Synthesis of alkaloids of Galipea officinalis by alkylation of an α-amino nitrile

Article abstract of DOI:10.1002/ejoc.200800512

A new synthetic approach directed towards the synthesis of naturally occurring 2-alkyl-tetrahydroquinolines is described. The C-C bonds in the α position relative to the nitrogen atom were formed by the reversal of the polarity of the C=N bond of α-amino nitrile 6, which was prepared electrochemically from 1-(phenylethyl)-tetrahydroquinoline. A NaBH ₄-mediated reductive decyanation process furnished benzylic amines 16a-d as mixtures of diastereomers (50-60% de). The catalytic hydrogenolysis of these amines was performed in the presence of Pearlman's catalyst to give the tetrahydroquinolines 17a-d in yields ranging from 70% to 95%. Methylation of the free nitrogen atom afforded the title compounds 1-4 in 70-90% yields. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800512

FULL PAPER
DOI: 10.1002/ejoc.200800512
Synthesis of Alkaloids of Galipea officinalis by Alkylation of an α-Amino
Nitrile
Saurabh Shahane,[a] Fadila Louafi,[a] Julie Moreau,[a] Jean-Pierre Hurvois,*[a]
Jean-Luc Renaud,[b] Pierre van de Weghe,[c] and Thierry Roisnel[d]
Keywords: Alkaloids / Alkylation / Tetrahydroquinolines / α-Amino nitriles / Umpolung
A new synthetic approach directed towards the synthesis of
naturally occurring 2-alkyl-tetrahydroquinolines is de-
scribed. The C–C bonds in the α position relative to the nitro-
gen atom were formed by the reversal of the polarity of the
C=N bond of α-amino nitrile 6, which was prepared electro-
60% de). The catalytic hydrogenolysis of these amines was
performed in the presence of Pearlman’s catalyst to give the
tetrahydroquinolines 17a–d in yields ranging from 70% to
95%. Methylation of the free nitrogen atom afforded the title
compounds 1–4 in 70–90% yields.
chemically from 1-(phenylethyl)-tetrahydroquinoline.
A
NaBH4-mediated reductive decyanation process furnished
benzylic amines 16a–d as mixtures of diastereomers (50–
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
N-Methyl-2-propyl-tetrahydroquinoline (1), angustureine
(2), cuspareine (3) and galipinine (4) are tetrahydroquino-
line alkaloids isolated by Jacquemont-Collet from the bark
of Galipea officinalis Hancock (Figure 1).[1] This shrub is
indigenous to the mountains of Venezuela and belongs to
the genus Galipea Aublet, which consists of approximately
20 species that are found in northern South America. Prep-
arations from Galipea officinalis have been used in folk
medicine for the treatment of various disorders such as dys-
entery and fever.[2] More recently, ethanolic extracts of the
trunk bark of Galipea officinalis have shown antiplasmodial
and cytotoxic activities that might further contribute to the
efficacy of the folklore preparations.[3]
These promising biological activities have incited chem-
ists to elaborate new approaches directed towards the syn-
thesis of tetrahydroquinolines 1–4. Key steps in these pre-
vious methodologies have included enantioselective hydro-
genation of quinolines,[4] ring-closing metathesis,[5] hydro-
amination of anilino-alkynes,[6] Petasis-type condensa-
Figure 1. Structures of 2-substituted tetrahydroquinolines isolated
from Galipea officinalis.
tion,[7] CuI-catalysed coupling of iodobenzene with homo-
chiral β-aminoesters[8] and aza-xylylene Diels–Alder cyclo-
addition.[9]
In the light of our previous experience in heterocyclic
chemistry,[10] and more particularly with nitrogen-based
compounds, we envisaged a new route to tetrahydroquino-
lines 1–4.[11] To this end, the use of an α-amino nitrile
seemed to us a promising possibility. These bifunctional de-
rivatives have been shown to be interesting synthetic inter-
mediates in the elaboration of numerous alkaloids through
the use of the reversible Umpolung of the reactivity of the
C=N bond.[12] In other words, when the α-amino nitrile be-
ars an α-hydrogen, it is possible to deprotonate it with a
strong base to yield a nitrile-stabilised carbanion, which can
then be condensed with a range of electrophiles.[13] Our ret-
rosynthetic plan is delineated in Scheme 1 and calls for the
α-amino nitrile 6 to be elaborated. This α-amino nitrile
moiety should ensure the formation of the new C–C bond,
and we were also curious to investigate the influence of the
[a] Sciences Chimiques de Rennes, Catalyse et Organométalliques,
UMR 6226: CNRS-Université de Rennes 1,
Campus de Beaulieu, 35042 Rennes Cedex, France
Fax: +33-2-23235967
E-mail: jean-pierre.hurvois@univ-rennes1.fr
[b] Sciences Chimiques de Rennes, Chimie Organique et Supramol-
éculaire, UMR 6226: CNRS-Ecole Nationale Supérieure de
Chimie de Rennes,
35700 Rennes, France
[c] Laboratoire de Chimie Pharmaceutique, UFR de Pharmacie,
Avenue du Pr. Léon Bernard, 35043 Rennes Cedex, France
[d] Sciences Chimiques de Rennes, Centre de Diffractométrie X,
UMR 6226: CNRS-Université de Rennes 1,
Campus de Beaulieu, 35042 Rennes Cedex, France
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Synthesis of Galipea officinalis Alkaloids
asymmetric carbon on the stereochemical outcome of the yield and as a separable mixture (60:40) of diastereomers.
chemical manipulations. In this study all compounds are We noticed the formation of intractable tars and passivation
racemic, and all the stereogenic centres are consequently of the working electrode through polymer formation. To
represented in relative configuration.
overcome these drawbacks, it was felt that the lifetime of
the nitrogen-centred cation radical should be reduced
through the rapid loss of an α-proton.[14] To this end, six
equivalents of sodium methoxide (formed in situ by the ad-
dition of Na) were added to the electrolysis medium. Under
these more basic reaction conditions, passivation of the
working electrode did not occur, and the α-amino nitrile 6
was obtained in a satisfactory 75% yield.[15]
Scheme 1. Retrosynthesis of tetrahydroquinolines 1–4.
Preparation of α-Amino Nitriles 7a–d
The condensation of the lithiated α-amino nitrile 6 with
the requisite alkyl halides is the key step in our synthetic
approach, as a new C–C bond is formed α to the nitrogen
atom (Scheme 3). The lithiation procedures were carried
out by dissolving α-amino nitrile 6 in THF at –78 °C, fol-
lowed by the slow addition of LDA (1.5 equiv., prepared
from n-BuLi and diisopropylamine) at the same tempera-
ture. The resulting anion solutions were allowed to warm
to –20 °C over a 2 h period, and the electrophiles were
added at temperatures ranging from –70 °C to –60 °C. Re-
sults are collected in Table 1 and deserve further comment.
Results and Discussion
Preparation and Alkylation of α-Amino Nitrile 6
As outlined in Scheme 2, our synthesis began with the
condensation of lithiated tetrahydroquinoline (nBuLi,
THF) with (1-bromoethyl)benzene. The reaction was car-
ried out at a temperature between –80 °C and –20 °C for
12 h. Under these conditions, 1-(1-phenylethyl)-tetra-
hydroquinoline (5) was obtained in 80% yield.
Scheme 2. Synthesis of α-amino nitrile 6.
For the synthesis of α-amino nitrile 6, several sets of re-
action conditions were investigated. Prior to the macroscale
electrolysis, an analytical study was carried out at a vitreous
carbon electrode at a sweep rate of 50 mVs–1. Amine 5
(20 mmolL–1) was dissolved in methanol containing lithium
acetate (20 gL–1) as a supporting electrolyte and sodium
cyanide (6 equiv. per mol of substrate) as a trapping agent.
The voltammogram revealed the presence of two successive
irreversible peaks at EpA = +0.95 V/SCE and EpB =
+1.25 V/SCE. These observations are consistent with pre-
vious results obtained in our laboratory and indicate that a
selective bielectronic oxidation process could be performed
at peak A. The controlled-potential oxidation of 5 was thus
carried out at +0.80 V/SCE on a 4 g scale in a divided cell
fitted with a glassy carbon electrode as anode and a carbon
rod as cathode. In our preliminary experiments, the current
dropped rapidly from 150 mA to 20 mA, and electrolysis
took place over a 24 h period. After the consumption of 2.2
Faradays per mol of substrate, the voltammogram showed
Scheme 3. Synthesis of α-amino nitriles 7a–d.
Addition of 1-iodopropane (Entry 1) at –60 °C, followed
the disappearance of the first oxidation peak at +0.95 V/ by 3 h stirring at –20 °C, led to the rapid formation of 7a
SCE. Classical workup and chromatographic purification in a 70% isolated yield as a separable mixture (52:48) of
over a silica column afforded the α-amino nitrile 6 in 45% diastereomers (Scheme 3). Upon chromatographic purifica-
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J.-P. Hurvois et al.
FULL PAPER
Table 1. Synthesis of α-amino nitriles 7a–d.
32% yield, along with a 20–25% yield of starting material.
Prolonged stirring of the anion solution at room tempera-
ture (Entry 4) had little effect. Interestingly, close examina-
tion of the 1H NMR spectrum of unreacted bromide 12
revealed the presence of 3,4-dimethoxy-1-vinylbenzene
(35%), which showed two characteristic doublets at δ =
5.15 ppm (J = 11.0 Hz) and 5.60 ppm (J = 17.0 Hz). This
result indicates that an unavoidable elimination process
took place between the lithiated α-amino nitrile 6 and the
bromide 12. This problem prompted us to investigate the
condensation of 6 with the more reactive iodide 14 (En-
try 5). The deprotonation step was carried out as above,
and the reaction mixture was maintained at –20 °C over-
night. Gratifyingly, the alkylation proceeded cleanly and re-
producibly to yield 7c (70%) as a mixture (57:43) of insepa-
rable diastereomers. Likewise, the alkylation of 6 (Entry 6)
with the iodide 15 afforded the adduct 7d in a 72% yield, as
a mixture (52:48) of inseparable diastereomers after column
chromatography. The crude mixture was taken up in etha-
nol to yield a white powder that melted at 159–161 °C. We
were pleased to find that spectroscopic data (1H, 13C NMR)
revealed the presence of only one geometric isomer. Inter-
estingly, single crystals could be obtained by a slow crystal-
lisation in a biphasic system (dichloromethane/pentane). A
subsequent X-ray diffraction study performed on one of
these crystals revealed a (R*,S*) relative configuration of
the two stereogenic centres C-2 and C-2Ј as shown in Fig-
ure 3.
