Synthesis of novel spirocyclopropylmalonates and barbiturates

Article abstract of DOI:10.1134/S0012500817090014

Alkylidenemalonates have been subjected to dichlorocyclopropanation to produce novel spiro-gem-dichlorocyclopropylmalonates in quantitative yields. The latter have been reacted with urea in the presence of sodium ethoxide to produce the corresponding barbiturates in 80–95% yields. The cleavage of the spiro-gem-dichlorocyclopropylmalonate carbocycle with ethanol with the aid of aluminum chloride has led to ethyl ethers, while carbocycle expansion with isobutyraldehyde has afforded polysubstituted tetrahydrofurans. The prepared compounds have been structurally characterized in detail by ¹H and ¹³C NMR spectroscopy.

Full text of DOI:10.1134/S0012500817090014

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ISSN 0012-5008, Doklady Chemistry, 2017, Vol. 476, Part 1, pp. 201–205. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © Yu.G. Borisova, G.Z. Raskil’dina, S.S. Zlotskii, 2017, published in Doklady Akademii Nauk, 2017, Vol. 476, No. 1, pp. 39–44.
CHEMISTRY
Synthesis of Novel Spirocyclopropylmalonates
and Barbiturates
Yu. G. Borisova, G. Z. Raskil’dina*, and S. S. Zlotskii
Presented by Academician A.A. Berlin February 22, 2017
Received March 28, 2017
Abstract—Alkylidenemalonates have been subjected to dichlorocyclopropanation to produce novel spiro-
gem-dichlorocyclopropylmalonates in quantitative yields. The latter have been reacted with urea in the pres-
ence of sodium ethoxide to produce the corresponding barbiturates in 80–95% yields. The cleavage of the
spiro-gem-dichlorocyclopropylmalonate carbocycle with ethanol with the aid of aluminum chloride has led
to ethyl ethers, while carbocycle expansion with isobutyraldehyde has afforded polysubstituted tetrahydrofu-
rans. The prepared compounds have been structurally characterized in detail by 1H and 13C NMR spectros-
copy.
DOI: 10.1134/S0012500817090014
Substituted malonates and barbiturates (pyrimi- condensation of diethyl malonate 1 with aldehydes 2a
dine-2,4,6-triones) exhibit high biological and phar- and 2b. The proton signal of the methyne group in
macological activity and are widely used in medicinal compound 3a appears at δH 6.95 ppm as a triplet with
chemistry [1–3]. This work describes the methods of
synthesis of spiro-gem-dichlorocyclopropylmalonates
and the corresponding barbiturates on their basis,
which are of considerable interest as NADH dehydro-
genase complex inhibitors. The presence of gem-
dichloromethyl group enhances the biological activity
and selectivity of these molecules as compared with
the known cyclopropane derivatives [1, 4, 5].
In this work, we carried out the condensation of
malonic ester 1 (Scheme 1) with aldehydes 2a and 2b
to form alkylidenemalonates 3a and 3b, which were
subjected to dichlorocarbonation for the first time to
afford spiro-gem-dichlorocyclopropylmalonates 4a
and 4b. In turn, the latter were used as initial com-
pounds for preparing new spirocyclic barbiturates 5a
and 5b. The yields of products 4a, 4b, 5a, and 5b were
80–90% as calculated for malonate 1.
spin–spin coupling constant J = 79 Hz. In compound
3b, it appears at δH 6.75 ppm as a doublet with spin–
13
spin coupling constant J = 10.5 Hz. The C NMR
spectra of compounds 3a and 3b display resonances of
carbon atoms of the CH groups under consideration at
δC 149.13 and 154.76 ppm, respectively. The carbon
atoms of ethoxycarbonyl groups in compounds 3a and 3b
show characteristic signals: at δC 165.60–168.43 ppm for
C=O group, at δC 61.09–61.44 ppm for CH2 group,
and at δC 14.03–14.07 ppm for CH3 group.
