The Nitro group in organic sysnthesis - Feuer

3.2 DERIVATIVES FROM β-NITRO ALCOHOLS 39

discussed in Chapters 4 and 8. Some typical nitroalkenes which are useful reagents in organic synthesis are presented here.42

•Nitroethylene: Dehydration of 2-nitroethanol44 using phthalic anhydride (80%) is the best choice of preparation;43 bp 38–39 °C/80 mm Hg.

•1-Nitro-1-propene: Preparation is accomplished by dehydration of 2-nitro-1- propanol with phthalic anhydride (73%)45 or acetic anhydride-AcONa46; bp 56–57

°C/80 mmHg.

•2-Nitro-1-propene: Preparation is accomplished by dehydration of 1-nitro-2- propanol with methanesulfonyl chloride and triethylamine (30% yield),47 acetic anhydride-AcONa (85% yield),46 or phthalic anhydride (55%)45; bp 58 °C/35

mmHg (Eq. 3.25).

					O
O2N R					O	O2N		R R = H (80%)
					O				(3.25)
		140–180 ºC						R = Me (73%)
HO
		80 mmHg

Dehydration of β-nitro alcohols is generally carried out by the following reagents, phthalic

anhydride,44 CH3SO2Cl-Et3N,47 dicyclohexylcarbodiimide (DCC),48 Ac2O-AcONa, Ph3P- CCl4,49 and TFAA-Et3N,50 as exemplified in Eqs. 3.2648 and 3.2747b.

n-C H

9

DCC, CuCl

n-C4H9

4

NO

NO2

(3.26)

2

35 ºC, 10 h

OH

90%

PhO

NO2

PhO

CHO

1) CH3NO2, Et3N

2) MeSO2Cl, Et3N

N

(3.27)

N

O

An

O

An

85%

Dehydration of β-nitro alcohols using DCC gives a mixture of E/Z nitroalkenes.48 The pure (E)-isomers are obtained on treatment with catalytic amounts of triethylamine or polymer-bound triphenylphosphine (TPP) (Eq. 3.28).51 When (Z) nitroalkenes are desired, the addition of PhSeNa to the E/Z mixture and protonation at –78 °C followed by oxidation with H2O2 gives (Z)-nitroalkenes (Eq. 3.29).52

n-C3H7

Me

n-C3H7 Me

NO2

TPP

NO2

(3.28)

20 h

E/Z = 55/45

100% (E/Z = 100/0)

Me

Me

Me

NO2

Me

NO2

PhSeNa

Me

H2O2

Me

NO2

AcOH

SePh

–78 ºC

70 % (anti/syn = 91/9)

99% (Z/E = 90/10)

(3.29)

40 THE NITRO-ALDOL (HENRY) REACTION

Al2O3 can be used both as a base for the Henry reaction and as a dehydrating agent. Thus, nitroalkenes are simply prepared by mixing of aldehydes and nitroalkanes with Al2O3 and subsequent warming at 40 °C (Eq. 3.30).53

		+ CH3CH2NO2	Al2O3			NO2
	CHO					(3.30)
			40 ºC, 44 h
O					O		Me

In general, base-catalyzed reactions of aromatic aldehydes with nitroalkanes give nitroalkenes directly (Knoevenagel reaction).54 The reaction is very simple; heating a mixture of aromatic aldehydes, nitroalkanes, and amines in benzene or toluene for several

hours using a Dean-Stark water separator gives the desired nitroalkenes in good yield, as shown in Eqs. 3.31–3.34.54–58

					NO2
CHO	+	CH3CH2NO2	C4H9NH2		Me	(3.31)
			toluene
				OMe
OMe			reflux
				80–90%
MeO					OMe
CHO			CH3CO2NH4			NO2
		+ CH3CH2NO2
MeO				MeO		Me
					65%	(3.32)
CH2NO2		+	C4H9NH2			(3.33)
			CHO
				O2N
					65%
Br
+		NO2	CH3CO2NH4
				Br		Br
CHO		NO2	CH3CO2H
				O2N	NO2	(3.34)
				82%

