Study of alkaloids of the Siberian and Altai flora 14. Synthesis of alkaloid-based tertiary N-(3-arylprop-2-ynyl)amines

Article abstract of DOI:10.1007/s11172-007-0191-0

3-Arylprop-2-ynylamines containing the key fragment of known alkaloids of the Altai flora were synthesized by the Sonogashira and Mannich reactions.

Full text of DOI:10.1007/s11172-007-0191-0

Russian Chemical Bulletin, International Edition, Vol. 56, No. 6, pp. 1261—1267, June, 2007
1261
Study of alkaloids of the Siberian and Altai flora
14.* Synthesis of alkaloidꢀbased tertiary Nꢀ(3ꢀarylpropꢀ2ꢀynyl)amines**
S. A. Osadchii,a E. E. Shults,aꢀ E. V. Polukhina,a M. M. Shakirov,a S. F. Vasilevskii,b
A. A. Stepanov,b and G. A. Tolstikova
aN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences,
9 prosp. Akad. Lavrent´eva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 330 9752. Eꢀmail: schultz@nioch.nsc.ru
bInstitute of Chemical Kinetics and Combustion, Siberian Branch of the Russian Academy of Sciences,
3 ul. Institutskaya, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 330 7350
3ꢀArylpropꢀ2ꢀynylamines containing the key fragment of known alkaloids of the Altai flora
were synthesized by the Sonogashira and Mannich reactions.
Key words: Sonogashira reaction, Mannich reaction, alkaloids, (–)ꢀanabasine, (–)ꢀcytisine,
(–)ꢀephedrine, (+)ꢀpseudoephedrine, alkynes.
Acetylenic nitrogenꢀcontaining compounds have
medically valuable biological properties. Some of these
compounds serve as efficient anticancer agents,2,3 antituꢀ
mor antibiotics,4 HIV reverse transcriptase inhibitors,5
and important synthetic intermediates.6—10 Among 3ꢀarylꢀ
propꢀ2ꢀynyldialkylamine derivatives of the general forꢀ
mula Ar—C≡C—CH2—N(Alk)2 (1), enzyme inhibitors,
viz., inhibitors of mammalian squalene epoxidase, were
found.11
The aim of the present study was to synthesize 3ꢀarylꢀ
propꢀ2ꢀynylamines 1 starting from 2ꢀ(Nꢀacetylamino)ꢀ5ꢀ
iodobenzoates and secondary amines, including those
based on available alkaloids of the Altai flora.
Initially, we have tested the synthesis of compounds 1
using one of the known modifications of the Sonogashira
crossꢀcoupling reaction of ethyl 2ꢀ(Nꢀacetylamino)ꢀ5ꢀ
iodobenzoate (2) with 3ꢀNꢀmorpholinopropyne (3) as
an example.16 This reaction afforded the target ethyl
2ꢀ(Nꢀacetylamino)ꢀ5ꢀ(3ꢀmorpholinopropꢀ1ꢀynꢀ1ꢀ
yl)benzoate (4) in 66% yield (Scheme 1).
Scheme 1
Results and Discussion
One of approaches to the synthesis of compounds 1 is
based on the Sonogashira reaction,12 viz., the crossꢀ
coupling of aryl halides with alkynes (in the case under
consideration, with 3ꢀdialkylaminopropꢀ1ꢀynes) catalyzed
by the palladium complex and copper(I) salts. Another
approach to the synthesis of these compounds is based on
the classical Mannich reaction involving the threeꢀcomꢀ
ponent reaction of terminal arylalkyne, formaldehyde
(generated in situ from paraformaldehyde), and secondꢀ
ary amine.13,14 The use of CuCl 5,9 or CuI 15 as the cataꢀ
lyst substantially extended the scope of the Mannich reꢀ
action, particularly, for poorly active alkynes.
The Mannich condensation proved to be the method
of choice for the synthesis of compounds 1 because the
starting reagents are more readily available. We chose
methyl 2ꢀ(Nꢀacetylamino)ꢀ5ꢀethynylbenzoate (5) as the
acetylenic component; diethylamine (6a), pyrrolidine
(6b), piperidine (6c), morpholine (6d), and alkaloids,
such as (–)ꢀanabasine (6e), (–)ꢀcytisine (6f), (–)ꢀepheꢀ
* For Part 13, see Ref. 1.
** Dedicated to the memory of Academician N. N. Vorozhtsov
on the 100th anniversary of his birth.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1215—1221, June, 2007.
1066ꢀ5285/07/5606ꢀ1261 © 2007 Springer Science+Business Media, Inc.

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Osadchii et al.
Scheme 2
Reagents and conditions: a. Me3SiC≡CH, Pd(PPh3)2Cl2, PPh3, CuI, Et3N, C6H6, 53—55 °C, 8 h. b. Bu4NF, CH2Cl2.
c. K2CO3, MeOH. d. CH2N2, Et2O.
Scheme 3
drine (6g), and (+)ꢀpseudoephedrine (6h), were used as
secondary amines.
Methyl 2ꢀ(Nꢀacetylamino)ꢀ5ꢀethynylbenzoate (5)
necessary for the Mannich reaction was synthesized acꢀ
cording to Scheme 2. The condensation reaction of meꢀ
thyl 2ꢀ(Nꢀacetylamino)ꢀ5ꢀiodobenzoate (7) with triꢀ
methylsilylacetylene was carried out under the conditions
described in the study.16 Desilylation of methyl 2ꢀ(Nꢀaceꢀ
tylamino)ꢀ5ꢀ(trimethylsilylethynyl)benzoate (8) thus preꢀ
pared (in 95% yield) with Bu4NF in CH2Cl2 afforded
target compound 5 in 77% yield. The use of the less exꢀ
pensive reagent, K2CO3, for the cleavage of silyl derivaꢀ
tive 8 also gave rise to product 5 (in 76% yield), but this
reaction additionally produced 2ꢀ(Nꢀacetylamino)ꢀ5ꢀ
ethynylbenzoic acid (9) in ~2% yield. The structure of the
latter product was confirmed by spectroscopic data and as
well as by its transformation into compound 5 by methyꢀ
lation with diazomethane.
The condensation of methyl 2ꢀ(Nꢀacetylamino)ꢀ5ꢀ
ethynylbenzoate (5) with secondary amines 6a—h and
formaldehyde, which was generated in situ from paraformꢀ
aldehyde, was carried out by the modified Mannich reacꢀ
tion5 in the presence of catalytic amounts of CuI in diꢀ
oxane at 85—90 °C. The yields of target compounds 10a—g
were 75—92% based on consumed arylacetylene 5
(Scheme 3); the yield of compound 10h was somewhat
lower (51%).
