Study of alkaloids of the Siberian and Altai flora 12. Synthesis of new lappaconitine derivatives containing olefinic substituents

Article abstract of DOI:10.1007/s11172-006-0380-2

Lappaconitine and N-deacetyllappaconitine derivatives containing bromine and iodine atoms in the aromatic moiety were synthesized. The Heck cross-coupling of these halides with ethyl acrylate or 2-methyl-5-vinylpyridine afforded new olefinated lappaconitine derivatives.

Full text of DOI:10.1007/s11172-006-0380-2

Russian Chemical Bulletin, International Edition, Vol. 55, No. 6, pp. 1077—1084, June, 2006
1077
Study of alkaloids of the Siberian and Altai flora
12.* Synthesis of new lappaconitine derivatives containing olef inic substituents**
S. A. Osadchii, E. E. Shul´ts,ꢀ E. V. Polukhina, M. M. Shakirov, and G. A. Tolstikov
N. 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
Lappaconitine and Nꢀdeacetyllappaconitine derivatives containing bromine and iodine
atoms in the aromatic moiety were synthesized. The Heck crossꢀcoupling of these halides with
ethyl acrylate or 2ꢀmethylꢀ5ꢀvinylpyridine afforded new olefinated lappaconitine derivatives.
Key words: diterpene alkaloids, anthranilic acid, lappaconitine, Nꢀdeacetyllappaconitine,
bromination, iodination, olefins, Heck reaction.
The diterpene alkaloid with the aconitane skeleton,
viz., lappaconitine (1), isolated from airꢀdried roots of
northern wolfsbane Aconitum septentrionale Koelle and
other plants of the Aconitum genus is the acting agent of
the antiarrhythmic drug allapinine (lappaconitine hydroꢀ
bromide).2—9 NꢀDeacetyllappaconitine (2) exhibits the
antiarrhythmic activity comparable to that of lappaꢀ
conitine.10 Lappaconitine was also found to have the
psychotropic11 and anesthetic12 activities.
stituent in the aromatic ring with an unsaturated fragꢀ
ment17 and oxidative bromination of compound 1 with
a mixture of Br2, NaIO4, and AcOH giving rise to
Nꢀdeethylꢀ5´ꢀbromolappaconitine18 were performed.
The aim of the present study was to develop proceꢀ
dures for the synthesis of new derivatives of lappaconitine
(1) containing functionalized olefinic substituents in the
aromatic fragment. The Heck reaction is a convenient
procedure for the introduction of such fragments into the
aromatic moiety.19—22 However, to solve this problem, it
was necessary to synthesize derivatives of lappaconitine
(1) and Nꢀdeacetyllappaconitine (2) containing bromine
or iodine atoms in the aromatic moiety.
It is known23 that methyl Nꢀacetylanthranilate is transꢀ
formed into methyl 5ꢀbromoꢀNꢀacetylanthranilate in 86%
yield in the reaction with bromine in AcOH. Unfortuꢀ
nately, the extension of this method to lappaconitine (1)
did not give the desired results, and compound 1 was
quantitatively recovered from the reaction mixture. At the
same time, we prepared 5´ꢀbromolappaconitine (3) in
76% yield by the reaction in concentrated hydrochloric
acid (the alkaloid : Br2 molar ratio was 1 : 1.2) (Scheme 1).
The reaction gave Nꢀdeacetylꢀ3´,5´ꢀdibromolappaconiꢀ
tine (4) as a byꢀproduct (in 4% yield). Acidic hydrolysis of
compound 3 afforded 5´ꢀbromoꢀNꢀdeacetyllappaconitine
(5) in 81% yield.
Under analogous conditions, bromination of methyl
Nꢀacetylanthranilate produced the 5ꢀbromo derivative in
93% yield.
According to the published data,24 iodination of meꢀ
thyl anthranilate with ICl in AcOH gave methyl 5ꢀiodoꢀ
anthranilate (6) in 49% yield. The application of this proꢀ
cedure to Nꢀdeacetyllappaconitine (2) made it possible to
prepare iodo derivative 7 in 74% yield (Scheme 2). Acetyꢀ
lation of iodide 7 with acetic anhydride gave rise to
However, it should be noted that high toxicity of
allapinine limits the use of this compound as an antiꢀ
arrhythmic drug.12,13 In this connection, the synthesis of
new analogs of lappaconitine (1), which exhibit high speꢀ
cific physiological activity but have lower toxicity, is of
considerable importance.
Modifications of the heterocyclic fragment of alkaloid
1 were documented.14,15 The modification of the nitroꢀ
genꢀcontaining substituent in the aromatic moiety of the
lappaconitine molecule was also described in the literaꢀ
ture.1,16 The replacement of the nitrogenꢀcontaining subꢀ
* For Part 11, see Ref. 1.
** Dedicated to the memory of Academician V. A. Koptyug on
the occasion of the 75th anniversary of his birth.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1038—1044, June, 2006.
1066ꢀ5285/06/5506ꢀ1077 © 2006 Springer Science+Business Media, Inc.

1078
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 6, June, 2006
Osadchii et al.
Scheme 1
Scheme 3
5´ꢀiodolappaconitine (8) in 96% yield. The correspondꢀ
ing acetamide 9 was prepared analogously from methyl
5ꢀiodoanthranilate (6) in 97% yield. It should be noted
that direct iodination of methyl Nꢀacetylanthranilate afꢀ
forded compound 9 in a yield as low as 37%.25
Scheme 2
6, 9—12: R″ = Me;
7, 8, 13—15: R″ = R´ (see Scheme 1)
Reagents and conditions: i. CH2=CHCO2Et, Pd(OAc)2,P(oꢀTol)3,
Et3N, DMF. ii. CH2=CHCO2Et, Pd(dba)2, P(oꢀTol)3, Et3N,
DMF. iii. 2ꢀMethylꢀ5ꢀvinylpyridine, Pd(dba)2, P(oꢀTol)3,
Et3N, DMF.
Note. The atomic numbering for compounds 10—12 is given
without parentheses; for compounds 13—15, in parentheses.
