Alkylation of CH acids with haloidalkyl-1,3-dioxolanes

Article abstract of DOI:10.1134/S1070363217050358

Alkylation of diethyl malonate and Meldrum acid with haloalkyl-1,3-dioxolanes has afforded the substituted malonates; their decarboxylation has led to the formation of esters containing a cycloacetal fragment. Reactions of the substituted malonates with urea have yielded the corresponding substituted barbiturates. Monodecarboxylation of the obtained malonates has led to the formation of 1,3-dioxolane-carboxylates.

Full text of DOI:10.1134/S1070363217050358

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 5, pp. 1097–1100. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © G.Z. Raskil’dina, Yu.G. Borisova, L.V. Spirikhin, S.S. Zlotsky, 2017, published in Zhurnal Obshchei Khimii, 2017, Vol. 87, No. 5,
pp. 872–875.
LETTERS
TO THE EDITOR
Alkylation of CH Acids with Haloidalkyl-1,3-dioxolanes
G. Z. Raskil’dina*, Yu. G. Borisova, L. V. Spirikhin, and S. S. Zlotsky
Ufa State Petroleum Technological University, ul. Kosmonavtov 1, Ufa, 450062 Russia
*e-mail: graskildina444@mail.ru
Received February 2, 2017
Abstract—Alkylation of diethyl malonate and Meldrum acid with haloalkyl-1,3-dioxolanes has afforded the
substituted malonates; their decarboxylation has led to the formation of esters containing a cycloacetal fragment.
Reactions of the substituted malonates with urea have yielded the corresponding substituted barbiturates.
Monodecarboxylation of the obtained malonates has led to the formation of 1,3-dioxolane-carboxylates.
Keywords: diethyl malonate, urea, haloalkyl-1,3-dioxolane, Meldrum acid, cis-1,4-dichlorobutene
DOI: 10.1134/S1070363217050358
We have earlier synthesized several polyfunctional
cyclic acetals via O- and N-alkylation of alcohols and
amines with haloalkyl-1,3-dioxolanes [1–3]. These
available halide derivatives are of interest for the
alkylation of CH acids.
containing dioxolane fragment can be of interest.
Hence, we performed condensation of compound 3a
with urea to obtain the corresponding 1,3-dioxolane
barbiturate 5 in 60% yield (Scheme 1).
Note that transformations of diethyl [2-(1,3-dioxo-
lan-2-yl)-ethyl]malonate 3a into compounds 4a and 5
proceeded with preservation of the 1,3-dioxolane ring.
For example, 1H NMR spectra of compounds 4a and 5
contained the triplet signal of the proton at the C2 atom
of the dioxolane ring at 4.85 and 4.90 ppm (3J = 4.6
and 4.9 Hz, respectively). The signals of the protons at
C4 and C5 atoms were manifested in the range of 3.82–
3.94 ppm as doublets of doublets with spin-spin
2-β-Bromoethyl-1,3-dioxolane 1a reacted with
diethyl malonate 2a under phase transfer catalysis
conditions to form the corresponding adduct 3a in 70%
yield (Scheme 1). Monodecarboxylation of compound
3a led to the formation of γ-1,3-dioxolanyl-2-butyric
acid ethyl ester 4a.
It is known that barbituric acids possess high
biological activity [4, 5], therefore their derivatives
Scheme 1.
O
O
Br
O
O
O
O
1а
O
O
O
O
2а
O
O
O
O
O
O
O
HN
NH
H2N
NH2
NH2
H2
N
O
O
O
O
O
O
4а
O
O
O
O
5
3а
1097

1098
RASKIL’DINA et al.
Scheme 2.
O
O
Y
X
O
O
O
O
O
O
O
O
Y
Cl
X
H3C
CH3
H3C
CH3
2b
1b, 1c
3b, 3c
X = O, Y = CH2 (1b, 3b); X = CH2, Y = O (1c, 3c).
Scheme 3.
