Michael addition at neutral pH: A facile synthesis of 1,3-dinitroalkanes

Article abstract of DOI:10.1139/cjc-2017-0257

Base-catalyzed Michael addition of nitroalkane to conjugated nitroalkene suffers serious practical difficulties due to the formation of oligomeric byproduct. Given its importance for synthesis of pharmacologically relevant organic compounds, a scalable synthesis of 1,3-dinitroalkane is developed by addition of nitroalkane to nitroalkene in aqueous phosphate buffer at pH 7.0 with no added traditional base catalyst.

Full text of DOI:10.1139/cjc-2017-0257

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Michael addition at neutral pH: A facile synthesis of 1,3-dinitroalkanes
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Porag Bora, Pranjal P Bora, Barisha Wahlang and Ghanashyam Bez*
Department of Chemistry, North Eastern Hill University, Shillongꢀ793022, India
ghanashyambez@yahoo.com
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Abstract: Base catalyzed Michael addition of nitroalkane to conjugated nitroalkene suffers
serious practical difficulties due to the formation of oligomeric byproduct. Given its importance
for synthesis of pharmacologically relevant organic compounds, a scalable synthesis of 1,3ꢀ
dinitroalkane is developed by addition of nitroalkane to nitroalkene in aqueous phosphate buffer
at pH 7.0 with no added traditional base catalyst.
Keywords: 1, 3ꢀDinitroalkanes; Michael addition; phosphate buffer; baseꢀfree, diastereoselective
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Introduction
In organic synthesis, methods for the development of carbonꢀcarbon bond forming reactions are
considered as the cornerstone of building complex molecular architechture.1ꢀ5 Many of such CꢀC
bond forming reactions are the results of reaction between carbanions and an electrophile.
Among the carbanions, nitroꢀstabilized carbanions have an advantage over others due to their
easier generation and requirement of a less sophisticated reaction environment. In fact, there is
no structural moiety that is more efficient than nitroalkanes due to its versatile reactivity profile6ꢀ
8
which makes them ideal synthetic precursors amenable to functional as well as structural
diversifications.9 One such rapidly emerging class among the its rank is 1,3ꢀdinitroalkanes that
works as a starting material for the synthesis of pharmaceutically important 1,3ꢀdiamines,10ꢀ11
polyfunctionalized carbacycles12ꢀ14 and bicycle[3.31]nonanes,15 highly substituted arenes16ꢀ18 and
phenols.19 Although conjugate addition of nitroalkanes to nitroalkenes generates 1, 3ꢀdinitro
compounds, the sensitivity of the nitroalkanes towards acid and base makes it a difficult reaction
to deal with. Therefore, control of pH is the key to most of the nitroalkane addition reactions to
nitroalkene which often gives polymeric byproducts resulting in low reaction yields. Especially
in the synthesis of 1, 3ꢀdinitro compounds by Michael addition nitroalkanes with nitroalkenes,
the suppression of the unfavored subsequent oligomerization under basic conditions is extremely
difficult.20 To avoid the formation of the undesired byproducts, many mild catalytic system such
as triphenylphosphine,21 DBU22 have found application. Recently, Baron et al. carried out
Michael addition of various active methylene compounds with βꢀnitroindoles using solid
potassium carbonate or sodium acetate as a base under ultrasonication.23
Recently, we reported that nitroalkanes undergoe the Henry reaction with aldehydes in phosphate
buffer at neutral pH to provide βꢀnitroalcohols in excellent yield.24 Given the complications
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attached to the base catalyzed synthesis of 1,3ꢀdinitroalkanes and their perceived importance as
versatile building blocks,the development of a synthetic methodology devoid of traditional base
catalysts may help circumvent the problem of oligomerization. We also envisaged that the use of
neutral phosphate buffer in aqueous medium will eliminate the formation of oligomeric
byproducts due to the poor solubility of the more hydrophobic 1,3ꢀdinitroalkane in aqueous
medium. To the best of knowledge, no report on the addition of nitroalkanes to nitroolefins in
the absence of a basic medium has been reported in the literature. Therefore, we wish to report
our findings on the addition of nitroalkanes to
successfully synthesize 1,3ꢀdinitropropanes (Scheme 1).
Scheme 1. Synthesis of 1,3ꢀdinitro compounds
βꢀnitrostyrene derivatives at neutral pH to
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Experimental
General remark
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All the products were characterized by H NMR, C NMR spectroscopy. H NMR (400 MHz)
and 13C NMR (100 MHz) spectra were obtained on a Bruker ACꢀ400 using CDCl3 as solvent and
TMS as internal standard, unless otherwise stated. Mass spectra were obtained on a Waters ZQ
4000 mass spectrometer by the ESI method, while the elemental analyses of the complexes were
performed on a Perkin–Elmerꢀ2400 CHN/S analyzer. HPLC analysis were performed on Waters
M515 series equipped with a chiral column (detailed for each compound below), using mixtures
of nꢀhexane/isopropyl alcohol (IPA) as mobile phase, diastereoselectivity was determined by
HPLC analysis of the crude products using chiral columns in comparison with the racemic
materials. For column chromatography, we employed Merck silica gel 60ꢀ120 mesh.
