Functionalized N-propargylanabazine derivatives

Article abstract of DOI:10.1007/s11172-009-0262-5

N-Propargyl derivatives of the alkaloid anabazine with carbonyl, ester, and cyano groups in the side chain were obtained by three-component condensation of anabazine hydrochloride with paraformaldehyde and appropriate terminal alkynes. Decyanoethylation a

Full text of DOI:10.1007/s11172-009-0262-5

Russian Chemical Bulletin, International Edition, Vol. 58, No. 9, pp. 1921—1926, September, 2009
1921
Functionalized Nꢀpropargylanabazine derivatives
M. V. Mavrov and S. G. Zlotin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
4
7 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 137 2944. Eꢀmail: zlotin@ioc.ac.ru
NꢀPropargyl derivatives of the alkaloid anabazine with carbonyl, ester, and cyano groups in
the side chain were obtained by threeꢀcomponent condensation of anabazine hydrochloride
with paraformaldehyde and appropriate terminal alkynes. Decyanoethylation and hydration of
the isopropylidene double bond resulted in monoꢀ and dihydroxy derivatives of Nꢀpropargylꢀ
anabazines, respectively.
Key words: anabazine, the Mannich reaction, Nꢀpropargylanabazines, decyanoethylation.
Functionalized acetylenes are employed for the
synthesis of biologically active and natural compounds
methyl propiolate 2o, which is an active Michael accepꢀ
tor, the Mannich and Michael reactions compete. As the
result, the yield of product 4o was only ~30% and its
(
steroids, amino acids, terpenoids, polyynes, antibiotics,
1
polymers, etc.) (see Refs 1—3). For instance, some alkaꢀ
loid derivatives containing alkyne fragments are agonists
of the nicotinic cholinergic system whose failure triggers
purity was ~85% ( H NMR). The reaction of anabazine 1
with diethyl propargylmalonate 2p containing an active
methine group gave hydroxymethyl derivative 6a in
67% yield.
4
development of neurodegenerative diseases. For example,
5
ꢀethynylnicotine is used in the treatment of Parkinson´s
The functional groups in the compounds obtained were
transformed to produce new functionalized anabazine
derivatives. For instance, alcohol 6a was converted into
acetate 6b under the action of Ac O in CH Cl ; Oꢀcyanoꢀ
5
disease. The propargylamine structural element is
contained in antidepressants (pargyline, chlorgyline),
cholinergics (tremorine, oxotremorine), and antihyperꢀ
tensive drugs (oxybutynin) (see Refs. 3, 6 and references
cited therein).
Recently, we have developed a simple and convenient
method for the synthesis of compounds comprising
anabazine and propargylamine fragments by threeꢀcomꢀ
ponent condensation of anabazine 1 (AnbꢀH) with formꢀ
aldehyde and terminal alkynes in the presence of copper
2
2
8
2
t
ethyl derivatives 4e,k were hydrolyzed with KOBu
or EtONa to the corresponding alcohols 4s,t. In the
anabazine series, this reaction was carried out for the first
time and used to obtain more complex anabazineꢀbased
alcohols, e.g., terpene diol 7 (Scheme 2) by roomꢀtemꢀ
perature hydration of the isopropylidene C=C bond in
compounds 4k,t in the presence of 3 M HCl. Usually,
alcohols are prepared from alkenes by hydroxymercuration
or hydrolysis with stronger mineral acids.9
7
salts. This method is used in the present work for the
synthesis of this kind of compounds containing the funcꢀ
tional groups CO, OCH CH CN, COOR, and C(OR) in
Functionalized Nꢀpropargylanabazines 4—7 are
liquids with high specific rotations, [α]D = –150—250,
which is indirect evidence for the retention of the
configuration of the chiral center C(2) in the anabazine
molecule upon the Mannich reaction. The structures of
2
2
2
the alkynyl substituents (Scheme 1).
It turned out that alkynes 2a—m containing the ester
and cyano groups and the double bonds C=C easily react
under the conditions studied to give various Nꢀpropargylꢀ
anabazines 4a—m. Reactions with diynes 3a,b yielded
compounds 5a and 5b each containing two anabazine
fragments. Attempted synthesis of monoadducts failed
despite the use of an excess of anabazine or variation of
the reaction conditions.
In these reactions, functionalized alkynes 2n—p show
some characteristic features. For instance, the anabazineꢀ
related ketal 4n generated in situ from alkyne 2n is transꢀ
formed into the corresponding hydroxy ketone 4q upon
acid treatment of the reaction mixture. In the case of
1
compounds 4—7 were proved by IR, H NMR, and mass
spectra (Table 1, Experimental), elemental analysis, and,
in some cases, by transformation into the corresponding
1
hydrochlorides. The H NMR spectra of the diastereoꢀ
mers of anabazine derivatives 4h,k,n,q,r with an asymꢀ
metric substituent in the side chain are similar. It should
only be noted that the signals for the H(2´) and H(6´)
atoms are usually broadened (δ ~0.2—1.0), probably
because of the inversion of the N atom of the piperidine
ring. The signals for the C(2´) and C(6´) atoms in the
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1860—1865, September, 2009.
066ꢀ5285/09/5809ꢀ1921 © 2009 Springer Science+Business Media, Inc.