Preliminarily, we devised conditions for the Heck reꢀ
action using methyl 5ꢀiodoanthranilate (6) and Nꢀacetꢀ
amide 9. Ethyl acrylate and 2ꢀmethylꢀ5ꢀvinylpyridine were
used as olefinic counterparts. The latter compound was
chosen because the known 5ꢀethylꢀ2ꢀmethylpyridine deꢀ
rivative, viz., dimebon, is the promising antiarrhythꢀ
mic drug.26
We found that the reaction of methyl 5ꢀiodoꢀ
anthranilate (6) with ethyl acrylate in DMF in the presꢀ
ence of Pd(OAc)2 and tris(oꢀtolyl)phosphine, as well as
triethylamine as a base, produced cinnamic derivative 10
in 63% yield (Scheme 3). Analogously, condensation of
methyl 5ꢀiodoꢀNꢀacetylanthranilate (9) with ethyl acryꢀ
late in the presence of bis(dibenzylideneacetone)palladium
(Pd(dba)2) gave product 11 in 71% yield. The Heck reacꢀ
tion of iodide 9 with 2ꢀmethylꢀ5ꢀvinylpyridine in the presꢀ
ence of Pd(dba)2, P(oꢀTol)3, and NEt3 in DMF produced
styrylpyridine derivative 12 in 72% yield.
lappaconitine (3) into the target product 14 was as low as
1
~30% (the H NMR spectroscopic data for the reaction
mixture). Condensation of iodide 8 with 2ꢀmethylꢀ5ꢀ
vinylpyridine (Pd(dba)2, P(oꢀTol)3, and Et3N in DMF)
afforded compound 15 in 86% yield.
It should be noted that the aboveꢀdescribed transforꢀ
mation of lappaconitine at the aromatic fragment seems
to be quite justified because the alternative synthesis of
these compounds by acylation of lappaconine (tertiary
alcohol) with the corresponding aromatic acid derivatives
will most likely present difficulties (cf. Ref. 27).
To conclude, we synthesized functional olefinic deꢀ
rivatives of lappaconitine (1) and Nꢀdeacetyllappaconitine
(2), which may be of interest as pharmacologically active
compounds.
The Heck reaction of 5´ꢀiodoꢀNꢀdeacetyllappaꢀ
conitine (7) with ethyl acrylate (Pd(dba)2, P(oꢀTol)3, and
Et3N in DMF) afforded compound 13 in 65% yield. Unꢀ
der the same conditions, the reaction of 5´ꢀiodolappaꢀ
conitine (8) produced ester 14 in higher yield (83%) (see
Scheme 3). It should be noted that under the aboveꢀ
mentioned conditions, the conversion of 5´ꢀbromoꢀ
Experimental
Freshly distilled solvents and reagents of chemical purity
grade were used. Lappaconitine (1) was isolated from airꢀdried
roots of northern wolfsbane Aconitum septentrionale Koelle. Its
physicochemical and spectroscopic characteristics have been

Heck reaction of anthranilates
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 6, June, 2006
1079
reported earlier.14,15 NꢀDeacetyllappaconitine (2) was preꢀ
pared by acidic hydrolysis of lappaconitine (1).28 The reagents
Solution B. Concentrated hydrochloric acid (d = 1.19, 45 mL)
was poured with vigorous stirring into a weighed sample of Br2
(7.38 g, 46.2 mmol). The solution B was added portionwise
(~3 mL) to the solution A at 20—25 °C. A copious brownish
nodular precipitate was obtained. After the addition of all broꢀ
mine, the reaction mixture was vigorously shaken for ~1 h until
the precipitate was dissolved. Then the mixture was diluted with
water (350 mL). A 25% ammonia solution was added portionwise
(3×50 mL) to the resulting solution with cooling (13—15 °C) to
pH ~8 and the mixture was extracted with dichloromethane
(5×50 mL). The extract was concentrated. The residue was dried
at 60 °C (30 Torr) and extracted with boiling 95% EtOH (65 mL).
After cooling of the extract, a crystalline product was obtained.
After 3 h, the precipitate was filtered off and washed on a filter
with a minimum amount of ethanol. 4βꢀ(2ꢀAcetylaminoꢀ5ꢀ
bromobenzoyloxy)ꢀ20ꢀethylꢀ1α,14α,16βꢀtrimethoxyaconitaneꢀ
8,9ꢀdiol (3) was obtained in a yield of 19.4 g (76%), m.p.
202—204 °C, [α]57820 +40 (c 5.3, CHCl3). Found (%): C, 57.55;
H, 6.73; Br, 12.40; N, 4.41. C32H43BrN2O8. Calculated (%):
C, 57.92; H, 6.53; Br, 12.04; N, 4.22. 1H NMR (CDCl3, 400.13
MHz), δ: 1.09 (t, 3 H, C(22)Me, J = 7.0 Hz); 1.51 (dd, 1 H,
Hb(6), J = 15.0 Hz, J = 8.0 Hz); 1.82 (m, 1 H, Hb(3)); 2.17 (s,
3 H, NHCOCH3); 2.68 (dd, 1 H, Ha(6), J = 15.0 Hz, J =
7.0 Hz); 2.98 (s, 1 H, H(17)); 3.16 (dd, 1 H, H(1), J = 10.0 Hz,
J = 7.0 Hz); 3.26, 3.27, and 3.37 (all s, 3 H each, C(1)OMe,
C(16)OMe, and C(14)OMe, respectively); 7.54 (dd, 1 H, H(4´),
J = 9.0 Hz, J = 2.0 Hz); 7.94 (d, 1 H, H(6´), J = 2.0 Hz); 8.56
(d, 1 H, H(3´), J = 9.0 Hz); 10.90 (s, 1 H, NHCOMe). IR,
ν/cm–1: 789; 837; 875; 899; 945; 968; 995; 1035; 1087; 1146;
1231; 1256; 1287; 1312; 1366; 1394; 1447; 1467; 1509;
1580; 1597; 1694, 1710 (NHC=O); 2819; 2927; 2962. UV,
29
30
Pd(OAc)2
and Pd(dba)2
were synthesized according to
known procedures.
Column chromatography was carried out with the use of
Al2O3 (50—150 µm, TU 6ꢀ09ꢀ3916ꢀ75, Russia, Brockmann acꢀ
tivity II). The chromatographic separation was visually moniꢀ
tored using UV irradiation, quartz columns, and the sorbent
mixed with the Kꢀ35 luminophore (1 wt.%, TU 6ꢀ09ꢀ458ꢀ76,
Russia). Preparative TLC with a nonfixed sorbent layer was
performed with the use of silica gel (35—70 µm, AcrosꢀOrꢀ
ganics) mixed with 1 wt.% of the same luminophore. The plate
size was 30×30 cm, and the thickness of the sorbent layer
was 2 mm.
The melting points were determined on a Kofler apparatus.
