Chemical modification of plant alkaloids. 5. Spirocyclic systems based on cotarnine and barbituric acids

Article abstract of DOI:10.1007/s10600-008-0013-0

Cotarnine was reacted with barbituric acid and its N-alkylbartituric and 1,3-dimethyl-2-thio analogs under forcing conditions to produce spirocyclic systems. Adducts, further transformations of which included skeletal rearrangements (a type of T-reaction) and subsequent deamination, were formed in the first step. The reaction of N-methylcotarnine and 1,3-dimethylbarbituric acid was analogous. The properties of the spirocyclic products were studied. They were further modified at the CH-acid and aromatic moieties.

Full text of DOI:10.1007/s10600-008-0013-0

Chemistry of Natural Compounds, Vol. 44, No. 1, 2008
CHEMICAL MODIFICATION OF PLANT ALKALOIDS.
5. SPIROCYCLIC SYSTEMS BASED ON COTARNINE
AND BARBITURIC ACIDS
K. A. Krasnov,1 V. G. Kartsev,2 and V. N. Khrustalev3
UDC 547.854+547.689.6+547.833.3
N
Cotarnine was reacted with barbituric acid and its -alkylbartituric and 1,3-dimethyl-2-thio analogs under
forcing conditions to produce spirocyclic systems. Adducts, further transformations of which included
skeletal rearrangements (a type of T-reaction) and subsequent deamination, were formed in the first step.
N
The reaction of -methylcotarnine and 1,3-dimethylbarbituric acid was analogous. The properties of the
spirocyclic products were studied. They were further modified at the CH-acid and aromatic moieties.
Key words: reaction of cotarnine with barbituric acid, spirocyclic products.
Cotarnine (1) is a biogenesis product of plants from the families Papaveraceae and Ranunculaceae. For example, it
is one of the main alkaloids from
agent [2].
[1]. Cotarnine hydrochloride is used in medicine as a hemostatic
P. pseudoorientale
The chemical properties and reactions of pseudobase 1 have been reviewed [3]. Many tetrahydroisoquinoline and
phenylethylamine derivatives of 1 have been prepared, including alkaloids and their analogs.
We were interested in the transformation of cotarnine by1,3-dimethylbarbituric acid (2a), which gave a Zwitter-ionic
adduct (3a) and then formed 1,3-dimethyl-2,4,6-trioxoperhydropyrimidin-5-spiro-6′-[4′-methoxy-7′-(1,3-dimethyl-2,4,6-
trioxoperhydropyrimidin-5-yl)-5′,6′,7′,8′-tetrahydro[1,3]-dioxolo[4,5- ]naphthalene (4a) [4]. The x-ray structure of 4a and a
g
hypothetical scheme of its formation have been discussed [5].
The goal of our work was to study similar reactions of cotarnine and the synthesis of new analogs of 4a.
We found that the reaction of 1 with barbituric acids 2a-e under forcing conditions (150-160°C) formed spirocyclic
products 4a-e. The reactions occurred through intermediate adducts 3a-e, which were identified in the reaction mixtures by
TLC and PMR. Pure standard 3a-e were prepared as before [6]. In separate experiments, we showed that adding pure 3a-e to
the reaction (Scheme 1) gave the same final products 4a-e in comparable yields (Table 1).
Thus, adducts 3a-e acted as precursors for further spirocyclization that probably occurred as two combined reactions.
In the first step, 3a-e (relatively slowly) isomerized through 5 and 6 into intermediate amino derivatives 7. In the second step,
these intermediates (7) (rapidly) were deaminated by the starting CH-acids 2a-e and converted into final products 4a-e.
It was noted earlier that using triethylamine as the catalyst increased the yield of 4a [5]. An analogous trend was
observed for the reaction of 1 with 1,3-diethylbarbituric acid (2b), which produced 4b. The yields of 4a and 4b under
corresponding conditions were almost the same (Table 1). This indicated that the 1,3-dimethyl- and 1,3-diethyl-2,4,6-
trioxopyrimidine moieties had almost the same reactivity in these conversions.
The reaction of 1 with unsubstituted barbituric acid (2c) was slightlymore difficult. Adduct 3c precipitated during the
reaction and reacted more slowly (25 min) owing to the low solubility than its , -dialkyl derivatives 3a and 3b (8 min).
