Synthesis of acetyl scopine. Intramolecular reactions of N-carbethoxy nortropine-3α-benzene-sulfenate

Article abstract of DOI:10.1055/s-1999-2658

The synthesis of acetyl scopine using tropine as a starting compound was achieved. Free radical phenylthio group transfer to the 6-position, in the reaction of N-carbethoxy nortropine-3α-benzenesulfenate with hexabutylditin, is a key step of this synthetic approach to scopine. The reaction of N- carbethoxy nortropine-benzenesulfenate with tributyltin hydride in the presence of a radicophilic olefin involves Michael type alkylation at the 6- position of tropine skeleton affording 6-(2-carbethoxyethyl)-N-carbethoxy nortropine in 31% yield.

Full text of DOI:10.1055/s-1999-2658

LETTER
635
Synthesis of Acetyl Scopine. Intramolecular Reactions of N-Carbethoxy
Nortropine-3a-benzenesulfenate
Goran PetroviÊ, Radomir N. SaiËiÊ, éivorad »ekoviÊ*
Faculty of Chemistry, University of Belgrade, Studentski trg 16, PO Box 158, 11000 Belgrade, Yugoslavia
Fax +381-11-636-061; E-mail: zcekovic@chem.bg.ac.yu
Received 14 January 1999
1,5-hydrogen shift. This functionalization of the 6-posi-
tion of tropine is possible only when N-alkoxycarbonyl
nortropine derivatives are used as precursors of alkoxyl
radicals.7 Several attempts to use tropine itself or its deriv-
Abstract: The synthesis of acetyl scopine using tropine as a starting
compound was achieved. Free radical phenylthio group transfer to
the 6-position, in the reaction of N-carbethoxy nortropine-3α-ben-
zenesulfenate with hexabutylditin, is a key step of this syn-
thetic approach to scopine. The reaction of N-carbethoxy atives, as a precursor of alkoxyl radical, have been unsuc-
cessful.8 However, by lead tetraacetate oxidation of N-
nortropine-benzenesulfenate with tributyltin hydride in the
presence of a radicophilic olefin involves Michael type alkyl-
alkoxycarbonyl nortropine an ether function has been in-
ation at the 6-position of tropine skeleton affording 6-(2-car-
troduced at the 6-position leading to 3α,6α-oxidotropine.7
bethoxyethyl)-N-carbethoxy nortropine in 31% yield.
N-Carbethoxy nortropine benzenesulfenate 5 was pre-
Key words: 6,7-dehydrotropine, scopine, tropine benzene-
pared from tropine 2 by the following sequence of reac-
tions: acetylation of the hydroxy group gave 3, then N-
carbethoxylation by chlorocarbonate followed by demeth-
ylation and hydrolysis of the acetate afforded N-carbe-
thoxy nortropine 4.9 Esterification by benzenesulfenyl
chloride gave O-sulfenyl carbamate 55,10 in 78% overall
yield from 2 (Scheme 2).