The IR spectra were recorded on a Vector 22 spectrometer in
KBr pellets. The UV spectra were measured on a Specord
UV—Vis spectrophotometer in ethanol (c = 10–4 mol L–1). The
highꢀresolution mass spectra were obtained on a Finnigan
MAT 8200 spectrometer (EI, 70 eV). The NMR spectra
were recorded on Bruker AMꢀ400 (400.13 MHz for 1H and
100.61 MHz for 13C) or Bruker AVꢀ300 (300.13 MHz for 1H and
75.47 MHz for 13C) spectrometers for 10% solutions at 25 °C.
The chemical shifts were measured relative to the residual sigꢀ
nals of the solvent: CHCl3 (δ 7.24 and δ 76.90), MeOH
H
C
(δ 3.34 (CH3) and δ 49.00), and H2O (δ 4.80). The multiꢀ
H
C
H
plicities of the signals in the 13C NMR spectra were determined
using J modulation (JMOD) and proton offꢀresonance. The
assignment of the signals for the carbon atoms of the aromatic
rings in the 13C NMR spectra of compounds 3—5, 7, 8, and
13—15 was made with the use of the additive scheme31 taking
into account the chemical shifts of the corresponding carbon
atoms of lappaconitine (1),15 Nꢀdeacetyllappaconitine (2),1 and
methyl Nꢀacetylanthranilate32 and the increments of the broꢀ
mine and iodine atoms31 and the (E)ꢀCH=CH—CO2Et group.17
The assignment of the signals in the 1H and 13C NMR spectra
of compounds 10 and 12 was made using correlation
2D 1H—1H COSY and 2D 13C—1H spectroscopy (CHꢀCOSY
(125 Hz) and COLOC (10 Hz)) on a Bruker DRXꢀ500 instruꢀ
ment (500.13 for 1H and 125.76 MHz for 13C). The chemical
shifts of the signals for the carbon atoms of the aromatic fragꢀ
ments of compounds 10 and 12 were used to assign the signals
for the carbon atoms of the analogous fragments in compounds
13 and 15. The 13C NMR spectroscopic data are given in Table 1.
The assignment of the signals for the hydrogen atoms of the
polycyclic moieties in compounds 3—5, 7, 8, and 13—15 in the
1H NMR spectra and the assignment of the signals for the carꢀ
bon atoms of these moieties in the 13C NMR spectra were
made by comparing with the corresponding spectra of lappaꢀ
conitine (1).14 Since the assignment of all signals in the 1H NMR
spectra presents difficulties, only the characteristic signals are
given for all the aboveꢀmentioned compounds.
λ
max/nm (logε): 225 (4.40), 258 (4.17), 321 (3.65).
The precipitate that remained undissolved after refluxing in
EtOH was dried and recrystallized from benzene. 4βꢀ(2ꢀAminoꢀ
3,5ꢀdibromobenzoyloxy)ꢀ20ꢀethylꢀ1α,14α,16βꢀtrimethoxyacoꢀ
nitaneꢀ8,9ꢀdiol (4) was obtained in a yield of 0.97 g (4%), m.p.
255—260 °C (with decomp.), [α]57820 +39 (c 3.1, CHCl3). Found
(%): C, 51.55; H, 5.80; Br, 22.49; N, 4.10. C30H40Br2N2O7.
Calculated (%): C, 51.44; H, 5.76; Br, 22.82; N, 4.00. 1H NMR
(CDCl3, 400.13 MHz), δ: 1.09 (t, 3 H, C(22)Me, J = 7.0 Hz);
1.54 (dd, 1 H, Hb(6), J = 15.0 Hz, J = 8.0 Hz); 1.78 (m, 1 H,
Hb(3)); 2.66 (dd, 1 H, Ha(6), J = 15.0 Hz, J = 7.0 Hz); 2.98 (s,
1 H, H(17)); 3.14 (dd, 1 H, H(1), J = 10.0 Hz, J = 7.0 Hz); 3.18,
3.20, and 3.30 (all s, 3 H each, C(1)OMe, C(16)OMe, and
C(14)OMe, respectively); 6.28 (br.s, 2 H, NH2); 7.63 and 7.80
(both d, 1 H each, H(3´), H(5´), J = 2.0 Hz). IR, ν/cm–1: 993;
1033; 1077; 1122; 1150; 1226; 1264; 1363; 1448; 1532; 1565;
1603; 1689 (C=O); 2820; 2935. UV, λmax/nm (logε): 229 (4.27),
251 (3.80), 356 (3.63).
Hydrobromide of base 3. A solution of 46% HBr (0.295 g,
1.70 mmol) in 95% EtOH (5.0 mL) was added dropwise with
stirring to a solution of base 3 (1.11 g, 1.67 mmol) in CH2Cl2
(2.5 mL). The solvent was distilled of in vacuo at 50 °C (30 Torr).
The resinous residue was triturated with diethyl ether (5 mL)
and a crystalline colorless powder was obtained. The suspension
in diethyl ether was kept for 15 h. The precipitate of the salt
was filtered off, washed with diethyl ether, and dried in air.
5´ꢀBromolappaconitine hydrobromide was obtained in a yield
of 1.25 g (100%), m.p.. 208—210 °C (with decomp.), [α]57820 +30
(c 5.6, H2O). Found (%): Br (bromometric titration), 11.04.
The angles of optical rotation were measured on a Polamat A
polarimeter (Carl Zeiss, λ = 578 nm). The specific rotation is
expressed in (deg mL) (g dm)–1. The concentrations of the soluꢀ
tions are given in g (100 mL)–1
.
Bromination of lappaconitine (1). Solution A. Powdered
lappaconitine (1) (22.4 g, 38.3 mmol) was added portionwise
with stirring to concentrated hydrochloric acid (d = 1.19, 57 mL).
The process was accompanied by a weak exothermic effect and
the gel formation. After stirring for 45 min, the gel was dissolved.
C
32H43BrN2O8•HBr. Calculated (%): Br (ionic), 10.74.

1080
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 6, June, 2006
Osadchii et al.
