Acetyl derivatives of 3-quinuclidone

Article abstract of DOI:10.1023/A:1011664807422

Methods have been developed for the synthesis of mono- and bisacetyl derivatives of 2-hydroxyarylmethylene-3-quinuclidone oximes.

Full text of DOI:10.1023/A:1011664807422

Chemistry of Heterocyclic Compounds, Vol. 37, No. 5, 2001
ACETYL DERIVATIVES
OF 3-QUINUCLIDONE
L. N. Koikov1, N. V. Alekseeva2, K. F. Turchin1, T. Ya. Filipenko1, and V. G. Granik2
Methods have been developed for the synthesis of mono- and bisacetyl derivatives of
2-hydroxyarylmethylene-3-quinuclidone oximes.
Keywords: quinuclidone oximes, NO donors, acetylation.
Certain 2-arylmethylene- and 2-arylmethyl-3-quinuclidone oximes are able to generate NO upon mild
oxidation and to stimulate soluble guanylate cyclase, i.e. the enzyme catalyzing the synthesis of cyclic
5'-guanosine monophosphate which is finally responsible for a whole series of biological effects, in particular
for vasodilation [1-3]. The aim of the given work was the preparation of the O-acetyl derivatives of
quinuclidone oximes, the large lipophilicities of which might effect their improved bioavailability and likely to
form oximes close to potential biotargets as NO donors. Since the greatest NO donor in vitro activity is found in
oximes with ortho-hydroxyphenyl substituents, our basic attention was focused on the synthesis of those
derivatives formed by acetylation at the oxime or phenol groups or, indeed, at both.
OAc
N
OAc
N
+
Ar
O
N
N
Ar
5a,b
6c
N
1c
AcCl
Et3N
H2O
Ac2O
ArCHO
NaOH
.
H2NOH HCl
Ac2O
O
OH
N
OH
N
N OH
.
H2NOH HCl
+
+
Ar
N
N
N
N
Ar
Ar
Ar
4b,c
1a,b
2a–c
3a–c
1–6 a Ar = Ph, b Ar = 2-HOC6H4 , c Ar = 2-AcOC6H4
__________________________________________________________________________________________
1
Center for Medicinal Chemistry, All-Russian Chemical-Pharmaceutical Institute, Moscow 119815.
2 Russian Federation State Scientific Center, Science Research Institute for Intermediate Products and Dyestuffs
(NIOPIK), Moscow 103787; e-mail: makar-cl@ropnet.ru. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 5, pp. 668-672, May, 2001. Original article submitted May 20, 1999.
0009-3122/01/3705-0615$25.00©2001 Plenum Publishing Corporation
615

TABLE 1. Characteristics of Compounds Synthesized
Found, %
——————
Com-
pound
Empirical
formula
Yield,
%
mp, °C
Rf*
0.95
Calculated, %
С
H
N
C16H17NO3
71.1
70.8
6.4
6.3
4.9
5.2
234-238
(dec.),
87
58
5
1c
i-PrOH
2/3c·HCl
4c·HCl
5a·HCl
C16H18N2O3·HCl·
0.25H2O
58.5
58.7
5.9
6.0
8.6
8.6
165-168
0.8/0.6
0.47
(dec.),
i-PrOH
C16H18N2O3·HCl
—
—
—
206
(dec.),
i-PrOH
C16H18N2O2·HCl
61.6
61.8
6.3
6.3
8.8
8.8
145-147
0.95
60
(dec.),
i-PrOH
5b·HCl
6c·HCl
C16H18N2O3·HCl
C18H20N2O4··HCl
—
—
—
75-76,
0.88
0.63
73
72
i-PrOH
59.3
59.3
6.2
5.9
7.6
7.7
164
(dec.),
i-PrOH
_______
* CHCl3–MeOH, 50 : 3
Reaction of the oxime 2a with acetic anhydride occurs readily at room temperature and, while the
Z-configuration of the phenylmethylene fragment in 5a is retained, the anti-hydroxy group is converted to a
syn-acetoxy group. Under analogous conditions, the oxime 4b forms the diacetyl derivative 6c with retention of
configuration both for the E-2-hydroxyphenylmethylene and the syn-acetoxyimino fragments. Of the two
1
acetoxy groups in 6c it is the N-acetoxyimino which is more readily hydrolyzed since the H NMR spectrum
shows the presence of 4c in the reaction mass (Table 2).
Acetylation of the mixture 2/3b using acetyl chloride in the presence of triethylamine at -20°C gives
only the N-acetoxyimino compound 5b in high yield. Moreover, similarly to 2a, a mixture of the syn-anti-
oximes gives only the syn-acetoxime 5b and this is likely due to the larger steric demand of the acetoxy when
compared with the hydroxy group. In the absence of triethylamine, the HCl formed hydrolyses the acetyl
derivative 5b and pure 3b is obtained in 78% yield from the reaction mixture. Hence acetylation of a mixture of
syn-anti-oximes and subsequent hydrolysis of the acetoxy derivatives may attract interest as a method for the
preparation of pure syn-oximes.
The isomeric acetoxyphenyl derivative 2/3c was prepared by the reaction of the acetylated ketone 1c
with NH2OH·HCl. According to 1H NMR spectroscopic data, the reaction mixture contains 2/3c in the ration 9:1
and heating increases the content of 3c. In the prepared crystalline sample the ration of isomers 2/3c·HCl is 2:1.
1
The structure of the acetylated ketones and oximes was proved on the basis of their H and 13C NMR
spectra (Tables 2 and 3). Comparison of the chemical shifts of analogous protons in the ketones 1b and 1c has
shown that acetylation of the phenolic hydroxyl leads to a marked low field shift of the signals for the meta
13
protons and that this is true for both the Z- and E-isomers. In the C NMR spectra, acetylation of the phenolic
hydroxyl leads to a low field shift of 6-7 ppm for the Cm,p signals and a high field shift for the Co signal.
Acetylation of the oxime group causes a shift of 7-9 ppm to low field for the C(3) signals and of 4-5 ppm for the
C(9) signals. Its effect on the chemical shifts of protons is ambiguous.
616