Entry
Electrophile T [°C] / t [h]
Product,
% yield[a]
% de[b]
1
2
3
4
5
6
n-C3H7I
n-C5H11I
–60Ǟ–20 / 3
–60Ǟ–20 / 3
–60Ǟ–20 / 12
–60Ǟ20 / 24
–60Ǟ–20 / 12
–60Ǟ–20 / 12
7a, 70
7b, 75
7c, 35
7c, 35
7c, 70
7d, 72
5
10
15
15
15
5
12
12
14
15
[a] Yields are of isolated products after column chromatography
1
through silica gel. [b] Determined by H NMR spectroscopy.
tion over a silica column, the more polar diastereomer was
collected as a white powder (m.p. 146–148 °C). Slow crys-
tallisation of this powder from a biphasic system (dichloro-
methane/pentane) afforded a single crystal, X-ray diffrac-
tion study of which revealed a (R*,S*) relative configura-
tion of the two stereogenic centres C-2 and C-2Ј, as shown
in Figure 2.
Figure 2. ORTEP drawing of α-amino nitrile (R*,S*)-7a (for details
see Table 5).
Having successfully installed a propyl chain on α-amino
nitrile 6, we turned our efforts towards the synthesis of 7b,
a potential precursor of angustureine (Entry 2). The anion
solution of 6 was allowed to react with 1-iodopentane at
1
–20 °C for 12 h, providing adduct 7b in 75% yield. The H
NMR spectrum of 7b closely resembles that of 7a, indicat-
ing that an inseparable mixture of diastereomers (55:45)
was produced during the formation of 7b.
Figure 3. ORTEP drawing of α-amino nitrile (R*,S*)-7d (for details
see Table 5).
To extend the scope of our methodology, we also decided
to prepare new precursors of cuspareine (3) and galipinine
(4). This involved the synthesis of alkyl halides 12–15 from
the corresponding carboxylic acids as shown in
Scheme 4.[16,17]
Reductive Decyanation of α-Amino Nitriles 7a–d
The reductive decyanation of α-amino nitriles consists of
Treatment of the anion solution of 6 with bromide 12 at the neat replacement of the cyano group by a hydrogen
–60 °C (Entry 3) and continuous stirring at –20 °C for 12 h atom (Scheme 5). The reaction proceeds through an ionic
afforded the bifunctional α-amino nitrile 7c in a modest or a radical pathway according to the nature of the reducing
Scheme 4. Synthesis of alkyl halides 12–15.
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Synthesis of Galipea officinalis Alkaloids
agent. In the first mode, the α-amino nitrile yields an inter- comes of the reductive decyanation processes were quite in-
mediate iminium cation, which is reduced in situ by a hy- sensitive to the lengths and the natures of the side chains
[20]
dride donor (NaBH4,[18] BH3,[19] AgBF4/Zn(BH4)2
or (Table 2, Entries 1–4).
Dibal-H[21]). In the second mode, the reduction proceeds by
electron transfer in the presence of an alkali metal such as
sodium, in a mixture of liquid ammonia and THF. An in-
termediary radical anion is formed and carries on to the
decyanated product through the loss of CN–.[22] Recently,
Husson reported the reductive decyanation of α-amino ni-
triles in the presence of Raney nickel under mild condi-
tions.[23] From a simple examination of these methods, it
was clear that for technical convenience, NaBH4 was the
reactant of choice. Reduction of the α-amino nitrile 7a was
therefore performed in EtOH at 20 °C for 24 h in the pres-
ence of four equivalents of NaBH4. After treatment, amine
16a was obtained in a low 25% yield, accompanied by unre-
acted starting material. In a second experiment, direct heat-
ing of 7a, even at reflux, did not improve the yield signifi-
cantly (30%). Apparently, it was difficult to obtain the in-
termediary iminium ion through the cleavage of the C–CN
bond. This problem was solved when the α-amino nitrile 7a
was kept in solution with NaBH4 in EtOH at 20 °C for a
12 h stirring period, with a subsequent 3 h at reflux. Under
these reaction conditions, amine 16a was obtained in a 93%
isolated yield. Apparently, in this sequence, the initial step
consist of the formation of a complex between the cyano
group and borane. This complex favoured a “push–pull”
mechanism to produce the intermediary iminium ion, which
is attacked by a hydride anion. These results are in keeping
with the observations of Ogura,[19] who pointed out that
both cyano groups of α,αЈ-dicyano amines could be re-
moved with NaBH4 in a moderate 47% yield. In our case,
delocalisation of the nitrogen lone pair onto the aromatic
ring decreases the n–σC–CN* interaction.[24] The well re-
Synthesis of Tetrahydroquinoline Alkaloids 1–4
In the penultimate step, the N-benzyl bond in amines
16a–d was cleaved by catalytic hydrogenolysis in the pres-
ence of Pd(OH)2-C (20%) in a mixture (4:1) of methanol
and ethyl acetate under hydrogen (2 atm; Scheme 6). After
purification over silica, the free amines 17a–d were obtained
as colourless oils in yields ranging between 70% and 95%
(Table 3).
Scheme 6. Synthesis of tetrahydroquinoline alkaloids 1–4.
Table 3. Hydrogenolysis of benzylic amines 16a–d.
Entry Product
% Yield[a]
1
2
3
4
17a, R = C3H7
70
93
72
95
17b, R = C5H11
17c, R = 3,4-(MeO)2Ph-(CH2)2
17d, R = 3,4-(OCH2O)2Ph-(CH2)2
[a] 20% Pd(OH)2–C, H2 (30 psi), MeOH/EtOAc (4:1), room temp.
48 h.
Methylation of the free nitrogen atom was carried out
under the experimental conditions described by Nishida, by
treatment of the tetrahydroquinolines 17a–d in THF at re-
flux in the presence of MeI (6 equiv.) and powdered K2CO3
(Scheme 6).[5] After workup, the expected tetrahydroquino-
lines 1–4 were obtained in yields ranging between 71% and
90% (Table 4). The high-field 1H NMR spectra of com-
pounds 1–4 confirm the molecular formulas, and the 13C
NMR spectra were consistent with the literature data.[6,7]
1
solved H NMR spectrum of 16a indicates the presence of
a mixture (80:20) of diastereomers that could not be sepa-
rated by column chromatography. When subjected to these
optimised reaction conditions, α-amino nitriles 7b–d under-
went clean reduction processes to produce the expected
amines 16b–d in yields ranging between 75% and 89%
(Table 2). It is worthy of note that the stereochemical out-
Table 4. N-Methylation of tetrahydroquinolines 17a–d.
Entry
Product
% Yield[a]
1
2
3
4
1
2
3
4
90
85
75
80
Scheme 5. Reductive decyanation of α-amino nitriles 7a–d.
Table 2. Reductive decyanation of α-amino nitrile 7a–d.
[a] MeI (6.0 equiv.), K2CO3, THF, reflux, 12 h.
Entry Product
% Yield[a]
% de
60[b]
60[b]
56[c]
51[c]
Conclusions
1
2
3
4
16a, R = C3H7
93
89
75
78
16b, R = C5H11
In summary, a new and reliable route to Galipea offici-
nalis alkaloids from tetrahydroquinoline has been devel-
oped. In this process, the α-CH bond of the tetrahydroquin-
oline nucleus was activated electrochemically to produce an
16c, R = 3,4-(MeO)2Ph-(CH2)2
16d, R = 3,4-(OCH2O)2Ph-(CH2)2
[a] NaBH4 (4 equiv.), EtOH, 12 h; then 3 h reflux. [b] Determined
by VPC. [c] Determined by H NMR spectroscopy.
1
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J.-P. Hurvois et al.
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125 MHz): δ = 15.9 (p), 22.2 (s), 28.5 (s), 42.5 (s), 54.6 (t), 110.6
(t), 115.47 (t), 122.8 (q), 126.7 (t), 126.9 (t), 127.1 (t), 128.3 (t),
129.2 (t), 142.7 (q), 145.5 (q) ppm. HRMS (C17H19N, [M]+): calcd.
for 237.1517; found 237.1517. C17H19N (237.34): calcd. C 86.03, H
8.07, N 5.90; found C 85.73, H 8.17, N 5.54.
α-amino nitrile. A reversal in polarity of the C=N bond
(“umpolung”) allows the formation of a nitrile-stabilised
carbanion, which was condensed with a range of alkyl io-
dides. A stereoselective approach to these alkaloids based
on the use of α-methylbenzylamine as a chiral auxiliary is
currently under investigation in our laboratory.
Electrolysis of Tetrahydroquinoline 5: Compound
5 (1.0 g,
4.21 mmol) was dissolved in MeOH (150 mL) containing lithium
acetate (1.5 g) and NaCN (1.0 g, 20.40 mmol). Sodium (0.40 g,
17.39 mmol) was then allowed to react with the resulting solution.
