Synthetic transformations of isoquinoline alkaloids. Synthesis of N′-substituted 1-alkynyl-7α,8α-(2,5-dioxopyrrolidino)-[3,4-h]- 6,14-endo-ethenotetrahydrothebaines and their transformations

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 11, pp. 1473−1482. © Pleiades Publishing, Ltd., 2012.

Original English Text © V.T. Bauman, E.E. Shults, M.M. Shakirov, G.A. Tolstikov, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48, No. 11,

pp. 1489−1499.

Synthetic Transformations of Isoquinoline Alkaloids.

Synthesis of N'-Substituted 1-Alkynyl-7α,8α-(2,5-

dioxopyrrolidino)-[3,4-h]-6,14-endo-ethenotetrahydrothebaines

and Their Transformations

V. T. Bauman, E. E. Shults, M. M. Shakirov, and G. A. Tolstikov

Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Division, Russian Academy of Sciences,

Novosibirsk, 630090 Russia

e-mail: schultz@nioch.nsc.ru

Received March 27, 2012

Abstract—The iodination of N'-substituted (2,5-dioxopyrrolidino)[3,4-h]-6,14-endo-ethenotetrahydrothebaines with

N-iodosuccinimide in triﬂuoroacetic acid afforded depending on the excess of the reagent either 1-iodo- or 1,2-diiodo-

endo-ethenotetrahydrothebaines. The Sonogashira reaction of 1-iodo-6,14-endo-ethenotetrahydrothebaines with

trimethylsilylacetylene led to the formation of N'-substituted 1-(trimethylsilylethynyl)-(2,5-dioxopyrrolidino)-

[3,4-h]-6,14-endo-ethenotetrahydrothebaines whose desilylation cleanly furnished the corresponding 1-ethynyl-

endo-ethenotetrahydrothebaines. The Mannich reaction of the acetylene derivatives of tetrahydrothebaine

with amines and formaldehyde catalyzed by compounds of Cu(I) provided 1-[3-(morpholin-4-yl)propynyl]-,

1-[3-(4-methylpiperazin-1-yl)propynyl]-, and 1-[3-(4-tert-butoxycarbonylpiperazin-1-yl)propynyl]-(2,5-

dioxopyrrolidino)[3,4-h]-6,14-endo-ethenotetrahydrothebaines.

DOI: 10.1134/S1070428012110103

Valuable pharmacological properties of 6,14-endo-

ethenotetrahydrothebaine derivatives, ethorfine and

buprenorﬁne, used in the clinical practice, attract an

interest to the structural modiﬁcation of thebaine by

the introduction of additional cyclic fragments in cycle

C [1–5]. The study of the properties of 6,14-endo-

ethenotetrahydrothebaines (oripavines) fused in the

positions C^7,8to the N-substituted pyrrolidine or

succinimide fragments made it possible to ﬁnd selective

agonists of μ-opiate receptors [6] and promising analgesic

agents [7]. Our attention was attracted by the possibility

to modify the N’-substituted (2,5-dioxopyrrolidino)[3,4-

h]fused 6,14-endo-ethenotetrahydrothebaine derivatives

by introducing diverse alkynyl substituents in the

aromatic ring A aiming at establishing the effect of the

acetylene substituents on the basic analgesic activity.

notetrahydrothebaines I, II with iodine monochloride

proceeded slowly and resulted in the formation of a

complex mixture of substances [8]. The iodination

of

7α,8α-(N-methyl-2,5-dioxopyrrolidino)-[3,4-h]-

6,14-endo-ethenotetrahydrothebaine (III) with iodine

monochloride, 1 : 1.5, in formic acid at heating at 45–

50°C gave 1-iodo(2,5-dioxo-N-methyl-pyrrolidino)-

[3,4-h]endo-ethenotetrahydrothebaine

(IV)

and

2-iodo(2,5-dioxo-N-methylpyrrolidino)[3,4-h]-endo-

ethenotetrahydrothebaine (V) in the ratio 10:2 and in

an overall yield 90% (Scheme 1). The presence in the

reaction mixture of compound V is indicated by the

¹H NMR spectrum of the mixture where two singlet

signals of protons H²[δ 7.02 ppm (IV)] and H¹[δ 6.66

ppm (V)] and also two pairs of proton signals at the

atoms C^5,10[2.97 d (1H, H¹⁰, J 18.9 Hz), 4.63 d (H⁵,

J 1.2 Hz) (IV); 3.11 d (1H, H¹⁰, J 19.0 Hz), 4.66 d (H⁵,

J 1.4 Hz) (V)] are observed; the signals of the other

protons of the morphinan skeleton H^{7,8,9,15,16,17,18}co-

incide. We failed to isolate compound V in the pure

state.

The most convenient procedure of introducing al-

kynyl fragments is Sonogashira reaction between the

appropriate iodo- and bromoarenes and terminal acety-

lenes. It was shown previously that the iodination of

(N-aryl-2,5-dioxopyrrolidino)[3,4-h]-6,14-endo-ethe-

1473

BAUMAN et al.

1474

Scheme 1.

I

H₃CO

I

2

H₃CO

O

1

3

11

1 equiv NIS,

CF₃COOH

10

NIS,

CF₃COOH

15

12

16

17

O⁴₅

O

9

+

14

13

18

19

7

NHCH₃

NCH₃

O

6

_

8

H₃CO

CF₃COO

O

H₃CO

O

H₃CO

5'

N^1'

O

2'

N

O

N

O

CH₃

_

III

IVa

IV

R

VI, VII

Al₂O₃/HO

I, II

R

I

H₃CO

1.3^_2 equiv NIS,

CF₃COOH

H₃CO

I

H₃CO

ICl,

HCOOH

O

IV

+

III

O

NCH₃

O

NCH₃

1 equiv NIS,

HCOOH

H₃CO

O

H₃CO

O

N

CH₃

N

O

N

O

CH₃

IV

R = H (I, VII), Br (II, VI).

IV

V

VIII

The iodination of compounds I–III with N-iodo-

succinimide (1 equiv) in triﬂuoroacetic acid proceeded at

room temperature and resulted in the selective formation

of individual 1-iodo-7α,8α-(2,5-dioxopyrrolidino)

atom of the dihydrofuran ring. The analogous direction

of the substitution into the meta-position with respect

to the methoxy group was observed at the chlorination,

bromination, and iodination of the aromatic ring of a

series of the other morphinans [8–11].

[3,4-h]-6,14-endo-ethenotetrahydrothebaines

IV,

VI, VII (yield 96–98%). Compound IV was easily

isolated in the form of salt IVa which was converted

into the base by treating with the alkaline alumina. The

reaction of compound III with N-iodosuccinimide (1

equiv) in formic acid under the mentioned conditions

gave 1-iododerivative V in 65% yield (conversion

86%). At the reaction of compound III with excess

N-iodosuccinimide (1.3 equiv) in the triﬂuoroacetic

acid we obtained a mixture of 1-iodo- and 1,2-diiodo-

1-Iodotetrahydrothebaines IV, VI, VII cleanly reacted

with trimethylsilylacetylene in benzene solution in the

presence of dichloro(bistriphenylphosphine)palladium,

copper(I) iodide, and triethylamine as a base. The cor-

responding 1-(trimethylsilylethynyl)-(N-R-2,5-dioxopyr-

rolidino)[3,4-h]-6,14-endo-ethenotetrahydrothebaines

IX–XI formed in 68–80% yield (Scheme 2). The con-

densation of trimethylsilylacetylene with the mixture

of iodides IV, V, 10 : 1.2 provided a mixture of 1-(tri-

methylsilylethynyl)- and 2-(trimethylsilylethynyl)-endo-

ethenotetrahydrothebaines XI, XII, 10:1.2, as showed the

integral intensity of the signals of protons H²[δ 6.76 ppm

substituted

7α,8α-(N-methyl-2,5-dioxopyrrolidino)

(IV,

[3,4-h]-6,14-endo-ethenotetrahydrothebaines

VIII), 1:1. At the increase of the N-iodosuccinimide

excess to 2 equiv compound VIII prevailed [(IV)–

(VIII), 1:11 according to ¹H NMR data].

1

(XI)] and H¹[δ 6.84 ppm (XII)] in the H NMR spec-

trum. The column chromatography on silica gel furnished

individual compound XI (yield 68%) and a fraction

containing substances XI and XII. At the repeated chro-

matographing of the latter on a plate with unﬁxed silica

gel layer we obtained a mixture enriched with compound

XII [(XI)–(XII), 0.6 : 1]. The attempt to bring 1,2-di-

iododerivative of 6,14-endo-ethenotetrahydrothebaine

VIII into the Sonogashira reaction was unsuccessful,

The obtained ﬁndings show that N-iodosuccinimide

is a convenient reagent fot iodination of the derivatives

of N’-substituted (2,5-dioxopyrrolidino)[3,4-h]-6,14-

endo-ethenotetrahydrothebaines and it makes it possible

to prepare selectively C¹-substituted 6,14-endo-

ethenotetrahydrothebaines. The direction of the attack of

the reagent may be attributed to the effect of the oxygen

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

SYNTHETIC TRANSFORMATIONS OF ISOQUINOLINE ALKALOIDS

1475

Scheme 2.