OH
O
O
O
O
H3C
CH3
O
O
6
O
O
Cl
Cl
7
O
O
O
2а
O
O
Cl
O
O
O
O
O
O
O
CH3
CH3
CH3
10
8
CH3
O
CH3
CH3
9
coupling constants 2J = 10.5 and 3J = 3.4 Hz (4a), 2J =
1H NMR spectrum of compound 3b contained two
3
10.9 and J = 7.2 Hz (5), further confirming the
doublets at 3.65 and 3.67 ppm with spin-spin coupling
presence of the dioxolane fragment. 13C NMR spectra
of compounds 4a and 5 contained the signals of
dioxolane CH2 groups in the range of 64.50–64.81
ppm and of methine group at 104.06–104.46 ppm.
constants J = 10.4 and J = 3.0 Hz, corresponding to
the protons of methyl groups at C4 and C5 atoms,
respectively. The proton of methine group at C2 atom
was registered as a multiplet at 5.03 ppm, indicating
the presence of the 2-alkyl-1,3-dioxolane fragment. In
the case of compound 3c, the protons of the methylene
group at C2 atom resonated at 4.80 and 4.90 ppm, and
there was also a triplet of doublets at 4.09 ppm (3J =
6.3 and 5.3 Hz) assigned to the proton of methine
group at C4 atom, indicating the presence of the 2-alkyl-
1,3-dioxolane fragment.
2
3
1
The H NMR spectrum of ethyl 4-(1,3-dioxolan-2-
yl)butanoate 4a contained the signal of CH3 group at
1.24 ppm (3J = 7.2 Hz). The signal of carboxyl group
was observed at 173.16 ppm in the 13C NMR spectrum.
In the 13C NMR spectrum of compound 5, two sym-
metric C=O groups resonated at 162.21 pm; the signal
of C=O group located between two NH moieties was
observed at 172.48 ppm, typical of barbiturates 5 [6].
In the 13C NMR spectra, the signals of C4 (62.11
ppm) and C2 atoms (92.50 ppm) were characteristic of
compounds 3b and 3c, respectively.
2-(4)-Chloromethyl-1,3-dioxolanes 1b reacted with
diethyl malonate 2a to give the target products with
extremely low yields (<3%). However, alkylation of
Meldrum acid 2b afforded the corresponding cyclo-
acetals 3b and 3c with yields of 25–30%.
Condensation of glycerol ketal 6 with cis-1,4-di-
chlorobutene 7 via the known procedure [7] led to the
formation of compound 8 with allyl CH2Cl group
(Scheme 3). Alkylation of diethyl malonate 2a with
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ALKYLATION OF CH ACIDS WITH HALOIDALKYL-1,3-DIOXOLANES
chloromethyl derivative 8 proceeded with the quan-
titative formation of diester 9, decarboxylation of
which resulted in the desired 1,3-dioxolane carboxylic
acid derivative 10.
(C2), 169.22 (C=О). Mass spectrum, m/e, (Irel, %): 215
(2), 171 (5), 99 (15), 73 (100), 45 (15).
5-(1,3-Dioxolan-2-ylmethyl)-2,2-dimethyl-1,3-di-
1
oxane-4,6-dione (3b). Yield 0.7 g (30%). H NMR
1
The H NMR spectrum of compound 10 contained
spectrum, δ, ppm (J, Hz): 1.84 s (6H, CH3), 2.20 d.d
3
2
3
3
(2H, C6H2, J = 5.6, J = 4.3), 3.55 d (1H, C7H, J =
a doublet of triplets at 5.62 ppm with a J = 10.9 Hz
5.6), 3.65 d.d (2H, C4HA, C5HA, J = 10.4, J = 5.6),
2
3
belonging to cis-oriented double bond. The presence of
dioxolane ring with two methyl groups was also
confirmed by the signals of diastereotopic protons at
C5 (4.03 and 3.70 ppm, 2J = 10.9 and 3J = 6.0 Hz) and
C4 atoms (4.20–4.28 ppm), as well as singlets of two
CH3 groups (1.42 ppm). In the 13C NMR spectrum the
signals of double bond fragment were observed at
128.99 and 129.13 ppm, characteristic of cis-isomers,
whereas in trans-isomers the signal is shifted
downfield [8, 9]. Note that the studied transformations
of cis-1,4-dichlorobutene derivatives 8 and 9 into
dioxolane carboxylic acid 10 proceeded with preserva-
tion of the cis-configuration. A similar result has been
obtained earlier during alkylation of diethyl malonate
with cis-1,4-dichlorobut-2-ene [10].
3.68 d.d (2H, C4HB, C5HB, J = 10.4, J = 3.0), 5.03 t
2
3
3
(1H, C2H, J = 4.3). 13C NMR spectrum, δC, ppm:
26.43 (CH3), 29.43 (C6), 45.77 (C7), 62.11 (C4, C5),
102.55 (C2), 104.32 (C10), 166.23 (C=О).