The solution was placed in a divided electrolysis cell fitted with a
planar vitreous carbon electrode (diameter: 100 mm) as anode and
a carbon rod as cathode. The working potential was adjusted +0.65
vs. SCE, and after 2.2 Fmol–1 had been consumed, the solvent was
evaporated under reduced pressure. The resulting paste was taken
up with water (50 mL) and extracted with diethyl ether
(100 mLϫ2). The combined organic layers were dried with MgSO4
and concentrated in vacuo. The residue was purified by column
chromatography (diethyl ether/petroleum ether, 90:10) to afford α-
amino nitrile 6 (0.83 g, 75%, orange paste) as a mixture of dia-
stereomers (60:40), which could be separated by careful chromatog-
raphy over a silica column. The (R*,S*) relative configuration of
the major diastereomer has been determined previously by X-ray
diffraction analysis.[15]
Experimental Section
General: Purification by column chromatography was performed
with 70–230 mesh silica gel (Merck). TLC analyses were carried
out on alumina sheets precoated with silica gel (60 F254) and visu-
alised with UV light; Rf values are given for guidance. NMR spec-
tra were recorded with a Bruker Avance DRX 500 FT spectrometer
[500 MHz (1H) and 100 MHz (13C)] or a Bruker AH 300 FT spec-
trometer [300 MHz (1H) and 75 MHz (13C)]. Chemical shifts are
expressed in ppm downfield from TMS. Data are reported as fol-
lows: chemical shift [multiplicity (s: singlet, d: doublet, dd: double
doublet, ddd: double double doublet, dm: double multiplet, dt:
double triplet, t: triplet, td triple doublet, tm, triple multiplet, tt:
triple triplet, q: quartet, quint: quintuplet, m: multiplet, br: broad),
coupling constants (J) in Hertz, integration]. The number of at-
tached proton(s) in the 13C NMR spectra were elucidated by use
of DEPT 135 and non-decoupling mode and are described as: (p)
primary, RCH3; (s) secondary, R2CH2; (t) tertiary, R3CH; (q) qua-
ternary, R4C. High-resolution mass spectra were obtained with a
Mat 311 double focussing instrument at the CRMPO “Centre de
Mesures Physiques de l’Ouest” with a source temperature of
170 °C. An ion accelerating potential of 3 kV and ionising electrons
of 70 eV were used. Elemental analyses were carried out on a Flash
EA 1112 CHNS/O Thermo Electron instrument and are expressed
as percentage values. Melting points were measured on a Kofler
apparatus; the values are reported in °C and are uncorrected. For
air-sensitive reactions, all glassware was oven-dried (120 °C) over a
24 h period and cooled under a stream of argon. All commercially
available reagents were used as supplied. THF was distilled from
sodium benzophenone ketyl and stored under argon. Diisopropyl-
amine was distilled from potassium hydroxide. Air-sensitive rea-
gents were transferred by syringe or with a double-ended needle.
Yields refer to chromatographically and spectroscopically (1H, 13C)
homogeneous material.
(R*,S*)-1-(1-Phenylethyl)-1,2,3,4-tetrahydroquinoline-2-carbonitrile
(6): Colourless plates, m.p. 96 °C (diethyl ether); Rf = 0.20 (diethyl
ether/petroleum ether, 10:90). 1H NMR (CDCl3, 300 MHz): δ =
1.75 (d, J = 7.0 Hz, 3 H), 1.84–1.95 (m, 1 H), 2.00–2.07 (m, 1 H),
2.80 (dd, J = 17.0, 5.3 Hz, 1 H), 3.17 (ddd, J = 17.0, 13.3, 6.3 Hz,
1 H), 4.06 (m, 1 H), 5.22 (q, J = 7.0 Hz, 1 H), 6.76 (td, J = 7.4,
1.0 Hz, 1 H), 6.88 (d, J = 8.3 Hz, 1 H), 7.06 (d, J = 7.4 Hz, 1 H),
7.13 (t, J = 7.8 Hz, 1 H), 7.26–7.40 (m, 5 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 14.8 (p), 24.3 (s), 25.4 (s), 42.9 (t), 55.0 (t),
112.1 (t), 118.3 (t), 120.3 (q), 121.4 (q), 127.3 (t), 127.5 (t), 127.7
(t), 128.8 (t), 128.89 (t), 140.5 (q), 142.2 (q) ppm. HRMS
(C18H18N2, [M]+): calcd. for 262.1470; found 262.1469. C18H18N2
(262.35): calcd. C 82.41, H 6.92, N 10.68; found C 82.10, H 7.10,
N 10.60.
(R*,R*)-6: Colourless plates, m.p. 83 °C (diethyl ether/petroleum
1
ether); Rf = 0.10 (diethyl ether/petroleum ether, 10:90). H NMR
(CDCl3, 300 MHz): δ = 1.62, (d, J = 6.9 Hz, 3 H), 2.02 (tt, J =
13.2, 4.7 Hz, 1 H), 2.20 (dm, J = 13.2 Hz, 1 H), 2.83 (dm, J =
16.6 Hz, 1 H), 3.16 (ddd, J = 16.6, 13.3, 5.7 Hz, 1 H), 4.37 (ddd, J
= 4.4, 3.1, 1.5 Hz, 1 H), 5.13 (q, J = 6.9 Hz, 1 H), 6.73 (td, J =
7.4, 1.0 Hz, 1 H), 6.78 (d, J = 8.1 Hz, 1 H), 7.02–7.07 (m, 2 H),
7.27–7.46 (m, 5 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 16.0 (p),
24.5 (s), 25.7 (s), 46.3 (t), 57.7 (t), 114.2 (t), 118.3 (t), 119.3 (q),
122.1 (q), 127.1 (t), 127.2 (t), 127.6 (t), 128.8 (t), 129.6 (t), 140.7
(q), 141.7 (q) ppm. HRMS (C18H18N2, [M]+): calcd. for 262.1470;
found 262.1469. C18H18N2 (262.35): calcd. C 82.41, H 6.92, N
10.68; found C 82.30, H 6.95, N 10.10.
1-(1-Phenylethyl)-1,2,3,4-tetrahydroquinoline (5): n-BuLi (1.6  in
hexane 30.50 mL, 48.80 mmol) was added by syringe, under argon
at –80 °C, to a stirred solution of 1,2,3,4-tetrahydroquinoline (5.0 g,
37.5 mmol) in THF (30 mL). The solution was allowed to warm to
–20 °C and was stirred at that temperature for 3 h. The solution
was cooled to –80 °C, and (1-bromoethyl)benzene (9.04 g, 6.67 mL,
48.84 mmol) was added by syringe. The mixture was allowed to
warm to 20 °C over a 3 h period and was stirred at that temperature
for 1 h. The reaction mixture was quenched with an excess of water,
and THF was evaporated under reduced pressure. The resulting
paste was taken up with water (100 mL) and was then extracted
with diethyl ether (100 mLϫ2). The combined organic layers were
dried with MgSO4 and concentrated in vacuo. The crude yellow oil
was purified by column chromatography (diethyl ether/petroleum
ether, 10:90) to afford 5 (7.12 g, 80%) as a viscous, colourless oil.
1-(1-Phenylethyl)-2-propyl-1,2,3,4-tetrahydroquinoline-2-carbonitrile
(7a): α-Amino nitrile 6 (1.5 g, 5.72 mmol, mixture of diastereomers,
60:40) was dissolved in THF (20 mL), and the system was cooled
to –80 °C. A THF solution (5 mL) of LDA [prepared from 1.6 
nBuLi in hexane (5.36 mL, 8.57 mmol) and diisopropylamine
(0.98 g, 1.38 mL, 9.68 mmol)] was added by syringe at the same
temperature over a 10 min period. The orange solution was stirred
at –20 °C for 3 h. The reaction mixture was cooled to –80 °C, and
1
Rf (diethyl ether/petroleum ether, 10:90) = 0.90. H NMR (CDCl3,
500 MHz): δ = 1.55 (d, J = 6.9 Hz, 3 H), 1.81–1.87 (m, 2 H), 2.70–
2.79 (m, 2 H), 3.00–3.03 (m, 1 H), 3.10–3.13 (m, 1 H), 5.10 (q, J 1-iodopropane (0.83 mL, 1.44 g, 8.51 mmol) was added dropwise.
= 6.9 Hz, 1 H), 6.55 (t, J = 7.3 Hz, 1 H), 6.68 (d, J = 8.3 Hz, 1 H), The reaction mixture was allowed to warm to –20 °C until TLC
6.95 (d, J = 7.4 Hz, 1 H), 7.01 (t, J = 8.5 Hz, 1 H), 7.21 (tm, J = indicated the absence of starting material. Water (15 mL) was then
7.4 Hz, 1 H), 7.28–7.39 (m, 4 H) ppm. 13C NMR (CDCl3,
added, and the resulting solution was extracted with diethyl ether
4626
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4622–4631

Synthesis of Galipea officinalis Alkaloids
(50 mLϫ3). The combined extracts were dried with MgSO4, and
the solvents were removed under reduced pressure. The crude prod-
uct was purified by rapid filtration through a chromatography col-
umn (diethyl ether/petroleum ether, 20:80) to afford 7a (1.22 g,
70 %) as a mixture (52:48) of diastereomers. The more polar
6.56 (t, J = 8.0 Hz, 1 H), 6.66 (t, J = 8.0 Hz, 1 H), 6.72–7.42 (m,
14 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 13.8 (p), 13.9 (p),
16.7 (p), 18.2 (p), 22.4 (s), 23.4 (s), 23.7 (s), 24.6 (s), 25.1 (s), 30.5
(s), 31.7 (s), 31.7 (s), 32.8 (s), 36.2 (s), 39.7 (s), 56.4 (t), 56.8 (t),
61.9 (q), 62.1 (q), 116.5 (t), 117.2 (t), 118.3 (t), 118.6 (t), 121.2 (q),
(R*,S*)-7a could be separated from (R*,R*)-7a by careful filtration 121.6 (q), 122.4 (t), 124.9 (t), 126.0 (t), 126.1 (t), 126.1 (t), 126.3
through a silica column (diethyl ether/petroleum ether, 10:90) to
afford a white powder. A further slow crystallisation (72 h) of this
powder from a biphasic system (dichloromethane/pentane, 1:5) af-
forded colourless crystals, which were analysed by X-ray diffrac-
tion.
(t), 126.5 (t), 126.6 (t), 126.8 (t), 128.4 (t), 128.5 (t), 140.1 (q), 141.0
(q), 142.2 (q), 143.6 (q) ppm. HRMS (C23H28N2, [M]+): calcd. for
332.2252; found 332.2251. C23H28N2 (332.48): calcd. C 83.09, H
8.49, N 8.43; found C 83.02, H 8.47, N 8.20.
