Reaction of Meldrum's acid with an aminomethylating agent and nitroalkanes

Article abstract of DOI:10.3184/174751917X14839766277251

5-(2-Nitroalkyl)isopropylidene malonate and 5,5′-(2-nitro-1,3-propylidene)bis(isopropylidene malonate) were easily synthesised by one-pot tandem reaction of substituted Meldrum's acids with the aminomethylating agent (Me₂NCH₂OAc) and nitroalkanes in the presence of a weak acid, such as acetic acid.

Full text of DOI:10.3184/174751917X14839766277251

72 RESEARCH PAPER
VOL. 41 FEBRUARY, 72–74
JOURNAL OF CHEMICAL RESEARCH 2017
Reaction of Meldrum’s acid with an aminomethylating agent and nitroalkanes
Jun-Wei Zhang, Jin-Hui Xue, Hua-He Zhang, Fan Xu, Qing-Guang Chen and Jing-Hua Li*
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, P.R. China
5-(2-Nitroalkyl)isopropylidene malonate and 5,5’-(2-nitro-1,3-propylidene)bis(isopropylidene malonate) were easily synthesised by one-
pot tandem reaction of substituted Meldrum’s acids with the aminomethylating agent (Me2NCH2OAc) and nitroalkanes in the presence of
a weak acid, such as acetic acid.
Keywords: Meldrum’s acid, aminomethylating agent, Mannich bases, nitroalkanes
Table 1 Yield of products 3 and 4a
Meldrum’s acid (isopropylidene malonate) and its
5-monosubstituted derivatives are versatile reagents with
a much stronger acidity than their corresponding acyclic
malonates.1–4 In contrast to normal Mannich bases,5–7 the
Mannich bases generated from isopropylidene malonates and
an aminomethylating agent, can be easily transformed into
their corresponding hydroxylated compounds under mild
conditions in the presence of a weak acid8,9 via hydrolysis of
the dialkylamino group. The condensation of Mannich base of
isopropylidene 5-alkylmalonates with methyl ketones can also
be readily performed using weak acid as a catalyst.10 These
reactions reveal the high reactivity of the Mannich bases.
Isolated
Yield /%
Entry Product
1
2
3
4
5
6
7
8
9
3a R = H, R1 = H, R2 = H
87
86
92
87
86
85
90
87
86
3b R = H, R1 = CH3,R2 = H
3c R = PhCH2, R1 = CH3, R2 = H
3d R = 4-CH3OC6H4CH2, R1 = CH3, R2 = H
3e R = cyclohexyl, R1 = CH3, R2 = H
3f R = PhCH2, R1 = CH2CH2CH3, R2 = H
4a R = PhCH2, R1 = H, R2 = H
4b R = 4-CH3OC6H4CH2, R1 = H, R2 = H
4c R = 3,4-(CH3)2C6H3CH2, R1 = H, R2 = H
aReaction conditions: 2.5 mmol 1, 2 mL acetonitrile, 2.5 mmol Me2NCH2OAc, 2.5 mL
Results and discussion
nitroalkane, 0.25 mL acetic acid, r.t., 4 h.
Since nitroalkanes are good nucleophiles,11 we were interested
in the condensation of Mannich base of Meldrum’s acid with
nitroalkanes. A series of nitroethyl derivatives of isopropylidene
5-alkylmalonates was successfully synthesised using the
isopropylidene 5-alkylmalonates 1 as the starting materials
(Scheme 1). This provides a new method for synthesising 3 and
4 without using thioalkylated Meldrum’s acid derivatives as
substrates.12 The results are listed in Table 1.
O
O
H
O
O
O
N
O
O
N
CH2
O
The Mannich bases generated from 5-alkyl-substituted
Meldrum’s acid 1 reacting with nitroalkanes R1R2CHNO2 2, in
the same vessel to give the single condensation products 3 (Table
1, entries 1–6, R1 = alkyl, R2 = H) and double condensation
products 4 (entries 7–9, R1 = R2 = H). Interestingly, when the
Mannich bases, generated from unsubstituted Meldrum’s acid
(entries 1, 2) and dimethylaminomethyl acetate (Me2NCH2OAc),
reacted with nitroalkanes (nitromethane and nitroethane) under
(inner salt)
Scheme 2 Mutual transformation between Mannich base and its inner salt.
the similar conditions, only the single condensation products 3
were obtained. This might be due to the formation of a stable
inner salt of the Mannich base which was formed during the
reaction (Scheme 2).13
O
R
O
O
R1=alkyl, R2=H
or
CH2CHNO2
O
R=H
R1
O
3
O
O
Me
2NCH2OAc
1.