TABLE 2. 1H NMR Chemical Shifts for the Compounds Synthesized, δ, ppm
Compound
Solvent
4Н*
5,8-CH2
6, 7-CH2
9-H
3'-H
4'-H
5'-H
6'-H
OAc
CDCl3–CD3OD, 1:3
DMSO-d6–D2O, 1:1
DMSO-d6–D2O, 1:1
CD3OD
DMSO-d6–D2O, 10:1
DMSO-d6
2.56
2.93
3.71
3.90
3.70
3.66
3.89
1.95-2.10
1.85-2.05
1.85-2.05
1.90-2.10
1.84, 2.03
1.82, 1.99
2.05-2.25
2.95, 3.19
3.30-3.45
3.30-3.45
3.47, 3.64
3.31, 3.45
3.19, 3.42
3.61, 3.78
7.07 (s)
8.12 (s)
7.10 (s)
7.09 (s)
7.47 (s)
7.21 (s)
7.33 (s)
7.10
7.20
7.17
7.07
7.39
7.48
7.46
7.33
7.26
7.30
7.32
7.17
8.56
7.40
7.35
8.01
2.35 (s)
2.18 (s)
2.20 (s)
2.29 (s)
2.17 (s)
2.20 (s)
2.04 (s)
2.36 (s)
1c
2c·HCl
3c·HCl
4c·HCl
5a·HCl
5b·HCl
6c·HCl
7.40-7.60
6.90
7.19
7.26
7.47
6.80
7.31
7.35
8.17
CD3OD
_______
* The 4H signal is a quintet; the remaining signals are multiplets unless indicated otherwise in the brackets.
TABLE 3. 13C NMR Shifts for the Compounds Synthesized, δ, ppm
Compound
Solvent
C(2)
C(3)
C(4)
C(5), C(8)
C(6), C(7)
C(9)
C(1')
C(2')
C(3')
C(4')
C(5')
C(6')
4с·HCl*3
5b·HCl*4
6c·HCl*5
CD3OD
DMSO-d6
CD3OD
135.5
131.6
133.3
151.8
162.7
159.4
24.5
25.6
27.2
22.3
22.0
21.8
51.3
48.4
51.1
120.9
122.0
126.7
126.3
118.7
125.7
150.5
157.0
150.3
123.3*2
117.4*2
123.4*2
131.8*
132.0*
132.3*
126.4*2
118.7*2
126.9*2
132.0*
134.0*
132.7*
_______
*,*2 Possible reversed signal assignments are marked equally.
*3 MeCOO: 21.1, MeCOO: 170.7.
*4 MeCOO: 19.6, MeCOO: 168.1.
*5 MeCOO 19.5 and 21.1, MeCOO: 171.0 and 171.1.