H

Si(CH₃)₃

H₃CO

HC

C Si(CH₃)₃

Bu₄NF

CH₂Cl₂

+

XV

O

IV + V

O

CuI, Pd(PPh₃)₂Cl₂,

PPh₃, NEt₃,

O

N

C

NCH₃

benzene

H

H₃CO

3

O

H₃CO

O

N

O

N

CH₃

O

CH₃

XI

XII

XVI

Si(CH₃)₃

H

H₃CO

C

HC

Si(CH₃)₃

Bu₄NF

CH₂Cl₂

O

IX^_XI

O

VI, VII

NCH₃

O

NCH₃

O

CuI, Pd(PPh₃)₂Cl₂,

PPh₃, NEt₃,

H₃CO

benzene

H₃CO

N

O

R

O

XIII^_XV

R

IX, X

R = H (IX), Br (X), Ph (XIII), 4-BrC₆H₄(XIV), CH₃(XV).

TLC indicated the formation of a mixture of compounds

which we failed to obtain in an individual state. By the

desilylation of compounds IX–XII (Scheme 2) with the

use of tetrabutylammonium ﬂuoride in dichloromethane

terminal acetylenes, 1-ethynyl(2,5-dioxopyrrolidino)

[3,4-h]endo-ethenotetrahydrothebaines XIII–XVI, were

obtained in high yields.

(XVIII) in 42% yield (Scheme 3). Compound XV was

more reactive in Mannich reaction. Its reaction with

paraformaldehyde and secondary amines [morpholine

(XVII), N-methylpiperazine (XIX), or N-Boc-piperazine

(XX)] afforded the corresponding 1-[3-(morpholin-4-yl)

propynyl]-, 1-[3-(4-methylpiperazin-1-yl)propynyl]-, or

1-[3-(4-tert-butoxycarbonylpiperazin-1-yl)propynyl]-(N-

R-2,5-dioxopyrrolidino)[3,4-h]-6,14-endo-ethenotetrahy-

drothebaines XXI–XXIII in the yield 77–88%.

Aiming at the extension of the range of the derivatives

of 6,14-endo-ethenotetrahydrothebaines containing the

acetylene substituents we investigated the possibility

of the preparation of aminopropargyl-substituted mor-

phinans. An efﬁcient approach to the synthesis of such

compounds is the classic Mannich reaction consisting

in the interaction between a terminal arylalkyne, form-

aldehyde (generated in situ from paraformaldehyde),

and a secondary amine. We examined the possibility

to involve the obtained acetylene tetrahydrothebaines

XIII, XV in the catalytic Mannich reaction [12]. The

reaction of compound XIII with morpholine (XVII)

and formaldehyde in dioxane in the presence of catalytic

quantity of CuI led to the formation of 1-[3-(morpholin-

4-yl)-propynyl]-6,14-endo-ethenotetrahydrothebaine

The structure of the synthesized compounds was

established combining the elemental analysis data and

spectral characteristics. The formation of individual

1-iododerivatives IV, VI, VII and 1,2-diiododerivative

VIII unambiguously follows from the data of ¹H NMR

spectra with accounting for the increments of iodine

substituent [13]. The signal of atom C¹in compounds IV,

VI, VII shifts upﬁeld to δ 86.47–86.65 ppm (a singlet in

the ¹³C NMR JMOD spectrum), and the signals of atom

C²(a doublet in the ¹³C NMR JMOD spectrum) shift

downﬁeld (δ 122.37–122.53 ppm) compared to their

position in the spectra of the initial compounds (doublets

at δ 119.86 and 113.60 ppm) [8]. Downﬁeld signals are

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

BAUMAN et al.

1476

Scheme 3.

N

X

CH₂

H

H₃CO

CuI,

propane

dioxane

O

NCH₃

+

NCH₃

CH₂O

+

HN

X

85^_90^oC

H₃CO

O

XVII, XIX, XX

O

N

O

R

XIII^_XV

XVIII, XXI^_XXIII

R = Ph (XIII, XVIII), CH₃(XV, XXI–XXIII); X = O (XVII, XVIII, XXI), NCH₃(XIX, XXII), N-Boc (XX, XXIII).

also characteristic of the atoms C¹⁰and C¹¹. The singlets

of the atoms C¹and C²in the spectrum of compound

VIII are observed at 104.03 and 107.55 ppm respectively,

and the signals of atoms C¹⁰, C¹¹and C¹²are even more

shifted downﬁeld. ¹H and ¹³C NMR spectra of acetylene

derivatives of 6,14-endo-ethenotetrahydrothebaines

IX–XI, XIII–XV, XVIII, XXI–XXIII are totally

consistent with their structure and contain a single set

of the characteristic signals of the morphinan skeleton

and the corresponding substituent. The presence of the

alkynyl substituent is also conﬁrmed by the IR spectra

(strong absorption bands at 2146 cm^–1in the spectra of

compounds X, XI with a trimethylsilylethynyl substituent;

2096 cm^–1in the spectra of compounds XIV, XV with

a terminal acetylene substituent; 2208–2214 cm^–1in the

spectra of compounds XXI–XXIII where the acetylene

linker binds the morphinan skeletone and the heterocyclic

fragment).

Bruker AV-300 [operating frequencies 300.13 (¹H) and

75.47 MHz (¹³C)], BrukerAV-400 [operating frequencies

400.13 (¹H) and 100.78 MHz (¹³C)], andAV-600 [operat-

ing frequencies 600.30 (¹H) and 150.96 MHz (¹³C)] with

the solvent signals serving as internal references (δ_H7.24,

δ_C77.0 ppm). The multiplicity of signals in the ¹³C NMR

spectra were determined by standard procedures in the

JMOD mode. The assignment of signals in the NMR

spectra was carried out with the help of various types of

proton-proton and carbon-proton correlation spectroscopy

(COSY, COLOC, COXH, HMCC). The numeration of

atoms of the morphinan skeleton used in the description

of ¹H and ¹³C NMR spectra is presented in the structure I.

The recording of mass spectra, measuring of the

molecular mass and of the elemental compositions was

performed using high resolution mass spectrometers DFS

Thermo Scientiﬁc and Finnigan MAT-8200 with the ion-

izing voltage 70V (evaporator temperature 270–300°C).

The previously performed investigations showed that

the variation of the substituents in the A ring essentially

affects the pharmacological properties of the morphi-

nan alkaloids [14–16]. The obtained new derivatives of

6,14-endo-ethenotetrahydrothebaine with acetylene frag-

ments in the position 1 provide wide opportunities for the

selective modiﬁcation in the aromatic fragment.

IR spectra were registered on a spectrophotometer

Vector-22 from pellets with KBr. The melting points were

measured on a Koefﬂer heating block.

The reaction progress was monitored by TLC on

Silufol UV-254 plates using as eluents: chloroform,

chloroform–ethanol, 10:1. Spots were visualized in the

iodine chamber or under UV irradiation.

The reaction products were isolated by column chro-

matography on silica gel Acros (0.035–0.070 mm, eluent

chloroform–ethanol) and when necessary by preparative

TLC on an unﬁxed silica gel layer on plates of the size 20 ×

20 cm with the sorbent layer 1 mm thick (eluents chloro-

form and chloroform–ethanol–ethyl acetate, 10 : 0.2 : 5).

EXPERIMENTAL¹

¹H and ¹³C NMR spectra were registered from

solutions of compounds in CDCl₃on spectrometers

___________________

¹Analytical and spectral studies were carried out in the Chemical

Service Center of the common use of the Siberian Division of the

Russian Academy of Sciences.