N N
Product 4c was obtained in up to 13% yield. The reason for this was probably the reduced reactivity of intermediate 3c and the
instabilityof final product 4c to hydrolysis and aminolysis side reactions. It is known that substituents on the N atoms increases
markedly the hydrolytic stability of barbiturates [7].
1) ZAO Interbioscreen, 142432, Chernogolovka, Moscow District, Institutskii pr., 8; 2) A. N. Nesmeyanov Institute
of Organoelement Compounds, Russian Academy of Sciences, 119991, Moscow, ul. Vavilova, 28, fax (095) 135 50 85, e-mail:
vkh@xrlab.ineos.ac.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 38-42, January-February, 2008. Original
article submitted July 11, 2005.
0009-3130/08/4401-0048 ©2008 Springer Science+Business Media, Inc.
48

4a e
1
3a e
TABLE 1. Yield of Spirocyclic Derivatives - from Reactions of Cotarnine ( ) or Adducts - with Acids
2a e
-
Starting material (ratio, mol)
Catalyst
Product
Yield, %
1 + 2a
1 + 2a
3a + 2a
1 + 2b
1 + 2b
3b + 2b
1 + 2c
3c + 2c
1 + 2d
1 + 2e
4a
4a
4a
4b
4b
4b
4c
4c
4d
4e
-
29
44
47
25
43
44
13
10
19
9
NEt3
NEt3
-
NEt3
NEt3
-
-
-
-
CH
O
O
3
O
O
N
O
O
O
+
N
R
CH
3
CH
CH
3
N
+
2a
CH
3
N
H
CH
3
O
H C
O
−
H O
2
_
3
O
OH
H C
3
-H O
2
O
O
O
O
H C
3
O
O
1
_
_
H C
3
3
N
N
8a
8b
O
O
R
R
1
R
2
X
N
N
3a-e, 9
2
R
1
X
2a - e
X
R
1
R
2
R
R
R
N
N
N
O
O
N
N
O
O
CH
3
CH
CH
3
+
3
O
O
R
O
O
O
R
O
O
O
2
2a - e
N
O
O
O
O
N
2
H C
3
H C
3
N
-MeNH
2
O
O
_
O
O
N
R
X
H C
3
N
N
N
O
O
N
R
X
R
1
R
2
R
1
H C
3
1
R
2
X
1
X
7, 12
4a-e
5, 10
6, 11
3a - e, 5, 6:
9 - 12:
R = H;
R = R1 = R2 = CH3
a:
b:
c:
d:
e:
R1 = R2 = Me, X = O; R1 = R2 = Et, X = O; R1 = R2 = H, X = O; R1 = Me, R2 = H, X = O, R1 = R2 = Me, X = S
Scheme 1.
4c
In a separate experiment it was shown that
was converted by 50% in 10 min under the reaction conditions whereas its
lost only 2% under these same conditions. Adding triethylamine to the reaction mixture increased even further
4c
4a
derivative
the rate of loss of
The reaction of with 1-methylbarbituric acid ( ) gave in 19% yield (Table 1). The reaction was also complicated
by hydrolytic reactions.
.
1
2d
4d
2e
3e
The reaction with 1,3-dimethyl-2-thiobarbituric acid ( ) went worst of all. Adduct was obtained quantitatively in
the first step. However, it was converted further slowly and nonspecifically, with release of volatile sulfur compounds as side
4e
products. This feature and the low yield of spirocyclic thiobarbiturate indicated that the thioamide was unstable under the
reaction conditions.
We studied the analogous reaction with N-methylcotarnine, a tautomeric system containing about 60% of the cyclic
8a
8b
(see Experimental), as an example of a new substrate.
Zwitter-ionic form
and up to 40% of the acyclic aldehyde form
2a
4a
Under the standard forcing conditions, the reaction with an excess of acid gave the expected known spirocyclic product
9
10
(16%), the contents of which were estimated from PMR spectra using the
(Scheme 1). Labile compounds (26%) and
49

characteristic resonances of the NCH and vinyl protons, were observed in the intermediate step in the product mixture at 20°C.
