The Nitro Group in Organic Synthesis
.pdf5.3 RING CLEAVAGE OF CYCLIC =-NITRO KETONES (RETRO-ACYLATION) |
131 |
5.3 RING CLEAVAGE OF CYCLIC =-NITRO KETONES (RETRO-ACYLATION)
Because the anions of nitroalkanes are stable, retro-acylation of α-nitro ketones proceeds smoothly in the presence of a base catalyst. This type of reaction provides an important tool in organic synthesis.28 Nucleophilic attack of water or alcohol to α-nitro cycloalkanones produces the ring cleavage with the formation of ω-nitro acids and ω-nitro esters. This type of cleavage is a well-known reaction,29 but it has not been used in organic synthesis until quite recently. Ballini and coworkers have studied the effect of base and solvent for this reaction. They have found a significant improvement of the ring cleavage of cyclic α-nitro ketones using a weakly basic ion-exchange resin (amberlyst A-21) (Eq. 5.15).30 α-Nitro cycloalkanones are cleaved to ω-nitro acids (71–97%) in aqueous media (0.05 M sodium hydroxide) and in the presence of a catalytic amount of cetyltrimethylammonium chloride (CTACl) as cationic surfactant.28
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amberlyst A-21 |
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CO2Me |
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reflux, 1–72 h |
75–99% |
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n = 1-4, 6-8, 11 |
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One-pot syntheses of 1,4-diketones, γ-oxoaldehydes, γ-ketoesters, and ω-oxoalkanoates have been reported by bond cleavage of cyclic α-nitroketones with KOH in methanol and subsequent Nef reaction (Section 6.1) with KMnO4 (Eq. 5.16).31
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n = 0–2, 6, 7, 10 R = H, Me, t-Bu
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KMnO4 |
MeO |
H |
MgSO4 |
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R O |
Regioselective reduction of 2-nitrocycloalkanones with sodium borohydride affords ω-nitro alcohols. This reaction is applied to the synthesis of spiroketals as shown in Eq. 5.17, in which spiro[4,5]- and spiro[4,6]ketal systems are obtained in good yields.32
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R = H, Me, Et; n = 1, 2 |
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60–75% |
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132 ALKYLATION, ACYLATION, AND HALOGENATION OF NITRO COMPOUNDS
Oxidative cleavage of 2-nitrocyclohexanones gives α,ω-dicarboxylic acids or their esters, as shown in Eq. 5.18.33
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K2S2O8, H2SO4 |
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MeOH, 80 ºC |
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80–92% |
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n = 0–7, 10 |
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R = Me, Ph, t-Bu |
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The reaction of organometallic reagents with cyclic α-nitroketones gives tertiary β-nitroal- kanols (Eq. 5.19).34 However, the reaction of the same nitro ketone with trimethylsilylmethylmagnesium gives ring cleavage products (Eq. 5.20).35 Ballini postulates that the silicon β effect assists the cleavage of the C-C bond in the sense of the arrows.
