Alkynation of chlorinated cotarnine by silver propargylamines

Article abstract of DOI:10.1023/B:CONC.0000033934.74690.21

Chlorinated cotarnine was alkynated in the 1-position upon brief heating in acetonitrile with silver acetylenides of propargylamines to form the corresponding propargylamine derivatives.

Full text of DOI:10.1023/B:CONC.0000033934.74690.21

Chemistry of Natural Compounds, Vol. 40, No. 2, 2004
ALKYNATION OF CHLORINATED COTARNINE BY
SILVER PROPARGYLAMINES
L. Yu. Ukhin,1 I. R. Gol′ding,2 and V. G. Kartsev3
UDC 547.833.6+547.314
Chlorinated cotarnine was alkynated in the 1-position upon brief heating in acetonitrile with silver
acetylenides of propargylamines to form the corresponding propargylamine derivatives.
Key words: cotarnine, propargylamines, silver organoacetylenides, alkynation.
Cotarnine is obtained by oxidative cleavage of one of the principal opium alkaloids narcotine, which has a broad
spectrum of physiological activity. It acts as a tonic and stimulant for smooth muscle, constricts vessels, exhibits local
hemostatic activity, and possesses sedative and analgesic effects [1]. Its modification can produce new compounds that exhibit
various types of physiological activity.
We previouslyreported [2, 3] the synthesis ofacetylenic derivatives ofcotarnine using acetylenides ofGroup 11 metals.
In this manner, alkyl- and arylacetylenes and propargyl alcohols and ethers were introduced into cotarnine. Dialkylaminoalkyl
groups are used widely in medicinal chemistry as pharmacophores [4]. Therefore, we developed a method of synthesizing
propargylamine derivatives ofcotarnine. Ofinterest on their own, theyare alsoconsidered convenient precursorsfor conversion
to aminopropyl derivatives. Propargylanilines and tertiary aliphatic propargylamines are used in alkynation reactions.
Propargylanilines were prepared from the corresponding anilines and propargyl bromide:
EtOH
BrCH C CH
K CO
2 3
ArNHCH C CH
2
ArNH
+
+
2
2
∆
1
2
CH
CH
3
3
Ar =
O N
O N
2
O N
2
S
O N
2
2
a
c
b
d
Silver derivatives of propargylanilines 2 form readily upon mixing their alcohol solutions with alcohol-ammonia
solutions of silver nitrate. However, standard methods were unsuitable for synthesizing acetylenides of tertiary aliphatic
propargylamines 4e-g owing to their higher solubility. A separate isolation procedure was developed for each of these
acetylenides.
1) Scientific-Research Institute of Physical and Organic Chemistry, Rostov State University, 344090, Rostov-on-Don,
pr. Stachki, 194/2, fax (8632) 28 56 67, e-mail: may@ipoc.rsu.ru; 2) A. N. Nesmeyanov Institute of Elementorganic
Compounds, Russian Academy of Sciences, 117813, Moscow, ul. Vavilova, 28; 3) OOO "Interbioscreen," 142432, p.
Chernogolovka, MoscowDistrict, Institutskii pr., 8, fax (095) 788 06 52, e-mail: screen@nsp.chg.ru. Translated from Khimiya
Prirodnykh Soedinenii, No. 2, pp. 133-135, March-April, 2004. Original article submitted January 15, 2004.
0009-3130/04/4002-0156 ©2004 Plenum Publishing Corporation
156