6, 10
NR1R2
NEt2
Yield of 10 (%)
a
90
b
c
d
92
87
75
e
f
77
92
The reaction of (–)ꢀephedrine (6g) produced target
Mannich base 10g (in 86% yield) along with (4S,5R)ꢀ3,4ꢀ
dimethylꢀ5ꢀphenyloxazolidine (11). The reaction of
(+)ꢀpseudoephedrine (6h) gave not only target product
10h (in 51% yield) but also (4S,5S)ꢀ3,4ꢀdimethylꢀ5ꢀ
phenyloxazolidine (12).
The formation of byꢀproducts 11 and 12 can be
explained as follows. The hemiaminals (1R,2S)ꢀ2ꢀ
(NꢀhydroxymethylꢀNꢀmethylamino)ꢀ1ꢀphenylpropanꢀ
1ꢀol (13) and (1S,2S)ꢀ2ꢀ(NꢀhydroxymethylꢀNꢀmethylꢀ
g
h
86
51

Mannich reaction of alkaloids
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
1263
plant sources. (–)ꢀAnabasine ((2R)ꢀ3ꢀ(2ꢀpiperidinyl)pyridine)
(6e), b.p. 104—105 °C (2 Torr) (cf. lit. data23: b.p. 145—146 °C
amino)ꢀ1ꢀphenylpropanꢀ1ꢀol (14) are potential intermeꢀ
diates of the reaction of formaldehyde with (–)ꢀepheꢀ
drine and (+)ꢀpseudoephedrine, respectively. These comꢀ
pounds can undergo also intramolecular cyclization to
form byꢀproducts, viz., oxazolidines 11 and 12, respecꢀ
tively (Scheme 4). Since oxazolidine 11 contains the pheꢀ
nyl and 4ꢀmethyl groups in the sterically hindered cis poꢀ
sitions, the cyclization of compound 13 evidently proꢀ
ceeds more slowly than the cyclization of compound 14
producing oxazolidine 12 with the nonhindered trans arꢀ
rangement of these groups. This accounts for the fact that
compound 14 is more rapidly consumed in the side cyꢀ
clization reaction yielding oxazolidine 12 compared to
compound 13 (cf. Ref. 17).
(14 Torr), nD 1.5428; cf. lit. data24: nD 1.5430, [α]23 –62
20
20
578
(c 5, C6H6), [α]D –71.24 (c 6.9, C6H6)) was extracted from the
aerial part of the plant Anabasis (Anabasis aphylla L.) according
to a known procedure.25 (–)ꢀCytisine ((1R,5S)ꢀmethanoꢀ8Hꢀ
pyrido[1,2ꢀa][1,5]diazocinꢀ8ꢀone) (6f), m.p. 153—154 °C (from
acetone) (cf. lit. data26: m.p. 153—154 °C (from acetone),
17
[α]20
–122 (c 2, H2O); cf. lit. data23: [α]D –119.6 (H2O))
578
was extracted from seeds of the plant Thermopsis lanceolata R. Br.
(lanceleaf false lupine) according to a procedure published earꢀ
lier.26 (–)ꢀEphedrine ((1R,2S)ꢀ2ꢀmethylaminoꢀ1ꢀphenylproꢀ
panꢀ1ꢀol) (6g), m.p. 38—39 °C (from hexane) (cf. lit. data27
:
m.p. 38—39 °C (from petroleum ether)) was prepared from
hydrochloride, m.p. 216—217 °C (from EtOH), [α]20
–36
578
(c 2, H2O) (cf. lit. data27: m.p. 216—217 °C (from EtOH),
[α]589 –34.4 (c 1.5, H2O)). The latter was synthesized from
ephedrine, which was extracted from the softwood aerial part of
Ephedra equisetina Bunge (Mongolian ephedra) according to a
known procedure.28 (+)ꢀPseudoephedrine ((1S,2S)ꢀ2ꢀmethylꢀ
aminoꢀ1ꢀphenylpropanꢀ1ꢀol) (6h), m.p. 118—119 °C (subꢀ
limed at 100 °C (12 Torr) after crystallization from benzene),
Scheme 4
[α]20 +53 (c 3, EtOH) (cf. lit. data27: m.p. 118—119 °C (was
578
purified as described above), [α]589 +55.5 (c 8.1, EtOH)) was
isolated from ephedra through hydrochloride without preꢀ
purification. Analytical TLC of compounds 5—8 was performed
on Silufol UV 254 (Kavalier, Czech Republic) or Sorbfil UV 254
(Sorbpolimer, Russia) plates using an ethyl acetate—hexane mixꢀ
ture (1 : 4, v/v) as the eluent. Analytical TLC of Mannich bases
10a—h was carried out on 7.5×2.5 cm glass plates coated with a
layer of the sorbent (0.04 g cm–2), viz., silica gel G with gypsum
(10—40 µm (Sigma)) containing 1 wt.% of the luminophore
Kꢀ35 (TU 6ꢀ09ꢀ458ꢀ76, Russia) and 1% Na2CO3, which were
prepared according to a known procedure,29 with the use of a
PriOH—Et2O mixture (5 : 95, v/v) as the eluent. The compoꢀ
nents of the mixtures were visualized with UV light or iodine
vapor. Iodoaromatic compounds 2 and 7 were detected by irraꢀ
diation of the plates with UV light for 5 min, resulting in the
appearance of brown spots. The preparative chromatography
was performed on Al2O3 (50—150 µm, TU 6ꢀ09ꢀ3916ꢀ75, Russia,
Brockmann activity II) and silica gel (35—70 µm, Acros Organꢀ
ics). To visually monitor the separation and elution of the comꢀ
pounds by the observation under UV light, the sorbents were
mixed with the luminophore Kꢀ35 (1 wt.%). The melting points
were determined on a Kofler apparatus. The optical rotation was
measured on a Polamat A polarimeter (Carl Zeiss, λ = 578 nm).
The specific rotation was expressed in (deg mL) (g dm)–1; the
concentrations of the solutions, in g (100 mL)–1. The IR spectra
were recorded on a Vector 22 spectrometer in KBr pellets or in
the pure state. The UV spectra were measured on a Specord
UVꢀVis spectrophotometer in ethanol (c = 10–4 mol L–1). The
highꢀresolution mass spectra were obtained on a Finnigan MAT
model 8200 instrument (EI, 70 eV). The elemental analysis was
carried out on a CHNꢀanalyzer (model 1106, Carlo Erba, Italy).