O
R
R
2. R1R2CHNO2
HOAc, rt
,
O
O
2
O
CH2
O
1
CHNO2
R=alkyl, R1=H, R2=H
O
O
O
CH2
R
O
4
Scheme 1 Synthesis of compounds 3 and 4.
* Correspondent. E-mail: lijh@zjut.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2016 73
O
O
O
O
O
O
O
C CH2CH2
O
O
O
O
O
CH2CH2COCH3
CH2COPh
Ph
O
O
CH2CH2
O
O
Ph
CH2
CH2
Ph
CH2
PhH
2C
O
5a
5c
5b
Scheme 3 Compounds 5a, 5b and 5c.
2,2-Dimethyl-5-(2-nitroethyl)-1,3-dioxane-4,6-dione (3a): Colourless
crystals; yield 87%; m.p. 134–136 °C (decomp., lit.12 135–136 °C);
1H NMR (500 MHz, CDCl3) δ 4.77 (t, J = 7 Hz, 2H), 3.90 (t, J = 6 Hz,
1H), 2.76–2.72 (dd, J = 7, 13 Hz, 2H), 1.86 (s, 3H), 1.80 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 164.27, 105.75, 71.81, 43.15, 28.51, 26.36, 23.59;
m/z (EI): 202 (10, [M – 15]), 142 (21), 113 (60), 68 (100).
2,2-Dimethyl-5-(2-nitropropyl)-1,3-dioxane-4,6-dione (3b): Colourless
crystals; yield 86%; m.p. 130–132 °C (lit.12 132 °C); 1H NMR (500 MHz,
CDCl3) δ 5.12–5.07 (m, 1H), 3.74 (dd, J = 3, 9 Hz, 1H), 2.89–2.83 (m,
1H), 2.30–2.24 (m, 1H), 1.83 (s, 3H), 1.79 (s, 3H), 1.65 (d, J = 7 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 164.77, 164.03, 105.72, 80.16, 43.2, 31.2,
28.3, 26.4, 19.5; m/z (EI, %): 216 (3, [M – 15]), 156 (20), 127 (69), 83 (40),
43 (100).
Unexpectedly, the Mannich bases generated from 5-alkyl-
substituted Meldrum’s acid 1 reacted with phenylnitroalkane
R1R2CHNO2 2 (R1 = Ph, R2 = H) to give ketone 5a (Scheme
3) instead of the target nitro product 3 or 4. Ketone 5a was
isolated by column chromatography in high yield (80%). It was
characterised by the 13C NMR signal from a carbonyl group
at 196 ppm. The most likely reason for this is that during the
course of the reaction the intermediate 3 (R1 = Ph), activated
by two electron-withdrawing groups of phenyl and nitro,
underwent hydrolysis extremely easily to give 5a. The incipient
nitronate ion can be oxidised by molecular oxygen to ultimately
afford the ketone.14
No target nitro product was obtained by reaction of Mannich
base of 5-alkyl-substituted Meldrum’s acid 1 with R1R2CHNO2 2
(R1 = R2 = Me, 2-nitropropane), but a small amount of the ketones
5, single condensation product (5b, Scheme 3, less than 20%
yield) and double condensation product (5c, less than 20% yield),
were isolated by chromatography. The probable mechanism
of the reaction is that 2-nitropropane was firstly converted into
acetone (Nef reaction), the latter then reacted with Mannich base
to give 5.15 This result reveals that reaction of Mannich base of
5-alkyl-substituted Meldrum’s acid 1 with R1R2CHNO2 2 (R1, R2
= alkyl) does not produce the nitro compounds 3 and 4 due to the
steric effect of α-position at nitroalkane.
In conclusion, an efficient method for synthesis of 5-nitroalkyl
derivatives of Meldrum’s acid has been developed under mild
conditions. This provides a feasible route, after reduction of the
nitro group, to the derivatives of γ-aminobutyric acid (GABA),
which are lipophilic structural analogues of the inhibitory
neurotransmitter.