Solvents (benzene, dichloromethane, chloroform,

dioxane), and also Et₃N were puriﬁed by standard proce-

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

SYNTHETIC TRANSFORMATIONS OF ISOQUINOLINE ALKALOIDS

1477

dures and were distilled in an argon ﬂow just before use in

experiments. N-Iodosuccinimide, trimethylsilylacetylene,

tetrabutylammonium ﬂuoride, morpholine, N-methyl-

piperazine, and N-Boc-piperazine were purchased from

Alfa Aesar. Iodine monochloride was obtained as de-

scribed in [17], Pd(PPh₃)₂Cl₂, as described in [18].

colorless precipitate was ﬁltered off to obtain 0.640 g of

1-iodo-7α,8α-(N-methyl-2,5-dioxopyrrolidino)-[3,4-

h]-6,14-endo-etheno-6,7,8,14-tetrahydrothebaine

triﬂuoroacetate (IVa). The water layer was extracted

with chloroform (4 × 15 ml). The extract was dried with

MgSO₄, evaporated in a vacuum, the residue was tritu-

rated in ether. We obtained additionally 0.141 g of salt

IVa. Overall yield 99%, mp 247°C. ¹H NMR spectrum,

δ, ppm (J, Hz): 2.07 d.d.d (1H, H¹⁵, J 14.9, 2.6, 0.8), 2.59

t.d (1H, H¹⁵, J 14.0, 3.8), 2.77 d.d (1H, H¹⁰, J 19.5, 7.0),

2.88 s (3H, CH₃N^1′), 2.89–2.93 m (1H, H¹⁶), 3.06 s (3H,

CH₃N¹⁷), 3.06–3.10 m (1H, H¹⁰), 3.25 d (1H, H⁸, J 7.6),

3.55–3.59 m (1H, H¹⁶), 3.68 s (3H, CH₃OC⁶), 3.82 s (3H,

CH₃OC³), 4.65–4.70 m (2H, H^7,9), 4.76 d (1H, H⁵, J 1.0),

5.33 d (1H, H¹⁸, J 8.8), 5.84–5.87 m (1H, H¹⁹), 7.08 s

(1H, H²). ¹³C NMR spectrum, δ, ppm: 24.80 (CH₃N^1′),

30.06 (C¹⁵), 30.45 (C¹⁰), 40.90 (C⁷), 40.99 (C⁸), 42.50

(CH₃N¹⁷), 43.83 (C¹⁴), 46.05 (C¹⁶), 46.78 (C¹³), 51.44

(CH₃OC⁶), 56.52 (CH₃OC³), 59.71 (C⁹), 79.77 (C⁶), 86.04

(C¹), 89.26 (C⁵), 123.56 (C²), 126.08 (C¹¹), 130.39 (C¹⁸),

131.03 (C¹⁹), 131.65 (C¹²), 144.19 (C³), 148.46 (C⁴),

172.62 (C^5′), 176.17 (C^2′). Found, %: C 43.71; H 3.55;

F 8.74; I 18.80; N 4.50. C₂₆H₂₆F₃IN₂O₇. Calculated, %:

C 47.13; H 3.93; F 8.61; I 19.18; N 4.20.

Synthesis and physicochemical properties of com-

pounds I–III were described in [19–21].

1-Iodo-7α,8α-(N-methyl-2,5-dioxopyrrolidino)

[3,4-h]-6,14-endo-etheno-6,7,8,14-tetra-hydrothebaine

(IV). a. Iodination with iodine monochloride. To a solu-

tion of 1 g (2.37 mmol) of compound III in 3.6 ml of

formic acid was added dropwise at stirring a solution of

0.578 g (4.74 mmol) of ICl in 1 ml of formic acid. The

reaction mixture was stirred for 10 h at 45–50°C (TLC

monitoring), then it was poured into a Petri dish and

evaporated. The solid residue was treated with 10 ml

of saturated sodium carbonate solution, the reaction

product was extracted into chloroform (4 × 30 ml). The

combined extracts were washed with brine, dried with

MgSO₄, evaporated in a vacuum, and the residue was

triturated with ether. We obtained 1.112 g (90%) of a

mixture of compound IV and 2-iodo-7α,8α-(N-methyl-

2,5-dioxopyrrolidino)[3,4-h]-6,14-endo-etheno-

6,7,8,14-tetrahydrothebaine (V), 10:2 (according to

the ¹H NMR data).

Compound IV. ¹H NMR spectrum, δ, ppm (J, Hz):

1.79–1.99 m (2H, H¹⁵), 2.26 d.d (1H, H¹⁰, J 18.3, 6.7),

2.33–2.52 m (1H, H¹⁶), 2.46 s (3H, CH₃N¹⁷), 2.53–2.63 m

(1H, H¹⁶), 2.84 s (3H, CH₃N^1′), 2.97 d (1H, H¹⁰, J 18.9),

3.04 d (1H, H⁸, J 7.9), 3.66 s (3H, CH₃OC⁶), 3.77 s (3H,

CH₃OC³), 4.02 d (1H, H⁹, J 6.5), 4.20 d (1H, H⁷, J 7.9),

4.62 d (1H, H⁵, J 1.2), 5.33 d (1H, H¹⁸, J 8.7), 5.74 d.d

(1H, H¹⁹, J 8.7, 1.2), 7.02 C (1H, H²).

A solution of 0.8 g of the obtained salt in a minimum

amount of chloroform was charged into a column of

15 mm diameter packed with 3 g of alkaline alumina,

elution with chloroform, the eluate was evaporated, the

residue was treated with ether to obtain 0.583 g (90%)

of compound IV, mp 276°C (from ether). ¹H NMR spec-

trum, δ, ppm (J, Hz): 1.83–1.99 m (2H, H¹⁵), 2.26 d.d

(1H, H¹⁰, J 18.3, 6.7), 2.36–2.46 m (1H, H¹⁶), 2.46 s (3H,

CH₃N¹⁷), 2.53–2.61 m (1H, H¹⁶), 2.86 s (3H, CH₃N^1′),

2.97 d (1H, H¹⁰, J 18.9), 3.04 d (1H, H⁸, J 8.0), 3.68 s

(3H, CH₃OC⁶), 3.78 s (3H, CH₃OC³), 4.02 d (1H, H⁹,

J 6.4), 4.20 d (1H, H⁷, J 8.0), 4.63 d (1H, H⁵, J 1.2), 5.35 d

(1H, H¹⁸, J 8.8), 5.75 d.d (1H, H¹⁹, J 8.8, 1.2), 7.02 s

(1H, H²). ¹³C NMR spectrum, δ, ppm: 24.58 (CH₃N^1′),

28.52 (C¹⁰), 33.40 (C¹⁵), 41.40 (C⁷), 42.07 (C⁸), 43.16

(CH₃N¹⁷), 44.78 (C¹⁴), 44.81 (C¹⁶), 48.17 (C¹³), 51.65

(CH₃OC⁶), 56.43 (CH₃OC³), 57.39 (C⁹), 80.37 (C⁶), 86.47

(C¹), 91.10 (C⁵), 122.37 (C²), 129.18 (C¹⁹), 130.53 (C¹¹),

133.33 (C¹⁸), 133.37 (C¹²), 143.14 (C³), 148.24 (C⁴),

173.85 (C^5′), 177.05 (C^2′). Mass spectrum, m/z (I_rel, %):

548 [M]⁺(99), 533 (17), 436 (30), 381 (12), 355 (18), 263

(18), 262 (100), 247 (54), 234 (48), 204 (42), 105 (19),

57 (25), 43 (22). Found m/z 548.0800 [M]⁺.C₂₄H₂₅IN₂O₅.

Calculated m 548.0803.

Characteristic signals of compound V, δ, ppm (J, Hz):

3.11 d (1H, H¹⁰, J 19), 4.66 d (1H, H⁵, J 1.4), 6.66 s (1H,

H¹). The chemical shifts of the other protons coincide with

the signals of protons of compound IV. Mass spectrum,

m/z (I_rel, %): 548 [M]⁺(100), 533 (23), 436 (41), 381 (15),

355 (26), 247 (69), 204 (59), 176 (13), 44 (14). Found m/z

[M]⁺548.0805. C₂₄H₂₅IN₂O₅. Calculated m 548.0803.

b. Iodination with N-iodosuccinimide in triﬂuoroacetic

acid. To a solution of 0.5 g (1.2 mmol) of compound

III in 10 ml of triﬂuoroacetic acid was added at stirring

0.266 g (1.2 mmol) of N-iodosuccinimide. The solution

was stirred at room temperature for 2 h (TLC monitoring),

then it was poured into 150 ml of cold water, and a concn.

ammonia solution was added to pH 10–11. The separated

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

BAUMAN et al.

1478

c. Iodination with N-iodosuccinimide in formic acid.

cold water, and a concn. ammonia solution was added to

pH 10–11. The separated precipitate was ﬁltered off to

obtain 0.208 g (83%) of compound VII. From the mother

liquor compound VII was extracted into chloroform (4 ×

15 ml), the extract was dried with MgSO₄, evaporated in

a vacuum, the residue was chromatographed on silica gel

(eluent chloroform). We obtained additionally 0.037 g

of compound VII. Overall yield 0.245 g (98%). The

analyses and spectral characteristics of compound VII

are in agreement with those published in [8].

