The Nitro group in organic sysnthesis - Feuer
.pdf6.2 NITRILE OXIDES AND NITRILES 169
conversion of alkyl bromides or nitroalkanes to carboxylic acids on treatment with NaNO2 and acetic acid, if the alkenes are absent. The reaction proceeds via nitrolic acids, which can be isolated when the reaction is carried out at 20 °C. When heated in THF, they allow corresponding nitrile oxides to be obtained under neutral conditions.60b
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NaNO2, AcOH |
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CO2Me |
PhCH2Br + |
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CO2Me |
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68% |
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Primary nitro ketones, ethyl nitroacetate, and (phenylsulfonyl)nitromethane react with alkenes in the presence of Lewis acids to give nitrile oxide cycloaddition.61a Similarly, the reaction of α-nitro ketones with TeCl4 generates the corresponding nitrile oxides, as shown in Eq. 6.36.61b
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TeCl4, Et3N |
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–78ºC ~RT |
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82% |
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The conversions of nitro compounds into nitrile oxides have been used extensively in organic synthesis (see Section 8.2.2). On the other hand, nitro compounds have rarely been used as precursors of nitriles in organic synthesis. Some recent procedures for conversion of nitro compounds into nitriles are presented in Eqs. 6.37–6.40. The oxygen transfer from nitrile oxides by isocyanide gives nitriles; thus, treatment of nitro compounds with t-butylisocyanide, n- butylisocyanate, and triethylamine gives nitriles in 70–80% yield (Eq. 6.37).62 A combined process of dehydration and deoxygenation from nitro compounds is also possible by various reagents such as Me3SiI,63 PI3 in the presence of triethylamine,64 PCl3 in pyridine,65 and (Me2N)3P.66 However, they suffer from low yield in some cases. Recently, a more effective method has been obtained, which is based on the reaction using Sn(SPh)4, Bu3P, and diethyl azodicarboxylate (DEAD), as in Eq. 6.38, in which the reaction is complete in 5–10 min to give nitriles in 85–98% yield. Similar results are obtained, although not so rapid, using only Bu3P (2 equiv) and DEAD (1 equiv), as shown in Eq. 6.39.67 Deoxygenation using disilane is also effective for the conversion of nitro compounds into nitriles (Eq. 6.40).68
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n-BuNCO, t-BuNC |
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Et3N |
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74% |
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Sn(SPh)4, Bu3P, DEAD |
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CO2t-Bu |
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95% |
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(6.38) |
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O |
NO2 |
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Bu3P, DEAD |
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0º C, 30 min |
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92%
170 CONVERSION OF NITRO COMPOUNDS INTO OTHER COMPOUNDS
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SLi |
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Ph |
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NO2 |
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2) Me3SiSiMe3 |
3) hν |
NC |
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82% |
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Radical fragmentation process using tin radical is applied to the conversion of nitro compounds into nitriles, as shown in Eq. 6.41.69
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NO2 |
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Bu3SnH |
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AIBN |
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NO2 |
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R C N |
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OSn |
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C |
Ar |
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-NO2• |
90–100% |
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Indirect conversion of nitro compounds into nitriles via dehydration of oximes (see Section 6.3.3) is also a useful method for this purpose.
6.3 REDUCTION OF NITRO COMPOUNDS INTO AMINES
Reduction of aromatic and aliphatic nitro compounds gives various nitrogen compounds, such as amines, imines, and oximes, where the N–O bonds are cleaved, which is one of the basic reactions of nitro compounds. The sequence of nitration and reduction is the most important method for the preparation of aromatic amines. In aliphatic cases, the recent development of the stereoselective nitro-aldol and Michael reaction using aliphatic nitro compounds makes this conversion important as a tool for the stereoselective synthesis of biologically active amino compounds. Although the cleavage of N–O bond is general in the reduction of both aromatic and aliphatic nitro compounds, the C–N bond cleavage is possible in aliphatic nitro compounds (Scheme 6.4). Kornblum and co-workers reported that some kinds of anion radicals derived from aliphatic nitro compounds cleave the carbon-nitrogen bond to give the carbon radicals. In line with this observation, Ono and Tanner have found that aliphatic nitro compounds are reduced to the corresponding hydrocarbons on treatment with tin hydride in the presence of radical initiators. The conversion of R–NO2 to R-H is now widely recognized as a useful tool for organic synthesis (see Section 7.2).