5-Benzyl-2,2-dimethyl-5-(2-nitropropyl)-1,3-dioxane-4,6-dione
(3c): Colourless crystals; yield 92%; m.p. 121–123 °C; 1H NMR (500
MHz, CDCl3) δ 7.31–7.27 (m, 3H), 7.17–7.15 (m, 2H), 4.72–4.67 (m,
1H), 3.30 (dd, J = 12, 22 Hz, 2H), 3.07–3.03 (m, 1H), 2.40 (dd, J = 3,
15 Hz, 1H), 1.67 (s, 3H), 1.59 (d, J = 6 Hz, 3H), 0.68 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 167.56, 166.66, 133.60, 130.38, 128.95, 128.28,
105.97, 79.33, 54.26, 45.81, 42.46, 28.95, 28.37, 20.44; m/z (EI, %): 264
(2, [M – 57]), 246 (7), 235 (25), 143 (77), 91 (100); m/z (ESI, %): 665
(24, [2M + Na]+), 344 (100, [M + Na]+), 339 (28, [M + NH4]+); Anal.
calcd for C16H19NO6: C, 59.81; H, 5.96; N, 4.36; found: C, 60.08; H,
5.96; N, 4.39%.
5-(4-Methoxybenzyl)-2,2-dimethyl-5-(2-nitropropyl)-1,3-dioxane-
4,6-dione (3d): Colourless crystals; yield 87%; m.p. 96–98 °C;
1H NMR (500 MHz, CDCl3) δ 7.07 (m, 2H), 6.82 (dd, J = 2, 7 Hz,
2H), 4.70–4.67 (m, 1H), 3.76 (s, 3H), 3.24 (dd, J = 13, 24 Hz, 2H), 3.00
(dd, J = 10, 15 Hz, 1H), 2.36 (dd, J = 3, 15 Hz, 1H), 1.67 (s, 3H), 1.59
(d, J = 7 Hz, 3H), 0.78 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 167.79,
166.89, 159.63, 131.56, 125.62, 114.36, 107.01, 79.41, 55.30, 54.46,
45.24, 42.39, 29.06, 28.67, 20.53; m/z (EI, %): 351 (4, [M]), 215 (7), 121
(100); Anal. calcd for C17H21NO7: C, 58.11; H, 6.02; N, 3.99; found: C,
58.02; H, 5.95; N, 3.88%.
Experimental
Commercially available reagents were used without further
purification unless specified. All reactions were monitored by TLC.
Melting points were recorded on a X-4 micro melting point apparatus
5-Cyclohexyl-2,2-dimethyl-5-(2-nitropropyl)-1,3-dioxane-4,6-
dione (3e): Colourless crystals; yield 86%; m.p. 102–104 °C; 1H NMR
(500 MHz, CDCl3) δ 4.65–4.58 (m, 1H), 2.76 (dd, J = 10, 15 Hz, 1H),
2.19 (dd, J = 3, 15 Hz, 1H), 1.87–1.59 (m, 6H), 1.75 (s, 3H), 1.70 (s, 3H),
1.50 (d, J = 7 Hz, 3H), 1.18–1.13 (m, 5H); 13C NMR (125 MHz, CDCl3)
δ 167.37, 166.01, 106.62, 79.54, 56.27, 48.55, 36.45, 30.22, 28.75, 28.56,
28.15, 26.55, 25.62, 20.38; m/z (EI, %): 298 (3, [M – 15]), 256 (8), 174
(29), 126 (52), 83 (100); Anal. calcd for C15H23NO6: C, 57.50; H, 7.40;
N, 4.47; found: C, 57.34; H, 7.35; N, 4.34%.
1
and uncorrected. H and 13C NMR spectra were obtained in CDCl3
on a Bruker Spectrospin 500 MHz or 400 MHz spectrometer using
tetramethylsilane (TMS) as internal standard. Mass spectroscopic
data were collected on a HRMS-ESI instrument. Elemental analyses
were performed on a Carlo-Erba 1106 analytical instrument. Column
chromatography was performed using silica gel (200–300 mesh) with
ethyl acetate/petroleum ether (b.p. 60–90 °C) as eluent.
