The Nitro Group in Organic Synthesis
.pdf3.2 DERIVATIVES FROM β-NITRO ALCOHOLS 41
filtered from the reaction mixture and may be reused.61 With the use of this new heterogeneous catalyst, nitroolefins are prepared directly by heating a mixture of aldehyde and nitroalkane at 100 °C in the absence of solvents (Eq. 3.36).
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Envirocat EPZG |
Me |
CHO |
+ |
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NO2 |
NO2 (3.36) |
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100 ºC, 20 min |
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95% |
Application of ultrasound62 or microwave irradiation63 greatly assists these condensation reactions as shown in Eqs. 3.37 and 3.38, respectively, rendering the use of a Dean-Stark apparatus unnecessary.
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OMe |
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Condition |
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Yield (%) |
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MeO |
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CHO |
+ |
CH3NO2 |
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NH4OAc/ AcOH |
35 |
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OMe |
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100 ºC, 3 h |
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MeO |
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NO2 NH4OAc/ AcOH |
99 |
(3.37) |
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22 ºC, 3 h, )))) |
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Cl |
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N |
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NO2 |
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+ |
CH3CH2NO2 |
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(3.38) |
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CHO |
Microwave |
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Me |
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400 W |
64% |
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8 min |
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Reactions of methyl nitroacetate with aldehydes are induced by TiCl4 in pyridine. They afford
nitroalkenyl-esters,64 which are used in the preparation of various nonnatural amino acids (Eq. 3.39).65
CHO |
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NO2 |
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TiCl4 |
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CO2Me |
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+ O2N |
CO2Me |
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N |
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O N Me |
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N |
(3.39) |
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Me |
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Me |
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THF, 0–25 ºC |
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75% |
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Nitroalkenes prepared from aromatic aldehydes are especially useful for natural product synthesis. For example, the products are directly converted into ketones via the Nef reaction (Section 6.1) or indoles (Section 10.2) via the reduction to phenylethylamines (Section 6.3.2). The application of these transformations are discussed later; here, some examples are presented to emphasize their utility. Schemes 3.3 and 3.4 present a synthesis of 5,6-dihydroxyindole66 and asperidophytine indole alkaloid,67 respectively.
Seebach and coworkers have developed the multiple coupling reagent, 2-nitro-2-propenyl 2,2-dimethylpropanoate (NPP). The reaction of nitromethane with formaldehyde gives 1,3- dihydroxy-2-nitropropane in 95% yield. Subsequent acylation with two equivalents of pivaloyl chloride and elimination of pivalic acid affords NPP. The reaction may be run on a 40to 200-g
42
HO
HO
MeO
MeO
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THE NITRO-ALDOL (HENRY) REACTION |
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CHO |
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HO |
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NO2 |
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CH3NO2 |
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C(NO2)4, ZnSO4 |
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NH4OAc-AcOH |
HO |
95% |
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EtOH |
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HO |
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NO2 |
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HO |
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Na2S2O4, ZnSO4 |
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HO |
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NO2 |
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pH 4 |
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HO |
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N |
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70% |
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H |
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52% |
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Scheme 3.3. Synthesis of 5,6-dihydroxyindole |
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NO2 1) Fe, AcOH, silica gel, |
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1) POCl |
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, DMF, 35 ºC, |
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toluene, ∆ |
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3 |
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MeO |
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1 h, then NaOH aq |
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NO2 |
2) MeI, KOH, Bu4NI, |
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Me |
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2) MeNO2, NH4OAc, |
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THF, 23 ºC |
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OMe |
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∆, 1 h |
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67% |
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NH2 |
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OHC |
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LiAlH4, THF, ∆, 1 h |
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SiMe3 |
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MeO |
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N |
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MeCN, 23 ºC, then TFA, |
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Me |
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Me |
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0 ºC, then NaBH3CN, |
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OMe |
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OMe |
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23 ºC |
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91% |
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88% |
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O |
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N H |
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Oi-Pr |
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N |
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MeO |
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N H |
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MeO |
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OMe |
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Me |
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OMe |
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66% |
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aspidophytine |
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Scheme 3.4. Synthesis of aspidophytine
scale without problems (Eq. 3.40).68 NPP allows successive introduction of two different nucleophiles Nu1 and Nu2 as shown in Eq. 3.41. The conversion of the resulting products via the Nef reaction or reduction into various compounds, makes NPP a useful reagent for convergent syntheses, as demonstrated in Eqs. 3.42 and 3.43.
