Organic Syntheses, Vol. 77, 236
Checked by James P. Davidson and Stephen F. Martin.
1. Procedure
B. 3-Nitropropanol (2). A 1-L, round-bottomed flask, equipped with a magnetic stirring bar and a Schlenk-type adapter (Note
1), is charged with
47.0 g (0.456 mol) of crude 3-nitropropanal and
450 mL of methanol (Note
10). To the stirred solution at −20°C (Note
11) is added
17.26 g (0.456 mol) of sodium borohydride (Note
12) in 10 portions over a period of 30 min; stirring at this temperature is continued for 1 hr.
Methyl orange (0.1 mL of 0.1% solution in water) is added to the solution, followed by about
50 mL of 7.5 N hydrochloric acid in
methanol (Note
13) until the suspension turns pink (Note
14). After stirring is continued at −20°C for another 30 min, the mixture is allowed to warm to room temperature over a period of 15 min and then concentrated by rotary evaporation (30°C, 20 mbar, 15 mm). The pink residue is treated with 85 g of ice and
450 mL of ethyl acetate (Note
7), then transferred to a 1-L separatory funnel. The organic layer is separated and washed with a mixture of 1 N aqueous
potassium bicarbonate and
brine (2 × 20 mL, 1:3). The aqueous layers are combined and extracted with
ethyl acetate (2 × 100 mL, (Note 7)) as described above. The combined organic solutes are thoroughly dried (MgSO
4, stirring for 2 hr), filtered, and concentrated by rotary evaporation (20 mbar, 15 mm, 30°C). The residual yellow oil is purified by distillation (Note
8) in a Kugelrohr apparatus (air bath temperature: 70°C, 0.034 mbar, 0.02 mm; the product is collected by cooling with ice; duration of the distillation: ca. 90 min) to yield
34.3-34.8 g (
73-74%;
65-66%, overall) of pure
3-nitropropanol as a pale yellow oil (Note
15).
2. Notes
1. The reaction mixture is kept under
nitrogen passed through a
Sicapent® (E. Merck) drying tube.
2.
Sodium nitrite (NaNO2) p.a. was obtained in 1-kg samples from Merck-Schuchardt, Hohenbrunn, Germany.
3. Smaller amounts of water decrease the yield of
3-nitropropanal. If absolute solvents and reagents are used, only 10% of the
nitroaldehyde is obtained.
4.
Tetrahydrofuran (THF) p.a. was purchased from Merck-Schuchardt, Hohenbrunn, Germany.
5.
Acrolein p.a. from Merck-Schuchardt, Hohenbrunn, Germany was distilled prior to use through a
20-cm, silver-plated, Vigreux column with a 4-cm outer and 1.5-cm inner diameter (bp
52°C).
6. The reaction is carried out in the dark to avoid decomposition and side reactions.
Acetic acid p.a. was obtained from Merck-Schuchardt, Hohenbrunn, Germany.
7.
Ethyl acetate (technical grade) was purified by distillation. The checkers found that
reagent grade ethyl acetate could be used without purification.
8.
Caution! See introductory warning. The submitters report that
1 can be distilled in a Kugelrohr apparatus using a manifold with high-vacuum stopcocks (air bath temperature: 55°C, 0.001 mbar, 0.0007 mm); the product is collected by cooling with ice; duration of the distillation: ca. 90 min; ventilation with
nitrogen should occur after ice-cooling of the distillation flask) to afford analytically pure, almost colorless
1 in 75% yield (GLC analysis: R
t = 7.1 min, content of
1 >99%, see (Note
9) for conditions).
Explosion hazard! Do not attempt to distill 1 unless 0.001 mbar (0.0007 mm) vacuum is available; the temperature of the bath should not exceed 60°C. The checkers found that distillation of the product at 0.04 mbar (0.03 mm), 70°C gave
35-40% yield of
1 as a yellow oil, and that the distillation residues, even when cooled and ventilated with an inert atmosphere, were prone to violent decomposition.
9. GLC analysis is as follows: R
t = 7.1 min, content of
1 >95% [column PS 086/.32 mm × 20 m glass capillary, 86:14 dimethyl/phenyl silicone; on-column injection; program: T
1 = 40°C (1 min), rate 5°C/min, T
2 = 300°C; carrier gas: 0.4 bar (300 mm) H
2]. The content of
1 is >90% according to
1H and
13C NMR. The product thus obtained decomposes on storage and should be used for further transformations within a few days. The spectroscopic data of
3-nitropropanal are as follows:
13C NMR (125 MHz, CDCl
3) δ: 39.5, 67.7, 197.2;
1H NMR (500 MHz, CDCl
3) δ: 3.19 (t, 2 H, J = 6.0), 4.69 (t, 2 H, J = 6.0), 9.79 (s, 1 H); IR (CHCl
3) cm
−1: 2844, 1723, 1561, 1375; mass spectrum (CI) m/z 104.0350 [C
3H
6NO
3(M+1) requires 104.0348] 104 (base), 86.
10.
Methanol p.a. was obtained from Merck-Schuchardt, Hohenbrunn, Germany.
11. The temperature of the
isopropyl alcohol bath was monitored by a cold finger device TK-300, Fryka Kältetechnik, Germany.
12.