6.3.1 Ar-NH2 From Ar-NO2
Particularly in the aromatic series, many amines have been prepared by the reduction of corresponding nitro compounds. A large number of reducing agents have been used for the reduction of nitro groups.70a–d The catalytic hydrogenation of aromatic nitro compounds to amines has long been recognized as one of the simplest procedures.71
6.3 REDUCTION OF NITRO COMPOUNDS INTO AMINES 171
N-O cleavage
Ar NO2 Ar-NO, Ar-NH2, etc.
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N-O cleavage |
R-NO, R-NHOH, R-NH2, etc. |
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C-N cleavage |
Scheme 6.4.
Procedures for the reduction of nitro compounds to amines are described precisely in the
series of books; Organic Synthesis, namely, Fe + AcOH,72 Zn + NaOH,73 Fe + HCl,74 Sn + HCl,75 H2-Raney Ni,76a–c H2-PtO2,77 H2-Pd/C,78 and N2H4-Pd/C79 are presented there. Sodium
sulfide and polysulfides are also effective for this transformation.80 The combination of sodium borohydride with cobalt(II), copper(II), and rhodium (III) halides has been used to reduce functional groups such as nitro, nitriles, amides, and olefins, which are inert to NaBH4 itself.81 Aromatic nitro compounds are reduced to amines with formic acid and triethylamine with Pd/C.82a Ammonium formate in the presence of Pd/C is a very convenient method for the reduction of both aromatic and aliphatic nitro compounds. For example, this method is applied for the preparation of indoles, as in Eq. 6.42.82b Synthesis of indoles via the reduction of the nitro group is presented in Section 10.2 (synthesis of heterocycles).
MeO |
OMe |
MeO |
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CO2Me |
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10 % Pd/C |
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(6.42) |
O O |
HCOONH4 |
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NO2 |
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H |
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84–89% |
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The reductive alkylation of aromatic nitro compounds using H2+Pd/C in the presence of 40% aqueous formaldehyde gives directly dimethylamino derivatives in good yield (Eq. 6.43).83
O2N |
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CH2COOEt |
CH2O, H2 |
Me2N |
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Pd/C |
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67–77% |
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Electrochemically generated nickel is very selective for the reduction of aromatic nitro compounds into anilines, in which alkenyl, alkynyl, halo, cyano, formyl, and benzyloxy groups are not affected.84 Sodium sulfide has been used for the selective reduction of aromatic nitro group in the presence of aliphatic nitro groups (Eq. 6.44).85
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Me |
Na2S•9H2O |
H2N |
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CH2 |
Me |
Me |
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NO2 |
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NO2 |
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70% |
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Treatment of aromatic nitro compounds with indium powder in aqueous ethanolic ammonium chloride results in selective reduction of nitro groups; ester, nitrile, amide, and halide substituents are unaffected.86 This method is more selective than the method of catalytic hydrogenation. For example, catalytic hydrogenation of 4-chloro-3-nitroacetophenone over Pd/C results in hydrogenolysis of the halide and reduction of the ketone as well as of the nitro group.87 Samarium iodide is a good reducing agent of both aromatic and aliphatic nitro
172 CONVERSION OF NITRO COMPOUNDS INTO OTHER COMPOUNDS
compounds. Because the nitro group is a better electron acceptor than other functional groups, the reduction of nitro compounds with SmI2 proceeds selectively. Thus, p-nitrobenzonitrile is reduced to p-cyanoaniline selectively.88 Ultrasound-promoted, highly efficient reduction of aromatic nitro compounds to the aromatic amines has been achieved by samarium ammonium chloride mediated reaction.88c Intermolecular and intramolecular reductive coupling reactions between aromatic nitro compounds and nitriles are induced by SmI2 to give amidines and 2-aminoqunolines.89
6.3.2 R-NH2 From R-NO2
In general, the reduction of aliphatic nitro compounds gives amines, in which various reducing agents are as effective as they are in the reduction of aromatic nitro compounds.70 The reduction of β-nitro alcohols to the corresponding amino alcohols is the most important application of this process in organic synthesis. Hydrogenation catalyzed by Raney Ni under high pressure has been widely used for this conversion,90 and some recent examples are presented in Eq. 6.45,91 and Eq. 6.46.92 The stereochemistry of the nitro alcohol is retained by the Raney Ni-catalyzed hydrogenation.