Compound 9 gave the set of resonances (CDCl , δ, ppm) 3.16 (2H, t, ArCH ), 3.23 (6H, s, 2NMe′), 3.39 (6H, s, NMe ′), 3.82
3
2
2
(3H, s, OMe), 3.94 (2H, t, NCH ), 5.42 (1H, s, NCH), 6.05 (2H, s, OCH O), 6.47 (1H, s, ArH) whereas the acyclic isomer 10
2
2
gave 2.91 (6H, s, NMe ′), 3.00 (2H, t, ArCH ), 3.17 (2H, t, NCH ), 3.33 (6H, s, 2NMe), 3.86 (3H, s, OMe), 5.76 (2H, s,
2
2
2
OCH O), 6.74 (1H, s, ArH), 8.21 (1H, s, =CH). Derivative 10 was an analog of intermediates 5 (Scheme 1) that could not be
2
recorded earlier.
The observation of tautomeric intermediate10 had fundamental significance for understanding the overall mechanism
of such processes, primarily the hydrogen transfer mechanism from the NCH group to C(1). (Such transfer is improbable in
2
cyclic 9.)
-
We propose that H transfer in 10 produced Zwitter-ion 11, which cyclized into the spirocyclic intermediate 12. Such
a rearrangement is very similar to the T-reaction of 5-(o-dialkylaminobenzylidene)barbituric acids (13) that isomerize into
spirocyclic derivatives 14 (Scheme 2) [8, 9].
X
+
N
Z
N
X
Z
X
N
N
Z
H
H
O
O
R
O
O
R
O
R
_
O
N R
O
N
N
N
R
N
R
O
O
13
14
Scheme 2.
Cyclizations initiated by hydride loss from a NCH group have been reviewed [10]. This type of conversion is known
2
in heterocyclic chemistry as the tert-amino effect although such processes have not been described for the chemistry of natural
compounds. The process shown in Scheme 1 is outside the scope of existing concepts of the tert-amino effect. The principle
of the tert-amino effect did not include the possible formation of a ring without a N heteroatom whereas the isomerization of
derivative 10 results in the closing of the carbocyclic system. The T-reaction of cotarnine adducts 3a-e (Scheme 1) is even more
unusual because the substrates, intermediates 5, contain a secondaryamino group whereas the tert-amino effect was known only
for tertiary amines (anilines).
Considering these features, the rearrangement of the cotarnine and N-methylcotarnine adducts in Scheme 1 can be
classified as a new type of T-reaction.
The properties and structures of spirocyclic derivatives 4a-e are also interesting. These compounds are unexpectedly
strong CH-acids. In particular, a pKa value of 1.10 was obtained for 4a byspectrophotometry. This is 3.5 orders of magnitude
greater than 1,3-dimethylbarbituric acid 2a (pKa 4.65 [11]).
The chemical properties of spirocyclic CH-acids 4a-e enable them to be used for further expansion of the range of this
type of derivatives. For this, we carried out several reactions of 4a with electrophilic reagents and prepared derivatives 15-21.
H C
3
O
N
O
N
CH
3
R
2
R
1
O
O
O
O
CH
3
N
O
O
N
O
H C
3
CH
3
15 - 21
15: R1 = Br, R2 = H; 16: R1 = R2 = Br; 17: R1 = H, R2 = Me
18: R1 = H, R2 = CH2CH=CH2; 19: R1 = H, R2 = CH2OH
20: R1 = H, R2 = CH2NMe2; 21: R1 = H, R2 = CH2CH2(4-Py)
50

The electrophile was readily incorporated into the aromatic ring upon bromination of 4a. The reaction of 4a with an
equivalent amount of Br in acetic acid gave derivative 15; with two equivalents of Br , dibromo derivative 16.
2
2
In other examples, 4a reacted with electrophilic reagents to form only the substitution products at the CH-acid atom
C(5). Alkylation with methyliodide or allylbromide in the presence of triethylamine in CHCl gave the corresponding alkyl
3
derivatives 17 and 18 in moderate yield. The dimethylammonium salt of acid 4a reacted with formaldehyde in water to form
Mannich base 19. For the trimethylammonium salt, hydroxymethyl derivative 20 was obtained. Addition of 4a to
4-vinylpyridine in acetic acid gave Michael adduct 21 in practically quantitative yield.
Thus, it was demonstrated that CH-acid 4a undergoes reactions characteristic of 5-monosubstituted barbituric acids
[7]. This can be used to modify this interesting system.