The NMR spectra were recorded on Bruker AVꢀ300 (300.13
3ꢀArylpropꢀ2ꢀynyldialkylamines synthesized in the
present study can be of interest as pharmacologically acꢀ
tive compounds or their precursors.
Experimental
Freshly distilled solvents were used. The reagents CuI,
K2CO3, PPh3, diethylamine, piperidine, and morpholine of highꢀ
purity grade (Russia) and the commercial reagents trimethylꢀ
silylacetylene and pyrrolidine were used without additional puꢀ
rification. Tetraꢀnꢀbutylammonium fluoride (Sigma—Aldrich)
was dried according to a known procedure.18 Methyl 2ꢀ(Nꢀaceꢀ
tylamino)ꢀ5ꢀiodobenzoate (7),19 ethyl 2ꢀ(Nꢀacetylamino)ꢀ5ꢀ
iodobenzoate (2),1 and 3ꢀNꢀmorpholinopropyne (3)20 were synꢀ
thesized according to known procedures. The Pd(PPh3)2Cl2
complex was synthesized in 90% yield according to a procedure
published earlier21 with the use of DMF (45 mL per gram of
PdCl2) instead of benzonitrile as the solvent under reflux until
the starting components were dissolved. The product was identiꢀ
fied as transꢀdichlorobis(triphenylphosphine)palladium(II) based
on the results of crystallographic analysis (Bruker P4 diffractoꢀ
meter).22 The alkaloids used in the reactions were isolated from
1
for 1H and 75.47 MHz for 13C), Bruker AMꢀ400 (400.13 for H
and 100.61 MHz for 13C), and Bruker DRXꢀ500 (500.13 for 1H
and 125.76 MHz for 13C) instruments for 10% solutions in CDCl3
at 25 °C, unless other solvent is indicated. The chemical shifts
were measured relative to the residual signals of the solvent
CHCl3 (δH 7.24 and δC 76.90) or DMSO (δH 2.50 and δC 39.50).

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Osadchii et al.
The multiplicities of the signals in the 13C NMR spectra were
determined using Jꢀmodulated (JMOD) experiments and proꢀ
ton offꢀresonance techniques. The assignment of the signals for
the carbon atoms in compound 5 was made by determining the
multiplicities of the signals based on the results of 13C—1H
decoupling experiments (monoresonance mode). The assignꢀ
ment of the signals for the carbon atoms in the anabasine and
cytisine fragments in the 13C NMR spectra of compounds 10e,f
was made taking into account the chemical shifts of the correꢀ
sponding carbon atoms for (–)ꢀanabasine30 and (–)ꢀcytisine.31
The assignment of the signals for the carbon atoms of the aroꢀ
matic rings in the 13C NMR spectra of acetylenic compounds 4,
5, 8, 9, and 10a—h was performed taking into account the chemiꢀ
cal shifts of the corresponding carbon atoms in methyl 2ꢀ(Nꢀaceꢀ
tylamino)ꢀ5ꢀ(3ꢀhydroxypropꢀ1ꢀynyl)benzoate.1
was crystallized from methanol. Compound 8 was obtained in
the crystalline state in a yield of 11.0 g (95%), m.p. 120—121 °C.
Highꢀresolution mass spectrum, found: m/z 289.1140 [M]+.
C15H19NO3Si. Calculated:
M =
289.1134. 1H NMR
(400.13 MHz), δ: 0.21 (s, 9 H, SiMe3); 2.18 (s, 3 H, MeCO);
3.88 (s, 3 H, OMe); 7.55 (dd, 1 H, H(4), J = 9 Hz, J = 2 Hz);
8.08 (d, 1 H, H(6), J = 2 Hz); 8.62 (d, 1 H, H(3), J = 9 Hz);
11.02 (br.s, 1 H, NH). 13C NMR (75.47 MHz), δ: –0.2 (SiMe3);
25.3 (CH3CO); 52.3 (OCH3); 94.1 (C(2´)); 103.6 (C(1´)); 114.4
(C(1)); 117.1 (C(5)); 119.9 (C(3)); 134.4 (C(6)); 137.6 (C(4));
141.3 (C(2)); 168.0 (COO); 168.9 (CH3CO). IR (CCl4, c = 2%,
d = 0.1 mm), ν/cm–1: 847, 858, 916, 985, 1088, 1218, 1236,
1250, 1268, 1293, 1316, 1367, 1399, 1438, 1511, 1586; 1694,
1710 (C=O); 2159 (C≡C); 2956; 3281, 3319 (NH). UV (EtOH),
λ
max/nm (logε): 237 (4.09), 277 (4.04), 285 (4.06), 325 (3.39).
Methyl 2ꢀ(Nꢀacetylamino)ꢀ5ꢀethynylbenzoate (5) (cf. lit.
Ethyl 2ꢀ(Nꢀacetylamino)ꢀ5ꢀ(3ꢀmorpholinopropꢀ1ꢀynꢀ1ꢀ
yl)benzoate (4). Ethyl 2ꢀ(Nꢀacetylamino)ꢀ5ꢀiodobenzoate (2)
(1.00 g, 3 mmol), CuI (7 mg, 0.04 mmol, 1.3 mol.%),
Pd(PPh3)2Cl2 (15 mg, 0.02 mmol, 0.7 mol.%), 3ꢀNꢀmorphoꢀ
linopropyne (3) (0.50 g, 4 mmol), and triethylamine (2 mL)
were successively added with stirring to benzene (20 mL) under
argon flow. The reaction mixture was heated at 53—55 °C for 6 h
and then cooled to 25 °C. Then Et3N•HI was filtered off, and
the precipitate was washed on a filter with benzene (3×5 mL).
The filtrate was concentrated in vacuo to ~3 mL, the residue was
chromatographed on a short column packed with Al2O3 (2×1 cm
layer of the sorbent), and the products were eluted with ethyl
acetate (30 mL). The eluate was concentrated in vacuo, and
the residue was crystallized from benzene. Compound 4 was
obtained in a yield of 0.65 g (66%), m.p. 113—115 °C.