Instead of using the Dean-Stark apparatus, the reaction can be carried out at reflux using MeNH3Cl/AcOK/MeOH with HC(OMe)3 as a water scavenger. A wide variety of nitroalkenes can be prepared in good yields by this method (Eq. 3.35).59

		MeO	NO2
MeO	MeO	CHO MeNH3Cl, AcOK	OMe
+		BzO
NO2	BzO	HC(OMe)3
BzO		MeOH, reflux	OBz
			77%

(3.35)

In recent years, there has been a considerable growth of interest in the catalysis of organic reactions by inorganic reagents supported on high surface areas.60 Envirocat, a new family of supported reagents, which exhibits both Brönstead and Lewis acid character, are ideal for environmentally friendly chemistry. These reagents are non-toxic powders that can be easily

3.2 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).

		Envirocat EPZG	Me
CHO	+
		NO2	NO2 (3.36)
		100 ºC, 20 min
			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.

OMe

Condition

Yield (%)

MeO

CHO

+

CH3NO2

NH4OAc/ AcOH

35

OMe

100 ºC, 3 h

MeO

NO2 NH4OAc/ AcOH

99

(3.37)

22 ºC, 3 h, ))))

Cl

Cl

N

NO2

+

CH3CH2NO2

H

(3.38)

CHO

Microwave

Me

400 W

64%

8 min

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										NO2
			TiCl4							CO2Me
+ O2N	CO2Me
N		O N Me						N		(3.39)
Me								Me
		THF, 0–25 ºC
						75%

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

THE NITRO-ALDOL (HENRY) REACTION

CHO

HO

NO2

CH3NO2

C(NO2)4, ZnSO4

NH4OAc-AcOH

HO

95%

EtOH

HO

NO2

HO

Na2S2O4, ZnSO4

HO

NO2

pH 4

HO

N

70%

H

52%

Scheme 3.3. Synthesis of 5,6-dihydroxyindole

NO2 1) Fe, AcOH, silica gel,

1) POCl

, DMF, 35 ºC,

toluene, ∆

3

MeO

N

1 h, then NaOH aq

NO2

2) MeI, KOH, Bu4NI,

Me

2) MeNO2, NH4OAc,

THF, 23 ºC

OMe

∆, 1 h

OMe

67%

NO2

NH2

CHO

OHC

O

LiAlH4, THF, ∆, 1 h

O

SiMe3

N

MeO

N

MeCN, 23 ºC, then TFA,

Me

Me

0 ºC, then NaBH3CN,

OMe

OMe

23 ºC

91%

88%

O

N H

Oi-Pr

N

O

O

MeO

N H

MeO

N H

OMe

Me

OMe

Me

66%

aspidophytine

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

NO

2

NO2

3 2

1) MeONa/MeOH

t-BuCOCl

t-Bu O

O t-Bu

+

HO

OH

HCHO

2) Salicylic acid

75%

NO2

O

O

AcONa

O

t-Bu

O

(3.40)

NPP

45%

				3.2 DERIVATIVES FROM β-NITRO ALCOHOLS 43
							O
		NO2		Nef	Nu	1	Nu	2
	Nu1		Nu2	NO2
NPP								(3.41)
		Nu1	Nu1	Nu2			NH2
				Reduction
					Nu1		Nu2
				NO2
	Li			OEt
		NPP		OLi
		THF, –70 °C		THF, –70 °C
			NO2	88%
							O
					N			(3.42)
			OEt	H2/Ni	H
				Et2O-EtOH
			O
		66%		82%
				OLi	O
			NO2
	NPP
n-C4H9Li
	THF, –70	°C		THF, –70 °C			NO2
			77%
				O	75%
	1) MeONa/ MeOH							(3.43)
	2) H2SO4			O
				78%