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Preparation of phosphate buffer25
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A 0.2 M stock solution of A was prepared by dissolving 27.6 g of monosodium phosphate
monohydrate in water to make a 1000 mL solution, while 1000 mL of 0.2 M stock solution of B
was prepared by dissolving 53.6 g of dibasic sodium phosphate heptahydrate in water. Then 100
mL of 0.4 M stock solution of phosphate buffer at pH 7 was prepared by mixing 39 mL of stock
solution A and 61 mL of the stock solution B.
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Typical procedure
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Aqueous phosphate buffer solution (pH 7.0, 0.5 mL) was added to a roundꢀbottomed flask
containing a mixture of (E)ꢀ(2ꢀnitrovinyl)benzene (37 mg, 0.25 mmol) and nitromethane (30 mg,
o
0.50 mmol). After vigorous stirring at 60 C for the specified time, the reaction was complete.
The reaction mixture was extracted with ethyl acetate (3×15 mL), The combined organic phases
was dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the resulting
mixture was purified by column chromatography (ethyl acetate/hexane 1:9) to obtain the pure
product.
Spectral data
1,3-Dinitro-2-phenylpropane (1a):26 90% yield; yellow gum; IR (KBr): 2917, 1551, 1492,
1
1427, 1371 cmꢀ1; H NMR (400 MHz, CDCl3): 4.22–4.33 (m, 1 H), 4.69–4.82 (m, 4 H), 7.17–
13
7.20 (m, 2 H), 7.22–7.38 (m, 3 H); C NMR (100 MHz, CDCl3): δ = 42.0, 77.0, 127.6, 129.3,
129.7, 134.5 MS (ESI): m/z = 233 [M + Na]+; Anal. Calcd. (%) for C9H10N2O4: C 51.43, H 4.80,
N 13.33; Found (%): C 51.37, H 4.79, N 13.38.
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1,3-Dinitro-2(4-fluorophenyl)propane (1b): 90% yield; yellow solid; m.p. 84ꢀ86 oC, IR (KBr):
2917, 1553, 1495, 1429, 1372 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ = 4.28ꢀ 4.35 (quintet, J = 7.2
Hz, 1 H), 4.70ꢀ 4.81 (m, 4 H), 7.06ꢀ 7.10 (m, 2 H), 7.20ꢀ7.23 (m, 2 H) ppm;13C NMR (100 MHz,
CDCl3): δ = 41.0, 76.7, 116.5 (d, J = 21.7 Hz), 129.2 (d, J = 8.6 Hz), 129.9 (d, J = 3 Hz), 164 (d, J
= 247 Hz), ppm; MS (ESI): m/z = 252 [M + Na]+; Anal. Calcd. (%) for C9H9FN2O4: C 47.37, H
3.98, N 12.28; Found (%): C 47.31, H 3.97, N 12.32.
o
1,3-Dinitro-2(4-chlorophenyl)propane (1c):27 82% yield; Yellow solid; mp 77ꢀ79 C; IR
(KBr): 2924, 1563, 1559, 1384, 825 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ = 4.27ꢀ4.34 (quintet, J
13
= 7.2 Hz, 1 H), 4.70ꢀ4.80 (m, 4 H), 7.16 (d, J = 8.0 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H) ppm; C
NMR (100 MHz, CDCl3):
δ = 41.1, 76.5, 128.7, 129.8, 132.6, 135.2 ppm; MS (ESI): m/z = 267
[35M + Na]+, 269 [37M + Na]+; Anal. Calcd. (%) for C9H9ClN2O4: C 44.19, H 3.71, N 11.45;
Found (%): C 44.11, H 3.69, N 11.50.
1,3-Dinitro-2(4-bromophenyl)propane (1d):28 78% yield; colourless liquid; IR (KBr): 2924,
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1561, 1548, 1386, 1373 cmꢀ1; H NMR (400 MHz, CDCl3): δ = 4.19ꢀ4.26 (m, 1 H), δ 4.63ꢀ4.74
(m, 4 H), δ 7.04 (d, J =8.4 Hz, 2 H), δ 7.44 (d, J =8.4 Hz, 2 H) ppm; 13C NMR (100 MHz, CDClꢀ
3):
δ
= 36.8, 75.7, 126.1, 128.5, 130.1, 134.1 ppm; MS (ESI): m/z = 311 [79M + Na]+, 313 [81M +
Na]+; Anal. Calcd. (%) for C9H9FN2O4: C 37.39, H 3.14, N 9.69; Found (%): C 37.44, H 3.13, N
9.74.