In conclusion, we note again that we managed not onlytoopen a newdirection for modifying cotarnine but alsotoshow
that the tert-amino effect and T-reactions are possible in principle for natural compounds.
EXPERIMENTAL
PMR spectra were recorded on a Bruker AM-500 spectrometer at operating frequency 500 MHz; mass spectra, in an
MX-1303 instrument with direct sample introduction into the ion source at 150°C and ionizing potential 70 eV. The purity of
the products was monitored byTLC on Silufol UV-254 plates (CHCl :EtOAc, 5:1, or CHCl :EtOAc:CH CO H, 4:2:0.1), PMR
3
3
3
2
spectra, and elemental analyses. Table 1 gives the yields for 4a-c.
4-Methoxy-6-methyl-5,6,7,8-tetrahydro-2H-1,3-methylenedioxy[4,5-g]isoquinolin-5-ol(cotarnine)(1)was isolated
from cotarnine hydrochloride by the literature method [8].
1,3-Dimethyl-2,4,6-trioxoperhydropyrimidine-5-spiro-6′-{4′-methoxy-7′-(1,3-dimethyl-2,4,6-
trioxoperhydropyrimidin-5-yl)-5′,6′,7′,8′-tetrahydro[1,3]dioxolo[4,5-g]naphthalene} (4a). A solution of 2a (4.68 g,
0.03 mol) in dimethylacetamide (15 mL) was stirred at 50°C, treated with cotarnine (1, 2.38 g, 0.01 mol) and triethylamine
(1.01 g, 0.01 mol), refluxed at 155°C for 5 min, cooled, and treated with aqueous ammonia (5%, 50 mL). The precipitate was
filtered off and washed with ammonia. The combined filtrate was acidified with conc. HCl. The resulting precipitate was
separated and washed with water. The crude product was transferred to a flask, washed at 70°C with a mixture of ethanol
(25 mL) and water (75 mL), and cooled. The precipitate was filtered offand washed with ethanol to afford 4a (2.20 g), colorless
13
crystals, mp 238-239°C (ethanol) (lit. [5] mp 234-235°C, CCl ). The PMR, C NMR, and mass spectra have been
4
published [5].
Compound 4a was prepared analogously from N-methylcotarnine (8, see below) and acid 2a, yield 27%.
1,3-Diethyl-2,4,6-trioxoperhydropyrimidine-5-spiro-6′-{4′-methoxy-7′-(1,3-diethyl-2,4,6-
trioxoperhydropyrimidin-5-yl)-5′,6′,7′,8′-tetrahydro[1,3]dioxolo[4,5-g]naphthalene} (4b) was prepared analogouslyto the
aforementioned method from 1 and 2b. Colorless crystals, C H N O , mp 188-190°C (ethanol).
27 32
4 9
PMR spectrum (CDCl , δ, ppm, J/Hz): 1.12 (3H, t, J = 7.1, CH ), 1.17 (3H, t, J = 7.1, CH ), 1.24 (6H, m, 2CH ′), 2.69
3
3
3
3
1
1
+ 3.36 (1H each, dd, ab-system, J = 15.5, 2H-8), 2.86 + 3.16 (1H each, d, J = 16.6, 2H-5), 3.50 (1H, m, J = 5.9, H-7), 3.78
(4H, m, J = 7.1, 2NCH ), 3.85 (1H, d, J = 5.9, H-15), 3.91 (3H, s, OCH ), 4.02 (4H, m, 2NCH ), 5.81 + 5.85 (1H each, d,
2
3
2
+
ab-system, J = 1.5, OCH O), 6.24 (1H, s, ArH). Mass spectrum (m/z, I, %): 557 (5) [M] , 542 (8), 528 (3), 372 (100), 357 (17),
2
287 (4), 257 (11), 185 (6), 170 (5).