1
The H NMR spectra of compounds 4a and 4b
exhibit characteristic proton signal of CH group of
gem-dichlorocyclopropane ring in the region δH
2.41 ppm as a multiplet for 4a and at δH 2.25 ppm as a
doublet with spin–spin coupling constant J = 10.8 Hz
for 4b. The methyl groups of the isopropyl moiety in
compound 4b display resonances as two doublets at δH
0.95 and 1.85 ppm with spin–spin coupling constant
J = 6.6 Hz, while the CH3 group of compound 4a
shows a signal at δH 0.95 ppm as a triplet with spin–
spin coupling constant J = 7.4 Hz. The proton signals
of ethoxycarbonyl groups in compounds 4a and 4b
have close chemical shits (the protons of CH2 groups
appear at δH 4.25–4.30 ppm as a triplet of doublets
with spin–spin coupling constant J = 2.4 and 7.2 Hz,
the protons of CH3 groups have δH 1.25–1.35 ppm as
quadruplet with spin–spin coupling constants J = 4.5,
4.8, and 7.2 Hz).
The cleavage of carbocycle in malonates 4a and 4b
with ethanol led to ethyl ethers 6a and 6b (yield 20–
30%). Ring expansion in compounds 4a and 4b under
the action of isobutyraldehyde 6b allowed the prepara-
tion of polysubstituted tetrahydrofurans 7a and 7b
(yield 15–20%).
1
The H NMR spectra of compounds 3a and 3b
confirmed the formation of double bond upon the
Ufa State Petroleum Technological University, Ufa, 450062 Russia
*e-mail: graskildina444@mail.ru
201

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202
BORISOVA et al.
R1
COOEt
COOEt
+R1CHO
2a, 2b
CH2(COOEt)2
1
3a, 3b
: CCl2
O
R1
COOEt
HN
NH
2b
O
COOEt
COOEt
COOEt
Cl Cl
O
O
Cl
Cl
R1
Cl
Cl
R1
4a, 4b
5a, 5b
7a, 7b
EtOH
O
COOEt
COOEt
R1
Cl Cl
6a, 6b
R1 = Bu (2a, 3a, 4a, 5a, 6a, 7a),
R1 = i-Bu (2b, 3b, 4b, 5b, 6b, 7b)
Scheme 1.
13
observed at 3.05 ppm, while the signal of the proton at
the C(1) atom appears as a singlet at 3.73 ppm.
The C NMR spectra of compounds 4a and 4b
show signals of quaternary carbon atoms (from cyclo-
propane ring at the CCl2 group and the carbon atom of
the malonic ester moiety) appear in the region δC
76.40–76.70 and 52.10–55.60 ppm, respectively. The
signal of CH group of this ring displays resonance at δC
39.03 for 4a and at δC 46.50 ppm for compound 4b.
The chemical shifts of carbon atoms of ethoxycarbonyl
groups for these compounds virtually coincide with
the similar signals for compounds 3a and 3b.
In the 13C NMR spectra of compounds 6a and 6b,
the signal of the tertiary carbon atom of the CCl2
group in the cyclopropane ring is shifted downfield (δC
88.40 ppm).
1
The H NMR spectra of compounds 7a and 7b,
display proton signals typical for isopropyl group. In
particular, the proton signal of the methyne group at
C(5) of this ring appears in the region δH 3.64 and
4.15 ppm for compounds 7a and 7b, respectively.
The data of H and 13C NMR and 2D COSY,
1
HSQC, and HMBC correlation spectra for prepared
5,7-diazaspiro[2.5]octane systems 5a and 5b indicate
that the gem-dichlorocyclopropane ring spiro-fused
with the pyrimidine-2,4,6-trione heterocycle persists
upon transformations of compounds 4a and 4b. This is
evidenced by the presence of characteristic signals of
the protons and carbon atoms of the gem-dichlorocy-
clopropane ring. The pyrimidine-2,4,6-trione moiety
of molecules 5a and 5b is confirmed by the presence of
13
The C NMR spectra of compounds 7a and 7b
exhibit carbon resonances with chemical shifts δC
74.29–74.81 ppm for C(1) and δC 75.40–76.20 ppm
for C(2) of the CCl2 group, which indicates ring
expansion in compounds 4a and 4b under the action of
isobutyraldehyde 2b.
Thus, we accomplished the synthesis of previously
unknown spiro-gem-dichlorocyclopropylmalonates
and barbiturates, which are of interest as biologically
and pharmacologically active compounds.
13
two symmetrical C=O groups appeared in C NMR
spectra as signals at δC 167.50 ppm and one C=O
group (between two NH groups) at δC 148.41 ppm,
which is typical for barbiturates 5 [3].