1

1
922
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009
Mavrov and Zlotin
Scheme 1
2
i. Cu Cl —AcONa/dioxane; ii. Ac O, NEt , DMAP/CH Cl
2
2
2
2
3
2
2
3
2
, 5: R1 = H, R2 = CO Me (a), R1 = R = CO Et (b)
2
2
t
, 4: R = MeOCH (a), 2,6,6ꢀtrimethyltetrahydropyranꢀ2ꢀyl (b), Bu OCH(Me)CH (c), N≡CCH CH OCH (d), N≡CCH CH OCH CH (е),
2
2
2
2
2
2
2
2
2
N≡CCH CH OCH(Me)CH (f), N≡CCH CH OCMe (g), N≡CCH CH OC(Me)Et (h), N≡CCH CH OCEt (i), [cycloꢀ(CH ) C]OCH CH C≡N (j),
2
2
2
2
2
2
2
2
2
2
2
2 5
2
2
Me C=CHCH CH C(Me)O CH CH C≡N (k), MeO CCH CH (l), EtO CCH CH (m), (cycloꢀOCH CH O) C(Me)CH C(Me)OH (n),
2
2
2
2
2
2
2
2
2
2
2
2
2
2
MeO C (o), (EtOOC) CHCH (p), O=C(Me)CH C(Me)OH (q), Me C(OH)CH CH CH C(Me)OCH CH C≡N (r), HOCH CH (s),
2
2
2
2
2
2
2
2
2
2
2
2
Me C=CHCH CH C(Me)OH (t).
2
2
2
Scheme 2
i: 3 M НСl, 20 °С, 5 h ii: EtONa/EtOH, 80 °С, 7 h.

Functionalized Nꢀpropargylanabazines
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009 1923
1
a
Table 1. H NMR spectra (DMSOꢀd , δ, J/Hz) of compounds 4, 6, and 7
6
Comꢀ
Н(2´) Н(4´)
Н(5´)
Н(6´)
H(2)
С(3,4,5)Н2 Н(6е) Н(6а) СН (7)
Н—R
2
pound (br.s) (d,
(dd,
(d,
(J = 10.8)
(2 m, 1 Н,
5 Н)
(br.d)
(t)
(two d,
1 Н each)
(J = 6.3—7.5)
J = 7.4) J = 7.4, J = 4.3)
J = 4.3)
J = 10.6
4
4
a
b
8.51
8.46
7.70
7.64
7.22
7.25
8.46
8.42
3.29 ddb
3.30 d
1.32—1.76
1.25—1.84
2.92
2.91
2.46 3.23, 2.96 3.28 (s, 3 Н), 4.13 (s, 2 Н)
c
2.55 3.10, 3.01 1.13, 1.40 (both s, 3 Н and 6 Н),
с
1
.25—1.84 , 1.96 (both m, 5 H
and 1 Н)
4c
8.42d 7.64
7.24
8.39
3.30 d
1.27,
2.94c –е
3.05, 2.94 1.18 (s, 9 Н), 1.19 (d, 3 Н),
2.19, 2.27 (both d, 1 Н each),
1.50—1.78
3
.69 (br.s, 1 Н)
4d
4e
4f
8.50
8.49
8.49
7.69
7.64
7.70
7.36
7.28
7.34
8.47
8.39
8.46
3.30c
1.32,
.44—1.77
1.34,
.45—1.78
1.34,
.44—1.76
2.92
2.98
2.88
2.41 3.22, 2.93 2.63, 3.65 (both t, 2 Н each),
4.25 (s, 2 Н)
1
3.28 ddb
3.31 d
—е
3.09, 2.89 2.48 (m, 2 Н), 2.78, 3.56,
3.64 (all t, 2 Н each)
3.10, 2.96 1.31 (d, 3 Н), 2.35—2.55
(m, 2 Н), 2.60, 3.74 (both t,
1
—е
1
2
Н each), 3.64 (br.s, 1 Н)
4
g
h
8.49
8.49
7.70
7.70
7.36
7.36
8.46
8.46
3.28 d
3.31 d
1.32,
.46—1.77
1.32,
.42—1.82с
2.88
2.88
—е
—е
3.18, 2.96 1.43, 1.44 (both s, 3 Н each),
2.48, 3.54 (both t, 2 Н each)
3.22, 3.01 0.97 (t, 3 Н), 1.37, 1.38
1
4
с
1
(both s, 1.5 Н each), 1.80 (m,
2
Н), 2.73, 3.71 (both m, 2 Н each)
4
4
4
i
8.49
8.49
—f
7.69
7.69
7.69
7.37
7.36
7.38
8.45
8.46
—f
3.32 d
3.32 d
3.32 d
1.25—1.82c 2.85
1.31—1.88с 2.9
1.24—1.88c 2.93
—е
—е
3.25, 3.02 0.81—0.92 (m, 6 Н), 1.64 (m,
Н), 2.75, 3.70 (both t, 2 Н each)
с
4
с
j
3.24, 3.02 1.31—1.88 (m, 10 Н), 2.75,
.70 (both t, 2 Н each)
3
c
k
2.58c 3.12, 3.19 1.24—1.88 (m, 2 Н), 1.42,
1
.64, 1.73 (all s, 3 Н each),
с
2.19 (m, 2 Н), 2.58 , 3.74
(
both m, 2 Н each), 5.12 (t, 1 Н)
4l
8.67d 7.68
7.24
8.51
3.29 d
1.32,
.54—1.86
2.9
—е
—е
3.12, 3.02 2.54 (t, 2 Н), 2.60—2.74
(m, 2 Н), 3.74, 3.77, 3.78
1
(all s, 3 Н total)
4
m
n
8.49
—f
7.68
7.82
7.35
8.48
—f
3.25 ddb
3.32 d
1.32,
.50—1.76
2.84
3.08, 2.85 1.21 (3 Н, s), 2.42—2.68
(m, 4 Н), 4.12 (q, 2 Н)
1
4
7.34g
1.20—1.89
3.02c 2.56g 3.13, 3.09 1.43, 1.49, 1.50 (all s, 6 H total),
1
3
.98, 2.16 (both m, 1 Н each),
.94 (s, 4 Н), 4.40 (br.s, 1 Н)
4
q
r
8.5а
8.58
7.71
7.81
7.37
7.26
8.46
8.49
~3.32 d
3.21 d
1.31,
2.83
2.91
2.46 3.21, 2.86 1.42, 2.19 (both s, 3 Н each),
2.67—2.76 (m, 2 Н), 5.02 (s, ОН)
1.44—1.78
c
2.51c 3.16, 3.08 1.18—1.92 (m, 6 Н), 1.21, 1.25,
с
4
1.18—1.92
1
.26, 1.39, 1.48 (all s, 9 H total),
с
2.51—2.70 (m, 2 Н), 3.76
(m, 2 Н)
6
6
7
а
8.47
8.51
—f
7.68
7.62
7.69
7.35
7.19
7.32
8.46
8.43f
—f
3.24 d
1.28,
2.82
—е
2.46с 3.11, ~2.87 1.22, 1.24 (both t, 3 Н each),
2.82 (s, 2 Н), 3.96 (dd, 2 H),
1.44—1.78
4
.11—4.22 (m, 4 Н), 5.22 (t, ОН)
b
3.22 ddb
3.31 d
1.08—1.82
2.47e 3.06, ~2.92 1.21 (t, 6 H), 2.02 (s, 3 Н)
2
4
.81 (br.s, 2 Н), 4.18 (q, 4 H),
.63 (s, 2 Н)
1.08—1.92c 2.88c 2.52 3.09, 2.92 1.11, 1.36 (both br.s, 6 Н,
с
3
Н), 1.08—1.92 (m, 6 Н),
4.08, 5.09 (both br.s, 1 Н each)
a
1
The H NMR spectra of compounds 4k,n,r were recorded on a Bruker AMꢀ300 instrument (300 MHz, CDCl ). The averaged
3
coupling constants (±0.3 Hz) are given.