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NO2 RMgX |
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HO |
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R = Me, Et, n-Bu, CH2=CH, |
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CH =C=CH,PhC |
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60–85% |
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2 Me SiCH MgCl |
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SiCH |
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Satd. soln |
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ClMgO |
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75–85% |
The reaction of α-nitrocycloalkanones with an aqueous solution of formaldehyde in the presence of potassium carbonate affords 2-nitro-1,3-diol-ω-alkanoic acids (Eq. 5.21).36
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NO2 |
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30% CH2O aq |
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K2CO3, RT |
HO |
OH |
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n = 0, 1, 2, 7, 10 |
48–75% |
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R = Me, t-Bu |
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5.4 ALKYLATION OF NITRO COMPOUNDS VIA ALKYL RADICALS 133
Ring enlargement of α-nitrocycloalkanones has been extensively used for the synthesis of macrocyclic compounds, as exemplified in Eq. 5.22.37
O OH NaH (cat.) or NaOH |
O |
O |
(5.22)
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MeOH |
NO2 |
NO2 |
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85% |
The retro-Henry reaction of 2-nitrocycloalkanols gives ω-nitro ketones, as shown in Eq. 5.23.38
OH |
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CuSO •SiO |
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NO2 |
NO |
2 |
2 |
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4 |
O |
(5.23) |
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benzene |
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reflux |
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73% |
5.4 ALKYLATION OF NITRO COMPOUNDS VIA ALKYL RADICALS
The ability of a nitro group in the substrate to bring about electron-transfer free radical chain nucleophilic substitution (SRN1) at a saturated carbon atom is well documented.39 Such electron transfer reactions are one of the characteristic features of nitro compounds. Kornblum and Russell have established the SRN1 reaction independently; the details of the early history have been well reviewed by them.39 The reaction of p-nitrobenzyl chloride with a salt of nitroalkane is in sharp contrast to the general behavior of the alkylation of the carbanions derived from nitroalkanes; here, carbon alkylation is predominant. The carbon alkylation process proceeds via a chain reaction involving anion radicals and free radicals, as shown in Eq. 5.24 and Scheme 5.4 (SRN1 reaction).40
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O2N |
CH2Cl |
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O2N |
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CH2Cl + |
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+ Cl– |
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CH2Cl |
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CH2 |
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CH2 |
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Me NO |
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CH2Cl |
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Scheme 5.4. SRN1 reaction.
134 ALKYLATION, ACYLATION, AND HALOGENATION OF NITRO COMPOUNDS
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Me |
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Me Li+ DMSO |
Me |
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O2N |
CH2Cl + |
NO2 |
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92% |
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SRN1 reactions using related p-nitrophenyl or p-nitrocumyl systems41 as reductive alkylating agents have been studied by Kornblum and co-workers; these are well summarized in the reviews.39 At the same time, Russell discovered the SRN1 reaction of geminal halonitroalkanes with stabilized carbanions (see Eq. 5.25).42 The products are readily converted into alkenes via elimination of nitro groups (see Section 7.3).
Me |
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NO2 |
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Me |
NO2 |
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CO2Et |
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68% |
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The cyano group is also a good electron acceptor for SRN1 substrates, as shown in Eq. 5.2643 and Eq. 5.27,44 but a nitro group is a better electron acceptor than a cyano group.
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84% |
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82% |
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Geminal dinitro compounds,45 α-nitro sulfones,46 α-nitro esters,47 or α-nitro nitriles48 react with anions derived from nitroalkanes to give the SRN1 products, as shown in Eqs. 5.28, 5.29, 5.30 and 5.31, respectively (Section 7.1).
