115.2 (CIV), 106.4 (CH), 37.0 (CH), 18.8
[8]
[9]
(CH ), 11.8 (CH ) ppm. IR (film, CH Cl ): ν = 1676, 1600,
˜
max
3
3
2
2
1536, 1331 cm–1. HRMS (ESI): calcd. for C24H19N5NaO10
560.1024 [M + Na]+; found 560.1006. Rf = 0.26 (CH2Cl2).
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra of compounds 10–19, 21, 23, 27, 29, 30, 35 and
36.
[10]
[11]
[12]
Acknowledgments
We thank Jean-Christophe Jullian and François Roblot for NMR
assistance.
[1] Review articles: a) J. Peng, K. V. Rao, Y.-M. Choo, M. T. Ham-
ann, in: Modern Alkaloids, Structure, Isolation, Synthesis and
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VCH, Weinheim, 2008, pp. 189–232; b) J.-F. Hu, M. T. Ham-
ann, R. Hill, M. Kelly, in: The Alkaloids, Chemistry and Biology
(Ed.: G. A. Cordell), Academic Press, San Diego, 2003, vol. 60,
pp. 207–285; c) R. Duval, E. Poupon in Biomimetic Organic
Synthesis (Eds.: E. Poupon, B. Nay), Wiley-VCH, Weinheim,
2011, pp. 181–224.
[2] To date, the only biosynthetic studies carried out by Fontana
and co-workers have shown the incorporation of nicotinic acid
in the biosynthesis of haminol by feeding experiments on the
marine mollusc Haminoea orbignyana; a) origin of the pyridine
nucleus of haminols (see structure of haminol-1 below): A. Cu-
tignano, A. Tramice, S. De Caro, G. Villani, G. Cimino, A.
Fontana, Angew. Chem. Int. Ed. 2003, 42, 2633–2636; Angew.
Chem. 2003, 115, 2737; b) origin of the side chain: A. Cutig-
nano, G. Cimino, A. Giordano, G. d’Ippolito, A. Fontana, Tet-
rahedron Lett. 2004, 45, 2627–2629.
[13]
[14]
A. D. Becke, J. Chem. Phys. 1998, 108, 9624–9631.
a) M. W. Schmidt, K. K. Baldridge, J. A. Boatz, S. T. Elbert,
M. S. Gordon, J. H. Jensen, S. Koseki, N. Matsunaga, K. A.
Nguyen, S. J. Su, T. L. Windus, M. Dupuis, J. A. Montgomery,
J. Comput. Chem. 1993, 14, 1347–1363; b) M. S. Gordon,
M. W. Schmidt in Theory and Applications of Computational
Chemistry – The First Forty Years (Eds.: C. E. Dykstra, G.
Frenking, K. S. Kim, G. E. Scuseria), Elsevier, Amsterdam,
2005, pp. 1167–1189.
a) M. M. Francl, W. J. Pietro, W. J. Hehre, J. S. Binkley, M. S.
Gordon, D. J. DeFrees, J. A. Pople, J. Chem. Phys. 1982, 77,
3654–3665; b) T. Clark, J. Chandrasekhar, G. W. Spitznagel, P.
von R. Schleyer, J. Comput. Chem. 1983, 4, 294–301.
[15]
[16]
HMO (Hückel Molecular Orbital) calculations were performed
on an acetoxy iminium compound lacking substitution on the
diene unit, see ref.[11]
[17]
[18]
J. Tomasi, B. Mennucci, R. Cammi, Chem. Rev. 2005, 105,
2999–3093.
a) C. Gonzalez, H. B. Schlegel, J. Chem. Phys. 1989, 90, 2154–
2161; b) Y. L. Dory, A.-L. Roy, P. Soucy, P. Deslongchamps,
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[3] R. T. Hill, M. T. Hamann, O. Peraud and N. Kasanah, patent
application PCT/US2003/024238, patent WO 2004/013297,
USA, 2004.
[19]
A. Arrieta, F. P. Cossio, B. Lecea, J. Org. Chem. 2001, 66,
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Eur. J. Org. Chem. 2014, 4973–4984
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4983

L.-H. Yan, A. Skiredj, Y. Dory, B. Delpech, E. Poupon
FULL PAPER
[20]
[23] N. Dennis, B. Ibrahim, A. R. Katritzky, I. G. Taulov, Y. Takeu-
chi, J. Chem. Soc. Perkin Trans. 1 1974, 1883–1887.
[24] 1-(2,4-Dinitrophenyl)-3-methylpyridinium chloride or Zincke
salt 9 was prepared according to a previous report: D. Gnecco,
J. Juárez, A. Galindo, C. Marazano, R. G. Enríquez, Synth.
Commun. 1999, 29, 281–287.
[25] NMR spectroscopic data of compound 22 correspond to pre-
viously reported data: P. Mäding, J. Steinbach, J. Labelled
Compd. Radiopharm. 1998, 41, 647–656.
The formation of compound 34 was already described by Mar-
azano and co-workers when glutaconaldehyde salt was submit-
ted to acidic conditions; see: M. del Rayo Sanchez-Salvatori,
A. López-Giral, K. Ben Abdeljelil, C. Marazano, Tetrahedron
Lett. 2006, 47, 5503–5506
[21] A low yield for this reaction that does not reflect the real
amount of compound 36 formed during the reaction. Several
iterations of column chromatography were required to purify
36, which was found to be silica-gel-sensitive.
Received: March 29, 2014
Published Online: July 2, 2014
[22] H. Möhrle, R. Niessen, Pharmazie 2001, 56, 139–145.
4984
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Eur. J. Org. Chem. 2014, 4973–4984