4-(2-Bromoethyl)-1,2-dimethoxybenzene
(12):
(3,4-Dimeth-
(R*,S*)-7a: White powder, m.p. 146–148 °C (petroleum ether); Rf oxyphenyl)acetic acid (8, 8.0 g, 40.77 mmol) and NaBH4 (4.0 g,
= 0.60 (diethyl ether/petroleum ether, 10:90). 1H NMR (CDCl3,
105.74 mmol) were dissolved in THF (100 mL), and the system was
300 MHz): δ = 1.02 (t, J = 7.2 Hz, 3 H), 1.48–1.63 (m, 2 H), 1.84 cooled to 0 °C. A THF solution (15.0 mL) of iodine (10.40 g,
(d, J = 6.9 Hz, 3 H), 1.85–1.92 (m, 1 H), 2.07 (ddd, J = 16.4, 10.5, 40.97 mmol) was added dropwise over a 1 h period. The resulting
5.8 Hz, 1 H), 2.32–2.45 (m, 2 H), 2.77–2.81 (m, 2 H), 5.15 (q, J = colourless solution was heated at reflux for 24 h. Methanol was
6.9 Hz, 1 H), 6.26 (d, J = 8.3 Hz, 1 H), 6.57 (t, J = 7.3 Hz, 1 H), added until evolution of H2 had ceased. The clear solution was
6.75 (t, J = 8.6 Hz, 1 H), 6.95 (d, J = 7.3 Hz, 1 H), 7.20 (t, J = stirred at 20 °C, and the solvents were evaporated under reduced
6.8 Hz, 1 H), 7.31 (t, J = 7.3 Hz, 2 H), 7.41 (d, J = 8.2 Hz, 2 pressure. The resulting paste was taken up with aqueous NaOH
H) ppm. 13C NMR (CDCl3, 75 MHz) δ = 14.1 (p), 17.4 (p), 18.2 (5%, 50 mL) and extracted with dichloromethane (50 mLϫ3). The
(s), 23.4 (s), 30.5 (s), 38.4 (s), 56.4 (t), 62.1 (q), 116.5 (t), 117.2 (t), combined organic layers were dried with MgSO4 and concentrated
121.6 (q), 122.4 (q), 126.0 (t), 126.3 (t), 126.6 (t), 128.5 (t), 128.8 in vacuo. The crude product was purified by column chromatog-
(t), 140.1 (q), 141.5 (q) ppm. HRMS (C21H24N2, [M]+): calcd. for
304.1939; found 304.1946. C21H24N2 (304.43): calcd. C 82.85, H
7.95, N 9.20; found C 82.57, H 8.00, N 9.19.
raphy (diethyl ether/petroleum ether, 80:20) to afford 2-(3,4-dimeth-
oxyphenyl)ethanol (10, 6.68 g, 90%) as a colourless, viscous oil. Rf
(diethyl ether/petroleum ether, 80:20) = 0.40. 1H NMR (CDCl3,
500 MHz): δ = 2.25 (br. s, 1 H), 2.78 (t, J = 6.6 Hz, 2 H), 3.79 (t,
J = 6.6 Hz, 2 H), 3.83 (s, 3 H), 3.85 (s, 3 H), 6.74–6.75 (m, 2 H),
6.79 (d, J = 6.8 Hz, 1 H) ppm. 13C NMR (CDCl3, 125 MHz): δ =
38.7 (s), 55.8 (p), 55.9 (p), 63.6 (s), 111.3 (t), 112.2 (t), 120.9 (t),
131.1 (q), 147.5 (q), 148.9 (q) ppm. HRMS (C10H14O3, [M]+):
calcd. for 182.0943; found 182.0942. C10H14O3 (182.22): calcd. C
65.91, H 7.74; found C 66.15, H 7.82.
(R*,R*)-1-(1-Phenylethyl)-2-propyl-1,2,3,4-tetrahydroquinoline-2-
carbonitrile (7a): Viscous, pale yellow oil; Rf = 0.70 (diethyl ether/
1
petroleum ether, 10:90). H NMR (CDCl3, 300 MHz): δ = 0.90 (t,
J = 7.2 Hz, 3 H), 1.48–1.62 (m, 2 H), 1.70–1.80 (m, 1 H), 1.74 (d,
J = 6.9 Hz, 3 H), 1.97–2.10 (m, 2 H), 2.48 (dt, J = 13.5, 3.7 Hz, 1
H), 2.71 (dt, J = 16.0, 3.6 Hz, 1 H), 3.11 (ddd, J = 16.0, 13.5,
3.6 Hz, 1 H), 5.03 (q, J = 6.9 Hz, 1 H), 6.36 (d, J = 7.8 Hz, 1 H),
6.66 (t, J = 7.3 Hz, 1 H), 6.81 (t, J = 8.8 Hz, 1 H), 6.97 (d, J = 2-(3,4-Dimethoxyphenyl)ethanol (10, 2.0 g, 10.97 mmol) was dis-
7.3 Hz, 1 H), 7.24 (t, J = 6.8 Hz, 1 H), 7.34 (m, 2 H), 7.40–7.42 solved in dichloromethane (25 mL) in the presence of carbon tetra-
(m, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 14.0 (p), 16.7 (p), bromide (4.37 g, 13.13 mmol). Triphenylphosphane (3.64 g,
18.3 (s), 25.1 (s), 32.8 (s), 41.8 (s), 56.8 (t), 61.8 (q), 118.3 (t), 118.6
(t), 121.2 (q), 124.9 (q), 126.1 (t), 126.1 (t), 126.5 (t), 128.4 (t), 128.5
(t), 141.0 (q), 143.6 (q) ppm.
13.88 mmol) was added in portions over a 30 min period, and the
solution was stirred at ambient temperature over 12 h. The white
precipitate was filtered off, and the resulting paste was taken up
with diethyl ether (100 mLϫ2). The combined organic layers were
concentrated, and the excess of carbon tetrabromide was removed
by vacuum sublimation (30–40 °C, 4·10–2 Torr). The resulting paste
was purified by column chromatography (diethyl ether/petroleum
ether, 90:10) to yield bromide 12 as a viscous oil (2.45 g, 91%),
which solidified upon cooling. White powder; m.p. 57 °C; Rf = 0.50
(diethyl ether/petroleum ether, 10:90). 1H NMR (CDCl3,
300 MHz): δ = 3.09 (t, J = 7.7 Hz, 2 H), 3.54 (t, J = 7.7 Hz, 2 H),
3.85 (s, 3 H), 3.87 (s, 3 H), 6.72–6.74 (m, 2 H), 6.82 (d, J = 8.0 Hz,
1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 33.2 (s), 39.0 (s), 55.8
(p), 55.8 (p), 111.2 (t), 111.8 (t), 120.6 (t), 131.4 (q), 147.9 (q), 148.3
(q) ppm. HRMS (C10H13BrO2, [M]+): calcd. for 244.0099; found
244.0110. C10H13BrO2 (245.11): calcd. C 49.00, H 5.35; found C
48.83, H 5.32.
2-Pentyl-1-(1-phenylethyl)-1,2,3,4-tetrahydroquinoline-2-carbonitrile
(7b): α-Amino nitrile 6 (1.5 g, 5.72 mmol, mixture of diastereomers,
60:40) was dissolved in THF (20 mL), and the system was cooled
to –80 °C. A THF solution (5 mL) of LDA [prepared from 1.6 
nBuLi in hexane (5.36 mL, 8.57 mmol) and diisopropylamine
(1.38 mL, 0.98 g, 9.68 mmol)] was added by syringe at the same
temperature over a 10 min period. The orange solution was stirred
at –20 °C for 3 h and cooled to –80 °C. 1-Iodopentane (1.12 mL,
1.69 g, 8.58 mmol) was added dropwise. The reaction mixture was
allowed to warm to –20 °C until TLC indicated the absence of
starting material. Water (15 mL) was then added, and the resulting
solution was extracted with diethyl ether (50 mLϫ3). The com-
bined extracts were dried with MgSO4 and the solvents were re-
moved under reduced pressure. The crude product was purified by
rapid filtration through a chromatography column (diethyl ether/
4-(2-Iodoethyl)-1,2-dimethoxybenzene (14): Bromide 12 (1.83 g,
petroleum ether, 20:80) to afford 7b (1.42 g, 75%) as an inseparable 7.46 mmol) was dissolved in acetone (25 mL) in the presence of
mixture (55:45) of diastereomers and as a pale yellow oil. Rf (di-
ethyl ether/petroleum ether, 10:80) = 0.70. 1H NMR (CDCl3,
300 MHz): δ = 0.84 (t, J = 7.0 Hz, 3 H), 0.90 (t, J = 7.0 Hz, 3 H),
sodium iodide (3.38 g, 22.55 mmol). The solution was heated at
reflux for 24 h, and excess sodium iodide was removed by filtration.
The solvent was evaporated under reduced pressure, and the resi-
1.20–1.60 (m, 10 H), 1.74 (d, J = 7.0 Hz, 3 H), 1.83 (d, J = 7.0 Hz, due was purified by column chromatography (diethyl ether/petro-
3 H), 1.70–1.90 (m, 2 H), 1.97–2.12 (m, 3 H), 2.35–2.40 (m, 2 H),
2.47 (dt, J = 13.5, 3.7 Hz, 1 H), 2.66–2.80 (m, 3 H), 3.12 (ddd, J
= 16.0, 13.0, 3.5 Hz, 1 H), 5.07 (q, J = 7.0 Hz, 1 H), 5.18 (q, J =
leum ether, 90:10) to yield iodide 14 (1.96 g, 90%) as a slightly
yellow, viscous oil. Rf = 0.50 (diethyl ether/petroleum ether, 10:90).
1H NMR (CDCl3, 300 MHz): δ = 3.10 (t, J = 7.9 Hz, 2 H), 3.32
7.0 Hz, 1 H), 6.26 (d, J = 8.0 Hz, 1 H), 6.36 (d, J = 8.0 Hz, 1 H), (t, J = 7.9 Hz, 2 H), 3.85 (s, 3 H), 3.87 (s, 3 H), 6.70–6.73 (m, 2
Eur. J. Org. Chem. 2008, 4622–4631
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4627

J.-P. Hurvois et al.
H), 6.81 (d, J = 8.0 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ (20 mL), and the system was cooled to –80 °C. A THF solution
FULL PAPER
= 6.1 (s), 39.9 (s), 55.8 (p, 2 C), 111.2 (t), 111.5 (t), 120.3 (t), 133.2
(5 mL) of LDA [prepared from 1.6  nBuLi in hexane (3.57 mL,
5.71 mmol) and diisopropylamine (0.90 mL, 0.64 g, 6.32 mmol)]
(q), 147.8 (q), 148.8 (q) ppm. HRMS (C10H13IO2, [M]+): calcd. for
291.9960; found 291.9941. C10H13IO2 (292.11): calcd. C 41.12, H was added by syringe at the same temperature over a 10 min period.
4.49; found C 40.15, H 4.48.