To a solution of 0.125 g (0.30 mmol) of compound III

in 4 ml of formic acid was added at stirring 0.066 g

(0.30 mmol) of N-iodosuccinimide. The reaction mixture

was stirred at room temperature for 2 h, then it was poured

into a Petri dish and evaporated. The solid residue was

treated with 10 ml of saturated sodium carbonate solution,

the reaction product was extracted into chloroform (4 ×

20 ml). The combined extracts were washed with brine,

dried with MgSO₄, evaporated in a vacuum. We obtained

0.145 g of a mixture of compounds IV, III, 10 : 1.3. By

the chromatography on a column packed with silica gel

we isolated 0.092 g (65%) of compound IV.

1,2-Diiodo-7α,8α-(N-methyl-2,5-dioxopyrrolidino)-

[3,4-h]-6,14-endo-etheno-6,7,8,14-tetra-hydrothebaine

(VIII). To a solution of 0.2 g (0.47 mmol) of compound

III in 4 ml of triﬂuoroacetic acid was added at stirring

0.211 g (0.94 mmol) of N-iodosuccinimide. The mixture

was stirred at room temperature for 2 h (TLC monitor-

ing), the mixture was poured into 50 ml of cold water,

and a concn. ammonia solution was added to pH 10–11.

The separated yellow precipitate containing 0.241 g of a

mixture of iodides VIII, IV, 10:1, was ﬁltered off. From

the water layer the reaction products were extracted into

chloroform (4 × 15 ml), the combined extracts were

dried with MgSO₄, evaporated in a vacuum, and the resi-

due was triturated with ether. We obtained additionally

0.087 g of a mixture of compounds VIII, IV, 12:1. The

chromatographic separation provided 0.165 g (53%) of

1,2-diiodotetrahydrothebaine VIII, mp 278°C. ¹H NMR

spectrum, δ, ppm (J, Hz): 1.86 d.d.d (1H, H¹⁵, J 13.6,

2.0, 1.3), 1.93 t.d (1H, H¹⁵, J 12.5, 5.2), 2.33–2.40 m

(2H, H^10,16), 2.47 s (3H, CH₃N^1′), 2.56–2.60 m (1H,

H¹⁶), 2.87 s (3H, CH₃N¹⁷), 2.97 d (1H, H¹⁰, J 18.8),

3.02 d (1H, H⁸, J 8.0), 3.68 s (3H, CH₃OC⁶), 3.88 s (3H,

CH₃OC³), 3.98 d (1H, H⁹, J 6.4), 4.18 d (1H, H⁷, J 8.0),

4.63 d (1H, H⁵, J 1.4), 5.37 d (1H, H¹⁸, J 8,8), 5.78 m

(1H, H¹⁹). ¹³C NMR spectrum, δ, ppm: 27.02 (CH₃N^1′),

35.27 (C¹⁰), 35.58 (C¹⁵), 44.19 (C⁷), 44.30 (C⁸), 45.55

(CH₃N¹⁷), 47.12 (C¹⁶), 50.43 (C^14,13), 54.48 (CH₃OC⁶),

60.31 (C⁹), 62.54 (CH₃OC³), 82.72 (C⁶), 94.52 (C⁵),

104.03 (C¹), 107.55 (C²), 131.23 (C¹⁹), 136.03 (C¹⁸),

136.94 (C¹¹), 137.67 (C¹²), 145.02 (C³), 151.61 (C⁴),

176.11 (C^5′), 179.27 (C^2′). Mass spectrum, m/z (I_rel, %):

674 [M]⁺(100), 659 (20), 562 (37), 548 (15), 354 (20),

247 (51), 204 (36), 44 (11). Found m/z 673.9767 [M]⁺.

C₂₄H₂₄I₂N₂O₅. Calculated m 673.9769.

1-Iodo-7α,8α-[N-(4-bromophenyl)-2,5-dioxo-

pyrrolidino][3,4-h]-6,14-endo-etheno-6,7,8,14-tetra-

hydrothebaine (VI). To a solution of 0.2 g (0.35 mmol)

of compound II in 4 ml of triﬂuoroacetic acid was added

at stirring 0.079 g (0.35 mmol) of N-iodosuccinimide.

The solution was stirred at room temperature for 2 h

(TLC monitoring), then it was poured into 50 ml of cold

water, and a concn. ammonia solution was added to pH

10–11. The separated precipitate was ﬁltered off. Yield

1

0.240 g (98%), mp 224–226°C. H NMR spectrum, δ,

ppm (J, Hz): 1.93 d.d.d (1H, H¹⁵, J 13.7, 2.9, 1.0), 2.03 t.d

(1H, H¹⁵, J 12.6, 5.3), 2.33 d.d (1H, H¹⁰, J 19.0, 6.4),

2.44–2.51 m (1H, H¹⁶), 2.53 s (3H, CH₃N¹⁷), 2.67–2.75 m

(1H, H¹⁶), 3.02 d (1H, H¹⁰, J 19.0), 3.21 d (1H, H⁸, J 8.0),

3.70 s (3H, CH₃OC⁶), 3.81 s (3H, CH₃OC³), 4.11 d (1H,

H⁷, J 8.0), 4.44 d (1H, H⁹, J 6.4), 4.70 d (1H, H⁵, J 1.3),

5.44 d (1H, H¹⁸, J 8.8), 5.89 m (1H, H¹⁹), 7.03–7.08 m

(2H, H^2″,6″), 7.05 s (1H, H²), 7.49–7.55 m (2H, H^3″,5″).

¹³C NMR spectrum, δ, ppm: 28.89 (C¹⁰), 33.23 (C¹⁵),

41.34 (C⁷), 42.01 (C⁸), 43.23 (CH₃N¹⁷), 45.06 (C¹⁴), 45.12

(C¹⁶), 48.22 (C¹³), 51.70 (CH₃OC⁶), 56.53 (CH₃OC³),

57.71 (C⁹), 80.57 (C⁶), 86.65 (C¹), 90.67 (C⁵), 122.39

(C^4″), 122.53 (C²), 127.80 (C^2″,6″), 129.68 (C¹⁹), 130.01

(C^1″), 130.54 (C¹¹), 132.16 (C^3″,5″), 133.04 (C¹²), 133.36

(C¹⁸), 143.39 (C³), 148.36 (C⁴), 172.38 (C^5′), 175.74

(C^2′). Mass spectrum, m/z (I_rel, %): 688 [M]⁺(97), 673

(19), 436 (78), 389 (41), 387 (42), 355 (41), 344 (34),

316 (27), 218 (15), 44 (20). Found m/z 688.0058 [M]⁺.

C₂₉H₂₆BrIN₂O₅. Calculated m 688.0064.

1-Iodo-7α,8α-(2,5-dioxo-N-phenylpyrrolidino)-

[3,4-h]-6,14-endo-etheno-6,7,8,14-tetrahydrothebaine

(VII). To a solution of 0.2 g (0.4 mmol) of compound

I in 4 ml of triﬂuoroacetic acid was added at stirring

0.093 g (0.4 mmol) of N-iodosuccinimide, 2 h later

(TLC monitoring) the mixture was poured into 50 ml of

1-(2-Trimethylsilylethynyl)-7α,8α-(2,5-dioxo-N-

phenylpyrrolidino)[3,4-h]-6,14-endo-etheno-6,7,8,14-

tetrahydrothebaine (IX). A two-neck ﬂask equipped

with a magnetic stirrer was thrice evacuated and ﬁlled

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

SYNTHETIC TRANSFORMATIONS OF ISOQUINOLINE ALKALOIDS

1479

with argon. In an argon flow the flask was charged

in succession with 0.714 g (1.4 mmol) of compound

VII, 0.006 g (0.03 mmol, 2.1 mol%) of CuI, 0.006 g

(0.009 mmol, 0.6 mol%) of Pd(PPh₃)₂Cl₂, 0.011 g

(0.023 mmol, 1.6 mol%) of PPh₃, 7.5 ml of benzene. The

mixture was evacuated, and 0.61 ml (4 mmol) of NEt₃

and 0.257 ml (1.8 mmol) of trimethylsilylacetylene were

added in an argon ﬂow. After 6 h 0.257 ml (1.8 mmol) of

trimethylsilylacetylene and 1 ml of benzene were added

again. The mixture was stirred at heating to 60°C in an

argon ﬂow for 12 h and was poured into a Petri dish for

a free evaporation. The solid residue was treated with

chloroform and water, the layers were separated, and the

product was extracted from the water layer into chloro-

form. The combined extracts were washed with water,

dried with MgSO₄, evaporated in a vacuum, the residue

was dissolved in a minimum volume of chloroform and

chromatographed on a column packed with silica gel

(eluent chloroform–ethanol), the fraction containing

the reaction product was triturated with ether, crystals

were ﬁltered off. Yield 0.461 g (68%), mp 234–236°C.