Highꢀresolution mass spectrum, found: m/z 330.1539 [M]+.
data5,32). A. A solution of Bu4NF (2.65 g, 10.1 mmol) in CH2Cl2
(15 mL) was added dropwise with stirring to a solution of comꢀ
pound 8 (2.17 g, 7.51 mmol) in CH2Cl2 (15 mL), the temperaꢀ
ture being maintained at 20—25 °C using external cooling. The
reaction mixture was kept at 25 °C for 5 min and then extracted
with water (3×7.5 mL). The organic layer was washed and then
dried with MgSO4. The solvent was removed, and the crystalline
precipitate was kept at 40 °C (3 Torr) and dissolved in ethyl
acetate (30 mL). The resulting solution was chromatographed
on a quartz column packed with silica gel (35—70 µm, Acrosꢀ
Organics, 15×2.5 cm layer of the sorbent) containing 1 wt.% of
the luminophore Kꢀ35 (the column was filled by suspending the
sorbent in hexane). Upon the elution with ethyl acetate, an
UVꢀabsorbing fraction was collected and concentrated to dryꢀ
ness. The residue was suspended in hexane. The precipitate was
filtered off, washed with hexane, and dried. Crystals of comꢀ
pound 5 were obtained in a yield of 1.26 g (77%), m.p.
147—148 °C (from AcOEt). Highꢀresolution mass specꢀ
trum, found: m/z 217.0736 [M]+. C12H11NO3. Calculated:
M = 217.0739. 1H NMR (500.13 MHz), δ: 2.18 (s, 3 H, MeCO);
3.02 (s, 1 H, ≡CH); 3.87 (s, 3 H, OMe); 7.55 (dd, 1 H, H(4), J =
9 Hz, J = 2 Hz); 8.08 (d, 1 H, H(6), J = 2 Hz); 8.62 (d, 1 H,
H(3), J = 9 Hz); 11.05 (br.s, 1 H, NH). 13C NMR (125.77 MHz,
monoresonance), δ: 25.3 (q, CH3CO, J = 129 Hz); 52.3 (q,
OMe, J = 148 Hz); 77.0 (d, C(2´), J = 252 Hz); 82.2 (dt, C(1´),
J = 50 Hz, J = 5 Hz); 114.4 (dd, C(1), J = 7 Hz, J = 2 Hz); 115.8
(dd, C(5), J = 9 Hz, J = 4 Hz); 119.9 (ddd, C(3), J = 169 Hz,
J = 5 Hz, J = 1.5 Hz); 134.4 (dd, C(6), J = 166 Hz, J = 7 Hz);
137.6 (dd, C(4), J = 164 Hz, J = 7 Hz); 141.5 (td, C(2), J =
C
18H22N2O4. Calculated:
M
=
330.1579. 1H NMR
(300.13 MHz), δ: 1.44 (t, 3 H, CH3CH2, J = 7 Hz); 2.25 (s, 3 H,
MeCO); 2.66 (t, 4 H, C(3)H2, C(5)H2, J = 6 Hz); 3.52 (s, 2 H,
C(1´)H2); 3.80 (t, 4 H, C(2)H2, C(6)H2, J = 6 Hz); 4.40 (q,
2 H, CH3CH2, J = 7 Hz); 7.58 (dd, 1 H, H(6″), J = 9 Hz, J =
2 Hz); 8.13 (d, 1 H, H(2″), J = 2 Hz); 8.68 (d, 1 H, H(5″), J =
9 Hz); 11.15 (br.s, 1 H, NH). 13C NMR (75.47 MHz), δ:
14.3 (CH2CH3); 25.5 (CH3CO); 48.1 (C(1´)); 52.5 (C(3)H2,
C(5)H2); 61.7 (CH2CH3); 66.9 (C(2)H2, C(6)H2); 84.1, 84.3
(C(2´), C(3´)); 114.9 (C(3″)); 117.0 (C(1″)); 120.2 (C(5″));
134.2 (C(2″)); 137.3 (C(6″)); 141.3 (C(4″)); 167.7 (COO); 169.0
(CH3CO). IR (KBr), ν/cm–1: 749, 791, 858, 908, 1026, 1092,
1118, 1222, 1262, 1313, 1450, 1472, 1524, 1592; 1682, 1702
(C=O); 2206 (C≡C); 2811, 2931; 3264, 3301, 3410 (NH).
UV (EtOH), λmax/nm (logε): 235 (4.21), 273 (4.11), 281 (4.12),
325 (3.46).
Methyl 2ꢀ(Nꢀacetylamino)ꢀ5ꢀ(trimethylsilylethynyl)benzoate
(8). Methyl 2ꢀ(acetylamino)ꢀ5ꢀiodobenzoate (7) (12.8 g,
40.1 mmol), CuI (160 mg, 0.84 mmol, 2.1 mol.%), Pd(PPh3)2Cl2
(167 mg, 0.24 mmol, 0.6 mol.%), PPh3 (165 mg, 0.63 mmol,
1.6 mol.%), triethylamine (16.0 mL, 11.6 g, 115 mmol), and
trimethylsilylacetylene (5.00 g, 7.2 mL, 50.9 mmol) were sucꢀ
cessively added with stirring to benzene (160 mL) under argon
flow. The reaction mixture was heated at 53—55 °C for 8 h
under argon flow, cooled to 25 °C (TLC monitoring), and kept
without stirring for 16 h. The precipitate of Et3N•HI was filꢀ
tered off and washed on a filter with benzene (3×5 mL). The
combined filtrates were concentrated in vacuo, and the resinous
residue was kept at 60 °C (3 Torr) and extracted with diethyl
ether (4×15 mL). The extract was concentrated, and the residue
9 Hz, J = 1.5 Hz); 167.8 (m, COO, ∆ν = 12 Hz); 168.9 (qd,
1/2
CH3CO, J = 6 Hz, J = 3 Hz). IR (KBr), ν/cm–1: 795, 848, 1087,
1201, 1235, 1267, 1294, 1322, 1436, 1516, 1595; 1680, 1699
(C=O); 2848, 2956, 3025. IR (CCl4, c = 2%, d = 0.1 mm),
ν/cm–1
max/nm (logε): 234 (4.08), 270 (3.93), 278 (3.04), 323 (3.34).
B. Finely dispersed anhydrous K2CO3 (0.60 g, 4.35 mmol)
: 2119 (C≡C), 3311 (NH, ≡CH). UV (EtOH),
λ
was added in one portion to a mixture of compound 8 (9.13 g,
31.6 mmol) and anhydrous MeOH (77 mL) with stirring at
50 °C under argon flow. Then the reaction mixture was stirred
without heating for 3 h. The precipitate was filtered off, dried,
and extracted with ethyl acetate (30 mL) under reflux. Comꢀ
pound 5 was isolated from the concentrated extract upon coolꢀ
ing in a yield of 5.21 g (76%), m.p. 147—148 °C, and identified
based on the IR spectrum. The solvent was removed from the
methanolic filtrate at 60 °C (30 Torr). Ethyl acetate (10 mL)

Mannich reaction of alkaloids
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
1265
was added to the residue, and the mixture was heated to boiling
and cooled. The precipitate was filtered off, dried, treated with
AcOH (2 mL), filtered off, washed with water, again dried, and
recrystallized from MeOH. 2ꢀ(NꢀAcetylamino)ꢀ5ꢀethynylbenzoic
acid (9) was obtained in a yield of 0.15 g (2%), m.p. 245—247 °C
(with decomp.). Highꢀresolution mass spectrum, found:
m/z 203.0580 [M]+. C11H9NO3. Calculated: M = 203.0582.