The orange solution was allowed to warm to –20 °C over 2 h and
the reaction mixture was then cooled to –80 °C. A THF solution
(5 mL) of iodide 14 (1.66 g, 5.68 mmol) was added dropwise to the
anion solution. The reaction mixture was allowed to warm to
–20 °C for 12 h, until TLC indicated the absence of starting mate-
rial. Water (15 mL) was then added, and the resulting solution was
extracted with diethyl ether (50 mLϫ3). The combined extracts
were dried with MgSO4, and the solvents were removed under re-
duced pressure. The crude product was purified by column
chromatography (diethyl ether/petroleum ether, 30:70) to afford 7c
(1.14 g, 70%) as a mixture (57:43) of diastereomers. Rf = 0.20 (di-
ethyl ether/petroleum ether, 30:70). 1H NMR (CDCl3, 500 MHz):
δ = 1.75 (d, J = 6.9 Hz, 3 H), 1.80 (d, J = 6.9 Hz, 3 H), 2.09–2.53
(m, 8 H), 2.69–2.87 (m, 7 H), 3.16 (ddd, J = 16.2, 17.2, 3.4 Hz, 1
H), 3.74 (s, 3 H), 3.79 (s, 3 H), 3.84 (s, 3 H), 3.88 (s, 3 H), 5.09 (q,
J = 6.9 Hz, 1 H), 5.18 (q, J = 6.9 Hz, 1 H), 6.30 (d, J = 8.3 Hz, 1
H), 6.44 (d, J = 8.2 Hz, 1 H), 6.50 (d, J = 2.0 Hz, 1 H), 6.58–6.60
(m, 2 H), 6.68–6.85 (m, 7 H), 6.97–7.00 (m, 2 H), 7.19–7.24 (m, 2
H), 7.29–7.34 (m, 4 H), 7.40–7.43 (m, 4 H) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 16.9 (p), 18.3 (p), 23.4 (s), 25.1 (s), 30.1
(s), 30.5 (s), 30.6 (s), 32.8 (s), 38.3 (s), 41.6 (s), 55.7 (p), 55.8 (p),
55.8 (p), 56.6 (t), 57.1 (t), 61.7 (q), 62.0 (q), 111.3 (t), 111.4 (t),
111.6 (t), 116.7 (t), 117.5 (t), 118.6 (t), 118.8 (t), 120.0 (t), 120.1 (t),
121.0 (q), 121.3 (q), 122.4 (q), 124.9 (q), 126.0 (t), 126.2 (t), 126.0
(t), 126.2 (t), 126.4 (t), 126.5 (t), 126.6 (t), 128.5 (t), 128.5 (t), 128.6
(t), 128.9 (t), 132.6 (q), 139.9 (q), 141.0 (q), 141.4 (q), 143.5 (q),
147.4 (q), 147.6 (q), 148.9 (q), 149.0 (q) ppm. HRMS (C28H30N2O2,
[M]+): calcd. for 399.2210; found 399.2210 (C27H29NO2, [M –
HCN]+). C28H30N2O2 (426.55): calcd. C 78.84, H 7.09, N 6.57;
found C 78.36, H 7.07, N 6.44.
5-(2-Bromoethyl)-1,3-benzodioxole
(13):
(3,4-Methylenedioxy-
phenyl)acetic acid (9, 4.0 g, 22.20 mmol) and NaBH4 (2.0 g,
52.86 mmol) were dissolved in THF (100 mL), and the system was
cooled to 0 °C. A THF solution (15 mL) of iodine (5.60 g,
22.06 mmol) was added dropwise over a 1 h period, and the re-
sulting colourless solution was heated at reflux for 24 h. Methanol
was added until evolution of H2 had ceased. The clear solution was
stirred at 20 °C, and the solvents were evaporated under reduced
pressure. The resulting paste was taken up with aqueous NaOH
(5%, 50 mL) and extracted with dichloromethane (50 mLϫ3). The
combined organic layers were dried with MgSO4 and concentrated
in vacuo. The crude material was purified by column chromatog-
raphy (diethyl ether/petroleum ether, 70:30) to afford 2-(1,3-benzo-
dioxol-5-yl)ethanol (11, 3.24 g, 88%) as a viscous, colourless oil. Rf
(diethyl ether/petroleum ether, 70:30) = 0.50. 1H NMR (CDCl3,
300 MHz): δ = 2.29 (br. s, 1 H), 2.73 (t, J = 6.6 Hz, 2 H), 3.74 (t,
J = 6.6 Hz, 2 H), 5.88 (s, 2 H), 6.63 (dd, J = 7.8, 1.5 Hz, 1 H),
6.69–6.74 (m, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 38.8 (s),
63.6 (s), 100.8 (s), 108.2 (t), 109.3 (t), 121.8 (t), 132.3 (q), 146.0 (q),
147.6 (q) ppm. HRMS (C9H10O3, [M]+): calcd. for 166.0630; found
166.0628. C9H10O3 (166.17): calcd. C 65.05, H 6.07; found C 64.73,
H 6.10.
2-(1,3-Benzodioxol-5-yl)ethanol (11, 2.0 g, 12.03 mmol) was dis-
solved in dichloromethane (25 mL) in the presence of carbon tetra-
bromide (4.80 g, 14.43 mmol). Triphenylphosphane (3.80 g,
14.48 mmol) was added in portions over a 30 min period, and the
solution was stirred at ambient temperature for 12 h. The white
precipitate was filtered off, and the resulting paste was taken up
with diethyl ether (100 mLϫ2). The combined organic layers were
concentrated to afford a viscous oil, which was distilled under re-
duced pressure (80 °C, 7.6·10–2 Torr) to yield bromide 13 (2.48 g,
89%) as a viscous, colourless oil. Rf (diethyl ether/petroleum ether,
10:90) = 0.70. 1H NMR (CDCl3, 300 MHz): δ = 3.05 (t, J = 7.6 Hz,
2 H), 3.49 (t, J = 7.6 Hz, 2 H), 5.91 (s, 2 H), 6.64–6.67 (m, 2 H),
6.74 (d, J = 7.8 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ =
33.2 (s), 39.0 (s), 100.9 (s), 108.3 (t), 108.9 (t), 121.7 (t), 132.6 (q),
146.4 (q), 147.7 (q) ppm. HRMS (C9H9BrO2, [M]+): calcd. for
227.9786; found 227.9786. C9H9BrO2 (229.07): calcd. C 47.19, H
3.96; found C 47.01, H 3.90.
2-[2-(1,3-Benzodioxol-5-yl)ethyl]-1-(1-phenylethyl)-1,2,3,4-tetrahy-
droquinoline-2-carbonitrile (7d): α-Amino nitrile 6 (1.0 g,
3.81 mmol, mixture of diastereomers, 60:40) was dissolved in THF
(20 mL), and the system was cooled to –80 °C. A THF solution
(5 mL) of LDA [prepared from 1.6  nBuLi in hexane (3.57 mL,
5.71 mmol) and diisopropylamine (0.90 mL, 0.64 g, 6.46 mmol)]
was added by syringe at that temperature over a 10 min period.
The orange solution was allowed to warm to –20 °C for 2 h, and
the reaction mixture was cooled to –80 °C. A THF solution (5 mL)
of iodide 15 (1.57 g, 5.68 mmol) was added dropwise to the anion
solution. The reaction mixture was allowed to warm to –20 °C for
12 h, until TLC indicated the absence of starting material. Water
(15 mL) was then added, and the resulting solution was extracted
with diethyl ether (50 mLϫ3). The combined extracts were dried
with MgSO4, and the solvents were removed under reduced pres-
sure. The crude product was purified by column chromatography
(diethyl ether/petroleum ether, 30:70) to afford 7d (1.12 g, 72%) as
a mixture (52:48) of diastereomers. The mixture was taken up in
ethanol to yield (R*,S*)-7d (0.35 g) as a white powder. A further
slow crystallisation (72 h) of this powder from a biphasic system
(dichloromethane/pentane, 1:5) afforded colourless crystals, which
were analysed by X-ray diffraction.
5-(2-Iodoethyl)-1,3-benzodioxole (15): Bromide 13 (1.72 g,
7.50 mmol) was dissolved in acetone (25 mL) in the presence of
sodium iodide (3.38 g, 22.55 mmol). The solution was heated at
reflux for 24 h, and the excess of sodium iodide was removed by
filtration. The solvent was evaporated under reduced pressure, and
the residue was taken up with diethyl ether and concentrated. Puri-
fication by column chromatography (diethyl ether/petroleum ether,
90:10) yielded iodide 15 (1.97 g, 95%) as a slightly yellow, viscous
oil. Rf = 0.70 (diethyl ether/petroleum ether, 10:90). 1H NMR
(CDCl3, 300 MHz): δ = 3.06 (t, J = 7.8 Hz, 2 H), 3.28 (t, J =
7.8 Hz, 2 H), 5.93 (s, 2 H), 6.62–6.66 (m, 2 H), 6.74 (d, J = 7.7 Hz,
1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 6.10 (s), 39.9 (s), 100.9
(s), 108.3 (t), 108.6 (t), 121.3 (t), 134.4 (q), 146.3 (q), 147.7 (q) ppm.
HRMS (C9H9IO2, [M]+): calcd. for 275.9647; found 275.9654.
C9H9IO2 (276.07): calcd. C 39.16, H 3.29; found C 39.92, H 3.37.
Isomer (R*,S*)-7d: White powder, m.p. 159–161 °C (petroleum
1
ether); Rf = 0.20 (diethyl ether/petroleum ether, 20:80). H NMR
(CDCl3, 300 MHz): δ = 1.81 (d, J = 6.9 Hz, 3 H), 2.09–2.20 (m, 1
H), 2.29–2.41 (m, 1 H), 2.44–2.53 (m, 2 H), 2.68–2.88 (m, 4 H),
5.17 (q, J = 6.9 Hz, 1 H), 5.92 (s, 2 H), 6.29 (d, J = 8.3 Hz, 1 H),
6.57–6.80 (m, 5 H), 6.98 (d, J = 7.2 Hz, 1 H), 7.21 (t, J = 6.6 Hz,
1 H), 7.32 (m, 2 H), 7.39–7.42 (m, 2 H) ppm. 13C NMR (CDCl3,
2-[2-(3,4-Dimethoxyphenyl)ethyl]-1-(1-phenylethyl)-1,2,3,4-tetrahy-
droquinoline-2-carbonitrile (7c): α-Amino nitrile 6 (1.0 g,
3.81 mmol, mixture of diastereomers, 60:40) was dissolved in THF
4628
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4622–4631

Synthesis of Galipea officinalis Alkaloids
75 MHz): δ = 18.3 (p), 23.3 (s), 30.3 (s), 30.5 (s), 38.4 (s), 56.7 (t),
for 401.2355; found 401.2365. C27H31NO2 (401.54): calcd. C 80.76,
61.9 (q), 100.9 (s), 108.4 (t), 108.7 (t), 116.8 (t), 117.5 (t), 121.1 (t), H 7.78, N 3.49; found C 81.20, H 7.80, N 3.50.