1,3-Dinitro-2(2-nitrophenyl)propane (1e): 90% yield; brown gum; IR (KBr): 2924, 1561,
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1549, 1429, 1377 cmꢀ1; H NMR (400 MHz, CDCl3) δ = 4.44ꢀ 4.51 (quintet, J = 7.2 Hz, 1H),
4.80ꢀ 4.90 (m, 4H), 7.57ꢀ7.67 (m, 2H), 8.15ꢀ 8.21 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3):
δ
= 41.2, 76.0, 122.4, 124.1, 130.7, 133.9, 136.5, 148.7 ppm; MS (ESI): m/z = 256 [M+H]+; Anal.
Calcd. (%) for C9H9N3O6: C 42.36 H, 3.55, N 16.47; Found (%): C 42.33, H 3.54, N 16.55.
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1,3-Dinitro-2(3-nitrophenyl)propane (1f):27 93% yield; brown gum; IR (KBr): 2921, 1559,
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1548, 1431, 1375 cmꢀ1; H NMR (400 MHz, CDCl3): δ = 4.44ꢀ 4.51 (m, 1 H), 4.80ꢀ 4.90 (m, 4
H), 7.59ꢀ 7.62 (m, 2 H), 8.16 (s, 1 H), 8.23ꢀ 8.25 (m, 1 H) ppm; 13C NMR (100 MHz, CDCl3):
δ
= 40.2, 75.0, 121.4, 123.2, 129.8, 132.8, 135.3, 147.7 ppm; MS (ESI): m/z = 256 [M + H]+;
Anal. Calcd. (%) for C9H9N3O6: C 42.36, H 3.55, N 16.47; Found (%): C 42.40, H 3.54, N 16.41.
o
1,3-Dinitro-2(4-methylphenyl)propane (1g):29 81% yield; brown solid; m.p. 47ꢀ49 C; IR
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(KBr): 2923, 1563, 1551, 1380, 815 cmꢀ1; H NMR (400 MHz, CDCl3): δ = 2.34 (s, 1 H), 4.24ꢀ
4.32 (quintet, J = 7.2 Hz, 1 H), 4.71ꢀ 4.80 (m, 4 H), 7.10 (d, J = 7.6 Hz, 2 H), 7.20 (d, J = 7.6 Hz,
2 H) ppm; 13C NMR (100 MHz, CDCl3):
δ = 21.0, 41.4, 77.3, 127.2, 130.2, 131.0, 139.0 ppm;
MS (ESI): m/z = 247 [M + Na]+; Anal. Calcd. (%) for C10H12N2O4: C 53.57, H 5.39, N 12.49;
Found (%): C 53.38, H 5.41, N 12.57.
1,3-Dinitro-2(2-methoxyphenyl)propane (1h): 80% yield; brown gum; IR (KBr): 2925, 1565,
1548, 1393, 1371, 1253 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ = 3.87 (s, 3H), 4.42ꢀ4.49 (m, 1 H),
4.85 (d, J = 7.2 Hz, 4 H), 6.91ꢀ6.95 (m, 2 H), 7.13 (d, J = 6.8 Hz, 1 H), 7.30 (t, J = 8 Hz, 1 H)
ppm; 13C NMR (100 MHz, CDCl3):
δ =39.2, 55.5, 75.3, 111.3, 121.3, 122.0, 130.0, 130.3, 157.0
ppm; MS (ESI): m/z = 241 [M + H]+; Anal. Calcd. (%) for C10H12N2O5: C 50.00, H 5.04, N
11.66; Found (%): C 49.89, H 5.03, N 11.71
1,3-Dinitro-2(4-methoxyphenyl)propane (1i):26 84% yield; brown gum; IR (KBr): 2921, 1562,
1550, 1386, 1372, 1244 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ = 3.78 (s, 3 H), 4.22ꢀ 4.29 (m, 1H),
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4.68ꢀ4.78 (m, 4 H), 6.87 (d, J = 8.0 Hz, 2 H), 7.12 (d, J = 8.0 Hz, 2 H) ppm; C NMR (100
MHz, CDCl3):
δ
= 41.1, 55.3, 76.9, 114.9, 128.5, 159.9 ppm; MS (ESI): m/z = 241 [M+H]+;
Anal. Calcd. (%) for C10H12N2O5: C 50.00, H 5.04, N 11.66; Found (%): C 50.10, H 5.05, N
11.73.
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1,3-Dinitro-2(3,4-methylenedioxyphenyl)propane (1j):29 77% yield; brown gum; IR (KBr):
2920, 1563, 1548, 1443, 1393, 1249, 1044 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ =4.19 (quintet, J
= 7.2 Hz, 1 H), 4.67ꢀ4.76 (m, 4 H), 5.97 (s, 2 H), 6.67 (d, J = 5.2 Hz, 1 H), 6.77 (d, J = 8.8 Hz, 2
13
H) ppm; C NMR (100 MHz, CDCl3):
δ = 41.5, 76.8, 101.6, 107.5, 107.5, 109.1, 121.0, 127.4,
148.0, 148.5; MS (ESI): m/z = 277 [M+Na]+; Anal. Calcd. (%) for C10H10N2O6: C 47.25, H 3.97,
N 11.02; Found (%): C 47.11, H 3.99, N 11.11.