In connection with the ease of deacetylation in basic medium we did not study the oxidation of the
acetylated oximes 4c, 5a,b, 6c by K3[Fe(CN)6]; this method having been developed for the rapid testing of the
ability of a compound to generate NO [2], In experiments in vivo their effect on arterial pressure did not exceed
those of oxime analogs [1, 2] and this may be linked to the kinetics of their conversion to NO.
EXPERIMENTAL
NMR spectra were taken on a Varian Unity Plus 400 instrument working at 400 MHz for protons and
100 MHz for carbon and mass spectra were recorded on a Finnigan MAT SSQ 710 instrument. TLC was carried
out on Silufol UV-254 plates with visualization in UV light and using the Dragendorff reagent. The
characteristics of the compounds obtained are given in Table 1.
Z-2-(2'-Acetoxyphenyl)methylene-3-quinuclidone
(1c).
Z-2-(2'-Hydroxyphenyl)methylene-3-
quinuclidone 1b (8.7 mmol) [2] and freshly distilled acetic anhydride (20 ml) were heated for 8 h at 100°C until
TLC showed the disappearance of the starting ketone and the acetic anhydride was distilled off in vacuo. The
residue was basified using K2CO3 solution, extracted with chloroform (3 × 40 ml), the extracts dried with
K2CO3, chloroform distilled off, and the residue was crystallized from 2-propanol.
Hydrochlorides of Z-2-(2'-Acetoxyphenyl)methylene-3-quinuclidone anti- and syn-Oxime
(2/3c·HCl). A mixture of ketone 1c (1.8 mmol) and NH2OH·HCl (2 mmol) in MeOH was allowed to stand for
2 days at room temperature. Evaporation of the clear solution and crystallization of the residue from 2-propanol
gave 2/3c·HCl in the ratio 2 : 1.
syn-3-N-Acetoxyimino-Z-phenylmethylene-3-quinuclidone (5a). The oxime 3a (6.5 mmol) [2] in
freshly distilled acetic anhydride (20 ml) was allowed to stand overnight at room temperature. The excess
anhydride was distilled off on a rotary evaporator, and the mixture was basified using K2CO3 solution, extracted
with chloroform (3 × 30 ml), the extracts dried with K2CO3, and the chloroform distilled off. The residue was
dissolved in 2-propanol (15 ml), HCl solution in anhydrous ether was added (6.5 mmol), and the precipitated
solid was filtered off.
syn-3-N-Acetoxyimino-Z-2-(2'-hydroxyphenyl)methylene-3-quinuclidone (5b). A solution of AcCl
(5.7 mmol) in CH2Cl2 (2 ml) was added dropwise with stirring to a solution of the mixture of bases 2/3b
(5.7 mmol) and Et3N (5.7 mmol) in anhydrous CH2Cl2 (40 ml) at -20°C. The product was held at -20°C for 1 h
and then left overnight at room temperature. Water (20 ml) was added and then a solution of NaHCO3 to pH 10
and the product was extracted with CH2Cl2 (3 × 30 ml) and the extracts dried with K2CO3. The solvent was
distilled off and the residue was dissolved in 2-propanol and then converted to the hydrochloride by addition of
a solution of HCl in anhydrous ether (5.1 mmol, 90% of that calculated).
E-2-(2'-Hydroxyphenyl)methylene-3-quinuclidone oxime (4b). A suspension of 4b·HCl (10 mmol)
[2] was stirred for 15 min with water (10 ml), MeOH (15 ml), and K2CO3 (11 mmol) and then subjected to
continuous extraction with refluxing chloroform until the solid phase had disappeared. Evaporation of the
chloroform gave 4b (2.5 g); mp 208-210°C.
syn-3-N-Acetoxyimino-E-2-(2-acetoxyphenyl)methylene-3-quinuclidone Hydrochloride (6c·HCl)
and E-2-(2'-acetoxyphenyl)methylene-3-quinuclidone syn-Oxime Hydrochloride (4c·HCl). A suspension of
4b (7.2 mmol) and acetic anhydride (30 ml) was stirred at room temperature until dissolved (4 days). The
reaction mass was decomposed using a saturated K2CO3 solution, extracted with chloroform (3 × 60 ml), the
extracts dried with K2CO3, and the chloroform distilled off. The residue was refluxed in 2-propanol (15 ml) with
activated carbon (0.1 g) for 30 min, filtered, and a solution of HCl in dry ether (6.5 mmol, 90% of that
calculated) was added to the cooled filtrate. The precipitated 6c·HCl was separated. When the filtrate was
evaporated to 5 ml, 4c·HCl (20 mg) was obtained after a week. M+ 286.
This work was supported by grant 96-04-48325 from the Russian fund for Basic Research.
618

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619