121.3 (q), 122.3 (q), 126.0 (t), 126.4 (t), 126.7 (t), 128.5 (t), 128.9
2-[2-(1,3-Benzodioxol-5-yl)ethyl]-1-(1-phenylethyl)-1,2,3,4-tetrahy-
(t), 133.8 (q), 139.9 (q), 141.4 (q), 146.1 (q), 147.8 (q) ppm. HRMS
(C27H26N2O2, [M]+): calcd. for 410.1994; found 433.1870
(C27H26N2O2Na, [M + Na]+). C27H26N2O2 (410.50): calcd. C
79.00, H 6.38, N 6.82; found C 78.88, H 6.42, N 6.76.
droquinoline (16d): Slightly yellow oil, 0.55 g, 78%. Rf = 0.85 (di-
ethyl ether/petroleum ether, 40:60). 1H NMR (CDCl3, 300 MHz):
δ = 1.25–1.40 (m, 1 H), 1.60 (d, J = 7.0 Hz, 3 H), 1.67–1.84 (m, 3
H), 2.36–2.84 (m, 4 H), 3.15–3.24 (m, 1 H), 5.01 (q, J = 7.0 Hz, 1
Isomer (R*,R*)-7d: 13C NMR (CDCl3, 75 MHz): δ = 16.8 (p), 25.1 H), 5.87 (s, 2 H), 6.53–6.60 (m, 3 H), 6.67 (d, J = 8.0 Hz, 1 H),
(s), 30.9 (s), 32.8 (s), 41.8 (s), 57.1 (t), 61.6 (q), 100.8 (s), 108.2 (t),
6.72 (d, J = 7.0 Hz, 1 H), 6.97–7.04 (m, 2 H), 7.17–7.25 (m, 5
108.6 (t), 118.6 (t), 118.8 (t), 120.9 (q), 121.0 (t), 124.9 (q), 126.1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 17.8 (p), 22.7 (s), 23.0
(t), 126.2 (t), 126.5 (t), 128.5 (t), 133.8 (q), 140.7 (q), 141.4 (q),
140.7 (q), 143.4 (q), 145.9 (q), 147.6 (q) ppm.
(s), 32.0 (s), 34.8 (s), 50.8 (t), 57.6 (t), 100.7 (s), 108.0 (t), 108.7 (t),
114.1 (t), 115.8 (t), 120.9 (t), 122.3 (q), 126.6 (t), 126.8 (t), 126.8
(t), 128.1 (t), 129.4 (t), 135.8 (q), 142.4 (q), 144.5 (q), 145.5 (q),
147.5 (q) ppm. HRMS (C26H27NO2, [M]+): calcd. for 385.2042;
found 385.2049. C26H27NO2 (385.50): calcd. C 81.01, H 7.06, N
3.63; found C 80.80, H 7.12, N 3.66.
General Procedure for the Reductive Decyanation of α-Aminonitriles
7a–d: NaBH4 (4 equiv.) was added in portions to an ethanolic solu-
tion (25 mL) of an α-aminonitrile 7a–d. After complete dissolution
(approximately 15 min) the solution was stirred at room tempera-
ture for 12 h. The solution was then heated at reflux for 3 h until
TLC indicated the absence of starting material. The solvent was
removed under reduced pressure, and the crude material was taken
up with ammonia solution (15 %, 50 mL) and extracted with
dichloromethane (50 mLϫ3). The combined organic layers were
dried with MgSO4 and concentrated under reduced pressure. The
crude mixtures of amines 16a–d were purified by column
chromatography.
General Procedure for the Hydrogenolysis of Tetrahydroquinolines
16a–d: Pearlman’s catalyst [20% Pd(OH)2–C, 20% in weight] was
placed in a low-pressure hydrogenator in the presence of tetra-
hydroquinolines 16a–d dissolved in a mixture (4:1) of methanol and
ethyl acetate. The desired hydrogen pressure (7.35ϫ102 Torr, 1 bar)
was applied, and the solution was stirred for 48 h. The catalyst was
removed by filtration through a Celite bed and washed with etha-
nol. The solvents were evaporated under reduced pressure, and the
crude mixture was purified by column chromatography to yield
tetrahydroquinolines 17a–d.
1-(1-Phenylethyl)-2-propyl-1,2,3,4-tetrahydroquinoline (16a):
Colourless oil, 1.23 g, 93 %. Rf = 0.80 (diethyl ether/petroleum
1
ether, 5:95). H NMR (CDCl3, 300 MHz): δ = 0.86 (t, J = 7.3 Hz,
2-Propyl-1,2,3,4-tetrahydroquinoline (17a): Colourless oil, 0.64 g,
3 H), 1.20–1.50 (m, 6 H), 1.64 (d, J = 7.0 Hz, 3 H), 2.54–2.60 (m, 70%. Rf = 0.80 (diethyl ether/petroleum ether, 10:90). 1H NMR
1 H), 2.72–2.76 (m, 1 H), 3.14–3.21 (m, 1 H), 5.02 (q, J = 7.0 Hz, (CDCl3, 500 MHz): δ = 0.94 (t, J = 7.2 Hz, 3 H), 1.37–1.47 (m, 4
1 H), 6.57 (t, J = 7.3 Hz, 1 H), 6.70 (d, J = 8.0 Hz, 1 H), 6.95–7.00
H), 1.54–1.61 (m, 1 H), 1.90–1.94 (m, 1 H), 2.73 (dt, J = 16.4,
(m, 2 H), 7.17–7.31 (m, 5 H) ppm. 13C NMR (CDCl3, 75 MHz): δ 4.9 Hz, 1 H), 2.79 (ddd, J = 16.4, 11.0, 5.6 Hz, 1 H), 3.19–3.24 (m,
= 14.2 (p), 17.8 (p), 19.2 (s), 22.8 (s), 23.1 (s), 35.2 (s), 51.3 (t), 57.5
1 H), 3.50–3.65 (br. s, 1 H), 6.44 (d, J = 7.6 Hz, 1 H), 6.57 (td, J
(t), 113.9 (t), 115.6 (t), 122.4 (q), 126.6 (t), 126.7 (t), 126.8 (t), 128.2 = 7.3, 1.1 Hz, 1 H), 6.92–6.95 (m, 2 H) ppm. 13C NMR (CDCl3,
(t), 129.4 (t), 142.7 (q), 144.6 (q) ppm. HRMS (C20H25N, [M]+): 125 MHz): δ = 14.1 (p), 18.8 (s), 26.4 (s), 28.0 (s), 38.8 (s), 51.2 (t),
calcd. for 279.1987; found 279.1984. C20H25N (279.42): calcd. C
85.97, H 9.02, N 5.01; found C 85.64, H 9.14, N 4.82.
114.0 (t), 116.8 (t), 121.3 (q), 126.6 (t), 129.2 (t), 144.6 (q) ppm.
HRMS (C12H17N, [M]+): calcd. for 175.1361; found 175.1358.
C12H17N (175.27): calcd. C 82.23, H 9.78, N 7.99; found C 82.36,
H 9.82, N 7.73.
2-Pentyl-1-(1-phenylethyl)-1,2,3,4-tetrahydroquinoline (16b):
Colourless oil, 1.5 g, 89%. Rf = 0.90 (diethyl ether/petroleum ether,
1
5:95). H NMR (CDCl3, 500 MHz): δ = 0.85 (t, J = 6.8 Hz, 3 H), 2-Pentyl-1,2,3,4-tetrahydroquinoline (17b): Colourless oil, 1.00 g,
1.00–1.52 (m, 9 H), 1.64 (d, J = 7.0 Hz, 3 H), 1.65–1.68 (m, 1 H), 93 %. Rf = 0.80 (diethyl ether/petroleum ether, 5:95). 1H NMR
2.56–2.60 (m, 1 H), 2.71–2.78 (m, 1 H), 3.14–3.18 (m, 1 H), 5.03
(q, J = 7.0 Hz, 1 H), 6.57 (td, J = 7.3, 1.0 Hz, 1 H), 6.70 (d, J =
(CDCl3, 500 MHz): δ = 0.90 (t, J = 6.9 Hz, 3 H), 1.25–1.37 (m, 6
H), 1.44–1.47 (m, 2 H), 1.52–1.61 (m, 1 H), 1.89–1.94 (m, 1 H),
8.2 Hz, 1 H), 6.96–7.00 (m, 2 H), 7.20–7.35 (m, 5 H) ppm. 13C 2.68 (dt, J = 16.3, 4.6 Hz, 1 H), 2.78 (ddd, J = 16.3, 11.1, 5.5 Hz,
NMR (CDCl3, 125 MHz): δ = 14.0 (p), 17.8 (p), 22.6 (s), 22.8 (s), 1 H), 3.16–3.21 (m, 1 H), 3.50–3.80 (br. s, 1 H), 6.43 (d, J = 7.6 Hz,
23.1 (s), 25.6 (s), 31.9 (s), 32.9 (s), 51.6 (t), 57.4 (t), 113.7 (t), 115.5
1 H), 6.57 (td, J = 7.4, 1.1 Hz, 1 H), 6.91–6.94 (m, 2 H) ppm. 13C
(t), 122.4 (q), 126.6 (t), 126.7 (t), 126.8 (t), 128.2 (t), 129.4 (t), 142.7 NMR (CDCl3, 125 MHz): δ = 14.0 (p), 22.6 (s), 25.3 (s), 26.4 (s),
(q), 144.6 (q) ppm. HRMS (C22H29N, [M]+): calcd. for 307.2300; 28.0 (s), 31.9 (s), 36.6 (s), 51.5 (t), 114.0 (t), 116.8 (t), 121.2 (q),
found 307.2307. C22H29N (307.47): calcd. C 85.94, H 9.51, N 4.56;
found C 85.85, H 9.43, N 4.60.