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1,3-Dinitro-2(1-naphthyl)propane (1k):29 82% yield; brown gum; IR (KBr): 2923, 1567, 1551,
1390, 1371, 810 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ = 4.88ꢀ4.98 (m, 4 H), 5.23ꢀ5.30 (m, 1 H),
7.32 (d, J = 7.6 Hz, 1 H), 7.44 (t, J = 8 Hz, 1 H), 7.56 (t, J = 7.2Hz, 1 H), 7.64 (m, 1 H), 7.85 (d,
13
J = 8.8 Hz, 1 H), 7.91 (d, J = 8.0 Hz,1 H), 8.18 (d, J = 8.4 Hz, 1H) ppm; C NMR (100 MHz,
CDCl3):
δ = 36.2, 76.2, 121.5, 123.8, 125.2, 126.5, 127.6, 129.5, 129.7, 129.9, 130.6, 134.3 ppm;
MS (ESI): m/z = 283 [M+Na]+; Anal. Calcd. (%) for C10H12N2O5: C 60.00, H 4.65, N 10.76;
Found (%): C 59.77, H 4.66, N 10.79.
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1,3-Dinitro-2(2-furyl)propane (1l):29 85% yield; yellow gum; IR (KBr): 2930, 1555, 1543,
1378 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ = 4.44 (q, J = 6.4 Hz, 1 H), 4.80 (d, J = 6.4 Hz, 4 H),
6.27 (d, J = 2.8 Hz, 1H), 6.34 (d, J = 1.6 Hz, 1H), 7.39 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3):
δ
= 35.8, 74.5, 108.9, 110.8, 143.4, 147.0 ppm. MS (ESI): m/z = 223 [M+Na]+; Anal.
Calcd. (%) for C7H8N2O5: C 42.01, H 4.03, N 14.00; Found (%): C 42.18, H 4.02, N 14.06.
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1-Nitro-2-(nitromethyl)pentane (1m):26 80% yield; yellow gum; IR (KBr): 2920, 1561, 1550,
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1393 cmꢀ1; H NMR (400 MHz, CDCl3): δ = 0.91 (t, J = 6.8 Hz, 3 H), 1.38ꢀ1.46 (m, 4 H), 2.87
(q, J = 6.0 Hz, 1 H), 4.46 (dd, J = 13.2 Hz, 8 Hz, 2 H), 4.55 (dd, J = 13.6 Hz, 7.2 Hz, 2 H) ppm;
13C NMR (100 MHz, CDCl3):
δ
= 13.6, 19.5, 31.0, 35.7, 76.0 ppm; MS (ESI): m/z = 177
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[M+H]+; Anal. Calcd. (%) for C6H12N2O4: C 40.91, H 6.87, N 15.90, Found (%): C 40.86, H
6.89, N 15.79.
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3-Phenyl-2,4-dinitrobutane (1n):31 80% yield; reddish brown gum; IR (KBr): 2933, 1557,
1550, 1374 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ = 1.35 (d, J = 6.4 Hz, 3 H), 1.51 (d, J = 6.8 Hz,
3 H), 3.97ꢀ4.00 (m, 1 H), 4.61 (dd, J =13.2, 8.8 Hz, 1 H), 4.76ꢀ4.94 (m, 3 H), 7.14ꢀ7.18 (m, 2 H),
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7.30ꢀ7.32 (m, 3 H) ppm; C NMR (100 MHz, CDCl3):
δ = 16.7, 17.8, 47.3, 47.7, 76.1, 76.8,
84.2, 84.6, 128.0, 129.0, 129.2, 129.5, 133.1, 133.7 133.9 ppm; The product was analyzed to
determine the diastereoselectivity of the reaction. The diastereoselectivity (70:30 d.r.) of the
reaction were determined by HPLC analysis using a CHIRALPAK AS column, hexane/2ꢀ
propanol 40:10, flow rate 0.5 mL/min, UV 210 nm, major diastereomer: 25.2, 27.0 min; minor
diastereomer: 20.0, 22.4 min. MS (ESI): m/z = 247 [M + Na]+; Anal. Calcd. (%) for C10H12N2O4:
C 53.57, H 5.39, N 12.49; Found (%): C 53.67, H 5.38, N 12.55.