¹H NMR spectrum, δ, ppm (J, Hz): 0.24 s [9H, (CH₃)₃Si)],

1.83–2.04 m (2H, H¹⁵), 2.40–2.64 m (3H, H^10,16,16), 2.45 s

(3H, CH₃N¹⁷), 3.18 m (2H, H^8,10), 3.68 s (3H, CH₃OC⁶),

3.78 s (3H, CH₃OC³), 4.06 d (1H, H⁹, J 5.8), 4.37 d (1H,

H⁷, J 7.5), 4.70 m (1H, H⁵), 5.47 d (1H, H¹⁸, J 9.2),

5.83 m (1H, H¹⁹), 6.78 s (1H, H²), 7.09–7.17 m (2H,

H^2″,6″), 7.28–7.43 m (3H, H^{3″,4″,5″}). ¹³C NMR spectrum,

δ, ppm: 0.01 [(CH₃)₃Si], 22.14 (C¹⁰), 33.37 (C¹⁵), 41.16

(C⁸), 42.09 (C⁷), 43.12 (CH₃N¹⁷), 44.48 (C¹³), 44.99

(C¹⁶), 47.81 (C¹⁴), 51.48 (CH₃OC⁶), 56.07 (CH₃OC³),

56.69 (C⁹), 80.55 (C⁶), 90.98 (C⁵), 97.17 (C^1b), 102.85

(C^1a), 114.11 (C¹), 116.57 (C²), 126.19 (C^2″,6″), 128.40

(C^4″), 128.83 (C^3″,5″), 128.94 (C¹⁹), 130.58 (C¹¹), 131.57

(C^1″), 132.48 (C¹²), 133.64 (C¹⁸), 141.92 (C³), 148.61

(C⁴), 172.78 (C^5′), 176.11 (C^4′). Mass spectrum, m/z (I_rel,

%): 580 [M]⁺(100), 406 (16), 326 (19), 325 (52), 266

(23), 203 (8), 174 (9), 121 (9), 73 (45), 44 (18), 28 (27).

Found m/z 580.23789 [M]⁺. C₃₄H₃₆N₂O₅Si.Calculated m

580.23933.

(2.8 mmol) of NEt₃and 0.08 ml (2.6 mmol) of trimeth-

ylsilylacetylene were added in an argon ﬂow. After 10 h

0.08 ml (2.6 mmol) of trimethylsilylacetylene and 0.09 ml

(2.8 mmol) of NEt₃were added again. The mixture was

stirred at heating to 60°C in an argon ﬂow for 18 h and

was poured into a Petri dish for evaporation in air. The

solid residue was treated with chloroform and water, the

layers were separated, and the product was extracted

from the water layer with chloroform (4 × 15 ml). The

combined extracts were washed with water, dried with

MgSO₄, evaporated in a vacuum, the residue was chro-

matographed on silica gel (eluent chloroform–ethanol),

the fraction containing the reaction product was triturated

with ether, the precipitate was ﬁltered off. Yield 0.110 g

(80%), mp 182°C. IR spectrum, cm^–1: 2146, 1778,

1714, 1618, 1595, 746, 705. ¹H NMR spectrum, δ, ppm

(J, Hz): 0.26 s [9H, (CH₃)₃Si], 1.90–2.04 m (2H, H¹⁵),

2.40–2.64 m (3H, H^10,16,16), 2.47 s (3H, CH₃N¹⁷), 3.21 d

(1H, H¹⁰, J 19.1), 3.23 d (1H, H⁸, J 8.3), 3.70 s (3H,

CH₃OC⁶), 3.80 s (3H, CH₃OC³), 4.06 d (1H, H⁹, J 6.2),

4.40 d (1H, H⁷, J 8.3), 4.65 d (1H, H⁵, J 1.3), 5.46 d (1H,

H¹⁸, J 8.5), 5.82 m (1H, H¹⁹), 6.80 s (1H, H²), 7.03–7.10 m

(2H, H^2″,6″), 7.50–7.56 m (2H, H^3″,5″). ¹³C NMR spectrum,

δ, ppm: 0.14 [(CH₃)₃Si], 22.31 (C¹⁰), 33.56 (C¹⁵), 41.37

(C⁷), 42.29 (C⁸), 43.27 (CH₃N¹⁷), 44.91 (C¹⁴), 45.18

(C¹⁶), 47.99 (C¹³), 51.68 (CH₃OC⁶), 56.25 (CH₃OC³),

56.84 (C⁹), 80.68 (C⁶), 91.09 (C⁵), 97.38 (C^1b), 102.93

(C^1a), 114.33 (C¹), 116.85 (C²), 122.33 (C^4″), 127.84

(C^2″,6″), 129.07 (C¹⁹), 130.67 (C¹¹), 131.57 (C^1′′), 132.13

(C^3″,5″), 132.53 (C¹²), 133.92 (C¹⁸), 142.09 (C³), 148.74

(C⁴), 172.55 (C^5′), 174.16 (C^2′). Mass spectrum, m/z (I_rel,

%): 658 [M]⁺(89), 645 (18), 643 (17), 406 (30), 387

(20), 351 (15), 325 (59), 318 (16), 174 (12), 121 (11), 73

(33), 44 (15). Found m/z 658.1491 [M]⁺.C₃₄H₃₅BrIN₂O₅.

Calculated m 658.1493.

1-(2-Trimethylsilylethynyl)-7α,8α-(N-methyl-2,5-

dioxopyrrolidino)[3,4-h]-6,14-endo-etheno-6,7,8,14-

tetrahydrothebaine (XI) was obtained under the above

conditions from 0.533 g (1.0 mmol) of compound

IV, 0.007 g (0.04 mmol, 4.1 mol%) of CuI, 0.008 g

(0.012 mmol, 1.2 mol%) of Pd(PPh₃)₂Cl₂, 0.015 g

(0.031 mmol, 3.2 mol%) of PPh₃, 12 ml of benzene,

0.41 ml (2.8 mmol) of NEt₃and 0.35 ml (2.6 mmol) of

trimethylsilylacetylene. After 6 h 0.35 ml (2.6 mmol) of

trimethylsilylacetylene and 1 ml of benzene were added

again. The total time of heating at 70–75°C in an argon

ﬂow was 19 h. The reaction mixture was poured in a Petri

dish and evaporated in air. The solid residue was treated

with chloroform and water, the layers were separated, and

1-(2-Trimethylsilylethynyl)-7α,8α-[N-(4-

bromophenyl)-2,5-dioxopyrrolidino][3,4-h]-6,14-

endo-etheno-6,7,8,14-tetrahydrothebaine (X). After

the above described preparation the ﬂask was charged in

an argon ﬂow in succession with 0.150 g (2.2 mmol) of

compound VI, 0.002 g (0.01 mmol, 4.2 mol%) of CuI,

0.0019 g (0.003 mmol, 1.2 mol%) of Pd(PPh₃)₂Cl₂,

0.0035 g (0.007 mmol, 3.2 mol%) of PPh₃, and 4 ml

of benzene. The mixture was evacuated, and 0.09 ml

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

BAUMAN et al.

1480

the product was extracted from the water layer with chlo-

roform (4 × 20 ml). The combined extracts were washed

with water, dried with MgSO₄, evaporated in a vacuum,

yield 0.8 g of oily substance containing according to

¹H NMR spectrum an impurity of trimethylsilylacety-

lene. The product was subjected to desilylation without

additional puriﬁcation.

(C¹³), 47.77 (C¹⁴), 51.60 (CH₃OC⁶), 56.16 (CH₃OC³),

56.74 (C⁹), 80.41 (C⁶), 91.31 (C⁵), 97.15 (C^1b), 102.91

(C^1a), 114.11 (C¹), 116.75 (C²), 128.75 (C¹⁹), 130.66

(C¹¹), 132.67 (C¹²), 133.58 (C¹⁸), 141.94 (C³), 148.66

(C⁴), 173.90 (C^5′), 177.12 (C^2′). Mass spectrum, m/z (I_rel,

%): 518 [M]⁺(100), 502 (30), 405 (18), 324 (57), 276

(84), 246 (31), 203 (30), 198 (16), 76 (19), 72 (35), 73

(35), 44 (21). Found m/z 518.22368 [M]⁺.C₂₉H₃₄N₂O₅Si.

Calculated m 518.22324.