126.6 (t), 129.2 (t), 144.7 (q) ppm. HRMS (C14H21N, [M]+): calcd.
for 203.1674; found 203.1670. C14H21N (203.32): calcd. C 82.70, H
10.41, N 6.89; found C 82.51, H 10.30, N 6.70.
2-[2-(3,4-Dimethoxyphenyl)ethyl]-1-(1-phenylethyl)-1,2,3,4-tetrahy-
droquinoline (16c): Slightly yellow oil, 0.63 g, 75%. Rf = 0.60 (di-
ethyl ether/petroleum ether, 40:60). 1H NMR (CDCl3, 300 MHz):
2-[2-(3,4-Dimethoxyphenyl)ethyl]-1,2,3,4-tetrahydroquinoline (17c):
Slightly yellow oil, 0.63 g, 72%. Rf = 0.40 (diethyl ether/petroleum
δ = 1.25–1.44 (m, 1 H), 1.59 (d, J = 7.0 Hz, 3 H), 1.65–1.89 (m, 3 ether, 40:60). 1H NMR (CDCl3, 500 MHz): δ = 1.63–1.67 (m, 1 H),
H), 2.39–2.49 (m, 1 H), 2.54–2.65 (m, 2 H), 2.70–2.86 (m, 1 H),
1.76–1.82 (m, 2 H), 1.95–2.00 (m, 1 H), 2.67 (t, J = 8.0 Hz, 2 H),
3.19–3.22 (m, 1 H), 3.81 (s, 3 H), 3.83 (s, 3 H), 5.01 (q, J = 7.0 Hz, 2.70–2.82 (m, 2 H), 3.25–3.30 (m, 1 H), 3.73 (s, 3 H), 3.40–3.70 (br.
1 H), 6.57–6.72 (m, 3 H), 6.73–6.76 (m, 2 H), 6.97–7.02 (m, 2 H),
7.18–7.29 (m, 5 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 17.8 (p),
22.7 (s), 23.1 (s), 31.9 (s), 34.6 (s), 50.9 (t), 55.8 (p), 55.9 (p), 57.7
s, 1 H), 3.87 (s, 3 H), 6.34 (d, J = 7.5 Hz, 1 H), 6.59 (t, J = 7.4, Hz,
1 H), 6.71–6.74 (m, 2 H), 6.78 (d, J = 8.0 Hz, 1 H), 6.92–6.94 (m,
2 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 26.1 (s), 27.9 (s), 31.7
(t), 111.2 (t), 111.5 (t), 114.1 (t), 115.8 (t), 120.0 (t), 122.3 (q), 126.6 (s), 38.3 (s), 51.1 (t), 55.8 (p), 55.9 (p), 111.2 (t), 111.5 (t), 114.1
(t), 126.7 (t), 126.8 (t), 128.1 (t), 129.4 (t), 134.6 (q), 142.4 (q), 144.6 (t), 116.9 (t), 120.0 (t), 121.2 (q), 126.6 (t), 129.2 (t), 134.4 (q), 144.4
(q), 147.1 (q), 148.7 (q) ppm. HRMS (C27H31NO2, [M]+): calcd. (q), 147.2 (q), 148.8 (q) ppm. HRMS (C19H23NO2, [M]+): calcd.
Eur. J. Org. Chem. 2008, 4622–4631
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4629

J.-P. Hurvois et al.
FULL PAPER
for 297.1729; found 297.1721. C19H23NO2 (297.39): calcd. C 76.73,
H 7.80, N 4.71; found C 77.50, H 7.97, N 4.78.
2-[2-(1,3-Benzodioxol-5-yl)ethyl]-1-methyl-1,2,3,4-tetrahydroquino-
line (4): Slightly yellow oil, 0.15 g, 80%. Rf = 0.50 (diethyl ether/
petroleum ether, 10:90). 1H NMR (CDCl3, 300 MHz): δ = 1.58–
1.73 (m, 1 H), 1.80–1.95 (m, 3 H), 2.46 (ddd, J = 16.4, 10.0, 6.6 Hz,
1 H), 2.56–2.70 (m, 2 H), 2.76–2.85 (m, 1 H), 2.87 (s, 3 H), 3.20–
3.27 (m, 1 H), 5.87 (s, 2 H), 6.50 (d, J = 8.2 Hz, 1 H), 6.55–6.62
(m, 2 H), 6.66 (d, J = 1.4 Hz, 1 H), 6.70 (d, J = 7.9 Hz, 1 H), 6.95
(d, J = 7.3 Hz, 1 H), 7.06 (t, J = 8.4 Hz, 1 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 23.5 (s), 24.3 (s), 31.9 (s), 33.0 (s), 38.0 (p),
58.1 (t), 100.7 (s), 108.1 (t), 108.6 (t), 110.5 (t), 115.4 (t), 120.9 (t),
121.6 (q), 127.0 (t), 128.6 (t), 135.7 (q), 145.2 (q), 145.5 (q), 147.5
(q) ppm. HRMS (C19H21NO2, [M]+): calcd. for 295.1572; found
295.1563. C19H21NO2 (295.38): calcd. C 77.26, H 7.17, N 4.74;
found C 77.10, H 7.11, N 4.63.
2-[2-(1,3-Benzodioxol-5-yl)ethyl]-1,2,3,4-tetrahydroquinoline (17d):
Slightly yellow oil, 0.30 g, 95%. Rf = 0.40 (diethyl ether/petroleum
ether, 10:10). 1H NMR (CDCl3, 300 MHz): δ = 1.55–1.81 (m, 3 H),
1.93–2.01 (m, 1 H), 2.62–2.86 (m, 4 H), 3.23–3.31 (m, 1 H), 3.50–
4.20 (br. s, 1 H), 5.91 (s, 2 H), 6.45 (d, J = 8.2 Hz, 1 H), 6.58 (t, J
= 7.3 Hz, 1 H), 6.62–6.74 (m, 3 H), 6.92–6.97 (m, 2 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 26.2 (s), 27.9 (s), 31.8 (s), 38.4 (s),
50.9 (t), 100.8 (s), 108.2 (t), 108.7 (t), 114.1 (t), 117.0 (t), 121.01 (t),
121.2 (q), 126.7 (t), 129.2 (t), 135.6 (q), 144.4 (q), 145.7 (q), 147.6
(q) ppm. HRMS (C18H19NO2, [M]+): calcd. for 281.1416; found
281.1435.
General Procedure for the Methylation of Tetrahydroquinolines 17a–
d: Iodomethane (6 equiv.) was added to a THF (15 mL) solution
of a tetrahydroquinoline 17a–d in the presence of powdered K2CO3
(1 equiv.). The reaction mixture was heated at reflux for 12 h. The
solvent was removed under reduced pressure, and the resulting
paste was taken up with ammonia solution (10%). The aqueous
layer was extracted with diethyl ether (50 mLϫ3), and the com-
bined organic layers were dried with MgSO4. The solvent was re-
moved under reduced pressure and the residues were purified by
column chromatography to yield compounds 1–4.
X-ray Crystallographic Study: Crystallographic data were collected
with an APEX-II, Bruker-AXS diffractometer with use of graphite-
monochromated Mo-Kα radiation. Details are given in Table 5. The
structures were solved by direct methods with SIR-97,[25] which
revealed the non-hydrogen atoms of the molecules. Refinement was
performed by full-matrix, least-squares techniques based on F2
with SHELXL-97,[26] with the aid of the WINGX[27] program. All
non-hydrogen atoms were refined with anisotropic thermal param-
eters. H atoms were finally included in their calculated positions.
Figures were drawn with ORTEP-3 for Windows.[28]
1-Methyl-2-propyl-1,2,3,4-tetrahydroquinoline (1): Colourless oil,
0.25 g, 90%. Rf = 0.80 (diethyl ether/petroleum ether, 5:95). 1H
NMR (CDCl3, 500 MHz): δ = 0.91 (t, J = 7.2 Hz, 3 H), 1.23–1.30
(m, 1 H), 1.33–1.41 (m, 2 H), 1.52–1.58 (m, 1 H), 1.84–1.86 (m, 2
H), 2.62 (dt, J = 16.2, 4.1 Hz, 1 H), 2.74–2.81 (m, 1 H), 2.89 (s, 3
H), 3.19–3.24 (m, 1 H), 6.49 (d, J = 8.2 Hz, 1 H), 6.56 (td, J = 7.3,
1.0 Hz, 1 H), 6.94 (d, J = 7.3 Hz, 1 H), 7.05 (t, J = 7.4 Hz, 1
H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 14.2 (p), 19.3 (s), 23.5
(s), 24.4 (s), 33.5 (s), 37.9 (p), 58.6 (t), 110.3 (t), 115.1 (t), 121.7
(q), 127.0 (t), 128.6 (t), 145.3 (q) ppm. HRMS (C13H19N, [M]+):
calcd. for 189.1517; found 189.1514. C13H19N (189.30): calcd. C
82.48, H 10.12, N 7.40; found C 82.43, H 10.22, N 7.27.
Table 5. X-ray crystallographic data for (R*,S*)-7a and (R*,S*)-7d.
(R*,S*)-7a
(R*,S*)-7d
Formula
Molecular mass
Crystal system
Space group
DX [Mgm–3]
a [Å]
b [Å]
c [Å]
α [°]
β [°]
C21H24N2
304.42
C27H26N2O2
410.50
triclinic
triclinic
¯
¯
P1
P1
1.183
1.301
8.2420(11)
8.5349(14)
12.174(2)
89.041(6)
86.935(5)
88.260(5)
854.7(2)
2
10.3357(12)
10.4684(12)
10.9313(13)
107.871(6)
109.627(6)
91.988(7)
1047.7(2)
2
1-Methyl-2-pentyl-1,2,3,4-tetrahydroquinoline (2): Colourless oil,
0.30 g, 85%. Rf = 0.85 (diethyl ether/petroleum ether, 5:95). 1H
NMR (CDCl3, 500 MHz): δ = 1.00 (t, J = 6.9 Hz, 3 H), 1.31–1.54
(m, 8 H), 1.65–1.72 (m, 1 H), 1.93–2.00 (m, 2 H), 2.74 (dt, J =
16.2, 4.1 Hz, 1 H), 2.86–2.93 (m, 1 H), 3.01 (s, 3 H), 3.29–3.34 (m,
1 H), 6.61 (d, J = 8.2 Hz, 1 H), 6.67 (td, J = 7.3, 1.0 Hz, 1 H), 7.06
(d, J = 7.3 Hz, 1 H), 7.17 (t, J = 7.0 Hz, 1 H) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 14.0 (p), 22.6 (s), 23.5 (s), 24.4 (s), 25.7 (s),
31.1 (s), 32.0 (s), 37.9 (p), 58.9 (t), 110.3 (t), 115.1 (t), 121.7 (q),
127.0 (t), 128.6 (t), 145.3 (q) ppm. HRMS (C15H23N, [M]+): calcd.
for 217.1830; found 189.1830. C15H23N (217.35): calcd. C 82.89, H
10.67, N 6.44; found C 82.13, H 10.48, N 6.40.