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91% |
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85% |
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Me |
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70%
5.4 |
ALKYLATION OF NITRO COMPOUNDS VIA ALKYL RADICALS |
135 |
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Me Li+ |
DMSO |
Me |
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+ |
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Me |
(5.31) |
CN |
Me NO2 |
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CN NO2 |
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92% |
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The anion of nitromethane is particularly reactive in SRN1 reactions. Various kinds of tertiary nitro groups are replaced by a nitromethyl group on treatment with the anion of nitromethane (Section 7.1).49 2-Iodoadamantane reacts with the anion of nitromethane in the presence of acetone enolate (entrainment reaction) under irradiation of a 400-W UV lamp to give 2-ni- tromethyladamantane in 68% yield, (see Eq. 5.32).50a 1-Iodoadamantane also reacts with the anion of nitromethane in a similar way.50b
I |
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hυ |
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CH2NO2 |
+ Na+ CH |
NO |
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2 |
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H |
C CH |
– |
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3 |
2 |
68% |
Crozet and co-workers have used SRN1 reactions for synthesis of new heterocycles, which are expected to be biologically active (see also Section 7.3, which discusses synthesis of alkenes). For example, 2-chloromethyl-5-nitroimidazole reacts with the anion of 2-nitropropane to give 2-isopropylidene-5-nitroimidazole. It is formed via C-alkylation of the nitronate ion
followed by elimination of HNO2 (Eq. 5.33).51a Other derivatives of nitroimidazoles are also good substrates for SRN1 reactions.51b,c
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CH2Cl |
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base |
O2N N |
Me |
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||||
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Me |
|
|
|
|
|
|
|
|
|
|
88% |
|
|
|
|
Reactions of nitrothiazole derivatives with anions of nitroalkanes, such as shown in Eq. 5.34, proceed via a SRN1 mechanism.52
|
|
N |
Me |
|
|
Me |
+ |
DMF |
N |
Me |
Me |
|
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|||||
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O2N |
S |
|
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+ |
|
Li |
|
O2N S |
|
NO2 (5.34) |
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||||||
|
NO |
|
Me NO2 |
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||||||
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Me |
2 |
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Me |
Me |
|||||
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|
71% |
|
The anion derived from ethyl 2-nitropropionate reacts with various reductive alkylating agents (SRN1 substrates) to give new unsymmetrically disubstituted nitro esters (Eq. 5.35), which are interesting precursors for unusual amino acids.53
|
N |
|
NO2 |
|
|
N |
Me NO2 |
|
|
|
NaH, DMSO |
|
|
OEt |
|||
|
|
|
OEt |
O2N |
|
|||
O2N |
|
CH2Cl + |
N |
(5.35) |
||||
N |
|
|||||||
hυ |
||||||||
|
|
Me |
|
Me |
O |
|||
|
Me |
|
O |
|
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|||
|
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||||
|
|
|
|
|
|
70%
136 ALKYLATION, ACYLATION, AND HALOGENATION OF NITRO COMPOUNDS
Gem-nitro imidazolyl alkanes undergo SRN1 reactions with the anion of various nitroalkanes, as shown in Eq. 5.36.54 The nitro group is replaced by hydrogen in 80–90% yield on treatment with Bu3SnH (see Chapter 7, which discusses radical denitration).
N |
|
Me |
|
N |
Me Me |
|
|
|
ηυ |
N |
|
||||
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|
|||||
N |
NO2 + |
Li+ |
|
||||
NO2 |
(5.36) |
||||||
|
|
||||||
Me |
Me |
NO2 |
|
|
Me Me |
|
|
Me |
|
|
|
65% |
|
||
|
|
|
|
|
|
SRN1 reactions are generally accelerated by irradiation with tungsten lamps (200–500 W) or fluorescent lamps. They are retarded in the presence of oxygen or other radical inhibitors. Recently, microwave irradiation has been shown to be effective in inducing SRN1 reactions; the reaction of Eq. 5.37 proceeds under microwave irradiation (900 W, 5 min) in the presence of trace amounts of water.55
|
Me |
Na+ |
|
O2N |
|
microwave (900 W) |
Me Me |
||
O2N |
CH2Cl + |
|
|
|
|
H2O, 4 min |
NO2 |
||
|
Me NO2 |
|||
|
|
|
|
82% |
(5.37)
Alkyl mercury halides participate in a photo-stimulated radical chain reaction of the anion of nitroalkanes (see Eq. 5.38) in which a 275-W sun lamp is used.56a–c Primary, secondary, and
tertiary alkyl radicals generated from alkyl mercury halides react with the anion of nitroalkanes to form new C-C bonds.