b
J = 11.8 Hz, J = 2.4 Hz.
Overlap of the signals.
The doublet with J = 1.8 Hz.
The signal for the H(6a) atom (δ ≈ 2.50) is masked by the signal for the solvent.
δ 8.5—9.5 (2 H, degenerate br.s).
The broadened singlet.
c
d
e
f
g

1
924
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009
Mavrov and Zlotin
13C NMR spectra are strongly broadened; in the case of
k, they appear at elevated temperature (70 °C). The charꢀ
Method B. The crude product was dissolved in benzene
60 mL) and extracted with 2 M HCl (2×15 mL). The aqueous
(
4
layer was alkalified with K CO to pH 10 and the product was
acteristic peaks in the mass spectra of the compounds
obtained correspond to the intense fragmentation ions
2
3
extracted with Et O (3×30 mL) (for 4a—j) or benzene—ethyl
2
acetate (4 : 1). The combined extracts were washed with water
+
+
+
[
M – C H N] , 199 [AnbCH C≡C] , and 161 [Anb]
5 4 2
and brine, dried with MgSO , concentrated, and chromatoꢀ
4
(
Anb is the anabazine moiety).
Thus, threeꢀcomponent condensation of anabazine
graphed as described above (see method A). This procedure was
used to isolate compounds 4a—j,e,m,o,q,r and 5a,b.
with paraformaldehyde and functionalized terminal alkynes
afforded functionalized Nꢀpropargylanabazines, useful
precursors of new biologically active anabazineꢀbased
compounds.
Compounds 4c,o,q,r, 5a,b, and 6a were rechromatographed
on SiO2 with CH Cl —MeOH as an eluent (gradient elution
2
2
from 0 to 20% MeOH).
S)ꢀNꢀ(4ꢀMethoxybutꢀ2ꢀynyl)anabazine (4a). Yield 83%, oil,
(
–
1
[
α]D –229.3 (c 0.60). IR, ν/cm : 2916, 1592, 1576, 1428, 1088,
1
9
2
1
08, 720. For H NMR data, see Table 1. MS, m/z (I (%)):
rel
Experimental
44 [M]+ (37); 213 (39); 199 (17); 166 [M – C H N] (100);
+
5
4
61 (25); 119 (25); 105 (41); 92 (25); 77 (26). Found (%):
IR spectra were recorded on a Specord Mꢀ80 instrument in
thin films for oils and in KBr pellets for solids. H NMR spectra
N, 11.24. C H N O. Calculated (%): N, 11.47.
15 20 2
1
Hydrochloride 4a•HCl. M.p. 135—137 °C, [α]D –100.5
1
were recorded on Bruker DRXꢀ500 and Bruker AMꢀ300 specꢀ
trometers in DMSOꢀd and CDCl with SiMe as the internal
(c 0.48). H NMR, δ: 3.19 (t, 1 H, H(6e), J = 13.0 Hz); 3.29 (s,
6
3
4
2 H, MeO); 3.67 (d, 1 H, H(6e), J = 13.0 Hz); 3.79, 4.00
standard. Mass spectra were measured on a Finnigan MAT 112S
INCOS 50 instrument (EI, 70 eV, direct inlet probe). Specific
(both d, 1 H each, ≡CCH N, J = 17.4 Hz); 4.21 (br.s, 2 H,
2
CH O); 4.64 (d, 1 H, H(2), J = 13.0 Hz); 8.03 (t, 1 H, H(5´),
2
–
1
rotation ([α] /deg mL (g dm) ) was determined on a PUꢀ07
J = 7.6 Hz); 8.91, 8.92 (s, 1 H each, H(4´), H(6´)); 9.20 (br.s,
1 H, H(2´)). Found (%): Cl, 13.46. C H N O•HCl. Calcuꢀ
D
polarimeter (Russian Federation) at 20—23 °C for solutions in
15
20
2
–
1
chloroform (C/g (100 mL) ). Elemental analysis data were
obtained on a PerkinꢀElmer CHN 2004 instrument.
lated (%): Cl, 12.98.
(S)ꢀNꢀ[3ꢀ(2,6,6ꢀTrimethyltetrahydropyranꢀ2ꢀyl)propꢀ
The reaction products were purified by flash chromatography
or dry column chromatography on Merck 60 silica gel (70—230
mesh). The course of the reactions was monitored by TLC on
Silufol UVꢀ254 plates in the solvent system chloroform—methaꢀ
2ꢀynyl]anabazine (4b). Yield 86%, light oil, [α] –194.1 (c 0.46).