CH NO |
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NO |
2 |
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NO2 |
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3 2 |
1) MeONa/MeOH |
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t-BuCOCl |
t-Bu O |
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O t-Bu |
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+ |
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HO |
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OH |
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HCHO |
2) Salicylic acid |
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75% |
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NO2 |
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O |
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O |
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AcONa |
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O |
t-Bu |
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O |
(3.40) |
NPP
45%
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3.2 DERIVATIVES FROM β-NITRO ALCOHOLS 43 |
||||
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O |
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NO2 |
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Nef |
Nu |
1 |
Nu |
2 |
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Nu1 |
Nu2 |
NO2 |
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NPP |
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(3.41) |
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Nu1 |
Nu1 |
Nu2 |
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NH2 |
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Reduction |
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Nu1 |
Nu2 |
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NO2 |
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Li |
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OEt |
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NPP |
OLi |
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THF, –70 °C |
THF, –70 °C |
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NO2 |
88% |
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O |
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N |
(3.42) |
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OEt |
H2/Ni |
H |
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Et2O-EtOH |
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O |
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66% |
82% |
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OLi |
O |
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NO2 |
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NPP |
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n-C4H9Li |
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THF, –70 |
°C |
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THF, –70 °C |
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NO2 |
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77% |
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O |
75% |
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1) MeONa/ MeOH |
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(3.43) |
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2) H2SO4 |
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O |
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78% |
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Chiral multiple-coupling reagents have been prepared in enantiomerically pure form by enantio-selective saponification of diesters of meso-2-nitrocyclohexane-1,3-diols (Eq. 3.44) with pig liver esterase (PLE).69
|
NO2 |
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NO2 |
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NO2 |
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HO |
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OAc |
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t-Bu |
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O |
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AcO |
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OAc |
PLE |
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1) Piv2O |
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2) MeOH/H+ |
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O |
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90% (95% ee) |
3) DCC/CuCl |
|
67% |
(3.44) |
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The nitro-aldol reaction followed by dehydration gives 2-nitro-1,3-dienes, which are useful reagents for cycloaddition (Eq. 3.45).70
|
CH3NO2 |
OH |
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O |
OTHP |
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NO2 |
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NO2 |
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O |
MeONa |
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H+ |
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1) HCHO, MeONa |
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O |
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(3.45) |
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O |
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Ph |
heat |
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2) PhCOCl |
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NO2 |
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NO2 |
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65% (overall) |
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44 THE NITRO-ALDOL (HENRY) REACTION
The nitro-aldol approach is impractical for the synthesis of 2,2-disubstituted 1-nitroalkenes due to the reversibility of the reaction when ketones are employed as substrates. Addition-elimination reactions are used for the preparation of such nitroalkenes (see Chapter 4).