|
|
|
|
|
Me |
Me |
|
|
|
|
|
hυ |
Ph |
||
Me3CHgCl + |
|
|
|
Me |
|||
PhCHNO2 |
|||||||
|
(5.38) |
||||||
DMSO |
|||||||
|
|
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|
|
NO2 |
||
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|
||
|
|
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|
|
|
71% |
Branchaud and coworkers have used cobaloximes as alkyl radical precursors for the cross-coupling reaction with nitronates.57 This method is very useful for producing branchedchain monosaccharides, as shown in Eq. 5.39.57b
|
|
|
|
CH2I |
|
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||||||
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O |
O |
|
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||||||
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O |
|
|
|
py(dmgH) Co- |
Na+ |
|
||||||
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|||||||||||
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2 |
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||
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O |
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||
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||||
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O |
|
|
|
|
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|
||||
|
CH2Co(dmgH)2py |
|
|
CH2CH2NO2 |
|
|||||||||||
O O |
|
|
1) hυ, CH2NO2– Na+ |
O O |
|
|||||||||||
|
O |
|
|
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|
O |
(5.39) |
|||||||||
|
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||||||||||||
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|
O |
|
|
2) AcOH |
|
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|
O |
||||
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|||||||
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||||||||
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O |
|
|
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|
O |
|
||||
82% |
|
|
|
|
|
|
|
76% |
|
Martin and coworkers have used this strategy for synthesis of α- and β-(1,6)-linked C-disaccharides (Eq. 5.40).58
|
|
|
5.4 |
ALKYLATION OF NITRO COMPOUNDS VIA ALKYL RADICALS |
137 |
||||||
|
OBn |
|
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|
|
OBn |
|
|
BnO |
O |
|
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|
||
BnO |
|
|
|
|
|
|
|
|
BnO |
O |
|
|
RO |
CH Co(dmgH) |
py |
|
hυ |
|
|
BnO |
NO2 |
||
|
|
|
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|
|||||||
|
|
2 |
2 |
|
|
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|
RO |
|
|
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|
+ |
|
|
|
|
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|
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|
R |
AcO |
O |
|||
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|
NO2 |
|
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|
|||||
|
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|||
|
AcO |
O |
|
|
|
O N |
|
N O |
AcO |
|
|
|
|
|
|
R-Co(dmgH)2py = H |
Co H |
AcO OMe |
|||||
|
AcO |
|
|
|
|
||||||
|
|
|
|
|
|
O N |
|
N O |
30% |
|
|
|
|
AcO OMe |
|
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Py |
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|||
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|
|
(5.40)
Carbon alkylation of simple nitronate anions is also possible by the reaction with N-substi- tuted pyridiniums, as exemplified in Eq. 5.41. Such types of reactions are classified as SRN2 reactions, in which electron transfer reactions from nitronate anions to pyridiniums are involved as key steps.59
Ph |
|
|
|
+ |
EtOH |
|
|
+ NaCH2NO2 |
|
PhCH2CH2NO2 |
(5.41) |
|
Ph N |
Ph |
|
82% |
CH2Ph
The anions derived from nitroalkanes are converted into the corresponding radicals on treatment with various oxidizing agents. The C-C bond-forming reactions using nitroalkyl radicals generated by this procedure are also important in organic synthesis. For example, aromatic nitromethylation can be carried out by heating a mixture of an aromatic compounds and Mn(III)OAc3 in acetic acid (see Eq. 5.42).60
Ar-H |
+ CH3NO2 |
Mn(III)OAc3 |
ArCH2NO2 |
Ar = Ph (4%) |
(5.42) |
|
AcOH |
Ar = Tol (55%) |
|||||
|
|
|
|
Recently, Narasaka and co-workers have found that 1-nitroalkyl radicals are generated by oxidation of aci-nitroanions with CAN, and they undergo the intermolecular addition to electron-rich olefins.61 For example, when oxidation is carried out in the presence of silylenol ethers, β-nitroketones are formed in good yield. β-Nitroketones are readily converted into enones on treatment with base (see Section 7.3), as shown in Eq. 5.43.
|
|
1) KOH |
|
O |
||
Ph(CH2)3 |
NO2 |
|
|
|
(5.43) |
|
2) |
CAN, OSiMe3 |
Ph(CH2)3 |
||||
Ph |
||||||
|
|
|||||
|
|
|
Ph |
99% |
|
|
|
|
3) |
Et3N, –78 ºC |
|
||
|
|
|
|
Interesting intramolecular cyclization of 1-nitroalkyl radicals generated by one-electron oxidation of aci-nitro anions with CAN is reported. As shown in Eq. 5.44, stereoselective formation of 3,4-functionalized tetrahydrofurans is observed.62 1-Nitro-6-heptenyl radicals generated by one electron oxidation of aci-nitroanions with CAN afford 2,3,4-trisubstituted tetrahydropyrans.63 The requisite nitro compounds are prepared by the Michael addition of 3-buten-1-al to nitroalkenes.