5-Benzyl-2,2-dimethyl-5- (2-nitropentyl) -1,3-dioxane-4,6-
1
dione (3f): Colourless crystals; yield 85%; m.p. 88–90 °C; H NMR
Synthesis of 2,2-dimethyl-5-(2-nitroethyl)-1,3-dioxane-4,6-diones
(500 MHz, CDCl3) δ 7.31–7.14 (m, 5H), 4.60–4.54 (m, 1H), 3.29 (dd,
J = 2, 13 Hz, 2H), 3.02 (dd, J = 10, 15 Hz, 1H), 2.41 (dd, J = 2, 15 Hz,
1H), 2.04–1.97 (m, 1H), 1.74–1.67 (m, 1H), 1.65 (s, 3H), 1.39–1.31 (m,
2H), 0.95 (t, J = 7 Hz, 3H), 0.66 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 167.7, 166.7, 133.7, 130.4, 129.0, 128.3, 106.9, 84.4, 54.6, 45.5, 41.4,
36.8, 29.0, 28.4, 18.7, 13.2; m/z (EI, %): 292 (5, [M – 57]), 227 (20), 199
(22), 129 (43), 115 (39), 91 (100); Anal. calcd for C18H23NO6: C, 61.88;
H, 6.64; N, 4.01; found: C, 62.01; H, 6.67; N, 3.98%.
(3); general procedure
A stirred solution of 1 (2.5 mmol) in acetonitrile (2 mL) was slowly
treated with Me2NCH2OAc (2.5 mmol) with cooling. The mixture
was stirred at room temperature for 30 min to complete the reaction.
Then nitromethane 2 (2.5 mL) and acetic acid (0.25 mL) were added
and the mixture was stirred at room temperature for 3 h to complete
the reaction. This was monitored by TLC (ethyl acetate:cyclohexane
= 1:3; v/v). The resulting mixture was concentrated in vacuo at 60
°C to recover the nitroalkane. Then the residue was cooled to room
temperature, the crystals were collected by filtration and washed
with cool methanol (with ether for 3f), and further purified by
recrystallisation in methanol to give product 3.
Synthesis of 5,5’-(2-nitropropane-1,3-diyl)bis(5-benzyl-2,2-dimethyl-
1,3-dioxane-4,6-diones) (4); general procedure
A stirred solution of 1 (2.5 mmol) in acetonitrile (2 mL) was slowly
treated with Me2NCH2OAc (2.5 mmol) with cooling. The mixture

74 JOURNAL OF CHEMICAL RESEARCH 2016
was stirred at room temperature for 30 min to complete the reaction.
Then nitromethane 2 (2.5 mL) and acetic acid (0.25 mL) were added
and the mixture was stirred at room temperature for 3 h to complete
the reaction which was monitored by TLC (ethyl acetate:cyclohexane
= 1:3; v/v). The resulting mixture was concentrated in vacuo at
60 °C to recover the nitroalkane. Then the residue was cooled to room
temperature, and the crystals were collected by filtration and washed
with cool methanol, and further purified by recrystallisation in
methanol to give product 4.
5,5’-(2-Nitropropane-1,3-diyl)bis(5-benzyl-2,2-dimethyl-1,3-
dioxane-4,6-dione) (4a): Colourless crystals; yield 90%; m.p.
172–174 °C; 1H NMR (400 MHz, CDCl3) δ 7.32–7.26 (m, 6H),
7.16–7.12 (m, 4H), 4.86–4.81 (m, 1H), 3.27 (s, 4H), 3.01 (dd,
J = 8, 15 Hz, 2H), 2.43 (dd, J = 3, 15 Hz, 2H), 1.68 (s, 6H), 0.77 (s, 6H);
13C NMR (125 MHz, CDCl3) δ 167.20, 166.71, 133.31, 130.53, 129.13,
128.53, 107.35, 79.80, 53.88, 46.18, 41.39, 29.23, 28.44; m/z (EI, %):
345 (20, [M – 208]), 169 (40), 117 (44), 91 (100); m/z (ESI, %): 1145
(51, [2M + 39]), 592 (100, [M+39]); Anal. calcd for C29H31NO10: C,
62.92; H, 5.64; N, 2.53; found: C, 62.76; H, 5.54; N, 2.42%.