1H NMR (DMSOꢀd6, 300.13 MHz), δ: 2.13 (s, 4 H, COMe,
CO2H); 4.12 (s, 1 H, ≡CH); 7.60 (dd, 1 H, H(4), J = 9 Hz, J =
2 Hz); 7.97 (d, 1 H, H(6), J = 2 Hz); 8.46 (d, 1 H, H(3), J =
9 Hz); 11.11 (br.s, 1 H, NH). 13C NMR (100.63 MHz), δ: 25.0
(CH3CO); 82.4 (C(1´)); 80.3 (C(2´)); 115.5 (C(1)); 116.5 (C(5));
120.0 (C(3)); 134.3 (C(6)); 136.8 (C(4)); 141.1 (C(2)); 168.6
(COO, CH3CO). IR (KBr), ν/cm–1: 791, 847, 1086, 1148, 1202,
1235, 1265, 1294, 1318, 1366, 1400, 1435, 1512, 1590; 1688,
1703 (C=O); 2151 (C≡C); 2957; 3266, 3317 (NH). UV (EtOH),
(1H NMR spectroscopic data) the following three compounds:
starting arylacetylene 5, compound 10h, and (4S,5S)ꢀ3,4ꢀdiꢀ
methylꢀ5ꢀphenyloxazolidine (12). After preparative TLC under
the conditions described above for compound 10g, starting
arylacetylene 5 was isolated from the upper band of the sorbent
in 48% yield. After the elution with the same mixture and reꢀ
moval of the solvents from the eluate at 80 °C (3 Torr), the
sorbent from the lower band gave an amorphous residue conꢀ
taining a mixture of compounds 10h and 12 (1H NMR spectroꢀ
scopic data). The latter compound was removed from this mixꢀ
ture by evacuation at 100 °C for 1 h (3 Torr).
Authentic samples of oxazolidines 11 ([α]20
+5.9 (c 4,
578
C6H6)) (cf. lit. data33: [α]21
+5.6 (c 0.36, C6H6)) and 12
589
([α]20
+49.5 (c 2, C6H6)) (cf. lit. data33: [α]21
+50.8
589
578
(c 0.56, C6H6)) were synthesized from (–)ꢀephedrine (6g) and
(+)ꢀpseudoephedrine (6h), respectively, under the conditions of
the Mannich reaction in the absence of arylacetylene 5 and CuI.
λ
max/nm (logε): 227 (4.48), 232 (4.47), 270 (4.38), 278 (4.38),
317 (3.69).
Acid 9 (29 mg) was treated with a 0.7 N ethereal solution of
1
The yield of the products was 90—92%. The H and 13C NMR
spectroscopic data were consistent with the published data.34
Methyl 2ꢀ(Nꢀacetylamino)ꢀ5ꢀ(3ꢀdiethylaminopropꢀ1ꢀynꢀ1ꢀ
yl)benzoate (10a). The yield was 90%, crystals, m.p. 65—66 °C.
Highꢀresolution mass spectrum, found: m/z 302.1623 [M]+.
CH2N2 (3 mL). After removal of excess CH2N2 and the solvent,
compound 5 was obtained in a yield of 28 mg, m.p. 147—148 °C.
Compound 5 was identified based on the 1H NMR spectrum.
Synthesis of Mannich bases 10a—h (general procedure).
Paraformaldehyde (67 mg, 2.2 mmol), the corresponding secꢀ
ondary amine 6 (2.0 mmol), CuI (8 mg, 0.02 mmol), and methyl
2ꢀ(acetylamino)ꢀ5ꢀethynylbenzoate (5) (439 mg, 2.0 mmol) were
successively added with stirring to dioxane (3.8 mL) under argon
flow. The reaction mixture was heated at 85—90 °C for 3 h and
cooled to 25 °C. The solvent was removed in vacuo (the bath
temperature was 80 °C). The residue was dried at 80 °C (3 Torr)
and extracted with diethyl ether (4×5 mL). The extract was
concentrated to 3 mL, and then the solvent was allowed to
spontaneously evaporate. The residue was triturated with hexꢀ
ane (3 mL), and the crystalline Mannich bases were filtered off.
Mannich base 10c was purified by preparative TLC on an
unfixed layer of Al2O3 (1 wt.% of the luminophore Kꢀ35, the
sorbent layer thickness was 2 mm, the length of the starting band
was 60 cm, Et2O as the eluent). The broadest UVꢀabsorbing
band was collected. The product was eluted from the sorbent
with chloroform.
C17H22N2O3. Calculated:
M
=
302.1630. 1H NMR
(300.13 MHz), δ: 1.03 (t, 6 H, (CH3CH2)2, J = 7 Hz); 2.14 (s,
3 H, MeCO); 2.53 (q, 4 H, (CH3CH2)2, J = 7 Hz); 3.54 (s, 2 H,
C(3)H2); 3.83 (s, 3 H, OMe); 7.46 (dd, 1 H, H(6´), J = 9 Hz,
J = 2 Hz); 7.98 (d, 1 H, H(2´), J = 2 Hz); 8.57 (d, 1 H, H(5´),
J = 9 Hz); 10.96 (br.s, 1 H, NH). 13C NMR (75.48 MHz),
δ: 12.4 ((CH3CH2)2); 25.2 (CH3CO); 41.2 (C(3)); 47.1
((CH3CH2)2); 52.2 (OMe); 83.4, 84.2 (C(1), C(2)); 114.3
(C(3´)); 117.2 (C(1´)); 119.8 (C(5´)); 133.8 (C(2´)); 137.3
(C(6´)); 140.7 (C(4´)); 167.8 (COO); 168.6 (CH3CO). IR (KBr),
ν/cm–1: 792, 846, 999, 1092, 1237, 1298, 1323, 1363, 1431,
1525, 1599; 1684, 1703 (C=O); 2815, 2969; 3268, 3317 (NH).
UV (EtOH), λmax/nm (logε): 235 (4.49), 273 (4.39), 281 (4.40),
326 (3.73).
Methyl 2ꢀ(Nꢀacetylamino)ꢀ5ꢀ(3ꢀpyrrolidinopropꢀ1ꢀynꢀ1ꢀ
yl)benzoate (10b). The yield was 92%, crystals, m.p. 80—81 °C.