138 ALKYLATION, ACYLATION, AND HALOGENATION OF NITRO COMPOUNDS
NO2 |
1) NaH, THF |
|
NO2 |
|
ONO2 |
|
|
||||
|
|||||
|
|
|
|
(5.44)
2) CAN, –78 ºC
O O H
58%
Radical cyclization of α,ω-dinitroalkanes is reported, as shown in Eq. 5.45. Oxidation of the dinitronate derived from 2,6-dinitroheptane with K3Fe(CN)6 in a two-phase system (water-ether) yields the cyclized vicinal dinitrocyclopentane in 71–85% yield in a cis-to-trans ratio of 60:40.64
NO2 |
NO2 1) MeONa |
NO2 |
|
|
|
|
(5.45) |
|
|
2) K3Fe(CN)3, Et2O-H2O |
NO2 |
|
|
|
|
|
|
|
71–85% |
Couplings of nitroalkyl radicals with nucleophiles such as CN–, N−3, NO−2, and other nitrogen nucleophiles provides a useful method for the preparation of nitro compounds with such groups at the α-position.49,65 The alkylation of nitromethane with trialkylborane is possible by electrolysis, in which alkyl radicals may be involved (Eq. 5.46).66
|
|
e–, Et4N+ |
X– |
NO2 |
|
B + |
CH3NO2 |
(5.46) |
|||
|
|
3
50%
Oxidative cross-coupling reactions of alkylated derivatives of activated CH compounds, such as malonic esters, acetylacetone, cyanoacetates, and certain ketones, with nitroalkanes promoted by silver nitrate or iodine lead to the formation of the nitroalkylated products.67 This is an alternative way of performing SRN1 reactions using α-halo-nitroalkanes.
5.5 ALKYLATION OF NITRO COMPOUNDS USING TRANSITION METAL CATALYSIS
Monoanions derived from nitroalkanes are more prone to alkylate on oxygen rather than on carbon in reactions with alkyl halides, as discussed in Section 5.1. Methods to circumvent O-alkylation of nitro compounds are presented in Sections 5.1 and 5.4, in which alkylation of the α,α-dianions of primary nitro compounds and radial reactions are described. Palladiumcatalyzed alkylation of nitro compounds offers another useful method for C-alkylation of nitro compounds. Tsuji and Trost have developed the carbon-carbon bond forming reactions using π-allyl Pd complexes. Various nucleophiles such as the anions derived from diethyl malonate or ethyl
acetoacetate are employed for this transformation, as shown in Scheme 5.7. This process is now one of the most important tools for synthesis of complex compounds.68a–b Nitro compounds can
participate in palladium-catalyzed alkylation, both as alkylating agents (see Section 7.1.2) and nucleophiles. This section summarizes the C-alkylation of nitro compounds using transition metals.
5.5.1 Butadiene Telomerization
The palladium-catalyzed linear telomerization of 1,3-butadienes provides a useful method for the preparation of functionalized alkenes. A proposed catalytic cycle for the palladium-catalyzed
5.5 ALKYLATION OF NITRO COMPOUNDS USING TRANSITION METAL CATALYSIS 139
|
LnPd(0) |
|
|
H X |
Pd L |
|
|
|
|
Pd |
L |
H |
|
|
|
|
|
|||
|
|
|
|
|
||
|
|
X |
+ L |
X |
|
|
X |
Pd |
L |
|
|||
+ |
LnPd(0) |
|||||
|
||||||
|
|
|
|
|||
|
|
|
|
CH2 |
|
|
|
H |
|
|
H |
|
Scheme 5.5. Catalytic cycle in the palladium-catalyzed telomerization of 1,3-butadiene
telomerization of 1,3-butadiene is shown in Scheme 5.5; a wide range of H-X trapping reagents (X = nucleophilic carbon, oxygen, nitrogen, or sulfur) are used.69
When nitromethane is used as a trapping reagent in the telomerization of butadiene using Pd(OAc)2 and Ph3P, mono-, diand trialkylated compounds of nitromethane are formed (Eq. 5.47).70 They are selectively formed by changing the ratio of nitromethane and butadiene. As the nitro groups are transformed into various functional groups, the reaction of Eq. 5.47 is very useful in organic synthesis.