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3(4-Fluorophenyl)-2,4-dinitrobutane (1o):32 80% yield; white solid, m.p. 125ꢀ 128 C. IR
(KBr): 2928, 1560, 1495, 1433, 1383 cmꢀ1; H NMR (400 MHz, CDCl3): δ = 1.41 (d, J = 6.4
1
Hz, 3 H), 1.58 (d, J = 6.4 Hz, 3 H), 3.97ꢀ 4.02 (m, 1 H), 4.76 (dd, J = 13.6 Hz, 4.8 Hz, 1 H),
4.88ꢀ 4.96 (m, 3 H), 7.02ꢀ 7.07 (m, 2 H), 7.12ꢀ7.15 (m, 2 H) ppm; 13C NMR (100 MHz, CDCl3):
δ
= 16.8, 46.7, 76.2, 84.0, 116.3 (d, J = 21.1 Hz), 129.7 (d, J = 2.7 Hz), 129.8 (d, J = 7.4 Hz),
164.1 (d, J = 247 Hz) ppm. The product was analyzed to determine the diastereoselectivity of the
reaction. The diastereoselectivity (97:3 d.r.) of the reaction were determined by HPLC analysis
using a CHIRALCEL ODꢀH column, hexane/2ꢀpropanol 44:6, flow rate 0.5 mL/min, UV 210
nm, major diastereomer: 58.0, 73.6 min; minor diastereomer: 46.2, 48.8 min. MS (ESI): m/z =
265 [M + Na]+; Anal. Calcd. (%) for C10H11FN2O4: C 49.59, H 4.58, N 11.57; Found (%): C
49.64, H 4.59, N 11.60.
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3(4-Chlorophenyl)-2,4-dinitrobutane (1p):33 82% yield; yellow solid; IR (KBr): 2930, 1563,
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1556, 1390, 823 cmꢀ1; H NMR (400 MHz, CDCl3): δ = 1.40 (d, J = 7.6 Hz, 3 H), 1.56 (d, J =
6.8 Hz, 3 H), 3.96ꢀ4.01 (m, 1 H), 4.62 (dd, J = 13.2, 8.0 Hz, 1 H), 4.75 (m, 1 H), 4.86ꢀ4.94 (m, 2
13
H), 7.08 (d, J = 8.0 Hz, 2 H), 7.31 (d, J = 8.0 Hz, 2 H) ppm; C NMR (100 MHz, CDCl3):
δ =
16.8, 17.8, 46.8, 47.1, 76.0, 76.5, 83.9, 84.3, 129.3, 129.5, 129.8, 132.0, 135.1 ppm. The product
was analyzed to determine the diastereoselectivity of the reaction. The diastereoselectivity (89:11
d.r.) of the reaction were determined by HPLC analysis using a CHIRALPAK AS column,
hexane/2ꢀpropanol 95:5, flow rate 1.0 mL/min, UV 210 nm, major diastereomer: 41.5, 48.0 min;
minor diastereomer: 32.3, 48.0 min. MS (ESI): m/z = 281 [M + Na]+; Anal. Calcd. (%) for
C10H11ClN2O4: C 46.43, H 4.29, N 10.83; Found (%): C 46.49, H 4.28, N 10.87.
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3(2-Nitrophenyl)-2,4-dinitrobutane (1q):31 89% yield; brown gum, IR (KBr): 2933, 1565,
1
1549, 1393 cmꢀ1; H NMR (400 MHz, CDCl3): δ = 1.60 (d, J = 6.8Hz, 3 H), 1.71 (d, J = 6.8 Hz,
3 H), 4.75ꢀ4.76 (m, 1 H), 4.91ꢀ5.05 (m, 2 H), 5.25ꢀ5.32 (m, 1 H), 7.36 (d, J = 7.2 Hz, 1 H), 7.53ꢀ
7.65 (m, 2 H), 7.96 (d, J = 8.0 Hz, 1 H) ppm; 13C NMR (100 MHz, CDCl3):
δ = 17.1, 18.1, 41.5,
75.2, 75.6, 83.5, 84.5, 125.6, 125.8, 128.6, 129.0, 129.6, 130.0, 133.8, 134.0, 134.2, 135.4,
1
149.8, 150.0 ppm. The diastereoselectivity of the compound was determined from H NMR
(82:18). MS (ESI): m/z= 292 [M + Na]+; Anal. Calcd. (%) for C10H11N3O6
: C 44.61, H 4.21, N 15.61; Found (%): C 44.55, H 4.20, N 15.64.
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3(3-Nitrophenyl)-2,4-dinitrobutane (1r): 92% yield; brown gum, IR (KBr): 2932, 1562, 1551,
1
1392 cmꢀ1; H NMR (400 MHz, CDCl3): δ = 1.44 (d, J = 6.8 Hz, 3 H), 1.63 (d, J = 6.8 Hz, 3 H),
4.14ꢀ 4.23 (m, 1H), 4.77ꢀ 5.04 (m, 3 H), 7.54ꢀ 7.60 (m, 2 H), 8.10ꢀ 8.21 (m, 1 H), ppm; 13C NMR
(100 MHz, CDCl3): δ = 17.0, 17.7, 46.9, 47.1, 75.7, 76.0, 83.9, 122.9, 123.1, 124.1, 130.5, 130.7,
134.2, 134.4, 135.9, 136.2, 148.5, 148.7 ppm. The diastereoselectivity of the compound was
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229
determined from H NMR (58:42). MS (ESI): m/z = 292 [M + Na]+; Anal. Calcd. (%) for
C10H11N3O6: C 44.61, H 4.21, N 15.61; Found (%): C 44.58, H 4.22, N 15.66.