5-(1,3-Dioxolan-4-ylmethyl)-2,2-dimethyl-1,3-di-
1
oxane-4,6-dione (3c). Yield 0.5 g (20%). H NMR
spectrum, δ, ppm (J, Hz): 1.25 s (6H, CH3), 1.60 d.d
3
3
(2H, C6H2, J = 6.3, 5.1), 3.45 d (1H, C7H, J = 5.1),
3.80 d.d (2H, C4HA, C5HA, 2J = 9.0, 3J = 5.3), 3.90 d.d
(2H, C4HB, C5HB, J = 10.4, J = 5.1), 4.09 m (1H,
2
3
C5H), 4.80 d (1H, C2H, J = 1.0), 4.90 d (1H, C2H,
3
3J = 1.0). 13C NMR spectrum, δC, ppm: 26.19 (CH3),
29.40 (C6), 49.55 (C7), 67.91 (C5), 77.15 (C4), 92.50
(C2), 105.44 (C10), 165.95 (C=О).
In summary, the studied reactions open the ways to
the synthesis of acid esters containing cycloacetal
fragments.
Diethyl (2Z)-4-[(2,2-dimethyl-1,3-dioxolan-4-yl)-
methoxy]but-2-en-1-yl)malonate (9). Yield 2.6 g
1
(80%). H NMR spectrum, δ, ppm (J, Hz): 1.23 t (6H,
3
Synthesis of compounds 3a–3c, 9. A mixture of
0.01 mol of CH acid 2, 0.015 mol of haloalkyl-1,3-
dioxolane 1 or 8, 0.01 mol of K2CO3 (or 0.01 mol of
triethylamine in the case of compound 2b), 50 mL of
acetonitrile, and 10% Catamine AB was stirred at 50°C
for 6–8 h. In the case of dioxolane 8, the reaction
mixture was microwave-irradiated for 1 h. After the
reaction was complete (GLC control), the mixture was
cooled, washed with water (in the case of compound
2b, the mixture was washed successively with a 30%
sodium bicarbonate solution and with water), extracted
with chloroform, dried with potassium carbonate, and
evaporated. The residue was distilled in vacuum (3a)
or purified by chromatography (3b, 3c, 9) using
benzene–ethyl acetate (9 : 1) as the eluent.
CH3, J = 7.0), 1.30 s (6H, CH3), 2.63–2.65 m (2H,
2
3
C13H2), 3.40 d.d (1H, C8HA, J = 9.8, J = 6.3), 3.49
d.d (1H, C8HB, 2J = 9.8, 3J = 5.9), 3.68 d.d (1H, C14H,
2J = 8.2, 3J = 6.5), 4.02 d. t (1H, C10HA, 2J = 8.2, 3J =
6.3), 4.06–4.30 m (8H, C4H2, C5H, C10HB, C17H2,
2
3
C18H2), 5.47 d. t (1H, C11H, J = 10.9, J = 7.5), 5.63
d.t (1H, C12H, 2J = 10.9, 2J = 6.3). 13C NMR spectrum,
δC, ppm: 13.98 (CH3), 26.30 (CH3), 51.60 (C14), 61.43
(C17, C18), 66.82 (C10), 71.19 (C8), 74.61 (C5), 109.35
(C2), 128.22 (C12), 129.13 (C11), 168.76 (2C=О). Mass
spectrum, m/e (Irel, %): 241(15), 213 (10), 184 (25),
126 (30), 101 (100), 95 (32), 73 (25), 67 (35), 43 (75),
41 (20).
Decarboxylation of compounds 3a and 9. A mix-
ture of 0.01 mol of ester 3a or 9, 0.03 mol of lithium
chloride, 0.02 mol of water, and 10 mL of DMSO was
stirred at 140°C for 8 h until complete conversion of
the substrate. The mixture was cooled to ambient,
washed with water, extracted with chloroform, dried
with freshly calcined sodium sulfate, and evaporated.
The residue was distilled in vacuum.
Diethyl [2-(1,3-dioxolan-2-yl)ethyl]malonate (3a).
1
Yield 1.8 g (70%), bp 161–162°C (3 mmHg). H
3
NMR spectrum, δ, ppm (J, Hz): 1.24 t (6H, CH3, J =
3
7.1), 1.70 t.d (2H, C6H2, J = 7.1, 4.5), 2.01 q (2H,
3
3
C7H2, J = 7.6), 3.38 t (1H, C8H, J = 7.6), 3.85 d.d
(2H, C4HA, C5HA, J = 10.5, J = 3.5), 3.95 d.d (2H,
2
3
C4HB, C5HB, J = 10.5, J = 3.5), 4.16 q (4H, C11H2,
2
3
3
3
13
C12H2, J = 7.1), 4.86 t (1H, C2H, J = 4.5). C NMR
spectrum, δC, ppm: 14.01 (CH3), 22.97 (C7), 31.16
(C6), 51.56 (8), 61.28 (C11, C12), 64.95 (C4, C5), 103.73
Ethyl 4-(1,3-dioxolan-2-yl)butanoate (4a). Yield
1
1.4 g (58%), bp 100–101°C (5 mmHg). H NMR
3
spectrum, δ, ppm (J, Hz): 1.24 t (3H, CH3, J = 7.2),
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RASKIL’DINA et al.