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SiO |
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CF3 |
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2) Bu4NF |
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76% |
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The reduction of nitro sugars with H2 in the presence of Raney Ni is one of the standard methods for the preparation of amino sugars (Eq. 6.47).93
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1 atm, 25 ºC, 4 h |
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73% |
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The hydrogenation in the presence of Pd/C is also effective for the conversion of nitro compounds to amines.94 The Michael addition of nitromethane to 2-alkenoic esters followed by catalytic hydrogenation using 10% Pd/C in acetic acid and hydrolysis is a convenient method for the preparation of 3-alkyl-4-aminobutanoic acids, which are important γ-amino acids for biological study (Eq. 6.48).94b The reduction can be carried out at room temperature and atmospheric pressure.
O2N |
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OEt |
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83%
6.3 REDUCTION OF NITRO COMPOUNDS INTO AMINES 173
Jager and co-workers have prepared various amino sugars by the reduction of the corresponding β-nitro alcohols with H2 and Pd/C, as exemplified in Eq. 6.49 (see Chapter 3).95
OH OH OEt |
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25 ºC, 24 h |
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98% |
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Hydrogen gas can be replaced by ammonium formate for the reduction of nitro compounds to amines. The ammonium formate method is efficient, and the rapid workup procedure by simple filtration makes it widely used for converting the NO2 to the NH2.96 For example, α-nitro esters are reduced to α-amino esters in excellent yields on treatment with HCO2NH4 and Pd/C in methanol.96
The reduction of γ-nitroketone acetals as in Eq. 6.50 with ammonium formate in the presence of Pd/C gives the corresponding amines in good yields. However, the reduction of γ-nitro ketones are reduced to cyclic nitrones (Eq. 6.51).97 This reduction is far superior to the classical method using Zn/NH4Cl due to improved yield and simple workup.
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HCO2NH4, Pd/C |
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94% |
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74% |
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The reduction of β-nitro alcohols with ammonium formate in the presence of Pd/C also proceeds with retention of their configurations (Eq. 6.52).98
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87% |
The reduction of β-nitro alcohols with LiAlH4 results in low yields of β-amino alcohols due to the occurrence of a retro-aldol reaction. This problem is resolved by protecting of OH of β-nitro alcohols, as shown in Eq. 6.53.99
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O Si |
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A reagent of nickel boride/hydrazine hydrate reduces both aromatic and aliphatic nitro compounds. For example, it has been used for synthesis of 4-(benzyloxy)indole and –alkyltryp-
174 CONVERSION OF NITRO COMPOUNDS INTO OTHER COMPOUNDS
tamines, as shown in Eq. 6.54.100 This reducing agent has advantages over the method using H2 and Raney Ni because double bonds are inert to Ni2B/N2H4.
OCH2Ph |
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NO2 |
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91% |
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NH2 |
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69% |
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Sodium borohydride is activated in the presence of Pd/C,101 CoCl26H2O,102 Ni(OAc)2,103 CuSO4,104 and NiCl2.105 Aromatic and aliphatic nitro compounds are reduced to the corresponding amines, by these reagents as summarized in Table 6.1. The active hydrogenation catalyst is formed by the reaction of NaBH4 with metal catalysts in such reductions.106 Because reaction proceeds rapidly under mild conditions, the method using activated NaBH4 is very convenient for the reduction of a variety of nitro compounds as shown in Table 6.1.