Table 1. 13C NMR spectra (100.61 MHz, CDCl3) of lappaconitine derivatives 3—5, 7, 8, and 13—15
Atom
δ
3
4
5
7
8
13
14
15*
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
83.9
26.7
31.7
85.5
48.1
24.0
47.6
75.5
78.5
49.8
51.0
26.1
36.3
90.0
44.6
82.8
61.3
55.4
48.8
13.3
84.0
26.6
31.7
84.2
48.3
23.9
47.4
75.5
78.4
49.7
50.8
26.1
36.2
90.0
44.7
82.8
61.4
55.4
48.8
13.4
83.9
26.5
31.6
83.3
48.1
23.7
47.4
75.2
78.3
49.6
50.6
25.9
36.0
89.8
44.3
82.6
61.1
55.3
48.6
13.2
83.9
26.5
31.6
83.4
48.0
23.7
47.4
75.2
78.3
49.6
50.6
25.9
36.0
89.8
44.3
82.6
61.1
55.3
48.6
13.2
83.8
26.5
31.6
84.6
48.0
23.8
47.4
75.3
78.3
49.7
50.8
26.0
36.1
89.9
44.5
82.7
61.2
55.3
48.7
13.3
84.1
26.7
31.8
83.4
48.3
23.8
47.5
75.4
78.4
49.7
50.8
26.1
36.2
90.0
44.6
82.8
61.3
55.5
48.8
13.3
83.9
26.6
31.6
85.2
48.0
23.9
47.4
75.3
78.3
49.7
50.9
26.0
36.1
89.9
44.5
82.7
61.1
55.3
48.7
13.3
83.9
26.6
31.6
84.8
48.3
24.0
47.4
75.3
78.4
49.7
50.8
26.0
36.1
89.9
44.5
82.7
61.3
55.3
48.8
13.4
C(9)
C(10)
C(11)
C(12)
C(13)
C(14)
C(15)
C(16)
C(17)
C(19)
C(21)
C(22)
C(1)OMe
56.4
56.4
56.1
56.1
56.4
56.3
56.3
56.3
C(14)OMe
C(16)OMe
C(1´)
C(2´)
C(3´)
C(4´)
C(5´)
C(6´)
C(7´)
CH3CO
CH3CO
C(1″)
C(2″)
C(3″)
C(4″)
C(5″)
C(6″)
57.8
56.0
117.3
140.6
121.9
136.9
114.6
133.2
166.1
25.3
168.8
—
—
—
—
—
—
—
—
—
57.8
56.0
113.7
146.4
110.9
138.7
106.3
132.9
165.5
—
—
—
—
—
—
—
—
—
57.6
55.7
112.8
149.1
118.1
136.1
106.8
133.1
165.9
—
—
—
—
—
—
—
—
—
57.6
55.8
113.6
149.6
118.5
141.7
75.5
139.1
165.7
—
—
—
—
—
—
—
—
—
57.8
56.0
117.4
141.0
121.9
142.7
85.4
138.9
165.8
25.3
168.8
—
—
—
—
—
—
—
—
—
57.7
55.9
122.5
131.9
111.3
151.9
117.1
133.1
166.7
—
57.7
55.9
128.3
131.4
115.7
142.8
117.6
132.4
166.7
25.4
168.9
166.7
120.4
142.8
—
—
—
—
—
—
14.1
60.3
57.7
55.9
130.9
140.9
120.4
131.0
115.8
129.5
167.0
25.4
—
168.8
—
167.3
113.9
144.1
—
—
—
—
—
—
14.2
60.0
147.7
129.7
132.7
123.0
157.2
25.2
128.0
124.5
—
C(6″)CH3
C(1″´)
C(2″´)
OCH2CH3
OCH2CH3
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
* 75.47 MHz.
1H NMR (D2O, 400.13 MHz), δ: 1.53 (t, 3 H, C(22)Me, J =
7.0 Hz); 2.37 (s, 3 H, NHCOMe); 3.51, 3.53, and 3.54 (all s,
3 H each, C(1)OMe, C(16)OMe, and C(14)OMe, respectively);
7.74 (dd, 1 H, H(4´), J = 9.0 Hz, J = 2.0 Hz); 7.82 (d, 1 H,
H(3´), J = 9.0 Hz); 8.03 (d, 1 H, H(6´), J = 2.0 Hz). IR,
ν/cm–1: 965; 1039; 1084; 1130; 1134; 1256; 1287; 1307; 1394;
1464; 1505; 1579; 1599; 1636; 1689, 1702 (C=O); 2823;
2878; 2934; 3015. UV, λmax/nm (logε): 226 (4.33), 258 (4.06),
324 (3.52).
4βꢀ(2ꢀAminoꢀ5ꢀbromobenzoyloxy)ꢀ20ꢀethylꢀ1α,14α,16βꢀ
trimethoxyaconitaneꢀ8,9ꢀdiol (5). A solution of 5´ꢀbromoꢀ
lappaconitine (3) (3.32 g, 5 mmol) in 10% H2SO4 (11.3 mL) was
heated at 95—98 °C for 5 h. The reaction mixture was cooled
to 5 °C. A 25% ammonia solution cooled to 5 °C was added
dropwise with stirring to pH ~8. The precipitate that formed was
extracted with chloroform (3×15 mL). The extract was dried
with anhydrous MgSO4, concentrated to 35 mL, and chromatoꢀ
graphed on Al2O3 (quartz column, the inner diameter was 3.5 cm,

Heck reaction of anthranilates
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 6, June, 2006
1081
the height of the sorbent layer was 15 cm) using chloroform as
the eluent. The fraction of a solution of an UVꢀabsorbing prodꢀ
uct was collected, and the solvent was removed. The residue was
recrystallized from ethanol. Compound 5 was obtained in a
yield of 2.52 g (81%), m.p. 255—257 °C (with decomp.).
Found (%): C, 57.57; H, 6.84; Br, 13.00; N, 4.37.
J = 7.0 Hz); 2.91 (s, 1 H, H(17)); 3.08 (dd, 1 H, H(1), J =
10.0 Hz, J = 7.0 Hz); 3.19, 3.22, and 3.32 (all s, 3 H each,
C(1)OMe, C(16)OMe, and C(14)OMe, respectively); 3.35 (d,
l H, H(14), J = 5.0 Hz); 3.46 (d, l H, Ha(19), J = 11.0 Hz); 5.75
(br.s, 2 H, NH2); 6.34 (d, 1 H, H(3´), J = 9.0 Hz); 7.34 (dd,
1 H, H(4´), J = 9.0 Hz, J = 2.0); 7.88 (d, 1 H, H(6´), J =
2.0 Hz). IR, ν/cm–1: 944; 964; 992; 1019; 1033; 1077; 1148;
1236; 1291; 1305; 1336; 1364; 1396; 1472; 1545; 1576; 1608;
1682 (C=O); 2816; 2923; 3368, 3466, 3539 (OH, NH). UV,
C
30H41BrN2O7. Calculated (%): C, 57.97; H, 6.65; Br, 12.86;
N, 4.51. 1H NMR (CDCl3, 400.13 MHz), δ: 1.03 (t, 3 H,
C(22)Me, J = 7.0 Hz); 1.50 (dd, 1 H, Hb(6), J = 15.0 Hz, J =
8.0 Hz); 1.72 (m, 1 H, Hb(3)); 2.92 (s, 1 H, H(17)); 3.09 (dd,
1 H, H(1), J = 10.0 Hz, J = 7.0 Hz); 3.20, 3.23, and 3.33 (all s,
3 H each, C(1)OMe, C(16)OMe, and C(14)OMe, respectively);
3.36 (d, l H, H(14), J = 5.0 Hz); 3.48 (d, l H, Ha(19), J =
11.0 Hz); 5.71 (br.s, 2 H, NH2); 6.44 (d, 1 H, H(3´), J =
9.0 Hz); 7.19 (dd, 1 H, H(4´), J = 9.0 Hz, J = 2.0 Hz); 7.73 (d,
1 H, H(6´), J = 2.0 Hz). IR, ν/ cm–1: 945; 966; 1020; 1033;
1079; 1112; 1149; 1234; 1291; 1305; 1339; 1364; 1395; 1449;
1476; 1550; 1583; 1611; 1684 (C=O); 2819; 2932; 3372; 3495;
3538 (OH, NH). UV, λmax/nm (logε): 222 (4.28), 258 (3.83),
352 (3.58).