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236
3(4-Nitrophenyl)-2,4-dinitrobutane (1s): 90% yield; brown gum, IR (KBr): 2935, 1559, 1544,
1389 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ = 1.45 (d, J = 6.8 Hz, 3 H), 1.64 (d, J = 6.8 Hz, 3 H),
4.16ꢀ4.21 (m,1 H), 4.75 (dd, J = 13.6, 9.2 Hz, 1 H), 4.87ꢀ5.05 (m, 3 H), 7.41ꢀ7.48 (m,2 H), 8.20ꢀ
13
8.26 (m, 2H) ppm; C NMR (100 MHz, CDCl3):
δ = 17.0, 17.7, 46.99, 47.1, 75.7, 76.0, 83.8,
124.3, 124.6, 129.3, 141.1, 141.3, 148.1 ppm. The diastereoselectivity of the compound was
1
determined from H NMR (76:24). MS (ESI): m/z = 292 [M+Na]+; Anal. Calcd. (%) for
C10H11N3O6: C 44.61, H 4.21, N 15.61; Found (%): C 44.66, H 4.22, N 15.57
237
238
239
240
241
242
243
244
245
246
3(4-Methoxyphenyl)-2,4-dinitrobutane (1t):31 81% yield; brown gum, IR (KBr): 2970, 1551,
1
1540, 1373 cmꢀ1; H NMR (400 MHz, CDCl3): δ = 1.39 (d, J = 6.8 Hz, 3 H), 1.54 (d, J = 6.8 Hz,
3 H), 3.76 (s,3 H), 3.90ꢀ3.97 (m, 1 H), 4.59 (dd, J = 13.2, 8.0 Hz, 1 H), 4.72ꢀ4.94 (m, 3 H), 6.83
(m, 2H), 7.05 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3):
δ = 16.7, 17.8, 46.7, 47.1, 55.2, 55.5,
76.3, 77.4, 84.2, 84.7, 114.6, 114.8, 129.1, 129.5, 130.5, 131.2, 159.9 ppm. The product was
analyzed to determine the diastereoselectivity of the reaction. The diastereoselectivity (64:36
d.r.) of the reaction were determined by HPLC analysis using a CHIRALPAK ADꢀH column,
hexane/2ꢀpropanol 36:4, flow rate 0.4 mL/min, UV 210 nm, major diastereomer: 42.51 min;
minor diastereomer: 34.2, 38.2 min. MS (ESI): m/z = 255 [M+H]+; Anal. Calcd. (%) for
C11H14N2O5: C 51.97, H 5.55, N 11.02; Found (%): C 51.88, H 5.54, N 11.07.
247
248
249
3(4-Methylphenyl)-2,4-dinitrobutane (1u):32 78% yield; brown gum, IR (KBr): 2936, 1565,
1553, 1378 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ = 1.41 (d, J = 6.4 Hz, 3 H), 1.56 (d, J = 6.4 Hz,
3 H), 2.32 (s, 3 H), 3.96ꢀ3.98 (m, 1 H), 4.61(dd, J = 12.8, 4.8 Hz, 1 H), 4.74ꢀ4.93 (m, 3 H), 7.02ꢀ
11

Page 12 of 24
13
250
251
252
253
254
255
256
7.08 (m, 2 H), 7.14ꢀ7.18 (m, 2 H) ppm; C NMR (100MHz, CDCl3): δ = 16.7, 17.9, 47.0, 47.5,
76.2, 76.9, 84.0, 84.7, 127.8, 130.0, 130.2, 130.6, 139.0. The product was analyzed to determine
the diastereoselectivity of the reaction. The diastereoselectivity (60:40 d.r.) of the reaction were
determined by HPLC analysis using a CHIRALPAK AS column, hexane/2ꢀpropanol 95:5, flow
rate 1.0 mL/min, UV 210 nm, major diastereomer: 24.7, 30.7 min; minor diastereomer: 17.3,
18.2 min. MS (ESI): m/z = 239 [M+H]+; Anal. Calcd. (%) for C11H14N2O4: C 55.46, H 5.92, N
11.76; Found (%): C 55.40, H 5.93, N 11.80.