5,5’-(2-Nitropropane-1,3-diyl)bis[5-(4-methoxybenzyl)-2,2-
dimethyl-1,3-dioxane- 4,6-dione] (4b): Colourless crystals; yield
87%; m.p. 200–202 °C; 1H NMR (500 MHz, CDCl3) δ 7.05 (m, 4H),
6.82 (m, 4H), 4.85–4.81 (m, 1H), 3.76 (s, 6H), 3.22 (s, 4H), 2.97 (dd,
J = 10, 15 Hz, 2H), 2.39 (dd, J = 3, 15 Hz, 2H), 1.70 (s, 6H), 0.88 (s,
6H); 13C NMR (125 MHz, CDCl3) δ 167.23, 166.77, 159.68, 131.57,
125.18, 114.36, 107.20, 79.61, 55.29, 53.87, 45.44, 41.07, 29.16, 28.55;
m/z (EI, %): 349 (3, [M – 264]), 215 (10), 162 (34), 121 (100); Anal.
calcd for C31H35NO12: C, 60.68; H, 5.75; N, 2.28; found: C, 60.51; H,
5.66; N, 2.30%.
the reaction which was monitored by TLC (ethyl acetate:cyclohexane =
1:3; v/v). The resulting mixture was diluted with ethyl acetate, washed
with 10% diluted hydrochloric acid and saturated sodium bicarbonate
solution. Finally, the organic layer was concentrated in vacuo and the
residue was isolated by a silica gel column chromatography (ethyl
acetate:petroleum ether = 1:8; v/v) to give product 5a.
5-Benzyl-2,2-dimethyl-5-(2-oxo-2-phenylethyl)-1,3-dioxane-4,6-
dione (5a):16 White crystals; yield 80%; m.p. 172–174 °C [no m.p.
reported in ref. 16]; 1H NMR (500 MHz, CDCl3) δ 7.98–7.96 (m, 2H),
7.64–7.48 (m, 3H), 7.37–7.21 (m, 5H), 4.08 (s, 2H), 3.33 (s, 2H), 1.99
(s, 3H), 0.72 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 196.52, 168.16,
135.02, 134.08, 133.65, 130.22, 128.97, 128.74, 128.35, 128.28, 107.60,
51.97, 47.97, 45.24, 28.49, 28.06; m/z (EI, %): 352 (2, [M]), 248 (65),
207 (30), 114 (8), 105 (100), 77 (52).
5-Benzyl-2,2-dimethyl-5-(3-oxobutyl)-1,3-dioxane-4,6-dione (5b):
1
m.p. 155–157 °C (decomp., lit.10 155–157 °C); H NMR (500 MHz,
CDCl3) δ 7.28–7.17 (m, 5H), 3.33 (s, 2H), 2.52 (dd, J = 6, 9 Hz, 2H),
2.44–2.40 (m, 2H), 2.16 (s, 3H), 1.62 (s, 3H), 0.69 (s, 3H).
5,5’-(3-Oxopentane-1,5-diyl)bis(5-benzyl-2,2-dimethyl-1,3-dioxane-
4,6-dione) (5c): m.p. 174–176 °C (decomp., lit.15 175–176 °C), 1H NMR
(500 MHz, CDCl3) δ 7.29–7.18 (m, 10H), 3.34 (s, 4H), 2.52 (dd, J = 6, 9
Hz, 4H), 2.42 (dd, J = 6, 9 Hz, 4H), 1.63 (s, 6H), 0.70 (s, 6H).
Received 7 November 2016; accepted 18 December 2016
Paper 1604416 DOI: 10.3184/174751917X14839766277251
Published online: 10 February 2017
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2
3
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7
8
9
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1
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3.20 (s, 4H), 2.96 (dd, J = 9, 15 Hz, 2H), 2.40 (dd, J = 4, 15 Hz, 2H),
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A stirred solution of 1 (2.5 mmol) in acetonitrile (2 mL) was slowly
treated with Me2NCH2OAc (2.5 mmol) with cooling. The mixture was
stirred at room temperature for 30 min to complete the reaction. Then
phenylnitroalkane 2 (3 mmol) and acetic acid (0.25 mL) were added
and the mixture was stirred at room temperature for 4 h to complete