3.2.2 Nitroalkanes
Reduction of nitroalkenes with NaBH4 has been widely used for the synthesis of nitroalkanes.71 In some cases, however, small amounts of dimeric products are also formed, although their formation can be completely suppressed using acidic conditions.72 Silica gel is also effective in preventing the dimerization of nitrostyrenes. 2-Aryl-1-nitroethanes are obtained in near quantitative yields by the reduction with NaBH4.73 This route provides a simple route to phenylethylamines of biochemical and pharmacological interest.74 A simple and efficient method for the large-scale preparation of phenylnitroethanes has been reported, in which solutions of nitrostyrenes in 1,4-dioxane are added to an efficiently stirred suspension of NaBH4 in a mixture of 1,4-dioxane and ethanol (Eq. 3.46).75 Hydrogenation of nitrostyrene derivatives with bis(triphenylphosphine)rhodium chloride (Wilkinson catalyst) gives also good yields of products.76
NO2 |
1) NaBH4, dioxane-EtOH |
|
|
NO2 |
|
30 ºC, 1.5 h |
|
|
|
(3.46) |
|
|
2) AcOH |
|
|
||
|
95% |
||||
|
|
|
The reduction of nitroalkenes with ZnBH4 in 1,2-dimethoxyethane (DME) gives the corresponding oximes or nitroalkanes depending on the structure of nitroalkenes. α-Substituted nitroalkenes are reduced to the oximes, whereas those having no α-substituents afford the nitroalkanes (Eq. 3.47).77
MeO |
NO2 |
MeO |
NO2 |
ZnBH4 |
|
||
|
|
|
DME |
MeO |
(3.47) |
|
MeO
86%
Very selective reduction of nitroalkenes into the corresponding nitroalkanes is achieved using NaCNBH3 in the presence of the zeolite H-ZSM 5 in methanol (Eq. 3.48).78
O |
|
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|
O |
||||||
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|
NaCNBH3 |
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(3.48) |
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Zeolite H-ZSM5 |
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NO2 |
||
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NO2 |
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70% |
||||||
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|
Nitromethylation of aldehydes has been carried out in a one pot procedure consisting of the Henry reaction, acetylation, and reduction with sodium borohydride, which provides a good method for the preparation of 1-nitroalkanes.16b,79 It has been improved by several modifications. The initial condensation reaction is accelerated by use of KF and 18-crown-6 in isopropanol. Acetylation is effected with acetic anhydride at 25 °C and 4-dimethylaminopyridine (DMAP) as a catalyst. These mild conditions are compatible with various functional groups which are often
3.2 DERIVATIVES FROM β-NITRO ALCOHOLS 45
present in the synthesis of natural products.16b Readily available methyl 6-oxohexanoate has been converted into methyl 7-oxoheptanoate via nitromethylation and subsequent Nef reaction (Eq. 3.49).79b
CHO |
1) CH3NO2, KF, i-PrOH |
|
NO2 |
Nef |
|
CHO |
||||
|
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|||||||
CO |
Me |
2) Ac2O, DMAP |
|
|
CO Me |
|
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|
CO |
Me |
|
|
|||||||||
2 |
|
3) NaBH4 |
2 |
2 |
|
|||||
|
|
100% |
(3.49) |
|||||||
|
|
|
|
Additional examples of the synthetic utility of this procedure are demonstrated in Eqs. 3.50–3.52.80 The nitro and nitroalkyl groups in the products are further converted into various functional groups such as carbonyl, amino, and alkyl groups. This is discussed in Chapter 6.