1-(2-Trimethylsilylethynyl)-7α, 8α-(N-

methyl-2,5-dioxopyrrolidino)[3,4-h]-6,14-endo-

etheno-6,7,8,14-tetrahydrothebaine (XI) and

2-(2-trimethylsilylethynyl)-7α,8α-(N-methyl-2,5-

dioxopyrrolidino)[3,4-h]-6,14-endo-etheno-6,7,8,14-

tetrahydrothebaine (XII) were obtained in similar con-

ditions from 0.6 g (1.1 mmol) of a mixture of compounds

IV, V, 10:1.2, 0.004 g (0.02 mmol, 2.5 mol%) of CuI,

0.0046 g (0.006 mmol, 0.74 mol%) of Pd(PPh₃)₂Cl₂,

0.087 g (0.02 mmol, 2.5 mol%) of PPh₃, 6.3 ml of ben-

zene. The mixture was evacuated, and 0.46 ml (3 mmol)

of NEt₃and 0.2 ml (1.4 mmol) of trimethylsilylacetylene

were added in an argon ﬂow. After 6 h 0.2 ml (3 mmol)

of trimethylsilylacetylene was added again. The mixture

was stirred at heating to 60°C in an argon ﬂow for 13 h

and was poured into a Petri dish for evaporation in air.

The solid residue was treated with chloroform and water,

the layers were separated, and the product was extracted

from the water layer with chloroform (4 × 20 ml). The

combined extracts were washed with water, dried with

MgSO₄, evaporated in a vacuum to obtain 0.626 g of

a mixture of compounds IV, XI, XII in a ratio 1 : 10 :

1.2. The mixture was dissolved in a minimum volume

of chloroform and was subjected to chromatography on

silica gel (eluent chloroform–ethanol) to isolate in suc-

cession 0.319 g (68%) of compound XI, 0.120 g of the

mixture of compounds XI, XII, 1:0.2, and 0.116 g of

compound IV. At a subsequent chromatography of the

mixture of compounds XI, XII on a plate with unﬁxed

silica gel layer we isolated 33 mg of a mixture enriched

with compound XII [(XI)–(XII), 0.6:1].

Characteristic signals of compound XII, δ, ppm

(J, Hz): 0.21 s [9H, (CH₃)₃Si], 3.19 d (1H, H¹⁰, J 19.4),

3.68 s (3H, CH₃OC⁶), 3.81 s (3H, CH₃OC³), 4.67 m (1H,

H⁵), 6.84 s (1H, H¹). The chemical shifts of the other pro-

tons coincide with the signals of protons of compound XI.

1-Ethynyl-7α,8α-(2,5-dioxo-N-phenylpyrrolidino)

[3,4-h]-6,14-endo-etheno-6,7,8,14-tetrahydrothebaine

(XIII). To a solution of 0.6 g (1 mmol) of compound IX

in 4 ml of dichloromethane was added dropwise at stirring

a solution of 0.4 g (1.5 mmol) of Bu₄NF in 2 ml of dichlo-

romethane. The mixture was stirred at room temperature

for 15 min, the separated precipitate was ﬁltered off. The

organic layer was washed with water, dried with magne-

sium sulfate, evaporated in a vacuum, the residue was

triturated with dichloromethane. Yield 0.367 g (70%),

mp 265–270°C. ¹H NMR spectrum (DMCO-d₆), δ, ppm

(J, Hz): 2.10 m (1H, H¹⁵), 2.28 m (1H, H¹⁵), 2.44–2.60 m

(3H, H^10,16,16), 2.49 s (3H, CH₃N¹⁷), 3.08 d (1H, H¹⁰,

J 18.8), 3.54 s (3H, CH₃OC⁶), 3.72 s (3H, CH₃OC³),

3.98 d (1H, H⁹, J 6.4), 3.77 d (1H, H⁸, J 7.5), 4.13 s (1H,

H^1b), 4.31 d (1H, H⁷, J 7.5), 4.93 m (1H, H⁵), 5.50 d (1H,

H¹⁸, J 8.8), 5.69 m (1H, H¹⁹), 6.81 s (1H, H²), 7.09 m (2H,

H^2″,6″), 7.37 m (1H, H^4″), 7.44 m (3H, H^3″,5″). ¹³C NMR

spectrum, δ, ppm: 21.75 (C¹⁰), 32.27 (C¹⁵), 40.66 (C⁸),

42.28 (C⁷), 42.96 (CH₃N^17′), 44.53 (C¹³), 44.64 (C¹⁶),

47.18 (C¹⁴), 50.58 (CH₃OC⁶), 56.06 (CH₃OC³), 56.49

(C⁹), 80.50 (C⁶), 80.53 (C^1b), 81.85 (C^1a), 89.22 (C⁵),

112.58 (C¹), 116.93 (C²), 126.89 (C^2″,6″), 128.35 (C^4″),

128.81 (C^3″,5″), 129.18 (C¹⁹), 130.89 (C¹¹), 132.20 (C^1″),

133.23 (C¹²), 133.68 (C¹⁸), 141.48 (C³), 148.50 (C⁴),

173.18 (C^5′), 176.27 (C^4′). Mass spectrum, m/z (I_rel,

%): 508 [M]⁺(100), 503 (21), 335 (44), 311 (41), 268

(41), 255 (49), 174 (19), 121 (16), 58 (22), 44 (61), 28

(21). Found [M]⁺508.18865. C₃₁H₂₈N₂O₅. Calculated m

508.19981.

Compound XI, mp 180–183°C (from ether). IR spec-

trum, cm^–1: 2146, 1772, 1699, 1618, 1594, 721, 702.

¹H NMR spectrum, δ, ppm (J, Hz): 0.23 s [9H, (CH₃)₃Si],

1.70–1.99 m (2H, H¹⁵), 2.36–2.60 m (3H, H^10,16,16), 2.45 s

(3H, CH₃N¹⁷), 2.84 s (3H, N¹CH₃), 3.03 d (1H, H⁸, J 8.0),

3.17 d (1H, H¹⁰, J 19.4), 3.67 s (3H, CH₃OC⁶), 3.76 s (3H,

CH₃OC³), 4.01 d (1H, H⁹, J 6.4), 4.18 d (1H, H⁷, J 8.0),

4.65 m (1H, H⁵), 5.34 d (1H, H¹⁸, J 9.2), 5.68 m (1H,

H¹⁹), 6.76 s (1H, H²). ¹³C NMR spectrum, δ, ppm: 0.023

[Si(CH₃)₃], 22.12 (C¹⁰), 24.54 (CH₃N^1′), 33.35 (C¹⁵),

41.35 (C⁷), 42.23 (C⁸), 43.12 (CH₃N¹⁷), 44.70 (C¹⁶), 44.79

1-Ethynyl-7α,8α-[N-(4-bromophenyl)-2,5-

dioxopyrrolidino][3,4-h]-6,14-endo-etheno-6,7,8,14-

tetrahydrothebaine (XIV). To a solution of 0.110 g

(0.16 mmol) of compound X in 3 ml of dichlorometh-

ane was added dropwise at stirring a solution of 0.12 g

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

SYNTHETIC TRANSFORMATIONS OF ISOQUINOLINE ALKALOIDS

1481

(0.47 mmol) of Bu₄NF in 1 ml of dichloromethane. The

mixture was stirred at room temperature for 15 min,

washed with water, the organic layer was dried with

magnesium sulfate, evaporated in a vacuum, the residue

was triturated with ether. Yield 0.090 g (92%), mp 202°C.

IR spectrum, cm^–1: 2096, 1776, 1714, 1616, 1595, 744,

705. ¹H NMR spectrum, δ, ppm (J, Hz): 1.86–2.04 m (2H,

H¹⁵), 2.40–2.62 m (3H, H^10,16,16), 2.44 s (3H, CH₃N¹⁷),

3.18 d (1H, H⁸, J 8.0), 3.22 s (1H, H^1b), 3.23 d (1H, H¹⁰,

J 19.3), 3.69 s (3H, CH₃OC⁶), 3.79 s (3H, CH₃OC³),

4.03 d (1H, H⁹, J 6.4), 4.38 d (1H, H⁷, J 8.0), 4.71 d (1H,

H⁵, J 1.0), 5.47 d (1H, H¹⁸, J 8.8), 5.83 d.d (1H, H¹⁹,

J 8.8, 1.0), 6.81 s (1H, H²), 7.02–7.06 m (2H, H^2″,6″),

7.48–7.53 m (2H, H^3″,5″). ¹³C NMR spectrum, δ, ppm:

22.34 (C¹⁰), 33.52 (C¹⁵), 41.37 (C⁷), 42.28 (C⁸), 43.25

(CH₃N¹⁷), 44.90 (C¹⁴), 45.14 (C¹⁶), 47.94 (C¹³), 51.70

(CH₃OC⁶), 56.30 (CH₃OC³), 56.81 (C⁹), 65.81 (C^1b),

80.10 (C^1a), 80.66 (C⁶), 91.11 (C⁵), 113.14 (C¹), 117.24

(C²), 122.32 (C^4″), 127.81 (C^2″,6″), 129.17 (C¹⁹), 130.61

(C¹¹), 130.82 (C^1″), 132.12 (C^3″,5″), 132.61 (C¹²), 133.84

(C¹⁸), 142.08 (C³), 148.66 (C⁴), 172.52 (C^5′), 175.86 (C^2′).