λ
max/nm (logε): 224 (4.20), 260 (3.83), 352 (3.42).
4βꢀ(2ꢀAcetylaminoꢀ5ꢀiodobenzoyloxy)ꢀ20ꢀethylꢀ1α,14α,16βꢀ
trimethoxyaconitaneꢀ8,9ꢀdiol (8). A mixture of compound 7
(1.56 g, 2.33 mmol) and Ac2O (2.3 mL, 2.48 g, 24.3 mmol) was
heated with stirring at 100 °C for 10 min. The resulting solution
was cooled and kept at 20 °C for 16 h. Then ice water (5 mL) and
a 25% ammonia solution were successively added dropwise with
stirring to pH ~8. The precipitate that formed was filtered off,
washed with water (2×5 mL), dried, and dissolved in ethanol
(3 mL). The solution was kept at 0 °C for 16 h. The precipitate
that formed was filtered off and dried at 50—60 °C (3 Torr). The
yield was 1.60 g (96%), colorless crystals, m.p. 183—185 °C.
Highꢀresolution mass spectrum, found: m/z 710.20740 [M]+.
C32H43IN2O8. Calculated: M = 710.20650. 1H NMR (CDCl3,
400.13 MHz), δ: 1.06 (t, 3 H, C(22)Me, J = 7.0 Hz); 1.48 (dd,
1 H, Hb(6), J = 15.0 Hz, J = 8.0 Hz); 1.79 (m, 1 H, Hb(3)); 2.32
(s, 3 H, MeCO); 2.65 (dd, 1 H, Ha(6), J = 15.0 Hz, J = 7.0 Hz);
2.95 (s, 1 H, H(17)); 3.12 (dd, 1 H, H(1), J = 10.0 Hz, J =
7.0 Hz); 3.23, 3.25, and 3.34 (all s, 3 H each, C(1)OMe,
C(16)OMe, and C(14)OMe, respectively); 3.38 (d, l H, H(14),
J = 5.0 Hz); 3.48 (d, l H, Ha(19), J = 11.0 Hz); 7.69 (dd, 1 H,
H(4´), J = 9.0 Hz, J = 2.0 Hz); 8.09 (d, 1 H, H(6´), J = 2.0 Hz);
8.40 (d, 1 H, H(3´), J = 9.0 Hz); 10.93 (s, 1 H, NH). IR,
ν/cm–1: 788; 834; 899; 995; 967; 1035; 1088; 1146; 1231; 1257;
1288; 1307; 1389; 1446; 1506; 1575; 1592; 1694, 1709 (C=O);
2818; 2926; 3519, 3482 (NH, OH). UV, λmax/nm (logε): 229
(4.21), 261 (3.98), 324 (3.41).
Methyl 2ꢀ(acetylamino)ꢀ5ꢀbromobenzoate. A solution of broꢀ
mine (0.789 g, 4.93 mmol) in concentrated HCl (4.8 mL) was
added dropwise with stirring to a solution of methyl Nꢀacetylꢀ
anthranilate (0.856 g, 4.44 mmol) in concentrated HCl (3.0 mL).
The formation of the precipitate was observed. The mixture was
shaken for 15 min and then diluted with water (27 mL). The
precipitate that formed was filtered off, dried, and recrystallized
from ethanol. The target bromo derivative was obtained in a
yield of 1.12 g (93%) as colorless needleꢀlike crystals, m.p.
134—135 °C (cf. lit. data23: m.p. 131—132 °C). Highꢀresolution
mass spectrum, found: m/z 270.98614 [M]+. C10H10BrNO3. Calꢀ
culated: M = 270.98445. 1H NMR (CDCl3, 400.13 MHz), δ:
2.17 and 3.87 (both s, 3 H each, MeCO and MeO, respectively);
7.53 (dd, 1 H, H(4), J = 9.0 Hz, J = 2.0 Hz); 8.03 (d, 1 H, H(6),
J = 2.0 Hz); 8.55 (d, 1 H, H(3), J = 9.0 Hz); 10.90 (br.s,
1 H, NH) (cf. lit. data23). 13C NMR of the same solution
(100.61 MHz), δ: 115.8 (C(1)), 140.3 (C(2)), 121.5 (C(3)),
136.9 (C(4)), 114.3 (C(5)), 132.8 (C(6)), 168.5 (CO2CH3), 52.2
(CO2CH3), 25.1 (CH3CO), 167.1 (CH3CO). IR, ν/cm–1: 509;
528; 719; 791; 836; 971; 1094; 1237; 1259; 1290; 1312; 1362;
1394; 1430; 1515; 1583; 1600; 1684, 1701 (C=O); 2950; 3004;
3025; 3064; 3090; 3307 (NH). UV, λmax/nm (logε): 226 (4.41),
257 (4.20), 319 (3.66).
4βꢀ(2ꢀAminoꢀ5ꢀiodobenzoyloxy)ꢀ20ꢀethylꢀ1α,14α,16βꢀtriꢀ
methoxyaconitaneꢀ8,9ꢀdiol (7). NꢀDeacetyllappaconitine (2)
(5.43 g, 10 mmol) was dissolved in glacial acetic acid (15 mL) at
50 °C. Iodine chloride (1.70 g, 10.5 mmol) was added dropwise
with stirring to the solution at 20 °C. The reaction mixture was
heated to 65 °C, stirred until the darkꢀcolored resinous precipiꢀ
tate was completely dissolved (~30 min), then kept at 20 °C for
16 h, and diluted with water (45 mL). Then a 25% ammonia
solution was added dropwise with stirring to pH ~8. The resultꢀ
ing mixture was extracted with chloroform (3×20 mL). The
extract was dried with anhydrous MgSO4. Compound 7 was
isolated by chromatography as described above for compound 5.
The yield was 4.98 g (74%), m.p. 230—232 °C (with decomp.,
from EtOH). Found (%): C, 54.39; H, 6.29; I, 18.85; N, 4.20.
C30H41IN2O7. Calculated (%): C, 53.89; H, 6.18; I, 18.98;
N, 4.19. 1H NMR (CDCl3, 400.13 MHz), δ: 1.02 (t, 3 H,
C(22)Me, J = 7.0 Hz); 1.49 (dd, 1 H, Hb(6), J = 15.0 Hz, J =
8.0 Hz); 1.72 (m, 1 H, Hb(3)); 2.59 (dd, 1 H, Ha(6), J = 15.0 Hz,
Methyl 2ꢀ(acetylamino)ꢀ5ꢀiodobenzoate (9). A solution of
methyl 2ꢀaminoꢀ5ꢀiodobenzoate (6)24 (0.734 g, 2.64 mmol) in
Ac2O (2.7 mL, 2.92 g, 28.6 mmol) was kept at 20 °C for 16 h.