+ CH3NO2 |
Pd(OAc)2 |
NO2 |
|
Ph3P |
|||
|
|
||
+ |
|
NO2 |
|
|
|
||
+ |
|
(5.47) |
|
|
NO2 |
Butadiene telomerization using nitroethane as a trapping reagent is applied to the total synthesis of the natural product, recifeiolide, where the secondary nitro group is converted into the ketogroup by the Nef reaction, and the terminal double bond is converted into the iodide via hydro alumination (Scheme 5.6).71
Extension to carbocyclization of butadiene telomerization using nitromethane as a trapping reagent is reported (Eq. 5.48).72 Palladium-catalyzed carbo-annulation of 1,3-dienes by aryl halides is also reported (Eq. 5.49).73 The nitro group is removed by radical denitration (see Section 7.2), or the nitroalkyl group is transformed into the carbonyl group via the Nef reaction (see Section 6.1).
O |
|
O |
NO2 |
EtO |
|
Pd(PPh3)4, PPh3 EtO |
|
+ CH3NO2 |
|
||
EtO |
EtO |
|
|
|
|
||
O |
|
O |
|
|
|
79% |
(5.48) |
|
|
|
NO2 |
NO2 |
|
Pd(OAc)2, PPh3, LiCO3 |
|
+ |
|
(5.49) |
|
|
H |
||
I |
|
|
|
|
|
|
73%
140 ALKYLATION, ACYLATION, AND HALOGENATION OF NITRO COMPOUNDS
|
|
Pd(OAc) |
NO2 |
1) TiCl3 |
||||
+ |
|
2 |
|
|
|
|||
2) (HOCH2)2, H+ |
||||||||
|
Ph3P |
|||||||
|
|
|
||||||
NO2 |
|
|
|
|
||||
|
|
|
|
56% |
|
|
|
|
|
|
|
|
|
|
O |
||
O O |
1) LiAlH4, TiCl3, I2 |
|
|
SPh |
||||
|
|
|
|
OH |
|
Cl |
||
|
2) NaBH4 |
|
|
|
||||
|
|
|
|
|||||
|
|
|
|
|
I
70%
O O
|
1) KN(SiMe3)2 |
O O |
|
SPh 2) Raney Ni |
|||
|
I
82%
Scheme 5.6. Synthesis of recifeiolide
Nitronate anions react with (π-allyl)cobalt complexes prepared from acylation of 1,3-dienes by acetylcobalt tetracarbonyl to produce nitro enones (Eq. 5.50).74
O |
+ - |
|
O2N |
O |
|
|
|
|
|
||
+ |
+ NaCH2NO2 |
|
|
Me |
(5.50) |
|
|||||
Me |
Co(CO)3 |
|
|||
74% |
|
||||
|
|
|
|
|
5.5.2 Pd-Catalyzed Allylic C-Alkylation of Nitro Compounds
The palladium-catalyzed allylic alkylation of soft nucleophiles (Tsuji-Trost reaction) represents one of the most useful organic transformations. Various allylating reagents and nucleophiles can participate in this reaction, as summarized in Scheme 5.7. Although allyl acetates, allyl carbonates, or 1,3-dienemonoepoxides are generally used as alkylating reagents, allylic nitro compounds also can be used as alkylating reagents (see Section 7.1). Active methylene compounds are generally used as nucleophiles in Tsuji-Trost reaction. Nitroalkanes, α-nitro ketones, α-nitro esters, and α-nitro sulfones can be also used as nucleophiles for this transformation.
|
Pd(0) |
R |
|
R |
Nu– |
Nu + Pd(0) + X– |
|
X |
R |
||
|
|
Pd |
|
|
|
X |
|
X = OAc , OC(O)OR, SO2Ph, NO2, OP(O)(OR)2, NR2, SR, etc.
NuH = CH2(CO2R)2, CH2(CN)CO2R, CH2(SO2Ph)CO2R, CH2(NO2)CO2R, CH2(NO2)SO2Ph,
CH2(SO2Ph)2, etc.
Scheme 5.7. Pd(0) catalyzed allylic alkylation