2,4,6-Trioxoperhydropyrimidine-5-spiro-6′-{4′-methoxy-7′-(2,4,6-trioxoperhydropyrimidin-5-yl)-5′,6′,7′,8′-
tetrahydro[1,3]dioxolo[4,5-g]naphthalene} (4c). Acid 2c (3.84 g, 0.03 mol) was dissolved in dimethylacetamide (25 mL),
treated at 50°C with 1 (2.38 g, 0.01 mol), stirred for 5 min to produce a suspension of adduct 3c, heated to 150°C, stirred at this
temperature for 20 min, cooled to 20°C, and treated with aqueous ammonia (2%, 75 mL). The resulting precipitate was
separated, treated with HCl (20%, 20 mL), washed with water, and extracted again with aqueous ammonia (3%, 20 mL). The
combined aqueous ammonia solution was acidified with AcOHand left for 30 min. The precipitate was separated. The solution
was acidified with conc. HCl (20 mL) and left for 3 h at 10°C. The resulting crystals were filtered off, washed with water, and
recrystallized from aqueous ethanol (50%) to afford 4c (580 mg), colorless crystals, C H N O , mp 340-342°C.
19 16
4 9
PMR spectrum (DMSO-d , δ, ppm, J/Hz): 2.67 + 3.30 (1Heach, dd, ab-system, J = 14.2, 2H-8), 2.81 + 3.17 (1H each,
6
1
d, J = 16.4, 2H-5), 3.50 (1H, m, J = 5.9, H-7), 3.91 (3H, s, OCH ), 3.93 (1H, d, J = 5.9, H-15), 5.85 + 5.86 (1H each, d,
1
3
51

ab-system, J = 1.5, OCH O), 6.32 (1H, s, ArH), 10.86 (1H, br.s, NH), 11.32 (2H, br.s, 2NH), 11.35 (1H, br.s, NH).
2
+
Mass- spectrum (m/z, I, %): 444 (9) [M] , 316 (100), 287 (13), 273 (3), 231 (15), 205 (23), 127 (11).
The following compounds were prepared analogously from 1 and the appropriate acids 2d and 2e.
1-Methyl-2,4,6-trioxoperhydropyrimidine-5-spiro-6′-{4′-methoxy-7′-(1-methyl-2,4,6-trioxoperhydropyrimidin-5-
yl)-5′,6′,7′,8′-tetrahydro[1,3]dioxolo[4,5-g]naphthalene} (4d). A mixture of four diastereomers, colorless crystals,
C H N O , mp 235-245°C (aqueous ethanol).
19 16
4 9
PMR spectrum of the main diastereomer (CDCl , δ, ppm, J/Hz): 2.63 + 3.28 (1H each, dd, ab-system, J = 15.4, 2H-8),
3
1
2.90 + 3.16 (1H each, d, J = 17.2, 2H-5), 3.32 (3H, s, NCH ), 3.37 (3H, s, NCH ), 3.55 (1H, m, J = 6.3, H-7), 3.81 (1H, d,
3
3
1
J = 6.3, H-15), 3.94 (3H, s, OCH ), 5.81-5.85 (1H each, d, ab-system, J = 1.5, OCH O), 6.27 (1H, s, ArH), 9.42 (1H, br.s, NH),
3
2
+
9.94 (1H, br.s, NH). Mass spectrum (m/z, I, %): 472 (9) [M] , 330 (100), 313 (17), 302 (2), 273 (3), 259 (5), 244 (6), 229 (11),
189 (2), 127 (5).
1,3-Dimethyl-2-thioxo-4,6-dioxoperhydropyrimidine-5-spiro-6′-{4′-methoxy-7′-(1,3-dimethyl-2-thioxo-4,6-
dioxoperhydropyrimidin-5-yl)-5′,6′,7′,8′-tetrahydro[1,3]dioxolo[4,5-g]naphthalene (4e), light-yellow crystals,
C H N O S , mp 155-169°C (aqueous ethanol).
23 24
4 7 2
PMR spectrum (CDCl , δ, ppm, J/Hz): 2.60 + 3.43 (1H each, m, ab-system, 2H-8), 2.71 + 3.22 (1H each, d, J = 17.1,
3
2H-5), 3.54 (1H, m, H-7), 3.57 (3H, s, NCH ), 3.58 (3H, s, NCH ), 3.63 (3H, s, NCH ), 3.75 (3H, s, NCH ), 3.87 (1H, d,
3
3
3
3
J = 6.9, H-15), 3.92 (3H, s, OCH ), 5.82 + 5.865 (1H each, d, ab-system, J = 1.5, OCH O), 6.30 (1H, s, ArH). Mass spectrum
3
2
+
(m/z, I, %): 532 (20) [M] , 488 (3), 360 (100), 303 (16), 259 (33), 229 (25), 189 (5), 172 (40), 157 (19).