EXPERIMENTAL
1
The H NMR spectra of compounds 6a and 6b
exhibit additional proton signals of the CH3CH2O
groups (δH 1.17 ppm for CH3CH2O and δH 3.60–
3.75 ppm for CH3CH2O protons), which confirms
ring cleavage with ethanol in malonates 4a and 4b. The
1H and 13C NMR spectra were recorded on a
Bruker AM-300 spectrometer operating at
300.13 MHz (1H) and 75.47 MHz (13C) in CDCl3
(D2O for 5a and 5b) using Me4Si as an internal refer-
signal of the methyne proton at the C(3) atom is ence. Mass spectra were obtained on a ThermoFisher
DOKLADY CHEMISTRY
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SYNTHESIS OF NOVEL SPIROCYCLOPROPYLMALONATES
Table 1. 1H and 13C NMR spectra of compounds 3a, 3b–7a, 7b
203
Compound (yield, %)
1H, ppm
13C, ppm
m/z, (Irel, %)
3a (95)
0.90 (t, 3H, C7H3, 3J 7.4), 1.25 (t,
13.03 (C7), 14.03 (C8+C9), M+ = 214 (>1), 169
6H, C10H3, C11H3, 3J 7.1), 1.50 (q,
21.56 (C6), 31.57 (C5),
(15), 127 (16), 122
(100), 99 (24), 94
(32), 68 (10), 55 (11),
41(9)
10
8
O
2H, C6H2 3J 7.4), 2.25 (q, 2H, C5H2 61.09 (C8 + C9), 128.75
3J 7.4; 7.6), 4.15 (q, 4H, C8H2, C9H2 (C2), 149.13 (C4), 165.60
1
3
O
O
5
7
2
4
4
6
3J 7.1), 6.95 (t, 1H, C4H1, 3J 7.9)
(C1), 168.43 (C3)
11
9
O
3b (93)
1.05 (d, 6H, C6H3, C7H3, 3J 6.6), 1.25 14.07 (C10+C11), 21.74
(t, 6H, C10H3, C11H3, 3J 7.3), 2.65 (m, (C6+C7), 29.33 (C5),
M+ = 214 (>1), 169
(20), 127 (20), 122
10
8
O
6
1H, C5H), 4.15 (q, 4H, C8H2, C9H2, 61.44(C8+C9), 126.50 (C2), (100), 99 (26), 68
1
3
O
O
3J 7.1), 6.75 d (1H, C4H, 3J 10.5)
154.76 (C4), 164.60 (C1),
168.43 (C3)
(20), 55 (13), 41(9)
5
2
7
11
9
O
4a (90)
0.95 (t, 3H, C6H3, 3J 7.4), 1.25 (q,
6H, C11H3, C12H3, 3J 4.5; 4.8; 7.2),
13.97 (C11 + C12), 21.21
(C6), 27.96 (C5), 39.03
M+ = 285 (absent),
258 (25), 225 (38),
215 (42), 195 (60),
169 (85), 160 (100),
141 (21), 123 (70), 99
(23), 79 (65), 43 (45)
11
9
O
6
1.50–1.60 (q, 4H, C4H2, C5H2,3J 6.8), (C4), 40.70 (C3), 52.10
4
5
7
8
O
O
3
2.41 (m, 1H, C3H), 4.25 (td, 4H,
(C1), 61.44 (C9 + C10),
1
C9H2, C10H2, 2J 2.4; 3J 7.2)
76.40 (C2), 164.2 (C11 + 12
)
2
Cl
12 10
O
Cl
4b (85)
0.95 (d, 3H, C5H3, 3J 6.6), 1.85 (d,
13.90 (C11+C12), 22.21
M+ = 294(absent),
259 (45), 225 (44),
215 (32), 195 (60),
169 (80), 160 (100),
141 (23), 123(73), 99
(24),79 (61), 43(43)
5
3H, C6H3, 3J 6.6), 1.35 (q, 6H, C11H3, (C5+6), 26.80 (C4), 46.50
C12H3, 3J 4.5; 4.8; 7.2), 2.70 (m, 1H, (C3), 55.60 (C1), 61.44
11
9
O
4
6
7
8
O
O
C4H), 2.25 (d, 1H, C3H, 3J 10.8),
4.30 (td, 4H, C9H2, C10H2,2J 2.4;
3J 7.2)
(C9 + C10), 76.70 (C2),
3