Then ice water (5.4 mL) was added with stirring to the reaction
mixture. Crystals were filtered off and dried at 50—60 °C (3 Torr).
Amide 9 was obtained in a yield of 0.820 g (97%) as colorless
needleꢀlike crystals, m.p. 132—133 °C (from EtOH) (cf. lit.
data25: m.p. 110 °C (from EtOH)). Highꢀresolution mass specꢀ
trum, found: m/z 318.97132 [M]+. C10H10INO3. Calculated:
M = 318.97072. 1H NMR (CDCl3, 300.13 MHz), δ: 2.18 and
3.88 (both s, 3 H each, MeCO and MeO, respectively); 7.73 (dd,
1 H, H(4), J = 9.0 Hz, J =2.0 Hz); 8.25 (d, 1 H, H(6), J =
2.0 Hz); 8.44 (d, 1 H, H(3), J = 9.0 Hz); 10.91 (br.s, 1 H, NH).
13C NMR of the same solution (CDCl3, 75.47 MHz), δ: 116.3
(C(1)), 141.0 (C(2)), 122.1 (C(3)), 142.9 (C(4)), 84.6 (C(5)),
139.1 (C(6)), 167.2 (CO2CH3), 52.5 (CO2CH3), 25.4 (CH3CO),
168.8 (CH3CO). 1H NMR (DMSOꢀd6, 300.13 MHz), δ: 2.12
and 3.84 (both s, 3 H each, MeCO and MeO, respectively); 7.90
(dd, 1 H, H(4), J = 9.0 Hz, J = 2.0 Hz); 7.96 (d, 1 H, H(3), J =
9.0 Hz); 8.13 (d, 1 H, H(6), J = 2.0 Hz); 10.91 (br.s, 1 H, NH).
The 1H NMR spectroscopic data in DMSOꢀd6 are consistent
1
with the published data.25 The difference in the H NMR specꢀ
tra recorded in CDCl3 and DMSOꢀd6 is, apparently, attributed
to the difference in solvation. IR, ν/cm–1: 790; 831; 950; 1089;
1186; 1234; 1259; 1289; 1306; 1387; 1430; 1511; 1578; 1596;

1082
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 6, June, 2006
Osadchii et al.
1685, 1708 (C=O); 2960; 3031; 3090; 3113; 3266 (NH). UV,
compound 11 starting from iodide 9 (0.212 g, 0.665 mmol),
DMF (1.05 mL), 2ꢀmethylꢀ5ꢀvinylpyridine (0.198 g, 1.66 mmol),
triethylamine (0.21 mL, 0.153 g, 1.51 mmol), tris(oꢀtolyl)phosꢀ
phine (0.020 g, 0.067 mmol, 10 mol.%), and Pd(dba)2 (0.020 g,
0.035 mmol, 5 mol.%). Compound 12 was obtained in a yield of
0.148 g (72%), m.p. 220—222 °C (from a CH2Cl2—EtOH
λ
max/nm (logε): 230 (4.36), 261 (4.16), 323 (354).
Ethyl 3ꢀ[(4ꢀaminoꢀ3ꢀmethoxycarbonyl)phenyl]propꢀ2Eꢀ
enoate (10). Methyl 5ꢀiodoanthranilate (6)24 (1.81 g, 6.54 mmol),
DMF (13.4 mL), ethyl acrylate (4.0 mL, 3.68 g, 36.8 mmol),
triethylamine (1.80 mL, 1.31 g, 12.9 mmol), tris(oꢀtolyl)phosꢀ
phine (0.226 g, 0.742 mmol, 11 mol.%), and Pd(OAc)2 (0.096 g,
0.428 mmol, 7.7 mol.%) (cf. lit. data33) were successively introꢀ
duced with stirring in a reaction vessel. The reaction mixture
was heated at 100 °C for 4 h under a stream of argon and then
cooled to 25 °C. Dichloromethane (90 mL) and 10% H2SO4
(20 mL) were successively added with stirring to the reaction
mixture. The organic layer was separated and dried with anhyꢀ
drous MgSO4. After removal of the solvent, the resinous residue
was extracted with hexane (4×30 mL) under reflux. The crystals
of compound 10 that formed upon storage of the extract were
filtered off. The yield was 1.03 g (63%), m.p. 94—95 °C. Highꢀ
resolution mass spectrum, found: m/z 249.10037 [M]+.
mixture).
Highꢀresolution
mass
spectrum,
found:
m/z 310.13052 [M]+. C18H18N2O3. Calculated: M = 310.13173.
1H NMR (CDCl3, 300.13 MHz), δ: 2.19 (s, 3 H, MeCO); 2.51
(s, 3 H, C(6´)Me); 3.90 (s, 3 H, CO2Me); 6.98 and 7.01 (both d,
1 H each, AB system, H(2″) and H(1″), respectively, J =
16.5 Hz); 7.08 (d, 1 H, H(5´), J = 8.1 Hz); 7.61 (dd, 1 H, H(4),
J = 8.8 Hz, J = 2.2 Hz); 7.66 (dd, 1 H, H(4´), J = 8.1 Hz, J =
2.3 Hz); 8.07 (d, 1 H, H(6), J = 2.2 Hz); 8.53 (d, 1 H, H(2´), J =
2.3 Hz); 8.66 (d, 1 H, H(3), J = 8.8 Hz); 11.00 (br.s, 1 H, NH).
13C NMR of the same solution (75.47 MHz), δ: 130.9 (C(1)),
140.8 (C(2)), 120.3 (C(3)), 132.0 (C(4)), 114.7 (C(5)), 128.6
(C(6)), 147.6 (C(2´)), 129.6 (C(3´)), 132.7 (C(4´)), 123.0
(C(5´)), 157.3 (C(6´)), 127.8 (C(1″)), 124.6 (C(2″)), 24.0
(CH3C(6´)), 25.3 (CH3CO), 168.8 (CH3CO), 52.2 (CO2CH3),
168.3 (CO2CH3). IR, ν/cm–1: 791; 847; 985; 1088; 1203; 1227;
1239; 1280; 1302; 1336; 1369; 1415; 1439; 1485; 1519;
1589; 1681, 1706 (C=O); 2845; 2948; 3016; 3260 (NH). UV,
C
13H15NO4. Calculated: M = 249.10010. 1H NMR (CDCl3,
400.13 MHz), δ: 1.27 (t, 3 H, CH3CH2, J = 7.0 Hz); 3.82 (s,
3 H, OMe); 4.19 (q, 2 H, CH3CH2, J = 7.0 Hz); 6.10 (br.s, 2 H,
NH2); 6.18 (d, 1 H, H(2), J = 16.0 Hz); 6.60 (d, 1 H, H(5´), J =
9.0 Hz); 7.39 (dd, 1 H, H(6´), J = 9.0 Hz, J = 2.0 Hz); 7.52 (d,
1 H, H(3), J = 16.0 Hz); 7.95 (d, 1 H, H(2´), J = 2.0 Hz).
13C NMR of the same solution (100.61 MHz), δ: 167.3 (C(1)),
113.8 (C(2)), 144.0 (C(3)), 122.4 (C(1´)), 132.4 (C(2´)), 110.0
(C(3´)), 151.8 (C(4´)), 116.9 (C(5´)), 132.6 (C(6´)), 167.8
(C(7´)), 14.1 (CH2CH3), 60.0 (CH2CH3), 52.2 (CO2CH3). IR,
ν/cm–1: 827; 935; 956; 986; 1036; 1088; 1182; 1248; 1316; 1368;
1441; 1500; 1613, 1690 (C=O); 2905; 2957; 2988; 3334, 3437
(NH2). UV, λmax/nm (logε): 227 (4.13), 330 (4.35).