Highꢀresolution mass spectrum, found: m/z 300.1477 [M]+.
C
17H20N2O3. Calculated:
M
=
300.1474. 1H NMR
Compounds 10e,f were isolated by filtration of the reaction
mixture from traces of impurities followed by the removal of the
solvent at 80 °C (30 Torr). The residues were dried at 80 °C
(3 Torr).
(300.13 MHz), δ: 1.73 (br.s, 4 H, C(3)H2, C(4)H2); 2.12 (s, 3 H,
MeCO); 2.57 (br.s, 4 H, C(2)H2, C(5)H2); 3.50 (br.s, 2 H,
C(1´)H2); 3.81 (s, 3 H, OMe); 7.45 (dd, 1 H, H(6″), J = 9 Hz,
J = 2 Hz); 7.97 (d, 1 H, H(2″), J = 2 Hz); 8.54 (d, 1 H, H(5″),
J = 9 Hz); 10.95 (br.s, 1 H, NH). 13C NMR (75.48 MHz), δ:
23.5 (C(3)); 25.1 (CH3CO, C(4)); 43.5 (C(1´)); 52.1 (CH3O);
52.5 (C(2), C(5)); 82.7, 85.2 (C(2´), C(3´)); 114.2 (C(3″));
117.1 (C(1″)); 119.7 (C(5″)); 133.8 (C(2″)); 137.2 (C(6″)); 140.7
(C(4″)); 167.8 (COO); 168.6 (CH3CO). IR (KBr), ν/cm–1: 791,
857, 1088, 1236, 1275, 1295, 1321, 1372, 1438, 1510, 1588;
1687, 1704 (C=O); 2731, 2791, 2874, 2955; 3268 (NH).
UV (EtOH), λmax/nm (logε): 235 (4.50), 273 (4.39), 280 (4.40),
325 (3.74).
To isolate compound 10g, the solvent was removed from the
1
reaction mixture at 80 °C (3 Torr). According to the H NMR
spectroscopic data, the residue contained the following three
compounds: starting arylacetylene 5, compound 10g, and
(4S,5R)ꢀ3,4ꢀdimethylꢀ5ꢀphenyloxazolidine (11). After preparaꢀ
tive TLC under the conditions described above for compound 10c
(CHCl3 as the eluent), two UVꢀabsorbing bands of the sorbent
were collected. The products were eluted from the sorbent with
a MeOH—CHCl3 mixture (1 : 10, v/v). Starting arylacetylene 5
(12%) was isolated from the upper band. After the elution with
the same mixture and removal of the solvents from the eluate at
80 °C (3 Torr), the sorbent from the lower band gave an amorꢀ
phous residue containing a mixture of compounds 10g and 11
(1H NMR spectroscopic data). The latter compound was reꢀ
moved from this mixture by evacuation at 100 °C (3 Torr) for 1 h.
To isolate compound 10h, the solvent was removed from the
reaction mixture at 80 °C (3 Torr). The residue contained
Methyl 2ꢀ(Nꢀacetylamino)ꢀ5ꢀ(3ꢀpiperidinopropꢀ1ꢀynꢀ1ꢀ
yl)benzoate (10c). The yield was 87%, crystals, m.p. 76—77 °C.
Highꢀresolution mass spectrum, found: m/z 314.1625 [M]+.
C18H22N2O3. Calculated:
M
=
314.1630. 1H NMR
(300.13 MHz), δ: 1.42 and 1.53 (both m, 2 H and 4 H, respecꢀ
tively, C(3)H2—C(5)H2); 2.11 (s, 3 H, CH3CO); 2.43 (m, 4 H,
C(2)H2, C(6)H2); 3.34 (br.s, 2 H, C(1´)H2); 3.80 (s, 3 H, MeO);
7.45 (dd, 1 H, H(6″), J = 9 Hz, J = 2 Hz); 7.97 (d, 1 H, H(2″),

1266
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
Osadchii et al.
J = 2 Hz); 8.54 (d, 1 H, H(5″), J = 9 Hz); 10.94 (br.s, 1 H, NH).
13C NMR (75.48 MHz), δ: 52.2 (C(2), C(6)); 25.6 (C(3), C(5));
23.6 (C(4)); 48.1 (C(1´)); 83.4, 84.8 (C(2´), C(3´)); 117.1
(C(1″)); 133.8 (C(2″)); 114.2 (C(3″)); 140.7 (C(4″)); 119.7
(C(5″)); 137.2 (C(6″)); 25.6 (CH3CO); 52.1 (CH3O); 167.8
(COO); 168.6 (CH3CO). IR (KBr), ν/cm–1: 791, 844, 1235,
1272, 1294, 1321, 1442, 1517, 1592; 1683, 1699 (C=O); 2770,
2814, 2851, 2937; 3267, 3317 (NH). UV (EtOH), λmax/nm (logε):
232 (4.45), 272 (4.37), 325 (3.75).
(both m, 2 H each, C(2)H2, C(4)H2); 3.34 and 3.26 (both d,
1 H each, AB system, C(1´)H2, J = 17 Hz); 3.79 (dd, 1 H,
H(6b), J = 15.5 Hz, J = 6.5 Hz); 3.82 (s, 3 H, OMe); 3.94 (d,
1 H, H(6a), J = 15.5 Hz); 5.87 (d, 1 H, H(9), J = 7 Hz); 6.30 (d,
1 H, H(11), J = 9 Hz); 7.15 (dd, 1 H, H(10), J = 9 Hz, J =
7 Hz); 7.42 (dd, 1 H, H(6″), J = 9 Hz, J = 2 Hz); 7.94 (d, 1 H,
H(2″), J = 2 Hz); 8.54 (d, 1 H, H(5″), J = 9 Hz); 10.93 (br.s,
1 H, NH). 13C NMR (75.48 MHz), δ: 25.0 (C(13)); 25.1
(CH3CO); 27.5 (C(5)); 35.0 (C(1)); 47.2 (C(1´)); 49.6 (C(2));
52.1 (OMe); 58.2 (C(4)); 58.8 (C(6)); 83.5, 84.2 (C(2´), C(3´));
104.3 (C(11)); 114.3 (C(3″)); 116.3 (C(9)); 116.8 (C(1″)); 119.8
(C(5″)); 133.7 (C(2″)); 137.1 (C(6″)); 138.3 (C(10)); 140.8
(C(4″)); 151.0 (C(12)); 163.3 (C(8)); 167.7 (COO), 168.6
(CH3CO). IR (KBr), ν/cm–1: 749, 793, 844, 1001, 1058, 1087,
1135, 1159, 1235, 1293, 1319, 1366, 1399, 1437, 1510, 1547,
1585; 1653, 1692 (C=O); 2801, 2938; 3312, 3393 (NH).