2
3
1.68 d.t (2H, C6H2, J = 4.6, J = 7.2), 1.74 m (2H,
detector temperature 250°C, evaporator temperature
300°C). Chromato–mass spectra were recorded using a
Fisons instrument (capillary quartz column DB 560,
50 m) and Focus Finingan DSQ II mass spectrometer
(ion source temperature 200°C, direct input tem-
perature 50–270°C, heating rate 10 deg/min,
ThermoTR-5MS column, 50 × 2.5 × 10–4 m, the flow
rate of helium 0.7 mL/min); electron impact ionization
method was used. NMR spectra were recorded with a
Bruker AVANCE-400 spectrometer in CDCl3.
C7H2, J = 7.1), 2.30 t (2H, CH2, J = 7.1), 3.82 d.d
3
3
(2H, C4HA, C5HA, J = 10.5, J = 3.4), 3.94 d.d (2H,
2
3
C4HB, C5HB, J = 10.5, J = 3.4), 4.10 q (2H, C10H2,
2
3
3J = 7.2), 4.85 t (1H, C2H, J = 4.6). 13C NMR
3
spectrum, δC, ppm: 14.18 (CH3), 19.36 (C7), 33.02
(C8), 33.92 (C6), 60.18 (C10), 64.81 (C4, C5), 104.46
(C2), 173.16 (C=О). Mass spectrum, m/e (Irel, %): 143
(2), 99 (20), 73 (100), 45 (20).
Ethyl
(4Z)-4-[(2,2-dimethyl-1,3-dioxolan-4-yl)
methoxy]hex-4-enoate (10). Yield 1.4 g (58%), bp
ACKNOWLEDGMENTS
1
160–162°C (2 mmHg). H NMR spectrum, δ, ppm (J,
3
Hz): 1.10 t (3H, CH3, J = 7.0), 1.42 s (6H, 2CH3),
This work was financially supported by the Russian
Science Foundation (project no. 15-13-10034) and the
President of the Russian Federation (Scholarship for
Young Scientists and Post-Graduates no. SP-
1960.2015.4).
2.40–2.45 m (4H, C13H2, C14H2), 3.40–3.45 m (4H,
2
3
C8H2,), 3.70 d.d (1H, C5HA, J = 8.0, J = 6.0), 4.03
d.d (1H, C5HB, J = 8.0, J = 6.0), 4.04 q (2H, C18H2,
3J = 7.2), 4.10–4.15 m (2H, C10H2), 4.20–4.28 m (1H,
C4H), 5.61 d. t (1H, C12H, 2J = 10.9, 3J = 7.6). 5.63 d.
2
3
t (1H, C11H, J = 10.9, J = 6.4). 13C NMR spectrum,
δC, ppm: 14.16 (C6, C7), 15.20 (CH3), 23.06 (C13),
33.66 (C14), 60.46 (C18), 65.80 (C5), 66.76 (C8), 70.50
(C4), 71.49 (C10), 109.55 (C2), 128.99 (C11), 129.13
(C12), 168.84 (C=О). Mass spectrum, m/e (Irel, %): 141
(45), 113 (75), 99 (42), 95 (20), 71 (98), 67 (100), 41
(45), 30 (22).
2
2
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3
2
3
2J = 7.5, J = 4.9), 1.72 t.d (1H, C7H2, J = 7.5, J =
3
7.7), 2.98 t (1H, C5'H, J = 7.7), 3.82 d.d (2H, C4HA,
2
3
C5HA, J = 10.9, J = 7.2), 3.95 d.d (2H, C4HB, C5HB,
2J = 10.5, J = 7.2), 4.60 br. s (NH, H2О), 4.90 t (1H,
3
C2H, J = 4.9). 13C NMR spectrum, δC, ppm: 24.72
3
(C7), 31.42 (C6), 58.23 (C5'), 64.50 (C4, C5), 104.06
(C2), 162.21 (2C=О), 172.48 (C=О).
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 5 2017