D
–
1
IR, ν/cm : 2936, 1592, 1576, 1428, 1220, 1076, 988, 716. For
1
+
H NMR data, see Table 1. MS, m/z (I (%)): 326 [M] (30);
rel
+
248 [M – C H N] (100); 199 (14); 161 (32); 92 (12); 43 (26).
5
4
nol—ethyl acetate (9 : 1 : 1, v/v) saturated with NH OH. Spots
Found (%): N, 8.47. C H N O. Calculated (%): N, 8.58.
21 30 2
4
were visualized in the iodine vapor.
Mixture of monoꢀ and dihydrochlorides (20—30%),
m.p. 155—157 °C, [α]D –85.0 (c 0.43). H NMR, δ: 1.08, 1.31,
1
Anabazine hydrochloride (1•HCl), m.p. 220—222 °C, >99%
purity, (S)ꢀbase, [α]D –82.5 (c 0.6, EtOH), R 0.17. Ethanol
1.32, 1.41 (all s, 3 H, 1.5 H, 1.5 H, 3 H, Me); 1.17—1.65,
f
was distilled over metallic Mg; THF was distilled from sodium
benzophenone ketyl.
1.76—1.97, 2.15 (all m, 5 H, 5 H, 2 H, CH ); 3.04 (br.s, 1 H,
2
H(6a)); 3.71 (dd, 2 H, ≡CCH N, H(6e), J =16.0 Hz, J = 9.0 Hz);
2
Compounds 2a,o,1 2b,11 2c,12 2d—k,13 2l,14 2m,p, 3a,b,15
0
3.86 (d, 1 H, ≡CCH N, J = 16.0 Hz); 4.35 (t, 1 H, H(2),
2
and 2n16 were prepared as described earlier.
J = 9.0 Hz); 7.39 (br.t, 1 H, H(5´), J = 7.8 Hz); 8.58 (br.s, 1 H,
H(4´)); 8.79 (d, 1 H, H(6´), J = 4.8 Hz); 8.96 (br.s, 1 H, H(2´));
12.60 (br.s, NH).
3
ꢀ(2ꢀCyanoethoxy)ꢀ3,7ꢀdimethyloctꢀ6ꢀenꢀ1ꢀyne (2k). Yield
2
0
6
6%, b.p. 160 °C (bath)/0.5 Torr, nD 1.4630. Found (%):
N, 8.49. C H NO. Calculated (%): N, 8.28. IR, ν/cm : 3288,
112 (—C≡CH); 2256 (C≡N). H NMR (CDCl , 300 MHz), δ:
.38, 1.59, 1.67 (all s, 3 H each, 3 Me); 1.62, 2.12 (both m, 2 H
–
1
10
19
(S)ꢀNꢀ(5ꢀtertꢀButoxyhexꢀ2ꢀynyl)anabazine (4c). Yield 62%,
1
–1
2
1
dark oil (unstable on storage), [α]D –189.0 (c 0.70). IR, ν/cm :
3
1
2928, 1592, 1576, 1428, 1082, 720. For H NMR data, see
Table 1. MS, m/z (Irel (%)): 314 [M]+ (49); 236 [M – C H N]
+
each, CH CH ); 2.49 (s, ≡CH); 2.64, 3.74 (both m, 2 H each,
2
2
5
4
CH CH ); 5.12 (t, 1 H, =CH, J = 6.4 Hz).
(100); 213 (60); 199 (19); 161 (Anb, 33); 84 (17); 57 (77); 41 (23).
2
2
NꢀPropargylanabazines 4, 5, and 6 (general procedure).
Anabazine hydrochloride 1•HCl (1.12 g, 5 mmol) was added
in one portion at 60—65 °C to a mixture of alkyne 2 or 3
(S)ꢀNꢀ[4ꢀ(2ꢀCyanoethoxy)butꢀ2ꢀynyl]anabazine (4d). Yield
–
1
84%, oil, [α]D –196.2 (c 0.58). IR, ν/cm : 2932, 2256 (C≡N),
1
1592, 1580, 1428, 1108, 716. For H NMR data, see Table 1.
+
+
(
(
8—10 mmol), paraformaldehyde (0.48 g, 16 mmol), Cu Cl2
0.5 g), and AcONa (1.0 g) in dry dioxane (30 mL). The reaction
MS, m/z (Irel (%)): 283 [M] (14); 213 (21); 205 [M – C H N]
4 4
2
(100); 161 (32); 77 (17). Found (%): N, 14.64. C H N O.
17 21 3
mixture was vigorously stirred for 5—8 h (TLC) and then at
5—90 °C for an additional 2—4 h. The mixture was passed hot
through a short column with SiO2 and concentrated under
reduced pressure. The residue was refluxed in light petroleum
Calculated (%): N, 14.83.
(S)ꢀNꢀ[5ꢀ(2ꢀCyanoethoxy)pentꢀ2ꢀynyl]anabazine (4e). Yield
8
–
1
82%, oil, [α]D –195.1 (c 0.74). IR, ν/cm : 2936, 2256 (C≡N),
1
1592, 1576, 1428, 1120, 720. For H NMR data, see Table 1.
+
+
(
15—20 mL) for 7—10 min, the solvent was decanted, and the
MS, m/z (Irel (%)): 297 [M] (22); 227 (24); 219 [M – C H N]
5 4
product was purified by method A or B.
(100); 161 (29); 77 (16). Found (%): N, 14.26. C H N O.
18 23 3
Method A. The crude product was dissolved in CH Cl (0.3 mL)
and chromatographed on silica gel (25—30 g, column 40×2.5 cm).