TABLE 1. PMR Spectra of Propargylamine Derivatives of Cotarnine
Compound
5a
Solvent, δ, ppm, J/Hz
HCl
(DMSO-d6 + CCl4): 2.76-3.38 (m, 4H, C(4)H2+C(3)H2), 2.82 (s, 3H, NCH3), 3.92 (s, 3H, OCH3), 4.04 (s, 2H, CH2N),
5.29 (s, 1H, C(1)H), 5.96 (split s, 2H, OCH2O), 6.39 (s, 1H, C(5)H), 6.74 (br.s, 1H, NH), 7.00-7.55 (m, 4H, CHarom),
12.17 (s, 1H, +NH)
5b
′
(CDCl3): 2.18 (s, 3H, C(2 )CH3), 2.40 (s, 3H, NCH3), 2.50-2.63 (m, 2H, C(4)H2), 2.71-2.94 (m, 2H, C(3)H2), 3.92 (s,
3H, OCH3), 3.98 (t, 1H, NH, J = 6), 4.07 (d, 2H, CH2N, J = 6), 4.65 (s, 1H, C(1)H), 5.85 (s, 2H, OCH2O), 6.27 (s, 1H,
C(5)H), 7.14 (d, 1H, C(3′)H, J = 8.1), 7.49 (d, 1H, C(6′)H, J = 2.2), 7.54 (dd, 1H, C(4′)H, 3J = 8.1, 4J = 2.2)
5c
′
(CDCl3): 2.16 (s, 3H, C(2 )CH3), 2.43 (s, 3H, NCH3), 2.53-2.97 (m, 4H, C(4)H2+C(3)H2), 3.92 (s, 3H, OCH3),
4.07 (dd, 2H, CH2N, 3J = 5.75, 4J = 1.75), 4.44 (t, 1H, NH, J = 5.75), 4.67 (s, 1H, C(1)H), 5.86 (split s, 2H, OCH2O),
6.29 (s, 1H, C(5)H), 6.63 (d, 1H, C(6′)H, J = 9), 7.96 (d, 1H, C(3′)H, J = 2.6), 8.02 (dd, 1H, (C(5′)H, 3J = 9.0, 4J = 2.6)
5d
HCl
(DMSO-d6): 2.79-3.40 (m, 4H,C(3)H2+C(4)H2), 2.83 (s, 3H, NCH3), 3.95 (s, 3H, OCH3), 4.00 (unresolv. d, CH2N),
5.31 (s, 1H, C(1)H), 5.97 (split s , 2H, OCH2O), 6.42 (s, 1H, C(5)H), 6.60 (br.s, 1H, NH), 6.74 (d, 2H, CHarom, J = 8.6),
7.08 (d, 2H, CHarom, J = 9), 7.27 (d, 2H, CHarom, J = 8.6), 8.04 (d, 2H, CHarom, J = 9.0), 12.11 (s, 1H, +NH)
5e
(CDCl3): 2.50 (s, 3H, NCH3), 2.53 (t, 4H, NCH2, J = 4.7), 2.60-2.70 (m, 2H, C(4)H), 2.80-2.95 (m, 2H, C(3)H2), 3.33
(d, 2H, CCH2, J = 1.7), 3.71 (t, 4H, OCH2, J = 4.7), 3.99 (s, 3H, OCH3), 4.72 (s, 1H, C(1)H), 5.85 (s, 2H, OCH2O),
6.29 (s, 1H, C(5)H)
5f
(CDCl3): 1.76 (m, 4H, CH2), 2.49 (s, 3H, NCH3), 2.52-2.71 (m, 6H, CH2), 2.80-2.98 (m, 2H, C(3)H2), 3.43 (s, 2H,
CH2N), 3.98 (s, 3H, OCH3), 4.71 (s, 1H, C(1)H), 5.85 (s, 2H, OCH2O), 6.28 (s, 1H, C(5)H)
5g
(CDCl3): 2.26 (s, 6H, N(CH3)2), 2.51 (s, 3H, NCH3), 2.57-2.71 (m, 2H, C(4)H2), 2.82-2.98 (m, 2H, C(3)H2),
3.27 (s, 2H, CH2N), 3.99 (s, 3H, OCH3), 4.73 (s, 1H, C(1)H), 5.83 (s, 2H, OCH2O), 6.29 (s, 1H, C(5)H)
Brief heating of cotarnine chloride 3 with silver acetylenides of propargylamines 4 in acetonitrile formed the
propargylamine derivatives of cotarnine 5:
O
O
O
CH CN
3
+
AgC CCH R
2
+
N
N
O
∆
CH
3
CH
3
4
H
OMe
R =
MeO
CCH R
2
5
3
CH
3
CH
3
NH
NH
O N
2
NH
O N
2
O N
2
a
b
c
O
N
O N
2
S
NH
N
(CH ) N
3 2
e
g
d
f
Acetylenides 4e-g were prepared from commercially available starting compounds.
A characteristic feature of 5 is the lack ofstretching vibrations for the triple bond in their IRspectra recorded in mineral
oil. This is applicable to all previouslydescribed [2, 3] acetylenic derivatives ofcotarnine. In viewofthe paucityofinformation,
we did not include these spectra in the present article. Table 1 lists the PMR spectra of 5a-g.
157