N-Methylcotarnine (8). Cotarnine (1, 2.38 g, 0.01 mol) was dissolved in CHCl (15 mL), treated with freshlydistilled
3
methyliodide (2.84 g, 0.02 mol), and left for 1 d at 20°C. The solvent was evaporated in vacuo. The crystalline solid was
washed with ether and dried in vacuo. The product was dissolved in water (20 mL). The insoluble solid was filtered off. The
filtrate was made basic with NaOH (0.5 g). The basic aqueous solution was extracted with CH Cl (2 × 25 mL). The combined
2
2
extracts were washed with water, dried over Na SO , and evaporated in vacuo to dryness to afford 8 (1.9 g, 77%), light-yellow
2
4
crystals, C H NO , mp 154-156°C, a tautomeric mixture of 8a and 8b.
13 17
4
PMR spectrum (CDCl , δ, ppm): 8a (60%) 3.37 (2H, m, CH Ar), 3.50 [6H, s, +N(CH ) ], 3.70 (2H, m, NCH ), 4.03
3
2
3 2
2
(3H, s, OCH ), 5.41 (1H, s, NCH), 5.87 (2H, s, OCH O), 6.31 (1H, s, ArH); 8b (40%) 2.48 [6H, s, N(CH ) ], 2.87 (2H, m,
3
2
3 2
NCH ), 3.05 (2H, m, CH Ar), 4.11 (3H, s, OCH ), 6.04 (2H, s, OCH O), 6.89 (1H, s, ArH), 10.32 (1H, s, CHO).
2
2
3
2
1,3-Dimethyl-2,4,6-trioxoperhydropyrimidine-5-spiro-6′-{4′-methoxy-7′-(1,3-dimethyl-2,4,6-
trioxoperhydropyrimidin-5-yl)-8′-bromo-5′,6′,7′,8′-tetrahydro[1,3]dioxolo[4,5-g]naphthalene} (15). Compound 4a
(0.50 g, 0.001 mol) was dissolved in glacial acetic acid (25 mL), treated at 10°C over 10 min dropwise with bromine (0.16 g,
0.001 mol) in glacial acetic acid (5 mL), stirred for another 10 min, and diluted with water (70 mL). The resulting precipitate
was separated, washed with water, and treated with aqueous ammonia (2%, 40 mL). The insoluble solid was separated. The
aqueous ammonia solution was acidified with conc. HCl. The resulting crystals were filtered off, washed with water, and dried
in air to afford 15 (0.44 g, 76%), colorless crystals, C H BrN O , mp 160-161°C (ethanol).
23 23
4 9
PMR spectrum (CDCl , δ, ppm, J/Hz): 2.82 + 3.15 (1H each, dd, ab-system, J = 15.6, 2H-8), 2.87 + 3.25 (1H each,
3
1
d, ab-system, J = 16.8, 2H-5), 3.18 (3H, s, NCH ), 3.21 (3H, s, NCH ), 3.33 (3H, s, NCH ), 3.39 (3H, s, NCH ), 3.49 (1H, m,
3
3
3
3
1
J = 6.0, H-7), 3.83 (1H, d, J = 6.0, H-15), 3.92 (3H, s, OCH ), 5.92 + 5.95 (1H each, d, ab-system, J = 1.5, OCH O), 6.42 (1H,
3
2
s, ArH).
1,3-Dimethyl-2,4,6-trioxoperhydropyrimidine-5-spiro-6′-{4′-methoxy-7′-(1,3-dimethyl-5-bromo-2,4,6-
trioxoperhydropyrimidin-5-yl)-8′-bromo-5′,6′,7′,8′-tetrahydro[1,3]dioxolo[4,5-g]naphthalene} (16). A solution of 4a
(0.50 g, 0.001 mol) in glacial acetic acid (25 mL) was treated at 10°C over 10 min dropwise with bromine (0.32 g, 0.002 mol)
in glacial acetic acid (5 mL), left for 40 min at room temperature, treated with water (several mL) until cloudy, and left at 10°C.
The resulting crystals were separated; washed with water, aqueous ammonia (1%), and methanol; and dried in air to afford 16
(0.54 g, 82%), colorless crystals, C H Br N O , mp 230°C (dec., MeOH:AcOH).