sulfenate, intramolecular radical reactions, 1,5-hydrogen shift
The synthesis of a variety of tropane alkaloids has been
achieved via 6,7-dehydrotropine as a common intermedi-
ate.1 By suitable oxidative transformations of the double
bond 6,7-dehydrotropine is generally converted into alka-
loids having an oxygen function at C6 (and/or C7).2 Sever-
al naturally occurring tropane alkaloids including
scopine,2 valerin, teloidine and others have been synthe-
sized from dehydrotropine.2,3 There are several approach-
es for the synthesis of 6,7-dehydrotropine.2a-c,3,4
We have recently discovered that photolytically induced
decomposition of alkyl benzenesulfenates in the presence
of hexabutylditin (to initiate a chain reaction) involves a
free radical intramolecular reaction at the non-activated
carbon atom with introduction of the phenylthio group at
the δ-position.5 Application of this type of functionaliza-
tion of a methylene group in the 6-position of the tropane
skeleton and other reactions involved in the conversion of
tropine 2 into acetyl scopine 1b (Scheme 1, R = Ac), are
summarized in this Letter. The key step in the conversion
of tropine to 6,7-dehydrotropine is the intramolecular 1,5-
hydrogen transfer6 from the 6-position in 8 to the 3α-
alkoxyl radical intermediate. The tropine molecule pos-
sesses an appropriate and fixed stereochemistry to favour
Scheme 2
The conversion of N-carbethoxy nortropine benzene-
sulfenate 5 to the N-carbethoxy-6-phenylthio nortropine
6, with introduction of phenylthio group at the non-acti-
vated carbon atom C-6, was achieved by irradiation of 5
with a high pressure mercury lamp in the presence of
hexabutylditin in benzene solution.5 N-Carbethoxy-6-phe-
nylthio nortropine 6 was obtained in 45% yield.11 By anal-
ysis of 1H NMR spectrum we found that product 6 was a
mixture of exo- and endo-isomers in the ratio of 2:1
(Scheme 3).
Functionalization of position 6 (or 7) in compound 5 in-
volves an intermediary alkoxyl radical 8 (arised by ho-
molytic substitution at sulfur by tributyltin and/or alkyl
radical) with appropriate stereochemistry accessible for a
l,5-hydrogen shift and the formation of an alkyl radical
9.5,6a The intermolecular transfer of phenylthio group from
the starting O-sulfenyl ester 5 takes place to give product
6 (Scheme 3). In addition to main product 6 a tropinone
Scheme 1
Synlett 1999, No. 5, 635–637 ISSN 0936-5214 © Thieme Stuttgart · New York

636
G. PetroviÊ et al.
LETTER
derivative 7 and alcohol 4 were also formed as side-prod- Bu3SnH an alkylation reaction took place and 6-(2-carbe-
ucts probably by disproportionation reaction of alkoxyl thoxyethyl)-N-carbethoxy nortropine 13 was obtained in
radical 8.
31% yield.15b Ten molar equivalents of excess of ethyl
acrylate is used to favour the intermolecular addition of
radical 9 to the olefin (Scheme 5).
Scheme 5
This methodology offers a convenient route for the intro-
duction of a functionalized alkyl chain into the 6-position
of tropine molecule and the synthesis of a variety of new
tropine derivatives.
Scheme 3
References and Notes
The oxidation of N-carbethoxy-6-phenylthio nortropine
by m-chloroperbenzoic acid afforded the corresponding
sulfoxide 1012 which, by heating in boiling toluene, under-
went the elimination reaction,13a thus giving the N-carbe-
thoxy-6,7-dehydro nortropine 11.13b The conversion of 11
to 6,7-dehydrotropine 12 was carried out with LiAlH4.2c,9
Acetylation of 12 and subsequent epoxidation by per-
formic acid afforded acetyl scopine 1b3 (Scheme 4).
1H NMR spectra indicate that the epoxide is in exo-posi-
tion.14 The synthesis of scopolamine 1c from acetyl
scopine 1b has been described.3
(1) Fodor, G. Prog. Phytochem., 1968, 1, 491; Experientia, 1955,
11, 129; Tetrahedron, 1957, 1, 86; Chem. Ind. (London),
1961, 1500; Tropane Alkaloids in Chemistry of the Alkaloids,
Pelletier, S. W., Ed. Van Nostrand-Reinhold, Princeton, N. J.
1970, Chapter 15.
(2) a) Fodor, G.; Toth, J.; Koczor, I.; Dobo, P.; Vincze, I. Chem.
Ind. (London), 1956, 764; b) Fodor, G.; Toth, J.; Koczor, I.
Chem. Ind. (London), 1955, 1260; c) Hayakawa, Y.; Baba, Y.;
Makino, S.; Noyori, R. J. Am. Chem. Soc., 1978, 100, 1786.