Mass spectrum, m/z (I_rel, %): 586 [M]⁺(97), 573 (16), 532

(29), 589 (25), 587 (25), 334 (78), 279 (38), 253 (71),

174 (14), 121 (16), 59 (17). Found m/z 568.1096 [M]⁺.

C₃₁H₂₇BrIN₂O₅. Calculated m 568.1098.

(C⁵), 112.63 (C¹), 117.34 (C²), 128.95 (C¹⁹), 131.78 (C¹¹),

132.91 (C¹²), 133.47 (C¹⁸), 142.08 (C³), 149.28 (C⁴),

173.86 (C^5′), 177.07 (C^2′). Mass spectrum, m/z (I_rel, %):

446 [M]⁺(100), 431 (17), 334 (26), 279 (11), 253 (22),

247 (29), 204 (25), 44 (3). Found m/z 446.1837 [M]⁺.

C₂₆H₂₆N₂O₅. Calculated m 446.1836.

2-Ethynyl-7α,8α-(N-methyl-2,5-dioxopyrrolidino)-

[3,4-h]-6,14-endo-etheno-6,7,8,14-tetrahydrothebaine

(XVI). To a solution of 0.158 g (0.31 mmol) of a mixture

of compounds XI, XII, 10:3, in 2.5 ml of dichlorometh-

ane was added dropwise at stirring a solution of 0.3 g

(1.2 mmol) of Bu₄NF in 1 ml of dichloromethane. The

mixture was stirred at room temperature for 15 min, the

separated precipitate was ﬁltered off, the organic layer

was washed with water, dried with magnesium sulfate,

evaporated in a vacuum to obtain 0.2 g of oily substance

containing compounds XV, XVI, 10:3. The residue was

dissolved in a minimum volume of chloroform and chro-

matographed on silica gel (eluent chloroform–ethanol).

We isolated in succession mixtures of compounds XV,

XVI from 1.7:1 to 4:1, and 0.095 g (70%) of compound

XV, mp 286°C. By the repeated chromatography of the

mixture of compounds XV, XVI on silica gel (eluent

chloroform–ethanol) we isolated 17 mg of the mixture en-

riched with compound XVI [(XV)–(XVI), 1.7:1]. Char-

acteristic signals of compound XVI (from the ¹H NMR

spectrum of the mixture of compounds XV, XVI, 1.7:1),

δ, ppm (J, Hz): 3.12 d (1H, H¹⁰, J 19.1), 4.22 d (1H, H⁸,

J 7.9), 4.65 d (1H, H⁵, J 1.3), 5.76 m (1H, H¹⁹), 6.66 C

(1H, H¹). The chemical shifts of the other protons coincide

with the signals of protons of compound XV.

1-Ethynyl-7α,8α-(N-methyl-2,5-dioxopyrrolidino)

[3,4-h]-6,14-endo-etheno-6,7,8,14-tetrahydrothebaine

(XV). To a solution of 0.8 g of oily substance contain-

ing compound XI in 6 ml of dichloromethane was added

dropwise at stirring 1.06 ml of 1 M solution of Bu₄NF

in THF. The mixture was stirred at room temperature for

15 min, washed with water, the organic layer was dried

with magnesium sulfate, evaporated in a vacuum, the resi-

due was dissolved in a minimum volume of chloroform

and chromatographed on silica gel (eluent chloroform).

Yield 0.337 g (78%) (calculated for two stages of the

reaction), mp 286°C. IR spectrum, cm^–1: 2096, 1770,

1695, 1622, 1602, 752, 705. ¹H NMR spectrum, δ, ppm

(J, Hz): 1.80–2.05 m (2H, H¹⁵), 2.36–2.50 m (1H, H¹⁶),

2.46 s (3H, CH₃N¹⁷), 2.52–2.63 m (2H, H^10,16), 2.86 s

(3H, N^1′CH₃), 3.04 d (1H, H⁸, J 8.3), 3.21 s (1H, H^1b),

3.27 d (1H, H¹⁰, J 19.2), 3.68 s (3H, CH₃OC⁶), 3.79 s

(3H, CH₃OC³), 4.03 d (1H, H⁹, J 6.6), 4.20 d (1H, H⁷,

J 8.3), 4.68 d (1H, H⁵, J 1.0), 5.36 d (1H, H¹⁸, J 8.5),

5.73 m (1H, H¹⁹), 6.83 s (1H, H²). ¹³C NMR spectrum,

δ, ppm: 22.31 (C¹⁰), 22.50 (C¹⁵), 24.60 (CH₃N^1′), 41.27

(C⁷), 42.22 (C⁸), 43.20 (CH₃N¹⁷), 44.65 (C¹⁶), 44.75

(C¹³), 47.74 (C¹⁴), 51.66 (CH₃OC⁶), 56.15 (CH₃OC³),

56.71 (C⁹), 76.66 (C^1b), 80.36 (C⁶), 80.50 (C^1a), 91.41

1-[(3-Morpholin-4-yl)propynyl]-7α,8α-(2,5-dioxo-

N-phenylpyrrolidino)[3,4-h]-6,14-endo-etheno-

6,7,8,14-tetrahydrothebaine (XVIII). A two-neck

ﬂask in an argon ﬂow was charged at stirring in succes-

sion with 0.011 g (0.35 mmol) of paraformaldehyde,

0.027 g (0.35 mmol) of morpholine (XVII), 0.0006 g

(0.003 mmol) of CuI, 2.2 ml of dioxane, and 0.16 g

(0.31 mmol) of compound XIII. The mixture was heated

at 90–92°C for 6 h, then 0.011 g (0.35 mmol) of para-

formaldehyde, 0.027 g (0.35 mmol) of morpholine, and

0.5 ml of dioxane were again added, and the heating was

continued for 6 h more. The separated precipitate was

ﬁltered off and washed with ether. Yield 0.06 g (32%).

The mother liquor was evaporated, the solid residue was

treated with chloroform (4 × 10 ml), the extract was

washed with water, the organic solutions were dried

with MgSO₄, evaporated in a vacuum, the residue was

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

BAUMAN et al.

1482

chromatographed on silica gel (eluent chloroform). We

isolated additionally 0.02 g of compound IV and 0.03 g

of compound XIII. Overall yield of compound XVIII

0.08 g (42% taking into account the conversion of

52%), mp 260–263°C. IR spectrum, cm^–1: 2208, 2131,

1775, 1712, 1595, 746, 694. ¹H NMR spectrum, δ, ppm

(J, Hz): 1.90 m (1H, H¹⁵), 1.98 m (1H, H¹⁵), 2.42–2.56 m

(4H, H^{3′′′,5′′′}), 2.46 s (3H, CH₃N¹⁷), 2.56–2.66 m (3H,

H^10,16,16), 3.18 d (1H, H⁸, J 8.2), 3.28 d (1H, H¹⁰, J 19.4),

3.65–3.78 m (4H, H^{2′′′, 6′′′}), 3.67 s (3H, H^1C), 3.70 s (3H,

CH₃OC⁶), 3.80 s (3H, CH₃OC³), 4.08 d (1H, H⁹, J 6.6),

4.38 d (1H, H⁷, J 8.2), 4.73 d (1H, H⁵, J 1.3), 5.47 d (1H,

H¹⁸, J 8.7), 5.87 m (1H, H¹⁹), 6.85 s (1H, H²), 7.12–7.16 m

(2H, H^{2″, 6″}), 7.32 m (2H, H^4″), 7.36–7.40 m (2H, H^{3″, 5″}).

¹³C NMR spectrum, δ, ppm: 22.42 (C¹⁰), 33.43 (C¹⁵),

42.16 (C⁷), 41.30 (C⁸), 43.20 (CH₃N¹⁷), 45.05 (C¹⁶),

44.81 (C¹³), 47.84 (C¹⁴), 51.62 (CH₃OC⁶), 51.90 (2C,

C^{2′′′, 6′′′}), 56.26 (CH₃OC³), 56.74 (C⁹), 66.91 (C^1C), 66.97

(2C, C^{3′′′, 5′′′}), 76.75 (C^1b), 80.54 (C⁶), 80.54 (C^1a), 91.32

(C⁵), 112.77 (C¹), 117.62 (C²), 126.24 (2C, C^2″,6″), 128.46

(C^4″), 128.88 (2C, C^3″,5″), 129.14 (C¹⁹), 131.59 (C^1″),

131.84 (C¹¹), 132.91 (C¹²), 133.70 (C¹⁸), 142.17 (C³),

149.42 (C⁴), 172.69 (C^5′), 176.04 (C^2′). Mass spectrum,

m/z (I_rel, %): 607 [M]⁺(5), 577 (6), 518 (24), 309 (18),

266 (17), 238 (13), 173 (19), 124 (96), 97 (32), 71 (36),

69 (43), 55 (52), 43 (48), 18 (100). Found m/z 607.2674

[M]⁺. C₃₆H₃₇N₃O₆. Calculated m 607.2677.