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

NO2

NO2

HO

OAc

t-Bu

O

AcO

OAc

PLE

1) Piv2O

2) MeOH/H+

O

90% (95% ee)

3) DCC/CuCl

67%

(3.44)

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				O	OTHP
		NO2					NO2
O	MeONa			H+

1) HCHO, MeONa				O						(3.45)
			O			Ph	heat
2) PhCOCl
										NO2
		NO2
								65% (overall)

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							O
					NaCNBH3					(3.48)
					Zeolite H-ZSM5
										NO2
				NO2
							70%

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
CO	Me	2) Ac2O, DMAP			CO Me				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
		N	N		Cbz
O2N	O	N	N			NH O
				+	BnO	H
	O	O				O			NHBz
						Cbz		N	N
						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)
							53%
			NHBz
		N	N			Boc
O2N	O	N	N			NH O
				+	Ph2CHO
						H
	O	O				O			NHBz
						Boc		N	N
						NH
	1) n-Bu4NF, THF, 18 h					Ph2CHO	O	N	N
	2) Ac2O, DMAP					O	NO2		(3.51)
	3) NaBH4, EtOH						O	O
							70%
							OAc
				CHO		AcO	O NO2
						AcO	OAc
				O
	OAc				O	1) KF	O O
				O					(3.52)
	O		+					O
AcO						2) Ac2O
		NO2			O
AcO	OAc							O
					O	3) NaBH4
								O

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).

+

O

OH

oxidation

O

NO2

X

(X = N N)

oxidizing agent

NO2

NO2

CrO3, Na2Cr2O7,

OM

PCC, etc.

NO2X

(3.54)

(X = Cl, OAc)

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

O

PCC

(3.55)

O2N O O

O O

12 h

O2N

78%

Me NO2

Me NO2

K2Cr2O7, 30% H2SO4

(3.56)

n-(C4H9)4N+HSO-4

O

OH

CH2Cl2, −10 ºC, 2 h

77%

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

O

O

NO2

O O

1) t-BuOK/ DMSO

n-C6H13

(3.57)

NO2

2) n-C H

N

O

N

6

13

88%

O

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.

NO2

Bu3SnH, AIBN

R1

R1

80 ºC

2

R2

R

O

O

NO2

(3.58)

TsNHNH

LiAlH

4

2

R1

R2

NNHTs

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

NO

2

+

O

1) Al2O3

O

O

NO2

TsNHNH2

O O

R

H

R 2) K2Cr2O7

O

NO2

H+

O

O

O

LiAlH4

O

O

R

R

R

acetone

O

NNHTs

NNHTs

O

OH−

R

R = CH

2

R = (CH2)4CH3

Scheme 3.5.

48 THE NITRO-ALDOL (HENRY) REACTION

NO2

NO2

O

amberlyst A-21

OCH3

+

OCH3

H3C

H

O

OH

O

86%

NO2

PCC

OCH3

Bu SnH, AIBN

3

CH2Cl2

O

O

benzene

71%

+

SCH3

OCH3

1) (CH2OH)2, H

OCH3

2) LDA, –78 ºC

O

O

3) (CH3S)2, HMPA, 0 ºC

O

O

71%

4) (CO2H)2

80%

1) NaIO4

OCH3

2) 100 ºC

O

O

86%

OH

O

O

Scheme 3.6.

O

C5H11

O

1) amberlyst A-21

C5H11

(CH2)9CH3

+

H

(CH ) CH

2) K2Cr2O7

NO

NO

2

2 9

3

2

NNHTs

78%

TsNHNH2

C5H11

(CH2)9CH3

LiAlH4

MeOH

THF, 0 ºC

NO2

NNHTs

90%

O

C5H11

(CH2)9CH3

amberlyst A-15

C5H11

(CH2)9CH3

Me2CO/ H2O

90%

95%

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