(3) a) Dobo, P.; Fodor, G.; Janzso, G.; Koczor, I.; Toth, J.;
Vincze, I. J. Chem. Soc., 1959, 3461; b) Fodor, G.; Toth, J.;
Romeike, A.; Vincze, I.; Dobo, P.; Janzso, G. Angew. Chem.,
1957, 69, 678.
(4) a) Stoll, A.; Lindenmann, A.; Jucker, E. Helv. Chim. Acta,
1953, 36, 1506, 1526; b) Meinwald, J.; Chapman, O. L. J. Am.
Chem. Soc., 1957, 79, 665; c) Willstatter, R.; Berner, E. Chem.
Ber., 1923, 56, 1079; d) Cowling, A. P.; Mann, J. J. Chem.
Soc. Perkin Trans. I, 1978, 1564.
(5) PetroviÊ, G.; SaiËiÊ, R. N.; »ekoviÊ, é. Tetrahedron Lett.,
1997, 38, 7107.
(6) a) PetroviÊ, G.; »ekoviÊ, é. Tetrahedron Lett., 1997, 38, 627;
b) MihailoviÊ, M. Lj.; »ekoviÊ, é. Synthesis, 1970, 209;
c) Majetich, G.; Wheless, K. J. Tetrahedron (Report No 375),
1995, 51, 7095; d) Barton, D. H. R.; Beaton, J. M.; Geller, L.
E.; Pechet, M. M. J. Am. Chem. Soc., 1961, 83, 4076;
e) Barton, D. H. R. Pure and Appl. Chem., 1968, 16, 1; Hesse,
R. H. Advan. in Free Radical Chem. 1969, 3, 83.
(7) Khuong-Huu, F.; Bennett, C. R.; Fouche, D. E.; Goutarel, G.
C. R. Acad. Sci. Paris Serie C, 1972, 275, 499.
(8) Intramolecular functionalization of tropine by hypoiodite and
hypobromite reactions, as well as by lead tetraacetate and
phenyliodoso diacetate oxidation have not been achieved;
»ekoviÊ, é. et al. unpublished results.
Scheme 4
(99 Maryanoff, B. E.; Almond, Jr., H. R. J. Org. Chem., 1986, 51,
3295; Kraiss, G.; Nador, K. Tetrahedron Lett., 1971, 57.
(10) Beckwith, A. L. J.; Hay, B. P.; Williams, G. M. J.Chem. Soc.,
Chem. Commun., 1989, 1202; Hartung, J.; Gallou, F. J. Org.
Chem., 1995, 60, 6706; Pasto, D. J.; Cottard, F. Tetrahedron
Lett. 1994, 35, 4306; Pasto, D. J.; L’Hermine, G. J. Org.
Chem. 1990, 55, 5815.
Functionalization of the non-activated carbon atom in the
6-position of the tropine skeleton was achieved via an
alkoxyl radical 8 and the carbon radical 9 as intermedi-
ates. This sequence of reactions offers some other synthet-
ically valuable possibilities such as Michael type
alkylation of carbon radical 9 by olefins.6a,15a Thus, by ir-
radiation of 5 in the presence of excess ethyl acrylate and
Synlett 1999, No. 5, 635–637 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Intramolecular Reactions of N-Carbethoxy Nortropine-3a-benzenesulfenate
637
N-Carbethoxy nortropine-3α-benzenesulfenate (5) was
and the mixture refluxed for 100 h. The mixture was diluted
with CH2Cl2, washed with water and dried (Na2SO4). Solvents
were evaporated and the residual oil was purified by column
chromatography on silica gel (petroleum ether, petroleum
ether/acetone 9:1, 8:2 and 7:3 successively) to give 1.25 g
(98%) of N-carbethoxy-6,7-dehydronortropine (11), m.p.