EXPERIMENTAL
IR spectra of propargylanilines 2a-d were recorded on a UR-20 instrument in KBr disks. PMR spectra were recorded
on a Varian UNITY-300 spectrometer. Elemental analyses of all compounds corresponded with those calculated.
General Method for Synthesizing N-Propargylanilines (2a-d). A mixture of arylamine (0.1 mol), freshly distilled
propargyl bromide (0.1 mol), and finely ground freshly calcined K CO (0.11 mol) in EtOH (95%, 250 mL) was boiled for
2
3
14 h. The precipitate was separated. The filtrate was evaporated in vacuum. The solid was chromatographed over a silica-gel
column (eluent benzene:acetone, 11:1). Theproduct wascrystallizedfrom benzene toafford yellowish-orange compounds, yield
-1
-1
55-65%. IR spectra of 2a-d contain strong absorptions
(3390-3410 cm ).
(1320-1350, 1530-1540 cm ),
(3290-3310 cm ), and
CH NH
NO2
-1
N-(2′-Propynyl)-3-nitroaniline (2a): mp 92-93°C.
N-(2′-Propynyl)-2-methyl-5-nitroaniline (2b): mp 121-123°C.
N-(2′-Propynyl)-2-methyl-4-nitroaniline (2c): mp 126-127°C (lit. [5] mp 121-123°C).
4-(N-Propargylamino)-4′-nitrodiphenylsulfide (2d): mp 88-90°C.
General Method of Synthesizing Silver Derivatives of N-Propargylanilines (4a-d). A solution of AgNO (1 g,
3
5.8 mmol) in EtOH (5 mL) and conc. NH OH (5 mL) was poured into a hot solution of the appropriate propargylaniline (2a-d,
4
5.5 mmol) in EtOH (40 mL). The reaction mixture was cooled with ice, transferred to a filter (Buchner funnel), separated,
washed with EtOH, and dried at 70-80°C. Yellowish-orange compounds, quantitative yields.
3-Morpholinoprop-1-yne Acetylenide (4e). Finelyground AgNO (1 g, 6 mmol) was dissolved in MeOH(1 mL) and
3
conc. NH OH (2 mL), stirred, treated with morpholinoprop-1-yne (1 mL, 7 mmol) and acetone (5 mL), poured into a Petri dish,
4
and evaporated with gentle heating almost to dryness. Distilled water was added. The solid was ground with a rod with cooling
on an ice bath. The solid was transferred to a filter, separated, washed with distilled water, and dried. Colorless compound,
yield 1.1 g (80%).
3-Pyrrolidinoprop-1-yne Acetylenide (4f). Finely ground AgNO (1 g, 6 mmol) was dissolved in MeOH (1 mL) and
3
conc. NH OH (2 mL), treated with 3-pyrrolidinoprop-1-yne (0.9 mL, 8 mmol) and acetone (3 mL), and left for 30 min. The
4
resulting precipitate was filtered off, washed with acetone, and dried. Yield 1.2 g (94%).
3-Dimethylaminoprop-1-yne Acetylenide (4g). Finely ground AgNO (1.5 g, 9 mmol) was dissolved in MeOH
3
(2 mL) and conc. NH OH (2 mL), treated with 3-dimethylaminoprop-1-yne (1 mL, 9 mmol), and left for 30 min. Acetone
4
(20 mL) was added. The mixture was cooled with ice. The solid was transferred to a filter, separated, washed with acetone,
and dried in vacuum at room temperature. Yield 1.6 g (95%).
1-[3′-(3′′-Nitrophenylamino)propyn-1-yl]-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-tetrahydroisoquinoline
Hydrochloride (5a). Cotarnine chloride (1.2 g, 4.7 mmol) and 2a (1.5 g, 5.3 mmol) in CH CN (10 mL) were stirred for
3
10 min at room temperature and 5 min at boiling and filtered. The solid was washed with hot CH CN. Addition of water to
3
the filtrate precipitated an orange oil that was cooled with ice and ground to solidify it. The solid was filtered off, washed with
water, dried, dissolved in CHCl , and passed over an Al O column, discarding the colorless lead fraction. Solvent was
3
2 3
evaporated. The orange oil was dissolved with heating in a small amount of i-PrOH, treated with conc. HCl (1 mL), cooled with
ice, and ground with a rod. The solid was filtered off and recrystallized from CH CN (100 mL). Orange compound, mp 220-
3
225°C (dec.). Yield 0.8 g (39%).
1-[3′-(2′′Methyl-4′′-nitrophenylamino)-propyn-1-yl]-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-
tetrahydroisoquinoline (5b). Cotarnine chloride (1.2 g, 4.7 mmol) and 2b (1.75 g, 5.9 mmol) in CH CN (10 mL) were stirred
3
for 10 min at room temperature and 5 min at boiling and filtered hot. The filtrate was cooled with ice. The resulting precipitate
was filtered off, washed with cold CH OH, and dried. Orange compound, mp 185-190°C. Yield 0.6 g (31%).
3
1-[3′-(2′′-Methyl-5′′-nitrophenylamino)propyn-1-yl]-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-
tetrahydroisoquinoline (5c). Cotarnine chloride (1.2 g, 4.7 mmol) and 2c (1.45 g, 4.9 mmol) in CH CN (10 mL) were stirred
3
for 10 min at room temperature and 5 min at boiling and filtered. The solid was washed with hot CH CN. Water precipitated
3
an oil from the filtrate that crystallized upon cooling with ice and grinding. The solid was filtered off, washed with water, and
dried. Bright yellow crystals, mp 90-95°C (CH OH). Yield 1.25 g (66%).
3
1-{3′-[4′′-(4′′′-Nitrophenylmercapto)phenylamino]propyn-1-yl}-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-
tetrahydroisoquinoline hydrochloride (5d). Cotarnine chloride (1.3 g, 5.1 mmol) and 2d (2.6 g, 6 mmol) in CH CN (15 mL)
3
were stirred for 10 min at room temperature and 10 min at boiling and filtered. The solid was washed with hot CH CN. Water
3
158