γ [°]
V [Å–3]
Z
F(000)
328
0.69
436
0.82
µ [cm–1]
λ (Mο–Kα) [Å]
T [K]
Crystal size [mm]
Radiation
Maximum θ [°]
Range of hkl
0.71073
100(2)
0.60ϫ0.40ϫ0.26
Mο-Kα
27.48
–10Ǟ6, –11Ǟ11,
–15Ǟ15
0.71073
100(2)
0.63ϫ0.48ϫ0.32
Mο-Kα
27.48
–13Ǟ13, –13Ǟ13,
–14Ǟ14
4797
Reflections measured 3880
Reflections observed 3100
[IϾ2.0σ(I)]
4143
2-[2-(3,4-Dimethoxyphenyl)ethyl]-1-methyl-1,2,3,4-tetrahydroquino-
line (3): Slightly yellow oil, 0.66 g, 75%. Rf = 0.45 (diethyl ether/
petroleum ether, 40:60). 1H NMR (CDCl3, 500 MHz): δ = 1.65–
1.73 (m, 1 H), 1.84–1.93 (m, 3 H), 2.48 (ddd, J = 16.5, 10.1, 6.4 Hz,
1 H), 2.59–2.66 (m, 2 H), 2.81 (ddd, J = 17.5, 12.2, 6.0 Hz, 1 H),
2.86 (s, 3 H), 3.21–3.25 (m, 1 H), 3.78 (s, 3 H), 3.81 (s, 3 H), 6.49
(d, J = 8.1 Hz, 1 H), 6.56 (td, J = 7.3, 1.0 Hz, 1 H), 6.67–6.69 (m,
2 H), 6.73 (d, J = 8.3 Hz, 1 H), 6.94 (d, J = 7.2 Hz, 1 H), 7.04 (t,
J = 8.3 Hz, 1 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 23.5 (s),
24.3 (s), 31.8 (s), 32.9 (s), 37.9 (p), 55.7 (p), 55.7 (p), 58.2 (t), 110.5
(t), 111.2 (t), 111.5 (t), 115.3 (t), 120.0 (t), 121.5 (q), 127.0 (t), 128.6
(t), 134.5 (q), 145.2 (q), 147.1 (q), 148.8 (q) ppm. HRMS
(C20H25NO2, [M]+): calcd. for 311.1885; found 311.1906.
C20H25NO2 (311.42): calcd. C 77.14, H 8.09, N 4.50; found C
77.10, H 8.11, N 4.53.
Final R1
wR2
0.0467
0.1142
0.0428
0.1144
CCDC-687864 [for (R*,S*)-7a] and -687865 [for (R*,S*)-7d] con-
tain the supplementary crystallographic data. These data can be
obtained from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgments
J. M. is grateful to the Région Bretagne for a three-year doctoral
fellowship, and F. L. is grateful to the Programme Franco-Algérien
4630
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4622–4631

Synthesis of Galipea officinalis Alkaloids
[14]
[15]
For a general survey on the anodic oxidation of nitrogen-con-
taining compounds see: a) E. Steckhan in Organic Electrochem-
istry (Eds.: H. Lund, O. Hammerich), Marcel Dekker, New
York, 2001, pp. 545–588; b) T. Shono, Tetrahedron 1984, 40,
811–850; c) C. Levraud, S. Calvet-Vitale, G. Bertho, H. Dhim-
ane, Eur. J. Org. Chem. 2008, 1901–1909.
E. Le Gall, J.-P. Hurvois, T. Renaud, C. Moinet, A. Tallec, P.
Uriac, S. Sinbandhit, L. Toupet, Liebigs Ann./Recueil 1997,
2089–2101. In this paper, α-amino nitrile 6 was prepared on a
1 g scale through the use of a flow cell with porous graphite
felt.
de Formation Supérieure en France (PROFAS) for a doctoral fel-
lowship. We are grateful for the financial support (Projet Thera-
quine) from the Région Bretagne.
[1] a) I. Jacquemond-Collet, S. Hannedouche, N. Fabre, I. Four-
asté, C. Moulis, Phytochemistry 1999, 51, 1167–1169; b) I. Jac-
quemond-Collet, J.-M. Bessière, S. Hannedouche, C. Bertrand,
I. Fourasté, C. Moulis, Phytochem. Anal. 2001, 12, 312–319.
[2] I. Mester, Fitoterapia 1973, 44, 123–152.
[3] I. Jacquemond-Collet, F. Benoit-Vical, Mustofa, A. Valentin,
E. Stanislas, M. Mallié, I. Fourasté, Planta Med. 2002, 68, 68–
69.
[16]
[17]
[18]
S. T. Handy, Y. Zhang, H. Bregman, J. Org. Chem. 2004, 69,
2362–2366.
P. D. Bailey, K. M. Morgan, D. I. Smith, J. M. Vernon, Tetra-
hedron 2003, 59, 3369–3378.
[4] a) W.-B. Wang, S.-M. Lu, P.-Y. Yang, X.-W. Han, Y.-G. Zhou,
J. Am. Chem. Soc. 2003, 125, 10536–10537; b) M. Rueping,
A. P. Antonchick, T. Theissmann, Angew. Chem. Int. Ed. 2006,
45, 3683–3686; c) S.-M. Lu, Y.-Q. Wang, X.-W. Han, Y.-G.
Zhou, Angew. Chem. Int. Ed. 2006, 45, 2260–2263; d) W.-J.
Tang, S.-F. Zhu, L.-J. Xu, Q.-L. Zhou, Q.-H. Fan, H.-F. Zhou,
K. Lam, A. S. C. Chan, Chem. Commun. 2007, 613–615.
[5] C. Theeraladanon, M. Arisawa, M. Nakagawa, A. Nishida,
Tetrahedron: Asymmetry 2005, 16, 827–831.
a) M. Bonin, J. R. Romero, D. S. Grierson, H.-P. Husson, Tet-
rahedron Lett. 1982, 23, 3369–3372; b) S.-I. Yamada, H. Akim-
oto, Tetrahedron Lett. 1969, 3105–3108; c) R. P. Polniaszek,
S. E. Belmont, J. Org. Chem. 1991, 56, 4868–4874; d) G. Stork,
R. M. Jacobson, R. Levitz, Tetrahedron Lett. 1979, 9, 771–774.
K. Ogura, Y. Shimamura, M. Fujita, J. Org. Chem. 1991, 56,
2920–2922.
a) L. Guerrier, J. Royer, D. S. Grierson, H.-P. Husson, J. Am.
Chem. Soc. 1983, 105, 7754–7755; b) D. S. Grierson, J. Royer,
L. Guerrier, H.-P. Husson, J. Org. Chem. 1986, 51, 4475–4477.
N. Girard, C. Gautier, R. Malassene, J.-P. Hurvois, C. Moinet,
L. Toupet, Synlett 2004, 2005–2009.
a) C. Fabre, Z. Welvart, C. R. Acad. Sci. 1970, 1887–1889; b)
W. H. Bunnelle, C. G. Shevlin, Tetrahedron Lett. 1989, 30,
4203–4206.
D. François, E. Poupon, N. Kunesch, H.-P. Husson, Eur. J.
Org. Chem. 2004, 4823–4829.
P. Deslongchamps, in Stereoelectronic Effects in Organic Chem-
istry, Pergamon, New York, 1983, chapter 6, pp. 209–287.
A. Altomare, M. C. Burla, M. Camalli, G. Cascarano, C. Gia-
covazzo, A. Guargliardi, A. G. G. Moliterni, G. Polidori, R.
Spagna, J. Appl. Cryst. 1999, 32, 115–119.
G. M. Sheldrick, SHELX97, Programs for Crystal Structure
Analysis (Release 97-2), University of Göttingen, Germany,
1998.
[19]
[20]
[6] N. T. Patil, H. Wu, Y. Yamamoto, J. Org. Chem. 2007, 72,
6577–6579.
[7] Y. Yamaoka, H. Miyabe, Y. Takemoto, J. Am. Chem. Soc. 2007,
129, 6686–6687.
[8] X.-F. Lin, Y. Li, D.-W. Ma, Chin. J. Chem. 2004, 22, 932–934.
[9] F. Avemaria, S. Vanderheiden, S. Bräse, Tetrahedron 2003, 59,
6785–6796.
[10] a) N. Girard, J.-P. Hurvois, Tetrahedron Lett. 2007, 48, 4097–
4099; b) J. Moreau, A. Duboc, C. Hubert, J.-P. Hurvois, J.-L.
Renaud, Tetrahedron Lett. 2007, 48, 8647–8650; c) N. Girard,
L. Pouchain, J.-P. Hurvois, C. Moinet, Synlett 2006, 1679–
1682.
[11] For a general survey see: a) M. Balasubramanian, J. G. Keay
in Comprehensive Heterocyclic Chemistry (Ed.: A. McKillop),
Pergamon Press, Oxford, 1996, vol. 5, chapter 5, pp. 245–300;
b) A. R. Katrizky, S. Rachwal, B. Rachwal, Tetrahedron 1996,
52, 15031–15070.
[12] a) D. Seebach, D. Enders, Angew. Chem. Int. Ed. Engl. 1975,
14, 15–32; b) for a general review on α-amino nitrile chemistry
see: D. Enders, J. P. Shilvock, Chem. Soc. Rev. 2000, 29, 359–
373.
[13] For synthetic application of metallated α-amino nitriles see: H.-
P. Husson, J. Royer, Chem. Soc. Rev. 1999, 28, 383–394.
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
L. J. Farrugia, J. Appl. Crystallogr. 1999, 32, 837–838.
L. J. Farrugia, J. Appl. Crystallogr. 1998, 30, 565–567.
Received: May 27, 2008
Published Online: August 19, 2008
Eur. J. Org. Chem. 2008, 4622–4631
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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