Various other reducing methods are employed for the conversion of β-nitro alcohols to amino alcohols, namely, electrochemical reduction.107 The selective electrohydrogenation of nitroaliphatic and nitroaromatic groups in molecules containing other groups that are easy to hydrogenate (triple bond, nitrile, C-I) are carried out in methanol-water solutions at Devarda copper and Raney cobalt electrodes (Eq. 6.55).107
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OEt |
pH = 3 |
Me |
NO2 |
OEt |
pH = 5 |
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NH2 |
OEt |
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OEt |
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72% |
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(6.55)
The sonochemical-promoted aluminum amalgam reduction of β-nitro alcohols provides an improved yield and accelerated conversion to the corresponding amino alcohols.108
The selective reduction of 4-nitrosteroid to the corresponding aminosteroid has been carried out by Pd/CaCO3 and quinoline (5 mol wt%) under H2 atmosphere (Eq. 6.56).109 This is the first reported catalytic reduction of an α-nitro enone to an α-amino enone. Other hydrogenation catalysts as well as the use of Na2S, Fe/AcOH, or Na2S2O4 fails to provide the aminosteroid. Reduction with SnCl2 in EtOH gives the aminosteroid in 46% yield.
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H2, Pd/CaCO3 |
(6.56) |
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quinoline |
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O |
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O |
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NH2 |
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NO2 |
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64% |
A variety of Group VIII transition metal phosphine complexes are shown to be active catalysts for hydrogenation of aliphatic nitro compounds. However, chiral phosphines have been found to be noneffective to induce asymmetric induction.110
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6.3 REDUCTION OF NITRO COMPOUNDS INTO AMINES |
175 |
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Table 6.1. |
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Nitro compound |
Reducing reagent |
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Product |
Yield (%) |
Ref. |
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NO2 |
NaBH4-CuSO4 |
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NH2 |
80 |
104 |
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OMe |
EtOH, reflux, 30 min |
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OMe |
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OMe |
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OMe |
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NO2 |
NaBH4-exchange |
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NH2 |
94 |
103 |
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Resin-Ni(OAc)2, RT, 1 h |
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NH2 |
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NO2 |
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NaBH4-10% Pd/C |
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75 |
103 |
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CO2Et |
THF, 40 min |
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CO2Et |
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NC |
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NO2 |
NaBH4-10% Pd/C |
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NC |
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NH2 |
90 |
103 |
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THF, 30 min |
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OH |
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O |
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O2N |
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NaBH4-NiCl2 |
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H2N |
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Me |
76 |
105 |
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Me |
MeOH, RT, 30 min |
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NO2 |
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OH NaBH |
-CoCl 6H |
2 |
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OH 73 |
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N |
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MeOH, 0 °C |
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NaBH4-ZrCl4 |
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84 |
129 |
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THF, reflux |
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NO2 |
NaBH4-ZrCl4 |
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NH2 |
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129 |
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THF, RT |
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6.3.3 Oximes, Hydroxylamines, and Other Nitrogen Derivatives
The final reduction products of nitro compounds are amines, but reduction intermediate products such as oximes and hydroxylamines have been also isolated on reduction of nitro compounds, as shown in Eq. 6.57, where the reaction is controlled by the applied reduction potentials. The partial reduction of nitroalkanes gives either oximes or alkyl-substituted hydroxylamines, depending on reaction conditions. Samarium diiodide is a good single electron-transfer reagent and it is very easy to control the reaction. Primary, secondary, or tertiary nitroalkanes can be reduced with SmI2 and CH3OH as the proton source to either alkyl hydroxylamines or amines, depending on the amount of SmI2. Reaction with 4 equiv of SmI2 in THF/MeOH for less than 5 min provides hydroxylamines in 60–90% yields. Reaction with 6 equiv of SmI2 for 8 h provides amines in 50–80% yields.111
R-NHOH |
4 equiv SmI2 |
R |
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NO2 |
