A new sustainable protocol for the synthesis of nitroaldol derivatives via
Henry reaction under solvent-free conditions.
Tommaso Angelini, Eleonora Ballerini, Simona Bonollo, Massimo Curini, Daniela Lanari,*
Supporting Information
General informations
GC-EIMS analyses were carried out by using a Hewett-Packard HP 6890 Series GC system/5973 Mass Selective
Detector equipped with an electron impact ionizer at 70 eV. All 1H NMR and 13C NMR spectra were recorded at
400 MHz, 100.6 MHz respectively, using a Bruker DRX-ADVANCE 400 MHz spectromer. CDCl3 was used as
deuterated solvent. Chemical shift was reported in ppm and coupling costants in Hertz. All melting points were
measured with Buchi Melting Point 510 apparatus and are uncorrected. Elemental analyses were realized by using
a FISONS instrument EA 1108 CHN. Column chromatographies were performed by using silica gel 230-400
mesh and eluting as reported in the following characterization charts. Benzaldehyde 1a was distilled before using.
All other chemicals were purchased and used without any further purification. PS-BEMP (200-400 mesh, 2%
DVB, 2.2 mmol BEMP/g) was purchased from Aldrich. Compounds 3aa (1), 3ab (2), 3ba(3), 3ca (3), 3ea (4),
3eb (1), 3ec (5), 3fb (1), 3ga (6), 3gb (2), 3gc (5), 3hc (7) and 3ic (7) are known compounds but essential
characterization data (1H NMR, 13C NMR and GC-EIMS) were reported for clarity, whereas products 3ad, 3ed,
3fa, 3fc, 3fd and 3gd are new compounds.
Representative batch procedure for Henry reaction of aromatic aldehydes 1a-d.
In a screw-capped vial equipped with a magnetic stirrer, PS-BEMP (0.044 g, 0.05 mmol, 2.2 mmol/g),
benzaldehyde (1a) (0.102 mL, 1.0 mmol) and nitroethane (2a) (0.072 mL, 1.0 mmol) were consecutively added
and the resulting mixture was left under stirring at 30 °C. After 15 hours, dichloromethane (1 mL) was added, the
catalyst was recovered by filtration and the solvent was removed under vacuum. The unreacted benzaldehyde was
removed by chromatography (eluent: petroleum ether/AcOEt, 95:5) to give a 38/62 mixture of two
diastereoisomers of 2-nitro-1-phenylpropan-1-ol (3aa) as a colorless oil (0.130 g, 72% yield).
1-phenyl-2-nitro-1-propanol (3aa): the product was isolate as a mixture of diasteroisomers (syn/anti 38/62). Oil;
1H
NMR (CDCl3, 400 MHz) δ (ppm) 1.32 (d, J = 6.8 Hz, 3H, anti), 1.50 (d, J = 6.8, 3H, syn), 2.40-2.90 (bs, 2H),
4.65-4.85 (m, 2H), 5.03 (d, J = 9.0 Hz, 1H, anti), 5.40 (d, J = 3.5 Hz, 1H, syn), 7.30-7.50 (m, 10H); 13C-NMR
(100.6 MHz) δ 138.3, 129.2, 129.0, 128.7, 128.5, 126.9, 125.9, 88.4, 87.4, 76.3, 73.9, 16.4, 12.1; GC/EIMS (m/z)
syn: 134 (89), 107 (100), 79 (80), 77 (67); anti: 181(M+, 1), 107 (100), 79 (60), 77 (48). Anal. Calcd. for
C9H11NO3: C, 59.66; H, 6.12; N, 7.73. Found: C, 59.87; H, 6.15; N, 7.69.
1-phenyl-2-nitro-1-ethanol (3ab): Oil; 1H NMR (CDCl3, 400 MHz) δ (ppm) 4.46 (dd, J= 2.9, 13.2 Hz, 1H), 4.56
(dd, J = 9.5 Hz, 1H), 5.39 (dd br, 1H), 7.37 (sb, 5H); 13C NMR (CDCl3, 100.6 MHz) δ (ppm) 138.2, 128.9 (2C),
125.6 (3C), 81.2, 70.9. Anal. Calcd. for C8H9NO3: C, 57.48; H, 5.43; N, 8.38. Found: C, 57.21; H, 5.40; N, 8.36.