257
258
259
260
261
262
263
264
265
266
267
3(1-Naphthyl)-2,4-dinitrobutane (1v):32 80% yield; brown gum, IR (KBr): 2939, 1567, 1550,
1
1383 cmꢀ1; H NMR (400 MHz, CDCl3): δ = 1.39 (d, J = 5.2 Hz, 3 H), 1.57 (d, J = 6.4 Hz, 3 H),
4.98 (d, J = 6.4 Hz, 2 H), 5.13ꢀ5.19 (m,2 H), 7.31 (d, J = 7.2 Hz, 1 H), 7.42ꢀ7.49 (m, 1 H), 7.54
(t, J = 7.2 Hz, 1 H), 7.63 (t, J = 8.0 Hz, 1 H), 7.84 (d, J = 8.0 Hz, 1 H), 7.89(d, J = 8.4 Hz, 1 H),
13
8.17 (d, J = 7.2 Hz, 1 H) ppm; C NMR (100MHz, CDCl3):
δ = 14.1, 15.6, 40.8, 74.9, 83.6,
121.8, 122.1, 125.2, 125.3, 126.4, 127.5, 129.4, 129.7, 129.9, 134.2. The product was analyzed
to determine the diastereoselectivity of the reaction. The diastereoselectivity (70:30 d.r.) of the
reaction were determined by HPLC analysis using a CHIRALPAK ADꢀH column, hexane/2ꢀ
propanol 36:4, flow rate 0.4 mL/min, UV 254 nm, major diastereomer: 29.4, 31.5 min; minor
diastereomer: 25.2, 27.0 min. MS (ESI): m/z = 297 [M+Na]; Anal. Calcd. (%) for C14H14N2O4: C
61.31, H 5.14, N 10.21; Found (%): C 61.43, H 5.13, N 10.17.
268
269
270
271
272
Ethyl-2-cyano-3-(3-nitrophenyl)-4-nitrobutanoate (2): 91% yield, yellow oil, IR (KBr): 3469,
2988, 2255, 1740, 1558, 1480, 1023 cmꢀ1, 1H NMR (400MHz, CDCl3): δ 1.20 (t, J = 7.2 Hz, 3
H), 1.25 (t, J = 7.6 Hz, 3 H), 4.17 – 4.28 (m, 2 H), 4.34 – 4.43 (m, 1 H), 4.83 ꢀ 4.93 (m, 1 H),
4.97 ꢀ 5.10 (m, 2 H), 7.62 (t, J = 7.6 Hz, 1 H), 7.71ꢀ7.76 (m, 1 H), 8.21 ꢀ 8.26 (m, 2 H) ppm. 13C
NMR (100MHz, CDCl3): δ 13.8, 41.1, 42.1, 42.4, 63.9, 64.1, 75.3, 75.6, 113.7, 113.8, 122.8,
12

Page 13 of 24
273
274
123.5, 124.3, 124.4, 130.8, 130.7, 134.0, 133.8, 135.6, 148.5, 148.6, 163.2, 163.4 ppm. MS
(ESI): m/z = 308 [M+H]+.
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
292
293
294
295
Procedure for the gram scale preparation of 1,3-Dinitro-2(3-nitrophenyl)propane (1f) A
mixture of 1ꢀNitroꢀ3ꢀ(2ꢀnitrovinyl)benzene (1.94 g,10 mmol), nitromethane (1.22 g, 20 mmol)
and phosphate buffer solution (pH 7.0, 20.0 mL) was vigorously stirred at 60 oC till the reaction
was complete (2 h). The reaction mixture was extracted with ethyl acetate (3×100 mL), The
solvent of the combined organic phases was dried with anhydrous sodium sulfate, evaporated
under reduced pressure, and the resulting reaction crude was purified by column chromatography
(ethyl acetate/hexane 15:85) to obtain the pure product 2.29 g (90% yield) as a white solid.
Results and discussion
To start with, a mixture of βꢀnitrostyrene (1 mmol) and nitromethane (5 mmol) in phosphate
buffer solution (2 mL) was vigorously stirred at room temperature. After 36 h, complete
conversion of the starting βꢀnitrostyrene to the corresponding 1,3ꢀdinitro compound was
observed and the product was isolated in 88% yield. When the reaction temperature was
o
increased to 60 C, the reaction gave the optimum yield within 3 h (Table 1). It is evident from
the Table 1 that changes in temperature led to either increase in reaction time (Entry 2) or
decrease in isolated yield (Entry 4). The fact that the reaction is catalyzed by phosphate anions in
the buffer, the volume of the buffer solution was also optimized and 2 mL phosphate buffer
against 1 mmol of nitroolefin was found to be optimum. Since the pH of water is also neutral, the
o
pilot reaction was carried out in water at 60 C as well, but the reaction did not proceed even
after 12 h of vigorous stirring.
Table 1
13

Page 14 of 24
296
297
298
299
300
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
Having optimized the reaction parameters, the substrate scope of our protocol was studied for the
synthesis of various 1,3ꢀdinitroalkenes (Chart 1). From the isolated yields, it can be concluded
the protocol works well for the entire range of nitroalkenes under investigation. It can be seen
from the Chart 1, that the addition of nitromethane to ring substituted βꢀnitrostyrenes hardly
depends upon the nature of the substituents on the phenyl ring. Even the 1,3ꢀdinitropropanes
bearing aliphatic chains (entry 1l) were formed in good yield with equal efficiency. In order to
see the efficiency of our method on a gram scale, we carried out the reaction of (E)ꢀ1ꢀNitroꢀ3ꢀ(2ꢀ
nitrovinyl)benzene with nitromethane under the optimized conditions to observe that the reaction
was complete within 2 h to give 90% isolated yield.