Calculated (%): N, 14.13.
(S)ꢀNꢀ[5ꢀ(2ꢀCyanoethoxy)hexꢀ2ꢀynyl]anabazine (4f). Yield
2
2
–
1
Light petroleum and then MeOH (0—10%)—NH OH (0—1%)
73%, oil, [α]D –190 (c 0.45). IR, ν/cm : 2932, 2256 (C≡N),
4
1
in CH Cl (stepwise gradient) were used as eluents. This proceꢀ
1428, 1108, 716. For H NMR data, see Table 1. MS, m/z
2
2
(Irel (%)): 311 [M]+ (13); 241 (18); 233 [M – C H N] (100);
+
dure was used to isolate compounds 4c,k,t and 6a.
5
4

Functionalized Nꢀpropargylanabazines
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009 1925
1
1
61 (24); 105 (20); 98 (35); 77 (18); 54 (49); 45 (66). Found (%):
(COOMe), 1624, 1436, 1252, 720. Partial H NMR (CDCl ), δ:
3
N, 13.21. C H N O. Calculated (%): N, 13.49.
1.34, 1.45—1.79 (both m, 1 H, 5 H, CH ); 2.44 (t, H(6a),
1
9
25
3
2
(
S)ꢀNꢀ[4ꢀ(2ꢀCyanoethoxy)ꢀ4ꢀmethylpentꢀ2ꢀynyl]anabazine
J = 12.5 Hz); 2.96 (br.d, 1 H, H(6e), J = 12.4 Hz); 3.15, 3.43
(
4g). Yield 78%, oil, [α]D –193.3 (c 0.55). IR, ν/cm–1: 2936,
(both d, 1 H each, ≡CCH N, J = 18.0 Hz); 3.27 (dd, 1 H, H(2),
2
2
256 (C≡N), 1584, 1560, 1428, 1244, 1156, 1096, 720. For
J = 12.8 Hz, J = 1.8 Hz); 3.73 (s, MeO); 7.40 (dd, 1 H, H(5´),
J = 7.8 Hz, J = 4.6 Hz); 7.70 (d, 1 H, H(4´), J = 7.8 Hz); 8.49,
8.50 (both s, 1 H each, H(4´), H(6´)).
1
H NMR data, see Table 1. MS, m/z (I (%)): 311 [M]+ (16);
rel
+
241 (25); 233 [M – C H N] (100); 213 (16); 162 (21); 161 (36);
5
4
1
06 (17); 79 (16); 45 (17). Found (%): N, 13.52. C H N O.
(S)ꢀNꢀ(4ꢀHydroxyꢀ4ꢀmethylꢀ6ꢀoxoheptꢀ2ꢀynyl)anabazine
1
9
25
3
Calculated (%): N, 13.49.
(4q). Yield 77%, oil, [α]D –172.0 (c 0.61). IR, ν/cm–1
:
(
S)ꢀNꢀ[4ꢀ(2ꢀCyanoethoxy)ꢀ4ꢀmethylhexꢀ2ꢀynyl]anabazine
3400—3200, 2936, 1708, 1590, 1580, 1428, 1364, 1328, 1216,
–
1
1
(
2
4h). Yield 76%, oil, [α]D –181.0 (c 0.74). IR, ν/cm : 2936,
256 (C≡N), 1592, 1576, 1428, 1124, 1096, 720. For H NMR
data, see Table 1. MS, m/z (I (%)): 325 [M]+ (11); 247
1100, 776. For H NMR data, see Table 1. MS, m/z (I (%)):
rel
1
300 [M]+ (8); 222 [M – C H N] (55); 199 (17); 164 (60); 161
+
5
4
(61); 105 (20); 58 (15); 43 [MeCO] (100). Found (%): N, 9.19.
C H N O . Calculated (%): N, 9.33.
rel
+
[
M – C H N] (100); 161 (30); 105 (21); 77 (24); 55 (18).
5
4
18 24
2
2
Found (%): N, 13.04. C H N O. Calculated (%): N, 12.91.
(S)ꢀNꢀ[4ꢀ(2ꢀCyanoethoxy)ꢀ8ꢀhydroxyꢀ4,8ꢀdimethylnonꢀ
2ꢀynyl]anabazine (4r) was obtained by aminomethylation
2
0
27
3
(
S)ꢀNꢀ[4ꢀ(2ꢀCyanoethoxy)ꢀ4ꢀethylhexꢀ2ꢀynyl]anabazine (4i).
–
1
Yield 81%, oil, [α]D –155.6 (c 0.53). IR, ν/cm : 2932, 2256
C≡N), 1592, 1576, 1428, 1096, 720. For H NMR data, see
Table 1. MS, m/z (Irel (%)): 339 [M] (12); 261 [M – C H N]
of anabazine according to general method B. Yield 52%, oil,
1
–1
(
R 0.63, [α]D –183.4 (c 0.91). IR, ν/cm : 3400, 2256, 1592,
f
+
+
1
1580, 1432, 1172, 1100, 716. For H NMR data, see Table 1.
C NMR (CDCl ), δ: 19.2, 24.4, 25.6, 26.2, 28.9, 29.3, 35.0,
3
5
4
13
(
100); 161 (40); 105 (16); 77 (19); 54 (16). Found (%): N, 12.19.
C H N O. Calculated (%): N, 12.38.