1-nitrocyclopentyl-1-phenyl-methanol (3ad): Oil; 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.48-1.69 (m, 4H), 2.002.10 (m, 2H), 2.35-2.37 (m, 1H), 2.57-2.59 (m, 1H), 2.78 (s broad, 1H), 5.30 (s, 1H), 7.30-7.38 (m, 5H); 13C NMR
(CDCl3, 100.6 MHz) δ (ppm) 138.5, 128.7, 128.4 (2C), 127.2 (2C), 104.1, 77.0, 34.7, 31.9, 23.8, 23.7; GC/EIMS
(m/z) 106 (17), 105 (16), 77 (21), 69 (100), 68 (18), 67 (29), 51 (15), 43 (30). Anal. Calcd. for C12H15NO3: C,
65.14; H, 6.83; N, 6.33. Found: C, 65.40; H, 6.79; N, 6.29.
1-(4-chlorophenyl)-2-nitro-1-propanol (3ba): the product was isolated as a mixture of diasteroisomers (syn/anti
43/57). Oil; 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.25 (d, J = 6.8 Hz, 3 H), 1.46 (d, J = 6.8 Hz, 3H), 2.91(d, J =
4.1 Hz, 1H), 4.64-4.68 (m, 1H), 4.69-4.76 (m, 1H), 4.97 (dd, J = 3.9, 8.9 Hz, 1H), 5.34 (t, J = 3.6 Hz, 1H), 7.337.40 (m, 8H); 13C NMR (CDCl3, 100.6 MHz) δ (ppm) 136.9, 136.7, 135.0, 134.3, 129.1, 128.9, 128.2, 127.3, 88.1,
87.2, 75.4, 73.2, 16.3, 11.9; GC/EIMS (m/z) 140 (73), 139 (100), 111 (46), 75 (31). Anal. Calcd. for C9H10ClNO3:
C, 50.13; H, 4.67; N, 6.50. Found: C, 50.34; H, 4.69; N, 6.46.
1-(4-nitrophenyl)-2-nitro-1-propanol (3ca): the product was isolated as a mixture of diasteroisomers (syn/anti
35/65). Pale yellow solid (m.p. 91-93°C); 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.38 (d, J = 6.9 Hz, 3H), 1.48 (d, J
= 6.8 Hz, 3H), 2.30-3.10 (bs, 2H), 4.65-4.81 (m, 2H), 5.19 (d, J = 8.5 Hz, 1H), 5.56 (d, J = 3.1 Hz, 1H), 7.50-7.70
(m, 4H), 8.20-8.30 (m, 4H);
13C
NMR (CDCl3, 100.6 MHz) δ (ppm) 148.3, 147.9, 145.4, 145.2, 127.9, 127.0,
124.1, 124.0, 87.7, 86.8, 75.0, 72.9, 16.2, 11.9; GC/EIMS (m/z) 151 (100), 150 (94), 77 (59). Anal. Calcd. for
C9H10N2O5: C, 47.79; H, 4.46; N, 12.39. Found: C, 48.01; H, 4.44; N, 12.82.
Representative batch procedure for Henry reaction of aliphatic aldehydes 1e-g.
In a screw-capped vial equipped with a magnetic stirrer, PS-BEMP (0.044 g, 0.05 mmol, 2.2 mmol/g), hexanal
(3f) (0.120 mL, 1.0 mmol) and nitroethane (2a) (0.072 mL, 1.0 mmol) were consecutively added and the resulting
mixture was left under stirring at 30°C. After 2 hours, dichloromethane (1 mL) was added, the catalyst was
recovered by filtration and the solvent and unreacted reagents were removed under vacuum to give pure 2nitrooctan-3-ol (3fa) as a colorless oil (0.160 g, 92% yield).
2-nitropentan-3-ol (3ea): the product was isolated as a mixture of diasteroisomers (syn/anti 46/54). Oil; 1H NMR
(CDCl3, 400 MHz) δ (ppm) 1.03 (dt, J = 2.9, 7.4 Hz, 6H), 1.45-1.70 (m, 10H), 2.10-2.40 (bs, 2H), 3.85 (m, 1H),
4.11 (m, 1H), 4.50-4.65 (m, 2H); 13C NMR (CDCl3, 100.6 MHz) δ (ppm) 87.5, 86.1, 74.1, 73.5, 26.1, 25.8, 16.1,
12.2, 10.1, 9.4; GC/EIMS (m/z) diasteroisomer A: 76 (45), 75 (34), 59 (32), 57 (42), 45 (100); diasteroisomer B:
76(34), 75 (35), 59 (32), 57 (48), 45 (100). Anal. Calcd. for C5H11NO3: C, 45.10; H, 8.33; N, 10.52. Found: C,
44.89; H, 8.29; N, 10.47.