23 22
2 4 9
PMR spectrum (CDCl , δ, ppm, J/Hz): 2.79 + 3.31 (1H each, d, ab-system, J = 16.1, 2H-5), 3.18 (3H, s, NCH ), 3.22
3
3
1
(3H, s, NCH ), 3.25 (3H, s, NCH ), 3.38 (3H, s, NCH ), 3.70 (2H, m, J = 9.0, 2H-8), 3.87 (3H, s, OCH ), 3.91 (1H, dd,
J = 7.5, H-7), 5.98 (2H, s, OCH O).
3
3
3
3
1
2
1,3-Dimethyl-2,4,6-trioxoperhydropyrimidine-5-spiro-6′-{4′-methoxy-7′-(1,3,5-trimethyl-2,4,6-
trioxoperhydropyrimidin-5-yl)-5′,6′,7′,8′-tetrahydro[1,3]dioxolo[4,5-g]naphthalene} (17). A solution of 4a (0.50 g,
0.001 mol) in CHCl (5 mL) was treated with freshly distilled triethylamine (0.101 g, 0.001 mol) and then methyliodide
3
52

(0.284 g, 0.002 mol), left for 3 d at room temperature, treated with CHCl (15 mL), and organic layer was separated, washed
3
with water, aqueous HCl (1%). The organic layer was dried over Na SO , and evaporated in vacuo to dryness. The solid was
2
4
treated with hot hexane, washed with hexane, and dried in air to afford 17 (0.21 g, 41%), colorless crystals, C H N O ,
24 26
4 9
mp 231-233°C (CCl :hexane).
4
PMR spectrum (CDCl , δ, ppm, J/Hz): 1.53 (3H, s, CCH ), 2.97 (2H, m, 2H-8), 2.99 + 3.26 (1H each, d, ab-system,
3
3
J = 16.0, 2H-5), 3.21 (6H, s, 2NCH ), 3.25 (3H, s, NCH ), 3.31 (3H, s, NCH ), 3.92 (3H, s, OCH ), 5.83 + 5.86 (1H, d,
1
3
3
3
3
ab-system, J = 1.5, OCH O), 6.36 (1H, s, ArH).
2
1,3-Dimethyl-2,4,6-trioxoperhydropyrimidine-5-spiro-6′-{4′-methoxy-7′-(1,3-dimethyl-5-allyl-2,4,6-
trioxoperhydropyrimidin-5-yl)-5′,6′,7′,8′-tetrahydro[1,3]dioxolo[4,5-g]naphthalene} (18) was prepared byalkylation of4a
with allylbromide using a method analogous to that above. Yield 48%, colorless crystals, C H N O , mp 219-221°C
26 28
4 9
(CCl :hexane).
4
PMR spectrum (CDCl , δ, ppm, J/Hz): 2.71 + 2.86 (1H each, dd, ab-system, J = 12.4, J = 7.5, 2H-8), 2.98 (2H, d,
3
1
2
J = 2.1, CHCH ), 3.11 + 3.40 (1H each, d, ab-system, J = 15.6, 2H-5), 3.17 (3H, s, NCH ), 3.21 (3H, s, NCH ), 3.24 (3H, s,
2
3
3
NCH ), 3.32 (3H, s, NCH ), 3.89 (3H, s, OCH ), 5.04 (2H, m, J = 14.0, =CH ), 5.35 (1H, m, J = 7.7, =CH), 5.84 + 5.86 (1H
3
3
3
1
2
1
each, d, ab-system, J = 1.4, OCH O), 6.37 (1H, s, ArH).
2
1,3-Dimethyl-2,4,6-trioxoperhydropyrimidine-5-spiro-6′-{4′-methoxy-7′-(1,3-diemthyl-5-dimethylaminomethyl-
2,4,6-trioxoperhydropyrimidin-5-yl)-5′,6′,7′,8′-tetrahydro[1,3]dioxolo[4,5-g]naphthalene} (19). A solution of 4a (0.50 g,
0.001 mol) in water (15 mL) with added aqueous dimethylamine (0.5 mL, 33%) was treated with aqueous formaldehyde
(0.2 mL, 40%), refluxed for 5 h, and left overnight at room temperature. The resulting precipitate was separated, washed with
water, and dried in air to afford 19 (0.28 g, 51%), colorless crystals, C H N O , mp 214-216°C.