Ethyl 3ꢀ[(4ꢀacetylaminoꢀ3ꢀmethoxycarbonyl)phenyl]propꢀ
2Eꢀenoate (11). Condensation was carried out as described above
for compound 10 starting from methyl 2ꢀ(acetylamino)ꢀ5ꢀ
iodobenzoate (9) (0.583 g, 1.83 mmol), DMF (2.9 mL), ethyl
acrylate 0.83 mL (0.76 g, 7.6 mmol), triethylamine (0.59 mL,
0.43 g, 4.3 mmol), tris(oꢀtolyl)phosphine (0.056 g, 0.183 mmol,
10 mol.%), and Pd(dba)2 (0.053 g, 0.092 mmol, 5 mol.%). After
cooling, the reaction mixture was kept for 16 h. The precipitate
that formed was filtered off, dried at 80 °C (3 Torr), and exꢀ
tracted with dichloromethane. The extract was concentrated
and compound 11 was obtained in a yield of 0.379 g (71%),
m.p. 162—163 °C (from EtOH). Highꢀresolution mass specꢀ
trum, found: m/z 291.11120 [M]+. C15H17NO5. Calculated:
M = 291.11066. 1H NMR (CDCl3, 300.13 MHz), δ: 1.31 (t,
3 H, CH3CH2, J = 7.0 Hz); 2.22 (s, 3 H, MeCO); 3.92 (s, 3 H,
OMe); 4.24 (q, 2 H, CH3CH2, J = 7.0 Hz); 6.36 (d, 1 H, H(2),
J = 16.0 Hz); 7.57 (d, 1 H, H(3), J = 16.0 Hz); 7.64 (dd, 1 H,
H(6´), J = 9.0 Hz, J = 2.0 Hz); 8.12 (d, 1 H, H(2´), J = 2.0 Hz);
8.70 (d, 1 H, H(5´), J = 9.0 Hz); 11.10 (br.s, 1 H, NH). 13C NMR
of the same solution (75.47 MHz), δ: 166.7 (C(1)), 120.5 (C(2)),
142.8 (C(3)), 128.5 (C(1´)), 130.8 (C(2´)), 114.8 (C(3´)), 142.8
(C(4´)), 117.9 (C(5´)), 133.5 (C(6´)), 14.3 (CH2CH3), 60.5
(CH2CH3), 25.5 (CH3CO), 168.1 (CH3CO), 52.5 (CO2CH3),
169.1 (C(7´)). IR, ν/cm–1: 751; 795; 854; 954; 981; 1013;
1036; 1088; 1181; 1208; 1238; 1280; 1305; 1321; 1339; 1368;
1415; 1442; 1478; 1524; 1589; 1634, 1703 (C=O); 2905; 2960;
2981; 3069; 3255 (NH). UV, λmax/nm (logε): 241 (4.22),
303 (4.38).
λ
max/nm (logε): 224 (3.94), 249 (3.96), 318 (4.22).
Ethyl 3ꢀ{4ꢀaminoꢀ3ꢀ[(8,9ꢀdihydroxyꢀ20ꢀethylꢀ1α,14α,16βꢀ
trimethoxyaconitꢀ4βꢀyloxy)carbonyl]phenyl}propꢀ2Eꢀenoate (13)
was prepared as described above for compound 11 starting from
iodide 7 (0.545 g, 0.815 mmol), DMF (0.86 mL), ethyl acrylate
(0.25 mL, 0.23 g, 2.3 mmol), triethylamine (0.21 mL, 0.153 g,
1.51 mmol), tris(oꢀtolyl)phosphine (0.020 g, 0.067 mmol,
8 mol.%), and Pd(dba)2 (0.020 g, 0.035 mmol, 4 mol.%). After
cooling, the reaction mixture was diluted with CH2Cl2 (10 mL)
and kept for 16 h. Then palladium black was filtered off.
The filtrate was concentrated and the resinous residue was
thoroughly dried at 100 °C (3 Torr) and dissolved in CHCl3
(10 mL). The solution was extracted with 10% H2SO4 (3×5 mL).
The acidic extract was filtered off and neutralized with stirring
with a 25% ammonia solution to pH ~8. The precipitate
that formed was extracted with chloroform (3×15 mL). The
extract was dried with anhydrous MgSO4, concentrated to 3 mL,
and subjected to preparative TLC on a nonfixed layer of
silica gel (Et2O as the eluent). The sorbent zone exhibiting blue
fluorescence under UV light was collected. The product
was eluted from the sorbent with an Et2O—MeOH mixture (9 : 1,
v/v). Compound 13 was obtained as an amorphous powder in a
yield of 0.339 g (65%). Found (%): C, 65.41; H, 7.46; N, 4.34.
C35H48N2O9. Calculated (%): C, 65.60; H, 7.55; N, 4.37.
1H NMR (CDCl3, 400.13 MHz), δ: 1.07 (t, 3 H, C(22)Me, J =
7.0); 1.56 (dd, 1 H, Hb(6), J = 15.0 Hz, J = 8.0 Hz); 1.78 (m,
1 H, Hb(3)); 2.96 (s, 1 H, H(17)); 3.14 (dd, 1 H, H(1), J = 10.0,
J = 7.0 Hz); 3.24, 3.26, and 3.36 (all s, 3 H each, C(1)OMe,
C(16)OMe, and C(14)OMe, respectively); 3.40 (d, l H, H(14),
J = 5.0 Hz); 3.52 (d, l H, Ha(19), J = 11.0 Hz); 4.20 (q, 2 H,
CO2CH2CH3, J = 7.0 Hz); 6.02 (br.s, 2 H, NH2); 6.15 (d, 1 H,
H(2″), J = 16.0 Hz); 6.58 (d, 1 H, H(5´), J = 9.0 Hz);
7.41 (dd, 1 H, H(6´), J = 9.0 Hz, J = 2.0 Hz); 7.52 (d, 1 H,
H(3″), J = 16.0 Hz); 7.81 (d, 1 H, H(2´), J = 2.0 Hz). IR,
ν/cm–1: 826; 893; 946; 967; 1036; 1088; 1159; 1201; 1269;
1299; 1368; 1426; 1450; 1466; 1501; 1614; 1688 (C=O); 2818;
2928; 3359, 3464 (NH, OH). UV, λmax/nm (logε): 226 (4.10),
331 (4.25).