1-nitro-2-butanol (3eb): Oil; 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.02 (t, J = 7.4 Hz, 3H), 1.50-1.70 (m, 2H),
2.20-2.60 (bs, 1H), 4.15-4.30 (m, 1H), 4.38 (dd, J = 13.2, 8.4 Hz, 1H), 4.44 (dd, J = 13.2, 2.9 Hz, 1H); 13C NMR
(CDCl3, 100.6 MHz) δ (ppm) 80.4, 70.0, 26.9, 9.5; GC/EIMS (m/z) 62(72), 59 (41), 55 (100), 44 (40), 43 (82).
Anal. Calcd. for C4H9NO3: C, 40.33; H, 7.62; N, 11.76. Found: C, 40.50; H, 7.58; N, 11.80.
2-nitro-2-methyl-3-pentanol (3ec): Oil; 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.02 (t, J = 7.3 Hz, 3H), 1.25-1.35
(m, 1H), 1.45-1.60 (m, 1H), 1.50 (s, 3H), 1.52 (s, 3H), 2.50-2.70 (bs, 1H), 3.88 (d, J = 10.6 Hz, 1H); 13C NMR
(CDCl3, 100.6 MHz) δ (ppm) 92.1, 77.4, 24.3, 23.5, 20.1, 10.8; GC/EIMS (m/z) 89 (51), 59 (100), 45 (69), 43
(45). Anal. Calcd. for C6H13NO3: C, 48.97; H, 8.90; N, 9.52. Found: C, 49.19; H, 8.92; N, 9.47.
1-(1-nitrocyclopentyl)-1-propanol (3ed): Oil; 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.02 (t, J = 7.3 Hz, 3H), 1.151.30 (m, 1H), 1.45-1.60 (m, 1H), 1.60-1.85 (m, 5H), 2.05-2.20 (m, 1H), 2.35-2.45 (m, 1H) 2.45-2.60 (m, 2H),
3.74 (dd, J = 10.5, 1.9 Hz, 1H); 13C NMR (CDCl3, 100.6 MHz) δ (ppm) 103.5, 77.3, 35.4, 33.6, 25.5, 24.7, 24.5,
10.9; GC/EIMS (m/z) 109 (41), 97 (41), 68 (66), 67 (100), 59 (42). Anal. Calcd. for C8H15NO3: C, 55.47; H, 8.73;
N, 8.09. Found: C, 55.20; H, 8.68; N, 8.05.
2-nitrooctan-3-ol (3fa): the product was isolated as a mixture of diasteroisomers (syn/anti 46/54). Oil; 1H NMR
(CDCl3, 400 MHz) δ (ppm) 0.75-0.90 (m, 6H), 1.15-1.60 (m, 22H), 3.00-3.20 (bs, 2H), 3.75-3.90 (m, 1H), 4.004.10 (m, 1H), 4.35-4.45 (m, 2H); 13C NMR (CDCl3, 100.6 MHz) δ (ppm) 87.6, 86.2, 72.7, 72.0, 32.8, 32.4, 31.3,
31.2, 25.1, 24.5, 22.2, 22.1, 15.6, 13.6, 11.9; GC/EIMS (m/z) diasteroisomer A: 76 (64), 69 (100), 57 (81), 55
(96), 43 (80): diasteroisomer B: 76 (43), 69 (100), 57 (68), 55 (87), 43 (65). Anal. Calcd. for C8H17NO3: C, 54.84;
H, 9.78; N, 7.99. Found: C, 55.09; H, 9.81; N, 8.02.
1-nitro-2-heptanol (3fb): Oil; 1H NMR (CDCl3, 400 MHz) δ (ppm) 0.84 (t, J = 6.6 Hz, 3H), 1.20-1.60 (m, 8H),
3.15-3.30 (bs, 1H), 4.20-4.30 (m, 1H), 4.30-4.40 (m, 2H);
13C
NMR (CDCl3, 100.6 MHz) δ (ppm) 80.6, 68.7,
33.6, 31.3, 24.7, 22.3, 13.7; GC/EIMS (m/z) 71 (27), 58 (23), 57 (22), 55 (100), 43 (74). Anal. Calcd. for
C7H15NO3: C, 52.16; H, 9.38; N, 8.69. Found: C, 52.38; H, 9.33; N, 8.73.