74 °C. IR (KBr):3432, 1682, 1601, 1471, 1435, 1385, 1351,
1316, 1262, 1219, 1172, 1107, 1065, 1023; 1H NMR(200
MHz) d:1.27 (t, J = 7.2 Hz, 3H), 1.77 (d, J = 14.6 Hz, 2H),
2.15 - 2.40 (m, 3H), 3.95 (t, J = 5.6 Hz, 1H), 4.17 (q, J = 7.2
Hz, 2H), 4.60 (s, broad, 2H), 6.40 (s, broad, 2H); 13C NMR(50
MHz) d: 152.75, 136.00, 135.56, 65.44, 60.86, 56.89, 35.47,
34.83, 14.61; MS (CI):198 (M++1) 100%, 180 [(M++1) -
H2O(25%. Anal. Calcd. C10H15NO3: C, 60.89; H, 7.66; N,
7.10; Found: C, 60.52; H, 7.40; N, 7.54.
prepared by addition of 3.65 g (2.5 mmol) of benzenesulfenyl
chloride to a solution of 4.02 g (20.18 mmol) of N-carbethoxy
nortropine (4) and 5.1 g (50 mmol) of triethylamine in 150 ml
of CH2Cl2 at -78 °C, under an argon atmosphere, over 15 min.
The mixture was stirred 40 min at -78 °C and left to warm to
room temperature. The mixture was diluted with CH2Cl2 and
the solution was washed with water, 2N HCl, saturated
NaHCO3 solution, water and dried (Na2SO4). Solvents were
evaporated and the oily residue was purified by flash
chromatography on silica gel (petroleum ether/acetone 9:1
and 8:2; 20 min, daylight). Yield: 6.01 g (97%) of pure
sulfenate carbamate 5, m. p. 45 °C. IR (KBr):2000-1600,
1696, 1583, 1477, 1439, 1383, 1354, 1325, 1314, 1225,
1212,1169, 1107, 1032; 1H NMR(200 MHz) δ:1.23 (t,
J = 7.00 Hz, 3H), 1.89-2.13 (m, 8H), 3.78 (m, 1H), 4.11 (q,
J = 7.00, 2H), 4.24 (m, 2H), 7.11-7.40 (m, 5H); 13C NMR(50
MHz) δ:153.67, 140.05, 128.92, 126.43, 123.74, 80.00, 60.70,
52.15, 36.13, 35.53, 28.24, 27.61, 14.64; MS (CI):308 (M++1)
100%, 183 [(M++1) - OSPh (50%. Anal. Calcd. C16H21NO3S:
C, 62.54; H, 6.84; N, 4.56; Found: C, 62.68; H, 7.05; N, 4.42.
(11) Typical experiment: A. solution of 1.50 g (4.88 mmol) of
sulfenyl carbamate 5 and 0.44 g (0.758 mmol) of
(14) Compound 1b: IR (film):1729, 1421, 1381, 1364, 1333, 1264,
1237, 1206, 1063, 1049, 1019; 1H NMR(200 MHz) δ:1.60 (d,
Jgem = 15.6 Hz, 2H), 2.02 (s, 3H), 2.14 (ddd, Jgem = 15.6 Hz,
J
J
vic 1 = 5.5 Hz, Jvic 2 = 4.1 Hz, 2H), 2.54 (s, 3H), 3.19 (dd,
vic 2 = 4.1 Hz, Jvic 3 = 1.7 Hz, 2H), 3.63 (s, 2H), 4.98 (t,
Jvic 1 = 5.5 Hz, 1H); 13C NMR(50 MHz) δ:169.98, 66.22, 58.03,
56.57, 42.37, 31.28, 21.56; MS (CI):198 (M++1) 100%, 138
(M+-AcO) 98%.