26 31
5 9
PMR spectrum (CDCl , δ, ppm, J/Hz): 2.89 + 3.33 (1H each, d, ab-system, J = 16.2, 2H-5), 2.94 (2H, m, 2H-8), 2.80
3
(6H, s, NMe ), 3.16 (3H, s, NCH ), 3.24 (3H, s, NCH ), 3.33 (3H, s, NCH ), 3.36 (3H, s, NCH ), 3.58 (1H, dd, J = 11.3, H-7),
2
3
3
3
3
1
3.97 (3H, s, OCH ), 5.84 + 5.85 (1H each, d, ab-system, J = 1.5, OCH O), 6.35 (1H, s, ArH).
3
2
1,3-Dimethyl-2,4,6-trioxoperhydropyrimidine-5-spiro-6′-{4′-methoxy-7′-(1,3-dimethyl-5-hydroxymethyl-2,4,6-
trioxoperhydropyrimidin-5-yl)-5′,6′,7′,8′-tetrahydro[1,3]dioxolo[4,5-g]naphthalene} (20). A solution of 4a (0.50 g,
0.001 mol) in water (15 mL) with added alcoholic trimethylamine (25%, 0.5 mL) was treated with aqueous formaldehyde
(0.4 mL, 40%), refluxed for 5 h, and left overnight at room temperature. The resulting precipitate was separated, washed with
aqueous trimethylamine, and dried in air to afford 20 (0.34 g, 64%), colorless crystals, C H N O , mp 220°C (dec.).
24 26
4 10
PMR spectrum (CDCl , δ, ppm, J/Hz): 2.50-2.75 (3H, br.s, 2H-8 + OH), 3.14 (6H, s, 2NCH ), 3.22 (3H, s, NCH ),
3
3
3
3.33 (3H, s, NCH ), 3.27 (3H, s, NCH ), 3.29 + 3.41 (1H each, d, ab-system, J = 13.0, HOCH ), 3.34 + 3.67 (1H each, d,
3
3
2
ab-system, J = 14.6, 2H-5), 3.96 (3H, s, OCH ), 4.07 (1H, dd, J = 11.0, J = 3.5, H-7), 5.85 + 5.92 (1H each, d, ab-system,
3
1
2
J = 1.0, OCH O), 6.46 (1H, s, ArH).
2
1,3-Dimethyl-2,4,6-trioxoperhydropyrimidine-5-spiro-6′-{4′-methoxy-7′-(1,3-dimethyl-5-[2-(4-pyridyl)ethyl]-2,4,6-
trioxoperhydropyrimidin-5-yl)-5′,6′,7′,8′-tetrahydro[1,3]dioxolo[4,5-g]naphthalene} (21). Compound4a(0.50g, 0.001mol)
was dissolved with heating in glacial acetic acid (3 mL), treated with 4-vinylpyridine (0.115 g, 0.0011 mol), heated on a water
bath for 30 min, and treated with water (10 mL). The precipitate was separated, washed with water and aqueous alcohol, and
dried in a vacuum desiccator over KOH to afford 21 (0.57 g, 94%), colorless crystals, C H N O , mp 225-226°C (AcOH).
30 31
5 9
PMR spectrum (CDCl , δ, ppm, J/Hz): 2.16-2.43 (4H, m, CH CH ), 2.94 + 3.26 (1H each, d, ab-system, J = 15.5,
3
2
2
2H-5), 2.99 (2H, m, 2H-8), 3.18 (3H, s, NCH ), 3.21 (3H, s, NCH ), 3.28 (3H, s, NCH ), 3.29 (3H, s, NCH ), 3.37 (1H, dd,
3
3
3
3
J = 12.5, H-7), 3.92 (3H, s, OCH ), 5.82 + 5.85 (1H each, d, ab-system, J = 1.5, OCH O), 6.33 (1H, s, ArH), 6.98 (2H, d,
1
3
2
J = 5.8, 2PyH), 8.46 (2H, d, J = 5.8, 2PyH).
ACKNOWLEDGMENT
The work was performed under the auspices of the RF President Program for Support of Scientific Schools (project
NSh-1060.2003.3).
53

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