2-nitro-2-methyloctan-3-olo (3fc): Oil; 1H NMR (CDCl3, 400 MHz) δ (ppm) 0.91 (t, J = 6.4 Hz, 3H), 1.20-1.50
(m, 8H), 1.55 (s, 3H), 1.57 (s, 3H), 2.50-2.60 (bs, 1H) 4.01 (d, J = 10.1 Hz, 1H); 13C NMR (100.6 MHz) δ (ppm)
92.1, 75.9, 31.5, 31.3, 26.0, 23.5, 22.5, 20.2, 13.9; GC/EIMS (m/z) 89 (100), 71 (41), 69 (48), 59 (62), 57 (47), 55
(46), 43 (64). Anal. Calcd. for C9H19NO3: C, 57.12; H, 10.12; N, 7.40. Found: C, 56.86; H, 10.07; N, 7.44.
1-(1-nitrocyclopentyl)-1-hexanol (3fd): Oil; 1H NMR (CDCl3, 400 MHz) δ (ppm) 0.89 (t, J = 6.3 Hz, 3H), 1.201.40 (m, 5H), 1.40-1.55 (m, 1H), 1.55-1.70 (m, 3H), 1.70-1.90 (m, 4H), 2.10-2.20 (m, 2H), 2.30-2.50 (m, 1H),
2.55-2.70 (m, 1H), 3.81 (d, J = 9.1 Hz, 1H); 13C NMR (100.6 MHz) δ (ppm) 103.5, 75.9, 35.6, 33.6, 32.4, 31.5,
25.9, 24.8, 24.6, 22.5, 13.9; GC/EIMS (m/z) 115 (100), 95 (53), 69 (48), 68 (70), 67 (73), 55 (50). Anal. Calcd. for
C11H21NO3: C, 61.37; H, 9.83; N, 6.51. Found: C, 61.10; H, 9.87; N, 6.47.
1-cyclohexyl-2-nitro-1-propanol (3ga): the product was isolated as a mixture of diasteroisomers (syn/anti 46/54).
Oil; 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.00-1.50 (m, 12H), 1.50-1.65 (m, 7H), 1.65-1.80 (m, 4H), 1.80-1.90
(m, 4H), 2.00-2.03 (m, 3H), 3.65 (dd, J = 6.7, 5.0 Hz, 1H),3.95 (dd, J = 8.3, 3.0 Hz, 1H), 4.60-4.70 (m, 1H), 4.704.80 (m, 1H); 13C NMR (100.6 MHz) δ (ppm) 85.6, 84.2, 76.8, 76.3, 40.1, 39.5, 29.7, 28.7, 26.0, 25.9, 25.8, 25.7,
25.5, 16.2, 11.6; GC/EIMS (m/z) diasteroisomer A: 123 (21), 95 (32), 83 (75), 81 (36), 55 (100); diasteroisomer
B: 123 (34), 95 (35), 83 (74), 81 (42), 55 (100). Anal. Calcd. for C9H17NO3: C, 57.73; H, 9.15; N, 7.48. Found: C,
58.00; H, 9.19; N, 7.44.
1-cyclohexyl-2-nitro-1-ethanol (3gb): Oil; 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.05-1.35 (m, 5H), 1.40-2.00 (m,
6H), 2.20-2.60 (bs, 1H), 4.10-4.15 (m, 1H), 4.35-4.50 (m, 2H); 13C NMR (100.6 MHz) δ (ppm) 79.2, 72.7, 41.2,
28.5, 27.7, 25.8, 25.6, 25.5; GC/EIMS (m/z) 99 (28), 83 (95), 67 (22), 55 (100). Anal. Calcd. for C8H15NO3: C,
55.47; H, 8.73; N, 8.09. Found: C, 55.23; H, 8.69; N, 8.13.
1-cyclohexyl-2-methyl-2-nitro-1-propanol (3gc): Oil; 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.57 (s, 3H), 1.58 (s,
3H), 1.15-1.74 (m, 11H), 2.97 (bs, 1H), 3.77 (d, J = 3.6 Hz, 1H); 13C NMR (100.6 MHz) δ (ppm) 92.0, 79.8, 39.8,
32.3, 28.9, 27.0, 26.6, 26.1, 23.8, 22.4; GC/EIMS (m/z) 95 (50), 89 (44), 83 (62), 55 (100). Anal. Calcd. for
C10H19NO3: C, 59.68; H, 9.52; N, 6.96. Found: C, 59.95; H, 9.56; N, 6.93.