42.0, 43.7, 44.0, 52.9, 58.7, 62.7, 65.6, 69.9, 74.0 and 79.6 (C≡C),
6.1, 117.8 (C≡N), 123.6, 134.9, 138.6, 148.4, 149.0. MS, m/z
(Irel (%)): 397 [M ] (1); 301 (7); 199 (13); 161 (59); 136 (29);
21
29
3
(
S)ꢀNꢀ{3ꢀ[1ꢀ(2ꢀCyanoethoxy)cyclohexyl]propꢀ2ꢀynyl}ꢀ
8
anabazine (4j). Yield 89%, oil, [α]D –166.8 (c 0.46). IR, ν/cm–1
:
+
2
936, 2256 (C≡N), 1592, 1580, 1428, 1172, 1096, 716. For
1
31 (74); 122 (61); 124 (62); 106 (31); 69 (57); 59 [Me COH]
2
1
H NMR data, see Table 1. MS, m/z (I (%)): 351 [M]+ (13);
rel
(100); 54 (78). Found (%): N, 10.30. C H N O . Calcuꢀ
24 35 3 2
lated (%): N, 10.57.
+
2
73 [M – C H N] (100); 161 (63); 105 (24); 91 (39); 77(31);
5
4
5
5 (37); 41 (44). Found (%): N, 11.83. C H N O. Calcuꢀ
22 29 3
Method C. A mixture of compound 4k (0.4 g, 1.0 mmol) and
M HCl (25 mL) was stirred at 20 °C for 5 h, neutralized with
lated (%): N, 11.96.
3
(
S)ꢀNꢀ[4ꢀ(2ꢀCyanoethoxy)ꢀ4,8ꢀdimethylnonꢀ7ꢀenꢀ2ꢀynyl]ꢀ
NH OH, and, after workꢀup (see method B), chromatographed
4
anabazine (4k). Yield 58%, oil, R 0.79, [α] –181.2 (c 0.93). IR,
f
D
on SiO . The resulting alcohol 4r (0.34 g, 68%) is spectroscopiꢀ
2
–
1
1
ν/cm : 2256, 1656, 1600, 1580, 1436, 1100, 708. For H NMR
data, see Table 1. C NMR (DMSOꢀd , 75 MHz, 70 °C), δ:
cally identical with the product obtained according to method B.
(S)ꢀNꢀ(5ꢀHydroxypentꢀ2ꢀynyl)anabazine (4s). Potassium
tertꢀbutoxide (0.6 g) was added to a solution of compound 4e
13
6
1
5
2
48.4, 148.1, 134.2, 130.6, 123.5, 118.4, 85.9, 79.8, 73.0, 62.3,
8.6, 52.1, 43.2, 41.0, 40.3, 38.6, 35.0, 26.0, 25.2, 24.9, 24.0,
(
0.30 g, 1 mmol) in anhydrous THF (10 mL). The reaction
+
2.5, 18.4, 17.0. MS, m/z (I (%)): 379 [M] (4); 309 (26); 301
rel
mixture was refluxed for 7 h. The excess of the base was neutralꢀ
+
[
M – C H N] (47); 199 (29); 162 (78); 161 (100); 160 (48);
+
5
4
ized with the KUꢀ2 cationꢀexchange resin (H ). The solvent
1
5
31 (81); 119 (80); 105 (89); 92 (70); 82 (42); 79 (65); 69 (83);
9 (76); 55 (72). Found (%): N, 10.72. C H N O. Calcuꢀ
was removed and the residue was chromatographed on SiO to
2
give alcohol 4s (175 mg, 72%). Its 1H NMR and IR spectra
2
4
33
3
lated (%): N, 11.07.
7
are identical with those of an authentic sample.
(
S)ꢀNꢀ(5ꢀMethoxycarbonylpentꢀ2ꢀynyl)anabazine (4l). Yield
(
S)ꢀNꢀ(4ꢀHydroxyꢀ4,8ꢀdimethylnonꢀ7ꢀenꢀ2ꢀynyl)anabazine
–
1
8
4%, oil, [α]D –205.2 (c 0.91). IR, ν/cm : 2936, 1744 (COOMe),
(4t). Compound 4k (0.30 g, 1 mmol) was refluxed in a 2%
solution of EtONa in EtOH (10 mL) for 7 h and, after workꢀup,
chromatographed. The yield of alcohol 4t was 172 mg (62%). Its
1
1
592, 1580, 1436, 1208, 1172, 720. For H NMR data, see
+
+
Table 1. MS, m/z (Irel (%)): 286 [M] (17); 208 [M – C H N]
5
4
(
100); 199 (16); 161 (33); 105 (14); 92 (14); 65 (22); 55 (21).
1
H NMR and IR spectra are identical with those of an authentic
Found (%): N, 9.47. C H N O . Calculated (%): N, 9.78.
7
17
22
2
2
sample.
(
S)ꢀNꢀ(5ꢀEthoxycarbonylpentꢀ2ꢀynyl)anabazine (4m). Yield
N,N´ꢀ(5ꢀMethoxycarbonylnonaꢀ2,7ꢀdiyneꢀ1,9ꢀdiyl)diꢀ(S)ꢀ
–
1
8
1
4%, oil, [α]D –210.1 (c 0.43). IR, ν/cm : 2936, 1740, 1592,
–1
anabazine (5a). Yield 61%, oil, [α]D –232.2 (c 0.57). IR, ν/cm
1
:
1
576, 1428, 1172, 720. For H NMR data, see Table 1. MS, m/z
736, 1592, 1576, 1428, 1128, 756, 716. 1H NMR, δ: 1.28
(m, 2 H); 1.44—1.77 (m, 10 H); 2.47 (overlap, 2 H, H(6a));
.56—2.68 (br.s, 4 H, CH C≡); 2.81—2.94 (m, 5 H, H(6e), CH,
+
+
(
Irel (%)): 300 [M] (15); 255 (17); 222 [M – C H N] (100);
5 4
199 (18); 161 (38); 105 (15); 92 (15); 65 (21); 55 (20). Found (%):
2
2
N, 9.18. C H N O . Calculated (%): N, 9.33.