|
|
|
NHBz |
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N |
N |
|
Cbz |
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|||
O2N |
O |
N |
N |
|
|
NH O |
|
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|
+ |
BnO |
H |
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||||
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O |
O |
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O |
|
|
NHBz |
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|||
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Cbz |
|
N |
N |
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|
NH |
|
|
|
|
|
1) KOt-Bu, t-BuOH, THF |
BnO |
O |
N |
N |
|||
|
|
2) Ac2O, DMAP, THF |
O |
NO2 |
|
|
|||
|
|
3) NaBH4, EtOH, THF |
|
O |
O |
(3.50) |
|||
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|
53% |
|
|
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|
NHBz |
|
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N |
N |
|
|
Boc |
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||
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|
O2N |
O |
N |
N |
|
|
NH O |
|
|
|
+ |
Ph2CHO |
|
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|
|||||
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|||
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H |
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O |
O |
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O |
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|
NHBz |
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|||
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Boc |
|
N |
N |
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|
NH |
|
|
|
|
1) n-Bu4NF, THF, 18 h |
|
Ph2CHO |
O |
N |
N |
|||
|
2) Ac2O, DMAP |
|
|
O |
NO2 |
|
(3.51) |
||
|
3) NaBH4, EtOH |
|
|
|
O |
O |
|
||
|
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|
|
70% |
|
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|
OAc |
|
|
|
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|
|
CHO |
AcO |
O NO2 |
|
||
|
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|
AcO |
OAc |
|
|
||
|
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|
O |
|
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|
||
|
OAc |
|
|
O |
1) KF |
O O |
|
||
|
|
|
O |
(3.52) |
|||||
|
O |
|
+ |
|
|
O |
|||
AcO |
|
|
2) Ac2O |
|
|||||
|
NO2 |
|
|
O |
|
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|
||
AcO |
OAc |
|
|
|
O |
|
|||
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|
O |
3) NaBH4 |
|
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||
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O |
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|
71%
46 THE NITRO-ALDOL (HENRY) REACTION
Reduction of 1-nitro-1-alkenes with fermenting Baker’s yeast proceeds enantioselectively to give optically active nitroalkanes (Eq. 3.53).81
Ph
Ph CH2NO2
Baker's yeast
Me |
|
NO2 |
|
Me H |
(3.53) |
|
|
||||
|
|
50% (98% ee) |
|
||
|
|
|
|
|
3.2.3 =-Nitro Ketones
α-Nitro ketones are useful intermediates in organic synthesis, and they are generally prepared either by nitration of ketones (Chapter 2.1) or by oxidation of β-nitro alcohols. Acylation of nitroalkanes with acylimidazoles or other acylating reagents is also a reliable method for the preparation of α-nitro ketones (see Chapter 5) (Eq. 3.54).
|
|
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|
|
+ |
|
O |
|||||
OH |
oxidation |
O |
|
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NO2 |
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X |
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(X = N N) |
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oxidizing agent |
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NO2 |
CrO3, Na2Cr2O7, |
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OM |
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PCC, etc. |
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NO2X |
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(3.54) |
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(X = Cl, OAc) |
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In this chapter the synthesis of α-nitro ketones by the hydroxyalkylation of nitroalkanes (Henry reaction) followed by oxidation is discussed. The oxidation is normally carried out by treating the nitro alcohols with CrO3 or Na2Cr2O7 in strong acidic media.82 To avoid acidic conditions, pyridinum chlorochromate (PCC)83 or K2Cr2O7 under phase-transfer conditions 84a has been used. Acid labile groups are retained under these conditions as shown in Eqs. 3.55 and 3.56. Recently, Ballini and coworkers established a one-pot, solvent-free synthesis of acyclic α-nitro ketones (by using neutral alumina) in the Henry reaction followed by in situ oxidation of the nitro alcohol using wet alumina supported with CrO3. 84b
OH |
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O |
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PCC |
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(3.55) |
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O2N O O |
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O O |
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12 h |
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O2N |
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78% |
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Me NO2 |
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Me NO2 |
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K2Cr2O7, 30% H2SO4 |
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(3.56) |
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n-(C4H9)4N+HSO-4 |
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OH |
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CH2Cl2, −10 ºC, 2 h |
77% |
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In general, alkylation or acylation of nitronate ions takes place at the oxygen to yield the O-alkylated or O-acylated products. However, the choice of alkylating or acylating reagents can alter the reaction course to give the C-alkylated or acylated products. The acylation of primary nitroalkane salts with acyl cyanides gives the O-acylated product in 30–70% yield.85 A combination of diethyl phosphorocyanidate and triethylamine allows the direct C-acylation of nitromethane by aromatic carboxylic acids to give α-nitro ketones.86 Acyl imidazoles are more effective as C-acylating agents of nitroalkane salts, and α-nitro ketones are obtained in good
3.2 DERIVATIVES FROM β-NITRO ALCOHOLS 47
yields.87 Although the isolated lithium salts of nitroalkanes are used in the original paper, the potassium salt prepared in situ by treatment of nitro compounds with t-BuOK in DMSO is reactive enough with acyl imidazoles to give α-nitro ketones in 60–90% yield (see Section 5.2, Acylation of Nitro Compounds) (Eq. 3.57).88
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O |
O |
NO2 |
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O O |
1) t-BuOK/ DMSO |
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n-C6H13 |
(3.57) |
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NO2 |
2) n-C H |
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N |
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O |
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N |
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6 |
13 |
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88% |
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O |
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The nitro group of α-nitro ketones is readily removed either by treatment with Bu3SnH89 or reduction with LiAlH4 of the corresponding tosylhydrazones (Eq. 3.58).90 Details of denitration are discussed in Section 7.2, and some applications of this process are shown in Schemes 3.5–3.7.