UV (EtOH), λmax/nm (logε): 234 (4.51), 281 (4.37), 312 (4.05).
(1R,2S)ꢀ2ꢀ{Nꢀ[3ꢀ(4ꢀAcetylaminoꢀ3ꢀmethoxycarbonylpheꢀ
nyl)propꢀ2ꢀynyl]ꢀNꢀmethylamino}ꢀ1ꢀphenylpropanꢀ1ꢀol (10g).
Methyl 2ꢀ(Nꢀacetylamino)ꢀ5ꢀ(3ꢀmorpholinopropꢀ1ꢀynꢀ1ꢀ
yl)benzoate (10d). The yield was 75%, crystals, m.p. 118—119 °C.
Highꢀresolution mass spectrum, found: m/z 316.1421 [M]+.
C
17H20N2O4. Calculated:
M
=
316.1423. 1H NMR
(300.13 MHz), δ: 2.17 (s, 3 H, COMe); 2.57 (t, 4 H, C(3)H2,
C(5)H2, J = 4.5 Hz); 3.43 (s, 2 H, C(1´)H2); 3.71 (t, 4 H,
C(2)H2, C(6)H2, J = 4.5 Hz); 3.86 (s, 3 H, OMe); 7.50 (dd, 1 H,
H(6″), J = 9 Hz, J = 2 Hz); 8.03 (d, 1 H, H(2″), J = 2 Hz); 8.60
(d, 1 H, H(5″), J = 9 Hz); 11.01 (br.s, 1 H, NH). 13C NMR
(100.63 MHz), δ: 25.3 (CH3CO); 47.8 (C(1´)); 52.2 (C(3)H2,
C(5)H2); 52.3 (OMe); 66.6 (C(2)H2, C(6)H2); 83.9, 84.1 (C(2´),
C(3´)); 114.4 (C(3″)); 116.8 (C(1″)); 119.9 (C(5″)); 134.0
(C(2″)); 137.3 (C(6″)); 141.0 (C(4″)); 167.9 (COO); 168.8
(CH3CO). IR (KBr), ν/cm–1: 842, 863, 888, 915, 1005, 1069,
1091, 1117, 1133, 1201, 1235, 1278, 1295, 1316, 1338, 1362,
1437, 1516, 1594; 1695 (C=O); 2815, 2855, 2926, 2960; 3311
(NH). UV (EtOH), λmax/nm (logε): 235 (4.45), 273 (4.35), 280
(4.36), 326 (3.73).
(2S)ꢀ1ꢀ{3ꢀ[4ꢀ(NꢀAcetylamino)ꢀ3ꢀ(methoxycarbonyl)pheꢀ
nyl]propꢀ2ꢀynyl}ꢀ2ꢀ(3ꢀpyridyl)piperidine (10e). The yield was
77%, viscous oil, [α]20578 –72.5 (c 7.7, CHCl3). Highꢀresolution
mass spectrum, found: m/z 391.1891 [M]+. C23H25N3O3. Calꢀ
culated: M = 391.1896. 1H NMR (400.14 MHz), δ: 1.31 (qt,
1 H, J = 12 Hz, J = 4 Hz), 1.52 (qd, 1 H, J = 12 Hz, J = 3 Hz),
1.62—1.75 (m, 4 H) (H(3a), H(3b), H(4a), H(4b), H(5a),
H(5b)); 2.14 (s, 3 H, MeCO); 2.54 (td, 1 H, J = 12 Hz, J =
3 Hz), 2.96 (br.d, 1 H, J = 12 Hz), 3.28 (dd, 1 H, J = 11 Hz, J =
3 Hz) (H(2), H(6a), H(6b)); 3.14 and 3.27 (both d, 1 H each,
AB system, C(1´)H2, J = 17 Hz); 3.84 (s, 3 H, OMe); 7.18 (dd,
1 H, H(5″´), J = 8 Hz, J = 5 Hz); 7.48 (dd, 1 H, H(6″), J = 9 Hz,
J = 2 Hz); 7.64 (br.d, 1 H, H(4″´), J = 8 Hz); 7.98 (d, 1 H,
H(2″), J = 2 Hz); 8.43 (dd, 1 H, H(6″´), J = 5 Hz, J = 1.5 Hz);
8.53 (d, 1 H, H(2″´), J = 1.5 Hz); 8.59 (d, 1 H, H(5″), J = 9 Hz);
10.94 (br.s, 1 H, NH). 13C NMR (100.63 MHz), δ: 24.4 (C(4));
25.2 (CH3CO); 25.7 (C(5)); 35.4 (C(3)); 44.7 (C(1´)); 52.2
(CH3O); 53.0 (C(6)); 63.1 (C(2)); 83.8, 84.4 (C(2´), C(3´));
114.4 (C(3″)); 117.0 (C(1″)); 119.9 (C(5″)); 123.3 (C(5″´)); 133.8
(C(2″)); 134.7 (C(4″´)); 137.3 (C(6″)); 138.9 (C(3″´)); 140.8
(C(4″)); 148.6 (C(6″´)); 149.3 (C(2″´)); 167.8 (COO); 168.7
(CH3CO). IR (film), ν/cm–1: 565, 664, 686, 717, 754, 793, 843,
984, 1002, 1026, 1088, 1113, 1236, 1294, 1320, 1367, 1400,
1438, 1513, 1589; 1691, 1700 (C=O); 2801, 2855, 2936; 3273,
3314 (NH). UV (EtOH), λmax/nm (logε): 235 (4.40), 272 (4.32),
281 (4.31), 325 (3.62).
The yield was 86%, viscous oil, [α]20 +52.8 (c 10, CHCl3).
578
Highꢀresolution mass spectrum, found: m/z 394.1896 [M]+.