18
24
2
2
≡CCH N); 3.13 (d, 2 H, ≡CH N, J = 17.0 Hz); 3.29 (br.d, 2 H,
2 2
H(2), J = 12.0 Hz); 3.71 (s, 3 H, MeO); 7.35 (dd, 2 H, H(5´),
J = 7.8 Hz, J = 4.6 Hz); 7.69 (br.d, 2 H, H(4´), J = 7.8 Hz);
(
S)ꢀNꢀ(6,6ꢀEthylenedioxyꢀ4ꢀhydroxyꢀ4ꢀmethylheptꢀ2ꢀynyl)ꢀ
anabazine (4n). Yield 67%, oil, [α]D –182.7 (c 0.83). IR, ν/cm–1
:
3
480, 2936, 1600, 1584, 1432, 1380, 1216, 1044, 736, 708. For
8
.48 (br.d, 2 H, H(6´), J = 4.6 Hz); 8.51 (br.s, 2 H, H(2´)).
1
H NMR data, see Table 1. MS, m/z (I (%)): 344 [M]+ (11);
rel
Found (%): N, 10.96. C H N O . Calculated (%): N, 11.24.
31
38
4
2
+
3
02 (27); 266 [M – C H N] (27); 199 (22); 164 (21); 133 (25);
5
4
N,N´ꢀ(5,5ꢀDiethoxycarbonylnonaꢀ2,7ꢀdiyneꢀ1,9ꢀdiyl)diꢀ
S)ꢀanabazine (5b). Yield 57%, oil, [α]D –249.3 (c 0.49). IR,
1
31 (38); 122 (37); 105 (40); 101 (92); 87 (100); 82 (42); 78 (28).
(
Found (%): N, 8.02. C H N O . Calculated (%): N, 8.13.
–1
1
2
0
28
2
3
ν/cm : 1736, 1600, 1592, 1428, 1124, 716. H NMR (DMSOꢀd ,
6
(
S)ꢀNꢀ(3ꢀMethoxycarbonylpropargyl)anabazine (4o) was
3
2
00 MHz), δ: 1.09—1.84 (m, 12 H); 1.22 (br.t, 6 H); 2.50 (td,
H, H(6A), J = 11.8 Hz, J = 2.4 Hz); 2.72—3.14 (m, 10 H,
purified by repeated column chromatography. Yield ~30%,
unstable dark oil (~85% purity). IR, ν/cm : 2232 (C≡C), 1720
–
1
H(6e), CH C≡CCH ); 3.23 (br.d, 2 H, H(2), J = 12.0 Hz); 4.18
2
2

1
926
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009
Mavrov and Zlotin
(
q, 4 H, CH O); 7.20 (br.s, 2 H, H(5´)); 7.62 (d, 2 H, H(4´),
2. P. G. Cozzi, R. Hilgrof, N. Zimmermann, Eur. J. Org. Chem.,
2004, 4095; S. T. Diver, A. G. Giessert, Chem. Rev., 2004,
104, 1317; J. Muzart, Tetrahedron, 2005, 61, 9423; L. Zani,
C. Bolm, Chem. Commun., 2006, 4263; L. Hintermann,
A. Labonne, Synthesis, 2007, 1121; R. Chinchilla, C. Najera,
Chem. Rev., 2007, 107, 874.
2
J = 7.6 Hz); 8.3—8.7 (br.s, 4 H, H(2´), H(6´)). MS, m/z
Irel (%)): 584 [M]+ (7); 423 (21); 409 (14); 349 (21); 248 (42);
14 (46); 213 (42); 199 (47); 187 (33); 175 (43); 161 (100); 131
79); 119 (74); 106 (78); 92 (69); 84 (96); 59 (91); 55 (54).
Found (%): N, 9.31. C H N O . Calculated (%): N, 9.58.
(
2
(
3
5
44
4
4
(
S)ꢀNꢀ(5,5ꢀDiethoxycarbonylꢀ6ꢀhydroxyhexꢀ2ꢀynyl)anabazine
3. C. Wei, Z. Li, ChaoꢀJun Li, Synlett., 2004, 1472; G. W.
Kabalka, L. L. Zhou, L. Wang, R. M. Pagni, Tetrahedron,
2006, 62, 857.
4. M. W. Holladay, M. J. Dart, J. K. Linch, J. Med. Chem.,
1997, 40, 4169; T. Kihara, S. Shimohama, Acta Neurobiol.
Exp., 2004, 64, 99; L. F. Martin, W. R. Kem, R. Freedman,
Psychopharmacology, 2004, 174, 54.
(
6a). Yield 67%, m.p. 64—65 °C, [α] –153.0 (c 0.33). IR,
ν/cm : 1732, 1598, 1590, 1426, 1120, 716. For H NMR data,
see Table 1. MS, m/z (Irel (%)): 402 [M] (15); 324 [M – C H N]
85); 294 (29); 214 (26); 213 (60); 199 [AnbCH C≡] (27); 161
Anb] (100); 119 (20); 105 (24); 92 (29); 77 (23); 65 (45);
5 (33). Found (%): N, 6.84. C H N O . Calculated (%):
22 30 2 5
D
–
1
1
+
+
5
4
(
[
5
2
N, 6.96.
5. L. S. Bleicher, N. D. P. Cosford, A. Herbaut, J. S. McCallum,
I. A. McDonald, J. Org. Chem., 1998, 63, 1109; D. L. Comins,
E. D. Smith, Tetrahedron Lett., 2006, 47, 1449.
6. K. E. Schulte, G. Rucker, in Progress Drug Research,
Birkhauser Verlag, Basel—Stuttgart, 1970, 14, 387—563;
S. V. Anichkov, N. V. KhromovꢀBorisov, N. A. Zakharova,
S. I. Gaft, E. P. Bekhtereva, A. P. Rudenko, Khim.ꢀFarm.
Zh., 1976, 10, No. 11, 53 [Pharm. Chem. J. (Engl. Transl.),
1976, 10, 1478].