Chart 1
In an attempt to study the compatibility of our reaction conditions against compounds containing
sensitive functional groups such as nitrile and ester, we carried out the Michael type addition of
ethyl cyanoacetate to (E)ꢀ2 (3ꢀnitrophenyl)ꢀ1ꢀnitroethene (Figure 1) to observe that these groups
o
were highly compatible even at 80 C and provided excellent yields of their corresponding
Michael adducts.
Figure 1: Studies on compatibility of the ester and nitrile group
As the reaction of
βꢀnitrostyrene with nitroethane should give a diastereomeric mixture, we
carried out chiral HPLC analysis in order to see if any diastereoselectivity exists for those
products (entries 1m ꢀ1u). It may be noted that our efforts to separate the diastereomeric mixture
employing reverse phase Cꢀ18 column using acetonitrileꢀwater mixture at various concentrations
14

Page 15 of 24
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337
338
339
340
341
failed as we observed only one peak in all the cases. When the reaction was carried out at 60 oC,
no diastereoselectivity was observed by HPLC upon employing chiralcel ODꢀH and ADꢀH
columns. When the reaction of βꢀnitrostyrene with nitroethane was carried out at room
temperature, the corresponding Michael addition product was formed with good
diastereoselectivity upon stirring for 60 h (Chart 2). Extension of the protocol revealed that most
of the products formed have diastereoselective preferences. Mention may be made for pꢀfluoroꢀ
β
ꢀnitrostyrene (dr 97:3) and pꢀchloroꢀβꢀnitrostyrene (dr 89:11) which might be influenced by Hꢀ
bond between the substituents with the reaction medium. From single crystal XRD data (CCDC
1559819) of the compound 1p (Figure 2), it was confirmed that antiꢀproduct was formed
predominantly over syn. It may be noted that in the absence of any stereoinducting factors such
as sterically hindered reactants and reagents, we have achieved significant diastereoselective
ratio (no enantioselective excess) in some cases due to participation of water in the sixꢀ
membered transition state to yield the anti diastereomer in preference to the syn.
Figure 2. Ortep diagram of single crystal of compound 1p
Chart 2
This preferential antiꢀselectivity might be explained by formation of the bicyclic transition states
TS1 and TS2 with water as the third participant (Figure 3). Since TS1 has no butane gaucheꢀ and
1,3ꢀdiaxial interactions while TS2 has two butane gaucheꢀ and one 1,3ꢀdiaxial interactions, the
formation of antiꢀMichael product might have been favored in comparison to the syn.
15

Page 16 of 24
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
358
359
360
361
362
363
364
Figure 3. Probable explanation for antiꢀselectivity
Conclusion
For the first time the nitroalkane addition to nitroalkene is reported in the presence of phosphate
buffer at neutral pH without employing traditional organic and inorganic bases. The commonly
encountered oligomerization products under basic reaction conditions were successfully avoided
under neutral pH. Simple operational procedure, short reaction time, excellent yields are some of
the highlights of our reaction protocol.
Acknowledgements: Authors acknowledge the support UGCꢀCAS programme of the
Department of Chemistry, North Eastern Hill University (NEHU), Shillong. The analytical
support from Sophisticated Analytical Instrumentation Facility, NEHU is gratefully
acknowledged.
Supplementary data
Supplementary data associated with this article can be found in the online version at
doi:…………………………………..
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19

Page 20 of 24
Table 1: Effect of temperature.a
Entry
Reaction conditions
Room temperature, 36 h
40 oC, 16 h
60 oC, 3 h
80 oC, 2.5 h
%Yieldb
88
1
2
3
4
85
90
75
aGeneral reaction conditions: Phosphate buffer (0.5 mL), β-nitrostyrene (0.25 mmol), nitroalkane (1.00 mmol);
bIsolated yields

Page 21 of 24
Chart 1: Synthesis of 1,3-dinitropropanes via Scheme 1.a, b
aGeneral reaction conditions: Phosphate buffer (0.5 mL), β-nitrostyrene (0.25 mmol), nitroalkane (1.25 mmol); 60
oC; bIsolated yields.

Page 22 of 24
Chart 2: Diastereoselective synthesis of 1,3-dinitropropanes.a,b
aGeneral reaction conditions: room temperature, phosphate buffer (0.5 mL), β-nitrostyrene (0.25 mmol), nitroethane
(1.25 mmol); bIsolated yields.

Page 23 of 24
Scheme 1. Synthesis of 1,3-dinitro compounds
Figure 1: Studies on compatibility of the ester and nitrile group

Page 24 of 24
Figure 2. Ortep diagram of single crystal of compound 1p
O
O
O
N
O
N
N
H
H
N
H
H
O
O
O
O
O
O
Ar
Ar
H
H
TS1
TS2
Figure 3. Probable explanation for anti-selectivity.