(1H, H⁸, J 7.9), 3.27 d (1H, H¹⁰, J 19.3), 3.60–3.75 m

(4H, H^{2′′′, 6′′′}), 3.65 s (2H, H^1γ), 3.68 s (3H, CH₃OC⁶),

3.79 s (3H, CH₃OC³), 4.03 d (1H, H⁹, J 6.3), 4.20 d (1H,

H⁷, J 7.9), 4.60 d (1H, H⁵, J 1.2), 5.36 d (1H, H¹⁸, J 8.7),

5.73 m (1H, H¹⁹), 6.83 s (1H, H²). ¹³C NMR spectrum,

δ, ppm: 22.33 (C¹⁰), 33.31 (C¹⁵), 24.62 (CH₃N^1’), 41.31

(C⁷), 42.24 (C⁸), 43.21 (CH₃N¹⁷), 44.50 (C¹⁶), 44.68

(C¹³), 47.77 (C¹⁴), 51.68 (CH₃OC⁶), 51.92 (2C, C^{2′′′, 6′′′}),

56.18 (CH₃OC³), 56.79 (C⁹), 66.90 (C^1C), 66.97 (2C,

C^{3′′′, 5′′′}), 76.68 (C^1b), 80.41 (C⁶), 80.51 (C^1a), 91.46 (C⁵),

112.66 (C¹), 117.40 (C²), 128.99 (C¹⁹), 131.81 (C¹¹),

132.94 (C¹²), 133.49 (C¹⁸), 149.31(C⁴), 142.10 (C³),

173.86 (C^5′), 177.07 (C^2′).

1-{[3-(4-Methylpiperazin-1-yl)]propynyl}-7α,8α-

(N-methyl-2,5-dioxopyrrolidino)[3,4-h]-6,14-endo-

etheno-6,7,8,14-tetrahydrothebaine (XXII). A ﬂask

in an argon flow was charged at stirring in succes-

sion with 0.009 g (0.30 mmol) of paraformaldehyde,

0.033 ml (0.30 mmol) of 4-methylpiperazine (XIX),

0.0004 g (0.002 mmol) of CuI, 4 ml of dioxane, and

0.1 g (0.24 mmol) of compound XV. The mixture was

heated at 90–92°C for 7 h, then 0.001 g (0.30 mmol) of

paraformaldehyde, 0.033 ml (0.30 mmol) of 4-methyl-

piperazine, 0.0004 g (0.002 mmol) of CuI were again

added, and the heating was continued for 7.5 h more. The

reaction mixture was evaporated in a Petri dish, the solid

residue was treated with chloroform and water, the layers

were separated, and the product was extracted from the

water layer with chloroform. The combined extracts were

washed with water, dried with MgSO₄, evaporated in a

vacuum, and the residue was chromatographed on silica

gel (eluent chloroform–ethanol). Yield 0.097 g (77%), mp

134°C. IR spectrum, Cm^–1: 2214, 1770, 1699, 1618, 1595,

752, 704. ¹H NMR spectrum, δ, ppm (J, Hz): 1.80–1.98 m

(2H, H¹⁵), 2.24–2.75 m (11H, H^{10,16,16,2′′′,2′′′,3′′′,3′′′,5′′′,5′′′,6′′′}

^,6′′′), 2.30 s (3H, N^4′′′CH₃), 2.44 s (3H, CH₃–N¹⁷), 2.85 s

(3H, CH₃N^1′), 3.03 d (1H, H⁸, J 8.0), 3.17 d (1H, H¹⁰,

J 19.0), 3.54 s (2H, H^1C), 3.67 s (3H, CH₃OC⁶), 3.76 s

(3H, CH₃OC³), 4.00 d (1H, H⁹, J 6.6), 4.18 d (1H, H⁷,

J 8.0), 4.64 d (1H, H⁵, J 0.9), 5.34 d (1H, H¹⁸, J 8.5),

5.71 m (1H, H¹⁹), 6.73 s (1H, H²). ¹³C NMR spectrum,

δ, ppm: 22.40 (C¹⁰), 24.66 (CH₃N^1’), 33.42 (C¹⁵), 41.40

(C⁷), 42.30 (C⁸), 43.24 (CH₃N¹⁷), 44.75 (C¹⁶), 44.90

(C¹³), 45.87 (CH₃N^4′′′), 47.79 (C¹⁴), 47.86 (2C, C^{3′′′, 5′′′}),

51.71 (CH₃OC⁶), 51.88 (2C, C^{2′′′, 6′′′}), 54.91 (C^1C), 56.22

(CH₃OC³), 56.83 (C⁹), 80.48 (C⁶), 83.14 (C^1b), 87.10

(C^1a), 91.28 (C⁵), 114.14 (C¹), 116.69 (C²), 128.88 (C¹⁹),

130.11 (C¹¹), 132.59 (C¹²), 133.60 (C¹⁸), 141.95 (C³),

148.24 (C⁴), 174.05 (C^5′), 177.27 (C^2′). Mass spectrum,

1-[(3-Morpholin-4-yl)propynyl]-7α,8α-(N-methyl-

2,5-dioxopyrrolidino)[3,4-h]-6,14-endo-etheno-

6,7,8,14-tetrahydrothebaine (XXI). A ﬂask in an argon

ﬂow was charged at stirring in succession with 0.011 g

(0.35 mmol) of paraformaldehyde, 0.027 g (0.35 mmol)

of morpholine, 0.001 g (0.005 mmol) of CuI, 3.2 ml of

dioxane, and 0.1 g (0.2 mmol) of compound XV. The

mixture was heated at 90–92°C for 6 h, then 0.011 g

(0.35 mmol) of paraformaldehyde, 0.027 g (0.35 mmol)

of morpholine, 0.001 g (0.005 mmol) of CuI, and 1 ml of

dioxane were again added, and the heating was continued

for 6 h more.. The reaction mixture was evaporated in a

Petri dish, the solid residue was treated with chloroform

and water, the layers were separated, and the product

was extracted from the water layer with chloroform. The

combined extracts were washed with water, dried with

MgSO₄, evaporated in a vacuum, the residue was crystal-

lized from ether. Yield 0.107 g (88%), mp 226–230°C.

IR spectrum, cm^–1: 2208, 2131, 1775, 1712, 1595, 746,

694. ¹H NMR spectrum, δ, ppm (J, Hz): 1.81–2.02 m (2H,

H¹⁵), 2.37–2.52 m (4H, H^{3′′′, 5′′′}), 2.46 s (3H, CH₃N¹⁷),

2.52–2.64 m (3H, H^10,16,16), 2.86 s (3H, CH₃N^1′), 3.04 d

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

SYNTHETIC TRANSFORMATIONS OF ISOQUINOLINE ALKALOIDS

1483

m/z (I_rel, %): 558 [M]⁺(15), 502 (68), 461 (100), 268 (41),

99 (49), 97 (70), 70 (37), 58 (64), 56 (35), 42 (26). Found

m/z 558.2841 [M]⁺.C₃₂H₃₈N₄O₅. Calculated m 558.2837.

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28.40 [C(CH₃)₃], 33.45 (C¹⁵), 41.42 (C⁷), 42.33 (C⁸),

43.28 (CH₃N¹⁷), 44.77 (C^13,14), 44.92 (C¹⁶), 47.86 (C^1C),

48.02 (2C, C^{2′′′, 4′′′}), 51.74 (CH₃OC⁶), 51.88 (2C, C^{2′′′, 6′′′}),

56.27 (CH₃OC³), 56.85 (C⁹), 79.72 [C(CH₃)₃], 80.52

(C⁶), 83.33 (C^1b), 86.85 (C^1a), 91.33 (C⁵), 113.99 (C¹),

116.74 (C²), 128.99 (C¹⁹), 130.13 (C¹¹), 132.73 (C¹²),

133.59 (C¹⁸), 142.03 (C³), 148.38 (C⁴), 154.69 (C=O),

174.05 (C^5′), 177.27 (C^2′). Mass spectrum, m/z (I_rel, %):

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266 (33), 204 (15), 57 (22). Found m/z 644.3191 [M]⁺.

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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

Article Doi

Synthetic transformations of isoquinoline alkaloids. Synthesis of N′-substituted 1-alkynyl-7α,8α-(2,5-dioxopyrrolidino)-[3,4-h]- 6,14-endo-ethenotetrahydrothebaines and their transformations

DOI: 10.1134/S1070428012110103

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