6 equiv SmI2 |
R-NH2 |
(6.57) |
THF-MeOH (2:1) |
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THF-MeOH (2:1) |
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176 CONVERSION OF NITRO COMPOUNDS INTO OTHER COMPOUNDS
The conversion of nitroalkanes to ketoximes can be achieved by the reduction with Zn in acetic acid,112 or Fe in acetic acid.113 Nitroalkenes are directly reduced into saturated ketoximes by these reagents, which are precursors for ketones (see Section 6.1.4 Nef reaction). Reduction of 3-O-ace- tylated sugar 1-nitro-1-alkenes with Zn in acetic acid gives the corresponding 2,3-unsaturated sugar oximes in high yield, which is a versatile route to 2,3-unsaturated sugar derivatives (Eq. 6.58).114
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CHNO2 |
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As shown in Eq. 6.59, Rapoport has prepared sinefungin, nucleoside antibiotics, via nitro-aldol reaction, dehydration, and reduction with Zn in acetic acid.115a β-Nitrostyrenes are selectivity reduced to the corresponding oximes by indium metal in aqueous methanol under neutral conditions.115b
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1) KF, CH3CN, 24 h |
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2) DCC, CuCl, CH3CN |
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3) Zn, THF, aq HOAc, |
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H3C CH3
69% overall
The conversion of nitroalkenes into the oximes can be achieved by electrochemical reduction (Eq. 6.60).116
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NO2 |
C-Pt, e– |
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MeOH, H2SO4 |
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Reaction ofthesaltsofprimaryandsecondaryalkylnitrocompoundswithdiboraneinTHFsolution at 25 °C yields the corresponding hydroxylamines.117 Kabalka has reported the reduction of nitroalkenes to hydroxylamines or amines with a variety of borane and borohydride reagents (Eq. 6.61).118
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NaBH4 |
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NO2 |
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78% |
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NO2 |
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79% |
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NH2
88%
6.3 REDUCTION OF NITRO COMPOUNDS INTO AMINES 177
Deoxygenation from nitroalkanes is possible by other various reagents, including TiCl3,119 Me3SiI,63 carbon disulfide in the presence of base,120 Me3SiSiMe3,121 and Sn(SPh)2-PhSH-Et3N
(Eq. 6.62).122
NO2 |
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N |
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Reagent |
Yield (%) |
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OH |
84 (6.62) |
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BuLi + Me3SiSiMe3 |
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A combination of tributylphosphine-diphenyldisulfide reduces secondary nitro compounds to imines, which is applied to pyrrole synthesis (Eq. 6.63).34
Ph |
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Bu3P, PhSSPh |
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Ph |
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Me |
N |
Ph |
NO2 |
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A new selective reduction of nitroalkenes into enamides has been carried out by a combination of iron powder, a carboxylic acid, and the corresponding anhydride (Eq. 6.64).123
NO2 |
NHAc |
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Ac2O |
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67% |
A new multicomponent reaction of nitro compounds with isocyanides gives α-oxyimi- noamides, which are important for drug synthesis such as cephalosporin and β-lactamase
inhibitor (Eq. 6.65).124a Multicomponent reactions using isocyanides (Ugi reaction) is reviewed.124b
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O |
O2N |
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N |
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63% |
Photoreduction of aromatic and aliphatic nitro compounds gives hydroxylamines or amines, which is well reviewed.125 The radical reaction of primary nitro compounds with tin hydride does not give the denitrated product (see Chapter 7), but give the corresponding oximes (Eq.
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OAc |
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OAc |
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Bu3SnH, AIBN |
AcO |
O |
OH |
AcO |
O |
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benzene, reflux |
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AcO |
NO2 |
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OAc |
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OAc |
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90% (6.66)
178 CONVERSION OF NITRO COMPOUNDS INTO OTHER COMPOUNDS
6.66).126a This reaction is useful in carbohydrate chemistry and a nitromethylene linked disaccharide is prepared via this reaction.126b
Nitroxides are N,N-disubstituted nitric oxide radicals, the unpaired electron being delocalized between the nitrogen and oxygen. The reduction of 2-methyl-2-nitropropane with sodium or electrochemically yields di-t-butyl nitroxide as the final product.127 Such nitroxide radicals are important for the study of a organic ferromagnet.128
Phosphorous reagents are well established as deoxygenating agents of nitro compounds. Cadogan and others have reported the abstraction of oxygen from aromatic nitro compounds by triethyl phosphite to form various heterocycles.130 These reactions proceed via nitrene intermediates to give heterocycles (Section 10.2). Diethyl chlorophosphite is more reactive than triethyl phosphite, and it reduces both aromatic and aliphatic nitro groups to the corresponding amino groups in the presence of tertiary amines.131
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