hexabutyditin in 40 ml of benzene, was irradiated by a 125 W
high pressure mercury lamp at r.t., in an argon atmosphere,
during 1.5 h. Benzene was evaporated and the residue was
purified by column chromatography on silica gel (benzene
and benzene/ethyl acetate 8:2) to afford 0.675 g (45%) of a
mixture of exo- and endo- isomers of 6-phenylthio-N-
carbethoxy nortropine (6), m.p. 119 °C (ratio determined
by13C NMR). IR (KBr):3413, 2000-1600, 1661, 1483, 1431,
1384, 1330, 1162, 1114, 1097, 1046, 1011; 1H NMR(200
MHz) δ:1.21-1.30 (m, 3H), 1.69-2.20 (m, 6H), 2.69-2.84 (m,
1H), 4.10-4.40 (m, 5H), 7.18-7.36 (m, 5H); 13C NMR(50
MHz) δ:154.59, 154.25, 136.86, 136.65, 129.92, 129.82,
128.90, 126.24, 64.54, 61.05, 59.55, 59.36, 53.02, 52.76,
47.88, 47.14, 38.29, 37.99, 37.69, 37.63, 36.92, 36.15; MS
(CI):308 (M++1) 100%. Anal. Calcd. C16H21NO3S: C, 62.54;
H, 6.84; N, 4.56; Found: C, 62.51; H, 6.71; N, 4.44. In
addition to compound 6, 0.15 g (15%) of N-carbethoxy
nortropinone 7 and 0.36 g (37%) of alcohol 4 were also
isolated.
(15) a) PetroviÊ, G.; »ekoviÊ, é. Tetrahedron, 1999, 55, 1377.
b) Typical experiment : A solution of 0.154 g (0.51 mmol) of
compound 5, 0.5 g (5 mmol) of ethyl acrylate and 0.146 g
(0.51 mmol) of Bu3SnH in 40 ml of benzene, under an argon
atmosphere, was irradiated by a 125 W high pressure mercury
lamp at r.t., in an argon atmosphere, during 10 min. Benzene
was evaporated and the residual oil was dissolved in ether (60
ml) and the solution washed with a sodium fluoride solution
(l0 h). The ethereal solution was concentrated and the residual
oil was purified by column chromatography on silica gel
(petroleum ether/acetone 9:1 and 8:2) to give 46 mg (31%) of
a mixture of exo- and endo-isomers (ratio determined by13C
NMR) of alkylated product 13 as a colorless oil. IR
(film):3444, 1734, 1699, 1674, 1427, 1259, 1155, 1099, 1048;
1H NMR(200 MHz) δ:1.25 (t, J = 7.2 Hz, 6H), 1.40-1.90 (m,
6H), 2.29 (t, J = 7.6 Hz, 2H), 1.90-2.70 (m, 4H), 3.86-3.92 (m,
broad, 1H), 4.12 (q, J = 7.2 Hz, 2H), 4.13 (q, J = 7.2 Hz, 2H),
4.10-4.40 (m broad, 2H); 13C NMR(50 MHz) δ: (173.57,
154.27) C, 64.97 C-H, (60.81, 60.31) CH2, (57.94, 57.65,
53.15, 52.99, 41.10, 40.37) C-H, (38.38, 38.22, 37.76, 35.93,
35.14, 32.59, 31.90) CH2, (14.71, 14.18) CH3; MS (CI) :300
(M++1) 100%.
(12) Trost, B. M.; Salzmann, T. N. J.; Hiroi, K. J. Am. Chem. Soc.,
1976, 98, 4887.
(13) a) Trost, B. M.; Salzmann, T. N. J.; J. Org. Chem., 1975, 40,
148; Grieco P. A.; Miyashita, M. J. Org. Chem., 1974, 39,
120; Sharpless, K. B.; Young, M. W. J. Org, Chem., 1975, 40,
947.
Article Identifier:
b) To the solution of sulfoxide 10 (2.1 g, 6.5 mmol) in 150 ml
of toluene 5.45 g (65 mmol) of sodium bicarbonate was added
1437-2096,E;1999,0,05,0635,0637,ftx,en;G01499ST.pdf
Synlett 1999, No. 5, 635–637 ISSN 0936-5214 © Thieme Stuttgart · New York