1-cyclohexyl-(1-nitrocyclopentyl)-methanol (3gd): Oil; 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.12-1.90 (m, 15H),
2.12-2.18 (m, 1H), 2.28-2.35 (m, 1H), 2.45-2.50 (m, 1H), 2.58-2.64 (m, 1H), 3.60 (d, J = 4.3 Hz, 1H); 13C NMR
(100.6 MHz) δ (ppm) 102.8, 80.0, 40.9, 36.1, 35.0, 31.6, 28.7, 25.6, 25.3, 24.4, 24.0; GC/EIMS (m/z) 128 (23), 83
(41), 73 (61), 69 (21), 68 (33), 67 (23), 56 (32), 55 (100), 45 (29), 43 (24). Anal. Calcd. for C12H21NO3: C, 63.41;
H, 9.31; N, 6.16. Found: C, 63.12; H, 9.26; N, 6.19.
General procedure for regeneration of PS-BEMP.
In a round bottom flask equipped with a magnetic stirrer, PS-BEMP (1.0 g, 2.2 mmol, 2.2 mmol/g) was suspended
in a solution of BEMP (1.270 mL, 4.4 mmol) in AcOEt (4.4 mL) and stirred at room temperature. After one hour,
the solvent was filtered off, the PS-BEMP was washed twice with AcOEt and dried under high vacuum for 48
hours at room temperature.
Representative batch procedure for tandem Michael-Henry reaction of α,β-unsaturated aldehydes 1h-i.
In a screw-capped vial equipped with a magnetic stirrer, PS-BEMP (0.088 g, 0.1 mmol, 2.2 mmol/g) and 2nitropropane (2c) (0.2 mL, 2.2 mmol) were consecutively added; trans-cinnamaldehyde (1h) (0.126 mL, 1mmol)
was slowly added (the reaction was exotermic) and the resulting mixture was left under stirring at 30°C. After 15
hours, dichloromethane (1 mL) was added, the catalyst was recovered by filtration and the solvent was removed
under vacuum to give pure 2,6-dimethyl-2,6-dinitro-5-phenylheptan-3-ol (3hc) as a white solid (0.285 g, 92%
yield).
2,6-dimethyl-2,6-dinitro-5-phenylheptan-3-ol (3hc): white solid, m.p. 111-112°C; 1H NMR (CDCl3, 400 MHz) δ
(ppm) 1.42-1.49 (m, 9H), 1.52-1.55 (m, 1H), 1.55 (s broad, 3H), 1.93 (t, J = 12.8 Hz, 1H), 2.45 (s broad, 1H), 3.52
(d broad, J = 10.7 Hz, 1H), 3.67 (dd, J = 2.2, 12.3 Hz, 1H), 7.14-7.20 (m, 2H), 7.30-7.36 (m, 3H);
13C
NMR
(100.6 MHz) δ (ppm) 136.5, 129.6, 129.4, 129.2, 128.7, 128.1, 91.6, 91.5, 72.9, 50.2, 31.2, 25.6, 23.0, 22.3, 20.7;
GC/EIMS (m/z) 174 (20), 157 (44), 131 (73), 129 (29), 117 (25), 116 (20), 115 (36), 105 (89), 103 (26), 91 (100),
77 (40), 51 (20), 43 (17). Anal. Calcd. for C10H20N2O5: C, 48.38; H, 8.12; N, 11.28. Found: C, 48.09; H, 8.16; N,
11.33.
2,5,6-trimethyl-2,6-dinitroheptan-3-ol (3ic): white solid, m.p. 84-85°C; 1H NMR (CDCl3, 400 MHz) δ (ppm) 0.96
(d, J = 6.8 Hz, 3H), 1.06-1.10 (m, 1H), 1.28-1.31 (m, 1H), 1.48-1.58 (m, 12H), 2.20-2.48 (s broad, 1H), 2.48-2.56
(m, 1H), 4.05 ( d, J = 10.8 Hz, 1H); 13C NMR (100.6 MHz) δ (ppm) 92.0, 91.9, 73.1, 37.9, 33.5, 23.6, 23.0, 22.6,
20.8, 14.1; GC/EIMS (m/z) 95 (70), 83 (12), 70 (21), 69 (63), 67 (16), 55 (36), 43 (100). Anal. Calcd. for
C15H22N2O5: C, 58.05; H, 7.15; N, 9.03. Found: C, 58.33; H, 7.18; N, 9.07.
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