Sodium borohydride (NaBH4) was obtained in 100-g samples (>97%) from Fluka Feinchemikalien GmbH, Neu-Ulm, Germany.
13.
Hydrogen chloride, passed through a Sicapent® (E. Merck) drying tube, was fed into
500 mL of methanol (Note
10) over a period of 15 min at 0°C. The titer of the solution (7.5 N) was determined by titration with 1.0 N
sodium hydroxide, Titriplex Merck-Schuchardt, Hohenbrunn, Germany against
phenolphthalein as indicator.
14. The checkers found that pH indicator paper (sensitivity +/− 1 pH unit) can also be used to monitor the acidity of the solution to pH 3.
15. GLC analysis (see (Note
9) for conditions): R
t = 8.3 min, content of
2 >98%. For further purification the submitters find that the product can be distilled under reduced pressure through a
35-cm, silver-plated Vigreux column with 6-cm outer and 2-cm inner diameter (bp = 65-67°C, 0.001 mbar, 0.0007 mm); purity from GLC analysis >99.5%). The spectroscopic data of
3-nitropropanol are as follows:
13C NMR (125 MHz, CDCl
3) δ: 29.8, 58.9, 72.6;
1H NMR (500 MHz, CDCl
3) δ: 2.24 (tt, 2 H, J = 5.8, 6.8), 2.56 (bt, 1 H, J = 4.6), 3.73 (dt, 2 H, J = 4.6, 5.8), 4.55 (t, 2 H, J = 6.8); IR (CHCl
3) cm
−1: 3620, 3424, 2939, 2891, 1552, 1433, 1382; mass spectrum (CI) m/z 106.0503 [C
3H
8NO
3(M+1) requires 106.0504] 106 (base), 88.
16.
Trimethyl orthoformate (>97%) was obtained from Fluka Feinchemikalien GmbH, Neu-Ulm, Germany and distilled prior to use, bp
101°C.
19.
Charcoal p.a., obtained from Merck-Schuchardt, Hohenbrunn, Germany, was used to decolorize the dark brown solution.
20. GLC analysis (see (Note
9) for conditions): R
t = 12.9 min, content of
3 >99%. The spectroscopic data of
3-nitropropanal dimethyl acetal 3 are as follows:
13C NMR (125 MHz, CDCl
3) δ: 30.5, 54.0, 71.2, 101.9;
1H NMR (500 MHz, CDCl
3) δ: 2.31 (dt, 2 H, J = 5.4, 6.8), 3.37 (s, 6 H), 4.46 (t, 2 H, J = 6.8), 4.48 (t, 1 H, J = 5.4); IR (CHCl
3) cm
−1: 2938, 2837, 1556, 1447, 1378; mass spectrum (CI) m/z 150.0761 [C
5H
12NO
4(M+1) requires 150.0766] 118 (base), 150.
21. From
1, various other acetals are available under standard conditions, cf. Section 3 (Discussion). For example, following the described procedure, submitters indicate that
3-nitropropanal diethyl acetal is prepared by reaction of
30.9 g (0.300 mol) of 3-nitropropanal,
53.4 g (0.360 mol) of triethyl orthoformate, and
1.0 g of p-toluenesulfonic acid monohydrate in
100 mL of ethanol; yield:
44.5 g (
84%). GLC analysis (see (Note
9) for conditions): R
t = 14.5 min, content >99.5%. The spectroscopic data of
3-nitropropanal diethyl acetal are as follows:
13C NMR (125 MHz, CDCl
3) δ: 15.2, 31.5, 62.6, 71.4, 100.0;
1H NMR (500 MHz, CDCl
3) δ: 1.21 (t, 6 H, J = 7.0), 2.30 (dt, 2 H, J = 5.3, 6.8), 3.51 (dq, 2 H, J = 7.0, 9.3), 3.68 (dq, 2 H, J = 7.0, 9.3), 4.49 (t, 2 H, J = 6.8), 4.61 (t, 1 H, J = 5.3).
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995 and "Neue Datenblätter für gefährliche Arbeitsstoffe nach der Gefahrstoffverordnung", Welzbacher, U. (Ed.); WEKA Fachverlage, Kissing, 1991.
3. Discussion
Aliphatic nitro compounds are versatile building blocks and intermediates in organic synthesis,
18 19 20 21,22 23 24 25 cf. the overview given in the
Organic Syntheses preparation of
nitroacetaldehyde diethyl acetal.
26 For example, Henry and Michael additions, respectively, lead to 1,2- and 1,4-difunctionalized derivatives.
18,19,20,21,22,23,24,25,26,27,28 29 30 1,3-Difunctional compounds, such as amino alcohols or aldols are accessible from primary nitroalkanes by dehydration/1,3-dipolar nitrile oxide cycloaddition with olefins (Mukaiyama reaction),
31 followed by ring cleavage of intermediate isoxazolines by reduction or reduction/hydrolysis.
32 33 34 35 36 37 38,39 40 41
For synthesis of more complex target molecules by these strategies, nitroalkanes with additional O-functions are often required. Specifically, the above CC-forming additions lead to a variety of 1,3,4-, 1,3,5- and 1,3,6-functionalized structures, as shown with 3 (or nitropropyl ethers, from 2).
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