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NO2 |
Bu3SnH, AIBN |
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R1 |
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R1 |
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80 ºC |
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NO2 |
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(3.58) |
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TsNHNH |
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LiAlH |
4 |
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2 |
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NNHTs |
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Construction of the carbon frameworks by using the activating property of the nitro group followed by denitration provides a useful tool for the preparation of various natural products as shown in Schemes 3.5–3.7. For example, (Z)-jasmone and dihydrojasmone, constituents of the essential oil of jasmone flowers, have been prepared as shown in Scheme
3.5.91 Schemes 3.6 and 3.7 present a synthesis of pheromones via denitration of α-nitro ketones.92,93
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NO |
2 |
+ |
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O |
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1) Al2O3 |
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O |
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O |
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NO2 |
TsNHNH2 |
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O O |
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R |
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H |
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R 2) K2Cr2O7 |
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O |
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NO2 |
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H+ |
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O |
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LiAlH4 |
O |
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O |
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R |
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R |
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R |
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acetone |
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O |
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NNHTs |
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NNHTs |
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O |
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OH− |
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R |
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R = CH |
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R = (CH2)4CH3 |
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Scheme 3.5.
48 THE NITRO-ALDOL (HENRY) REACTION
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NO2 |
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NO2 |
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O |
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amberlyst A-21 |
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OCH3 |
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+ |
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OCH3 |
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H3C |
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H |
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O |
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OH |
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O |
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86% |
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NO2 |
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PCC |
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OCH3 |
Bu SnH, AIBN |
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3 |
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CH2Cl2 |
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O |
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O |
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benzene |
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71% |
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+ |
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SCH3 |
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OCH3 |
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1) (CH2OH)2, H |
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OCH3 |
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2) LDA, –78 ºC |
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O |
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O |
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3) (CH3S)2, HMPA, 0 ºC |
O |
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O |
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71% |
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4) (CO2H)2 |
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80% |
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1) NaIO4 |
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OCH3 |
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2) 100 ºC |
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O |
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O |
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86% |
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OH |
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O |
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O |
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Scheme 3.6. |
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O |
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C5H11 |
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O |
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1) amberlyst A-21 |
C5H11 |
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(CH2)9CH3 |
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+ |
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H |
(CH ) CH |
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2) K2Cr2O7 |
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NO |
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NO |
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2 |
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2 9 |
3 |
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2 |
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NNHTs |
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78% |
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TsNHNH2 |
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C5H11 |
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(CH2)9CH3 |
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LiAlH4 |
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|||||||
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MeOH |
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THF, 0 ºC |
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NO2 |
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NNHTs |
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90% |
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O |
||||
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C5H11 |
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(CH2)9CH3 |
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amberlyst A-15 |
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C5H11 |
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(CH2)9CH3 |
||||||||||
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Me2CO/ H2O |
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90% |
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95% |
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Scheme 3.7.