Methyl (E )ꢀ2ꢀ(acetylamino)ꢀ5ꢀ[2ꢀ(6ꢀmethylpyridinꢀ3ꢀ
yl)ethenyl]benzoate (12) was prepared as described above for

Heck reaction of anthranilates
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 6, June, 2006
1083
Ethyl
3ꢀ{4ꢀacetylaminoꢀ3ꢀ[(8,9ꢀdihydroxyꢀ20ꢀethylꢀ
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 05ꢀ03ꢀ
32365).
1α,14α,16βꢀtrimethoxyaconitꢀ4βꢀyloxy)carbonyl]phenyl}propꢀ
2Eꢀenoate (14) was prepared as described above for compound
13 starting from 5´ꢀiodolappaconitine (8) (0.110 g, 0.155 mmol),
DMF (0.5 mL), ethyl acrylate (0.07 mL, 0.064 g, 0.64 mmol),
triethylamine (0.05 mL, 0.036 g, 0.36 mmol), tris(oꢀtolyl)phosꢀ
phine (0.005 g, 0.016 mmol, 10 mol.%), and Pd(dba)2 (0.005 g,
0.009 mmol, 6 mol.%). After preparative TLC (a nonfixed layer
of silica gel; Et2O as the eluent), the UVꢀabsorbing sorbent zone
was collected. The product was eluted from the sorbent with
an Et2O—MeOH mixture (9 : 1, v/v). Compound 14 was obꢀ
tained as an amorphous powder in a yield of 0.088 g (83%).
Highꢀresolution mass spectrum, found: m/z 682.34747 [M]+.
C37H50N2O10. Calculated: M = 682.34652. 1H NMR (CDCl3,
400.13 MHz), δ: 1.05 (t, 3 H, C(22)Me, J = 7.0 Hz); 1.26 (t,
3 H, CO2CH2CH3, J = 7.0 Hz); 1.49 (dd, 1 H, Hb(6), J =
15.0 Hz, J = 8.0 Hz); 2.16 (s, 3 H, MeCO); 2.65 (dd, 1 H,
Ha(6), J = 15.0 Hz, J = 7.0 Hz); 2.94 (s, 1 H, H(17)); 3.12 (dd,
1 H, H(1), J = 10.0 Hz, J = 7.0 Hz); 3.22, 3.23, and 3.33 (all s,
3 H each, C(1)OMe, C(16)OMe, and C(14)OMe, respectively);
3.37 (d, l H, H(14), J = 5.0 Hz); 3.48 (d, l H, Ha(19), J =
11.0 Hz); 4.18 (q, 2 H, CO2CH2CH3, J = 7.0 Hz); 6.28 (d, 1 H,
H(2″), J = 16.0 Hz); 7.52 (d, 1 H, H(3″), J = 16.0 Hz); 7.61 (dd,
1 H, H(6´), J = 9.0 Hz, J = 2.0 Hz); 7.91 (d, 1 H, H(2´), J =
2.0 Hz); 8.64 (d, 1 H, H(5´), J = 9.0 Hz); 11.08 (s, 1 H, NH).
IR, ν/cm–1: 1036; 1087; 1176; 1202; 1235; 1269; 1333; 1367;
1411; 1449; 1517; 1588; 1637; 1684, 1709 (C=O); 2819; 2928;
2983; 3256, 3308, 3394 (NH, OH). UV, λmax/nm (logε): 229
(4.02), 246 (4.04), 303 (4.10).
References
1. N. V. Anferova, I. Yu. Bagryanskaya, Yu. V. Gatilov, S. A.
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(E )ꢀ4βꢀ{2ꢀ(Acetylamino)ꢀ5ꢀ[2ꢀ(6ꢀmethylpyridinꢀ3ꢀyl)etheꢀ
nyl]}benzoyloxyꢀ20ꢀethylꢀ1α,14α,16βꢀtrimethoxyaconitaneꢀ8,9ꢀ
diol (15) was prepared as described above for compound 13
starting from 5´ꢀiodolappaconitine (8) (0.580 g, 0.665 mmol),
DMF (1.05 mL), 2ꢀmethylꢀ5ꢀvinylpyridine (0.24 mL, 0.235 g,
1.96 mmol), triethylamine (0.21 mL, 0.153 g, 1.51 mmol),
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lated (%): C, 68.43; H, 7.33; N, 5.99. 1H NMR (CDCl3,
300.13 MHz), δ: 1.08 (t, 3 H, C(22)Me, J = 7.0 Hz); 1.57 (dd,
1 H, Hb(6), J = 15.0 Hz, J = 8.0 Hz); 1.78 (m, 1 H, Hb(3)); 2.18
(s, 3 H, MeCO); 2.50 (s, 3 H, C(6″)Me); 2.72 (dd, 1 H, Ha(6),
J = 15.0 Hz, J = 7.0 Hz); 2.97 (s, 1 H, H(17)); 3.15 (dd, 1 H,
H(1), J = 10.0 Hz, J = 7.0 Hz); 3.25, 3.26, and 3.36 (all s,
3 H each, C(1)OMe, C(16)OMe, and C(14)OMe, respectively);
3.40 (d, l H, H(14), J = 5.0 Hz); 3.55 (d, l H, Ha(19), J =
11.0 Hz); 6.91 and 6.99 (both d, 1 H each, AB system, H(2″´)
and H(1″´), respectively, J = 16.5 Hz); 7.08 (d, 1 H, H(5″), J =
8.1 Hz); 7.65 (dd, 1 H, H(4´), J = 8.8 Hz, J = 2.2 Hz); 7.71 (dd,
1 H, H(4″), J = 8.1 Hz, J = 2.3 Hz); 7.90 (d, 1 H, H(6´), J =
2.2 Hz); 8.52 (d, 1 H, H(2″), J = 2.3 Hz); 8.64 (d, 1 H, H(3´),
J = 8.8 Hz); 11.01 (br.s, 1 H, NH). IR, ν/cm–1: 839; 893; 946;
966; 997; 1035; 1086; 1115; 1147; 1211; 1234; 1276; 1299; 1332;
1367; 1413; 1450; 1465; 1515; 1588; 1685, 1700 (C=O); 2820;
2925; 3266, 3311, 3400 (NH, OH). UV, λmax/nm (logε): 226
(4.00), 253 (4.05), 316 (4.23).
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Received March 20, 2006;
in revised form June 4, 2006