2
1
164.82 (C7 + 8
)
Cl
12 10
O
Cl
5a (85)
0.90 (t, 3H, C11H3,3J 7.0), 1.30 (dd,
13.09 (C11), 21.17 (C10),
–
1H, C9Ha,2J 7.3; 3J 4.8), 1.50 (q, 2H, 28.96 (C9), 37.36 (C2),
O
6
C10H2, 3J 7.3), 1.70 (dd, 1H, C9Hb,
2J 7.1; 3J = 4.5), 2.10 (d, 1H, C2H,
3J 5.3), 4.60 (br s, NH, H2О)
52.71 (C3), 84.56 (C1),
148.41 (C6), 167.50 (C4 + 8
HN7 5NH
)
8
4
3
O
Cl
O
1
2
9
Cl
10
11
5b (80)
1.00 (m, 1H, C9H), 1.10 (dd, 6H,
21.00 (C10 + 11), 31.33 (C9),
–
–
C10+11H3, 3J 6.5), 2.20 (d, 1H, C2H, 53.21 (C3), 148.41(C6),
O
6
3J 10.8)
167.50 (C4 + 8
)
HN7 5NH
8
4
3
O
O
1
Cl
2
9
10
Cl
11
6a (20)
1.00 (t, 3H, C8H3, 3J 7.0), 1.17 (t, 3H, 14.03 (C8), 14.77 (C7),
5
C5H3, 3J 7.1), 1.30 (t, 6H, C13H3,
C14H3, 3J 7.3), 2.65–2.70 (m, 4H,
C6H2, C7H2), 3.05 (s, 1H, C3H),
3.60–3.70 (m, 2H, C4H2), 3.73 (s,
C1H), 4.15 (q, 4H, C11H2, C12H2,
3J 7.2)
15.00 (C13 + 14), 21.17(C6),
33.22 (C5), 63.61 (C11+12),
64.21 (C4), 65.33 (C1),
88.40 (C2), 102.33 (C3),
4
13 11
O
O
3
7
8
9
O
6
166.21 (C9 + 10
)
1
2
Cl
10
O
Cl
14 12
O
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204
BORISOVA et al.
Table 1. (Contd.)
Compound (yield, %)
1H, ppm
13C, ppm
m/z, (Irel, %)
6b (30)
0.95 (d, 3H, C7H3, 3J 6.6), 0.95 (d,
15.00 (C13 + 14), 22.21 (C7 + 8),
–
5
3H, C8H3, 3J 6.6), 1.30 (t, 6H, C13H3, 26.80 (C6), 33.22 (C5),
C14H3, 3J 7.3), 2.65–2.70 (m, C6H), 63.61 (C11+12), 64.21 (C4),
3.05 (s, 1H, C3H), 3.60–3.71 (m, 2H, 65.33 (C1), 88.40 (C2),
4
13 11
O
O
3
7
C3H2), 3.73 (s, C1H), 4.15 (q, 4H,
102.33 (C3), 166.21 (C9 + 10
)
9
O
6
C11H2, C12H2, 3J 7.2)
1
8
2
Cl
10
O
Cl
14 12
O
7a (15)
1.00 (d, 6H, C8H3, C11H3, 3J 8.0),
1.09 (d, 6H, C9H3, C10H3, 3J 8.1),
1.30 (t, 6H, C16H3, C17H3, 3J 7.0),
1.75 (m, 1H, C6H), 2.68 (m, 1H,
C7H), 3.64 (d, 1H, C5H, 3J 6.4),
14.33 (C11), 15.01 (C16+17),
16.77 (C10), 18.51 (C8+9),
31.21 (C6), 33.11 (C7),
–
–
16
14
8
9
6 O
O
65.22 (C14+15), 74.29 (C1),
75.40 (C2), 90.33 (C3),
12
1
5
17
O
O
11
10
13
15
4.00 (d, 1H, C2H, 3J 6.5), 4.15 (q, 4H, 96.21 (C5), 167.25 (C12+13
C14H2, C15H2, 3J 7.1)
)
3
2
O
7
Cl
Cl
7b (20)
1.00 (d, 6H, C8H3, C11H3, 3J 8.0),
1.09 (d, 6H, C9H3, C10H3, 3J 8.1),
1.30 (t, 6H, C16H3, C17H3, 3J 7.0),
1.75 (m, 1H, C6H), 2.68 (m, 1H,
C7H), 4.00 (d, 1H, C2H, 3J 6.5),
4.15 (d, 1H, C5H, 3J 6.5), 4.15 (q, 4H,
C11H2, C12H2, 3J 7.1)
15.21 (C16+17), 16.77 (C8+11),
18.55 (C9+10), 31.71 (C6+7),
65.77 (C14+15), 74.81 (C1),
76.20 (C2), 90.36 (C3),
16
14
8
9
6 O
O
12
1
5
96.22 (C5), 165.35 (C12+13
)
17
O
O
13
15
3
2
10
O
7
Cl
Cl
11
Dash indicates that spectra were not recorded.