3.2.4 >-Amino Alcohols
β-Nitro alcohols prepared by the Henry reaction are important precursors for β-amino alcohols. The reduction of the nitro group to the amino function is commonly carried out by hydrogenation in the presence of Raney Ni in EtOH or Pd/C in THF and MeOH (see Section 4.2). The conversion into β-amino alcohols is also described in the Sections 3.2.5 and 3.3.
3.2.5 Nitro Sugars and Amino Sugars
The chemistry and biochemistry of nitro sugars and amino sugars have stimulated extensive research. They are the components of various antibiotics, which show important biological
3.2 DERIVATIVES FROM β-NITRO ALCOHOLS 49
activities.94 Synthesis of nitro and amino sugars is one of the most important applications of nitro-aldol condensation. Synthesis of nitro sugars has been well reviewed by Wade and Giuliano,95 also there are many other excellent reviews on this topic.96 Only selected recent papers are described here to show the importance of nitro-aldol reaction in carbohydrate chemistry. The Baer-Fisher procedure is one of the simplest and shortest methods for obtaining 3-deoxy-3-nitrohexopyranosides and 3-amino-3-deoxyhexose derivatives by means of the
Henry reaction with sugar dialdehydes. Sugar dialdehydes are obtained by glycol cleavage of glycosides.95,96 The reaction of nitromethane with sugar dialdehydes as shown in Eq. 3.59 is
catalyzed with KF in isopropanol to give one isomer. If this reaction is carried out with sodium methoxide, the stereoselective becomes poor.97
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Base-catalyzed nitromethane cyclization of the dialdehyde generated by periodate oxidation of 1,2-O-cyclohexylidene-myo-inositol affords the nitrodiol with 1,4/2,3,5-configuration. This is converted into the α-mannosidase inhibitor, mannostatin A (Eq. 3.60).98
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A mixture of methyl 3-deoxy-3-C-methyl-3-nitro-α-D- and β-L-glucopyranosides (1:1) is formed by the reaction of nitroethane with the sugar dialdehyde obtained from D-glucose. The
products are separated and converted into branched-chain fluoro nitro D- and L-sugars (Eq. 3.61).99
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(3.61)
The anion of nitromethane adds easily to the carbonyl functions of sugars. This is a useful strategy for extension of the carbon chain.100 2-Acetamido-2-deoxy-β-D-glucose (N-acetyl-D- glucosamine) is the carbohydrate unit of glycoproteins that occurs most often. The nitromethylation method provides a straightforward route to a series of C-glycosyl compounds with the acetamido functionality (Eq. 3.62).101
50 THE NITRO-ALDOL (HENRY) REACTION |
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If a carbohydrate already contains a nitro group, the nitro-bearing carbon atom can become the nucleophilic center for the coupling of two monosaccharide units (see Section 3.2.2). Suami and coworkers have used this method for the synthesis of antibiotics bearing sugars.102 A typical example is presented in Eq. 3.63.102b
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3-Nitro and 3-amino sugars have been prepared via stepwise construction from acyclic precursors by the nitro-aldol strategy as shown in Scheme 3.8.103
3-Amino-2,3,6-trideoxy-L-hexoses (A-D in Scheme 3.9) occur naturally, forming the glycone part of anthracyclinone antibiotics, important in anti-tumor treatment.104
Several approaches based on nitro-aldol for the synthesis of amino sugars have been reported. Alumina-catalyzed reaction of methyl 3-nitropropanoate with O-benzyl-D-
lactaldehyde gives the D-ribo-nitro-aldol (anti, anti isomer) in 63% yield, which is converted into L-daunosamine17b,105 (see Section 3.3). Jager and coworkers have reported a
short synthesis of L-acosamine based on the stereoselective nitro-aldol reaction of 2-O-benzyl-L-lactaldehyde with 3-nitropropanal dimethyl acetal as shown in Scheme 3.10.106 The stereoselective nitro-aldol reaction is carried out by the silyl nitronate approach as discussed in Section 3.3.
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NO2 |
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Scheme 3.8.