(
S)ꢀNꢀ[6ꢀAcetoxyꢀ5,5ꢀdi(ethoxycarbonyl)hexꢀ2ꢀynyl]anabazine
6b) was obtained by acetylation of alcohol 6a with acetic anhyꢀ
dride in CH Cl in the presence of DMAP and triethylamine at
(
2
2
2
0 °C for 48 h. Yield 87%, oil, [α]D –148.1 (c 0.41). IR, ν/cm–1
:
1
752, 1736, 1592, 1576, 1428, 1212, 1100, 1040, 720. For
1
H NMR data, see Table 1. MS, m/z (Irel (%)): 444 [M]+ (10);
+
4
16 (14); 367 (16); 366 [M – C H N] (100); 213 (17); 199
5
4
(
12); 161 (17); 105 (16); 77 (19); 55 (27); 43 (23). Found (%):
N, 6.36. C H N O . Calculated (%): N, 6.30.
7. M. V. Mavrov, S. G. Zlotin, Izv. Akad. Nauk, Ser. Khim.,
2007, 1576 [Russ. Chem. Bull., Int. Ed., 2007, 56, 1637].
8. A. N. Kost, V. G. Yashunskii, Dokl. Akad. Nauk SSSR, 1952,
83, 93 [Chem. Abstr., 1953, 47, 15644]; M. F Shostakovskii,
A. S. Atavin, B. A. Trofimov, N. A. Vodbol´skaya, N. K.
Gusarova, V. I. Lavrov, Dokl. Akad. Nauk SSSR, 1966, 166,
1381 [Chem. Abstr., 1966, 64, 92854].
2
4
32
2
6
(
S)ꢀNꢀ(4,8ꢀDihydroxyꢀ4,8ꢀdimethylnonꢀ2ꢀynyl)anabazine
(
7). Method A. Nitrile 4r (0.40 g) was heated at 80 °C in a 2%
solution of EtONa in EtOH (10 mL) for 7 h. The yield of
diol 7 was 0.23 g (68%), glass, R 0.45, [α] –176.4 (c 0.92).
f
D
IR, ν/cm–1: 3390 (br.s, OH), 1590, 1584, 1432, 1172, 1116,
100, 756, 516. For 1H NMR data, see Table 1. C NMR
13
1
(
4
1
CDCl ), δ: 19.7, 24.4, 25.6, 28.9, 29.3,30.2,34.9, 42.9, 43.8,
9. C. A. Buehler, D. E. Pearson, Survey of Organic Synthesis,
WileyꢀInterscience, New York, 1970; H. Pakdel, S. Sarron,
C. Roy, J. Agric. Food Chem., 2001, 49, 4337.
3
4.2, 52.9, 62.8, 67.5, 70.3, 76.2, 90.5, 123.6, 135.3, 138.9,
+
48.1, 149.0. MS, m/z (Irel (%)): 344 [M] (13); 328 (26); 312
(
1
59); 268 (53); 250 (90); 245 (58); 226 (50); 200 (66); 162 (100);
61 (31); 123 (96); 85 (86); 77 (60); 69 (50); 55 (52). Found (%):
N, 8.37. C H N O . Calculated (%): N, 8.13.
10. L. Brandsma, Preparative Acetylenic Chemistry (2nd ed.),
Amsterdam, Elsevier, 1988.
11. D. Merkel, Z. Chem., 1969, No. 2, 63.
21
32
2
2
Method D. A mixture of compound 4t (0.24 g) and 3 M HCl
12. M. V. Mavrov, E. P. Serebryakov, Izv. Akad. Nauk, Ser.
Khim., 1993, 2122 [Russ. Chem. Bull. (Engl. Transl.), 1993,
42, 2035].
13. I. N. Nazarov, G. A. Shvekhgeimer, Izv. Akad. Nauk SSSR,
Otd. Khim. Nauk, 1956, 199 [Bull. Acad. Sci. USSR, Div.
Chem. Sci. (Engl. Transl.), 1956, 5].
(
15 mL) was stirred at 20 °C for 5 h and alkalified with NH OH
4
to pH 10. The product was isolated as described above (see
method B). The yield of diol 7 was 0.15 g (60%). Its spectroꢀ
scopic characteristics are identical with those of the product
obtained according to method A.
1
4. A. R. Derzhinskii, M. V. Mavrov, V. F. Kucherov, Izv. Akad.
Nauk SSSR, Ser. Khim., 1965, 1237 [Bull. Acad. Sci. USSR,
Div. Chem. Sci. (Engl. Transl.), 1965, 14].
This work was financially supported in part by Chemical
Block Ltd. and InterBioScreen Ltd.
1
1
5. J. Colonge, R. Gelin, Bull. Soc. Chim. Fr., 1954, 208, 797.
6. M. V. Mavrov, N. K. Khao, I. M. Vol´pin, M. P. Zabokritskii,
E. P. Serebryakov, L. I. Shinyaeva, N. S. Nazarenko, V. N.
Burov, Bioorg. Khim., 1986, 12, 961 [Sov. J. Bioorg. Chem.
(Engl. Transl.), 1986].
References
1
. V. F. Kucherov, M. V. Mavrov, A. R. Derzhinskii, Prirodnye
poliatsetilenovye soedineniya [Natural Polyacetylene Comꢀ
pounds], Nauka, Moscow, 1972, 391 pp. (in Russian);
Modern Acetylenic Chemistry, Eds P. J. Stang, F. Diederich,
WileyꢀVCH, Weinheim, 1995; A. A. Semenov, Ocherk khimii
prirodnykh soedinenii [An Essay on the Chemistry of Natural
Compounds], Nauka, Novosibirsk, 2000, 664 pp. (in Russian);
K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem., Int.
Ed., 2005, 44, 4442; U. Galm, M. H. Hager, S. G. Van Lanen,
J. Ju, J. S. Thorson, B. Shen, Chem. Rev., 2005, 105, 739.
Received December 23, 2008,
in revised form April 6, 2009