Scientific Thermo Finnigan MAT 95 XP high-resolu- (2 mmHg); diethyl 2,2-dichloro-3-isopropylcyclo-
tion GC-mass spectrometer system at ionizing voltage propane-1,1-dicarboxylate (4b), yield 14 g (85%), bp
70 eV (ionizing chamber temperature 250°C, direct 154°C (2 mmHg) were obtained.
inlet temperature 50–270°C, heating rate 10 K/min).
Synthesis of substituted barbiturates 5a and 5b.
Gas-liquid chromatography was performed on a
Three grams (0.04 mol) of urea was added to a solution
Chrom-5 instrument (Laboratory Equipment,
of sodium ethoxide prepared by dissolution of 0.5 g
Czechoslovakia, column 1.2 m long, 5% SE-30 sili-
(0.024 mol) of sodium in 11 mL of anhydrous ethanol,
cone as a stationary phase) using Chromaton N-AW-
2.3 g (0.008 mol) of diethyl 2,2-dichloro-3-propylcy-
DMCS as a sorbent (Ekolan, Russia, 0.16–0.20 mm,
clopropane-1,1-dicarboxylate (4a) or 2.3 g of diethyl
working temperature 50–300°C, helium as a carrier
2,2-dichloro-3-isopropylcyclopropane-1,1-dicarbox-
gas).
ylate (4b) was added dropwise with stirring. The mix-
Synthesis of alkylidenemalonates 3a and 3b. A solu-
tion of 8 g (0.1 mol) of aldehyde 2a or 2b, 16 g
(0.1 mol) of diethyl malonate 1, 0.85 g (0.01 mol) of
piperidine, and 1.2 g (0.02 mol) of acetic acid in 40 mL
of C6H6 was heated at reflux with a Dean–Stark trap
for 3 h until water evolution ceased. The resultant mix-
ture was cooled and washed with water until the pH in
the solution became neutral, dried with Na2SO4, the
solvent was removed by rotary evaporation to give 20 g
of diethyl butylidenemalonate (3a) (yield 95%), bp
101°C (6 mmHg) and 19.7 g of diethyl (2-methylpro-
pylidene)malonate (3b) (yield 93%), bp 106°C
(6 mmHg).
ture was heated under reflux for 4 h until precipitate
formed. The mixture was cooled to ambient tempera-
ture, the precipitate was separated by filtration, and
the filtrate was evaporated. The solid residue was
washed with hexane using a Buchner funnel. The
resultant powder was dried in air. 1,1-Dichloro-2-pro-
pyl-5,7-diazaspiro[2.5]octane-4,6,8-trione
(5a),
yield 1.9 g (85%), mp 149°C; 1,1-dichloro-2-isopro-
pyl-5,7-diazaspiro[2.5]octane-4,6,8-trione (5b), yield
1.7 g (80%), mp 151°C.
Cleavage of malonates 4a and 4b with ethyl alcohol.
A solution of 1.35 g (0.01 mol) of AlCl3 in 50 mL of
methylene chloride was added dropwise with stirring
Dichlorocarbonylation of alkylidenemalonates 3a to a mixture of 2.3 g (0.008 mol) of diethyl 2,2-
and 3b were carried out by previously described proce- dichloro-3-propylcyclopropane-1,1-dicarboxylate
dure [6]. Diethyl 2,2-dichloro-3-propylcyclopropane- (4a) or 2.3 g of diethyl 2,2-dichloro-3-isopropylcyclo-
1,1-dicarboxylate (4a), yield 12.6 g (90%), bp 145°C propane-1,1-dicarboxylate (4b), 0.9 g (0.009 mol) of
DOKLADY CHEMISTRY
Vol. 476
Part 1
2017