C
23H26N2O4. Calculated:
M
=
394.1892. 1H NMR
(300.13 MHz), δ: 0.87 (d, 3 H, C(2)H3, J = 6.7 Hz); 2.18 (s,
3 H, MeCO); 2.48 (s, 3 H, H(1), MeN); 2.85 (dq, 1 H, H(2),
J = 3.2 Hz, J = 6.7 Hz); 3.38 (br.s, 1 H, OH); 3.64 and 3.70
(both d, 1 H each, AB system, C(1´)H2, J = 17.6 Hz); 3.88 (s,
3 H, OMe); 4.97 (d, 1 H, H(1), J = 3.2 Hz); 7.16—7.31 (m, 5 H,
Ph); 7.52 (dd, 1 H, H(6″), J = 9 Hz, J = 2 Hz); 8.04 (d, 1 H,
H(2″), J = 2 Hz); 8.63 (d, 1 H, H(5″), J = 9 Hz); 11.02 (br.s,
1 H, NH). 13C NMR (75.48 MHz), δ: 10.13 (C(2)H3); 25.2
(CH3CO); 39.5 (MeN); 44.2 (C(1´)); 52.2 (OMe); 62.3 (C(2));
71.8 (C(1)); 83.9, 84.5 (C(2´), C(3´)); 114.4 (C(3″)); 117.0
(C(1″)); 119.9 (C(5″)); 125.6 (C(2″´), C(6″´)); 126.6 (C(4″´));
127.8 (C(3″´), C(5″´)); 133.8 (C(2″)); 137.3 (C(6″)); 140.9
(C(1″´)); 141.9 (C(4″)); 167.8 (COO); 168.7 (CH3CO).
IR (film), ν/cm–1: 685, 703, 754, 793, 844, 1001, 1088, 1151,
1236, 1294, 1320, 1368, 1399, 1438, 1517, 1589; 1696 (C=O);
2797, 2891, 2953, 2986; 3272, 3314, 3421 (NH, OH).
UV (EtOH), λmax/nm (logε): 231 (4.40), 273 (4.31), 281 (4.30),
326 (3.66).
(1S,2S)ꢀ2ꢀ{Nꢀ[3ꢀ(4ꢀAcetylaminoꢀ3ꢀmethoxycarbonylpheꢀ
nyl)propꢀ2ꢀynyl]ꢀNꢀmethylamino}ꢀ1ꢀphenylpropanꢀ1ꢀol (10h).
The yield was 51%, m.p. 123—124 °C (from CHCl3),
[α]20
+54.8 (c 9.3, CHCl3). Highꢀresolution mass specꢀ
578
trum, found: m/z 394.1884 [M]+. C23H26N2O4. Calculated:
M = 394.1892. 1H NMR (300.13 MHz), δ: 0.86 (d, 3 H, C(2)H3,
J = 6.7 Hz); 2.23 (s, 3 H, MeCO); 2.44 (s, 3 H, H(1), MeN);
2.89 (dq, 1 H, H(2), J = 9.5 Hz, J = 6.7 Hz); 3.57 and 3.65
(both d, 1 H each, AB system, C(1´)H2, J = 16.7 Hz); 3.92 (s,
3 H, OMe); 4.26 (d, 1 H, H(1), J = 9.5 Hz); 7.28—7.39 (m, 5 H,
Ph); 7.57 (dd, 1 H, H(6″), J = 9 Hz, J = 2 Hz); 8.10 (d, 1 H,
H(2″), J = 2 Hz); 8.69 (d, 1 H, H(5″), J = 9 Hz); 11.08 (br.s,
1 H, NH). 13C NMR (75.48 MHz), δ: 8.07 (C(2)H3); 25.0
(CH3CO); 35.2 (MeN); 44.5 (C(1´)); 52.2 (OMe); 64.6 (C(2));
74.7 (C(1)); 83.3, 85.8 (C(2´), C(3´)); 114.5 (C(3″)); 116.9
(C(1″)); 120.0 (C(5″)); 127.2 (C(2″´), C(6″´)); 127.5 (C(4″´));
128.0 (C(3″´), C(5″´)); 133.8 (C(2″)); 137.1 (C(6″)); 141.0
(C(1″´)); 141.6 (C(4″)); 167.9 (COO), 168.7 (CH3CO).
IR (KBr), ν/cm–1: 685, 707, 767, 792, 849, 1040, 1087,
1234, 1296, 1316, 1372, 1399, 1433, 1455, 1519, 1596; 1689,
1708 (C=O); 2797, 2857, 2927, 2953, 2958; 3255, 3320, 3416
(1R,5S)ꢀ3ꢀ{3ꢀ[4ꢀ(NꢀAcetylamino)ꢀ3ꢀ(methoxycarbonyl)pheꢀ
nyl]propꢀ2ꢀynyl}ꢀ1,2,3,4,5,6ꢀhexahydroꢀ8Hꢀ1,5ꢀmethanopyriꢀ
do[1,2ꢀa][1,5]diazocinꢀ8ꢀone (10f). The yield was 92%, amorꢀ
phous powder, [α]20 –102.9 (c 4.0, CHCl3). Highꢀresolution
578
mass spectrum, found: m/z 419.1847 [M]+. C24H25N3O4. Calꢀ
culated: M = 419.1845. 1H NMR (300.13 MHz) δ: 1.65—1.79
(m, 2 H, C(13)H2); 2.12 (s, 3 H, MeCO); 2.38 and 2.89
(both br.s, 1 H each, H(1), H(5)); 2.54—2.60 and 2.71—2.82

Mannich reaction of alkaloids
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
1267
(NH, OH). UV (EtOH), λmax/nm (logε): 232 (4.45), 273
(4.36), 326 (3.72).
15. L. W. Bieber and M. F. da Silva, Tetrahedron Lett., 2004,
45, 8281.
16. K. Edo, T. Sakamoto, and H. Yamanaka, Chem. Pharm.
Bull., 1978, 26, 3843.
17. H. Pfanz and G. Kirchner, Justus Liebigs Ann. Chem., 1958,
614, 149.
18. E. J. Corey and A. Venkateswarlu, J. Am. Chem. Soc., 1972,
94, 6190.
19. C. A. Osadchii, E. E. Shults, E. V. Polukhina, M. M.
Shakirov, and G. A. Tolstikov, Izv. Akad. Nauk, Ser. Khim.,
2006, 1038 [Russ. Chem. Bull., Int. Ed., 2006, 55, 1077].
20. V. B. Mochalin and T. S. Minervina, Zh. Org. Khim., 1965,
1, 1726 [J. Org. Chem. USSR, 1965, 1 (Engl. Transl.)].
21. N. Miyaura and A. Suzuki, in Organic Syntheses, 1993, Coll.
Vol. 8, 532; 1990, Coll. Vol. 68, 130.
We thank Yu. V. Gatilov and I. Yu. Bagryanskaya for
help in performing the crystallographic identification of
transꢀdichlorobis(triphenylphosphine)palladium(II).
This study was financially supported by the Siberian
Branch of the Russian Academy of Sciences (Integration
Grant 54), the Russian Foundation for Basic Research
(Project No. 05ꢀ03ꢀ32365), and the Chemical Service
Center of the Siberian Branch of the Russian Academy of
Sciences.
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Received March 27, 2007