precipitated an oil from the filtrate that was separated, dissolved in i-PrOH(4 mL), treated with conc. HCl (1.5 mL), cooled with
ice, and ground with a rod. The solid was filtered off, washed with i-PrOH, dried, dissolved with heating in CH OH (100 mL),
3
and left for 12 h in a refrigerator. The resulting precipitate was filtered off, washed with cold CH OH, and dried. Yellow
3
compound, mp 170-175°C (dec.). Yield 0.68 g (26.5%).
1-(3′-Morpholinopropyn-1-yl)-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-tetrahydroisoquinoline (5e).
Cotarnine chloride (1 g, 3.9 mmol) and 2e (1.1 g, 4.7 mmol) in CH CN (10 mL) were stirred for 10 min at room temperature
3
and 5 min at boiling and filtered hot. The solvent was evaporated. The resulting oil was solidified by cooling with ice and
ground. The solid was dissolved in CHCl and chromatographed over a column of Al O . The solvent was evaporated. The
3
2 3
colorless oil crystallized on cooling with ice and grinding with petroleum ether. The solid was filtered off, washed with
petroleum ether, and dried. Colorless crystals, mp 77-80°C. Yield 0.6 g (45%).
1-(3′-Pyrrolidinopropyn-1-yl)-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-tetrahydroisoquinoline (5f).
Cotarnine chloride (1 g, 3.9 mmol) and 2f (1.2 g, 5.5 mmol) in CH CN (10 mL) were stirred for 10 min at room temperature
3
and 5 min at boiling and filtered hot. The solvent was evaporated. The resulting oil solidified on cooling with ice and grinding.
The solid was chromatographed over a column of Al O with CHCl eluent. The solvent was evaporated. The resulting oil
2
3
3
crystallized on cooling and grinding with petroleum ether. The solid was filtered off, washed with petroleum ether, and dried
in vacuum. Colorless crystals, mp 70-75°C. Yield 0.61 g (45.5%).
1-(3′-Dimethylaminopropyn-1-yl)-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-tetrahydroisoquinoline (5g).
Cotarnine chloride (1 g, 3.9 mmol) and 2g (1.6 g, 8.4 mmol) in CH CN (10 mL) were stirred for 10 min at room temperature
3
and 5 min at boiling and filtered hot. The solvent was evaporated. The resulting oil solidified on grinding. The solid was
dissolved in CHCl and passed over a column of Al O . The solvent was evaporated. The colorless oil crystallized on cooling
3
2 3
with ice and grinding with petroleum ether. The solid was filtered off, washed with cold petroleum ether, and dried in vacuum.
Colorless crystals, mp 65-67°C. Yield 0.3 g (25%).
REFERENCES
1.
2.
F. P. Trinus, Pharmacotherapeutic Handbook "Health," Kiev (1976).
L. Yu. Ukhin, K. Yu. Suponitskii, and V. G. Kartsev, in: Abstracts of the First International Conference "Chemistry
and Biological Activity of Nitrogenous Heterocycles and Alkaloids," October 2001, Moscow, Vol. 1, p. 552.
L. Yu. Ukhin, K. Yu. Suponitskii, and V. G. Kartsev, Khim. Prir. Soedin., 395 (2003).
A. T. Soldatenkov, N. M. Kolyadina, and I. V. Shendrik, Principles of the Organic Chemistry of Medicinal
Compounds, Khimiya, Moscow (2001).
3.
4.
5.
A. F. Garito and C. J. Horner, Macromol. Chem., 181, 1605 (1980).
159