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The Nitro group in organic sysnthesis - Feuer

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4.3

MICHAEL ADDITION OF NITROALKANES

109

OAc

KF, Bu4NBr,

Ac O, py, RT

OMe

DMSO

NO2

NO2 methyl propiolate

98%

62%

OAc

15% TiCl3, pH 5.3

OMe

HO(CH2)2OH

OMe

p-TsOH

60%

95%

KOH

OMe

MeOH
	O
95%	O
	O
	(–)-(R, R)-Pyrenophorin I

Scheme 4.23.

Conjugate addition of nitroalkanes to allyl Baylis-Hillman acetates in the presence of NaOH (0.6 N) in THF gives 2-alkylidene-4-nitro ketones with high stereoselectivity; these are converted via the Nef reaction into the corresponding 1,4-diketones (Eq. 4.119).164

Et
OAc		NaOH
+	MeCH2NO2	NaOH

		THF, 0–20 ºC
O		THF, 0–20 ºC
O
Me		NO2		O
	Et	NO2		O
	Et		NaOH	Et
		Me	NaOH	Me (4.119)
		Me
		O	H+, MeOH
	Me	O	H+, MeOH	O
	Me		–50 ºC	Me
	78%			61%

Polyfunctionalized nitro compounds are prepared by the Michael addition using 2-alkenyl- substituted 2-siloxycyclopropanecarboxylates as Michael acceptors (Eq. 4.120).165

				O
Me3SiO	CO2Me	NO2	Triton B	CO2Me (4.120)
	+
	+		∆
			∆	NO2
				NO2
				80%

Newkome and coworkers have developed synthesis of dendritic molecules using the Michael addition of nitromethane to α,β-unsaturated esters as a key reaction (Scheme 4.24).166

The addition of alkyl nitronate anions to imines in the presence of a Lewis acid proceeds in high yield with up to 10:1 diastereoselection favoring the anti isomer. This reaction is used for the stereoselective synthesis of 1,2-diamines (Eq. 4.121).167 Scandium triflate catalyzes the addition of 1-trimethylsilyl nitropropanoate to imines with a similar selectivity.35

110 MICHAEL ADDITION

	OH
O2N	OH
O2N
	O
	OH
O
+	DCC, HOBT	R
O	DMF
O
	O
3 H2N	O
3 H2N
	O
	O
O

DCC: dicyclohexylcarbodiimide

HOBT: 1-hydroxybenzotriazole

			O O
			O
		O	O
		O	HN
			HN
		O	NH
	O	O	O
	OH	O
	OH	O
	OH	O	O
O2N	OH		O
O2N	O
	O
	OH
	O		R
DCC, HOBT			R
DCC, HOBT
	DMF
		O
		O	O
		O

O NHO

		O O		O
	O			O
				O
	O			O
	O			O
		NH		O
		NH		O
		H		O
		H		O
		N		O
		O		O
		NH		O
	O			O O
				O
	O	O		O
		O		O
		O
	R = NO2		H2, Raney Ni
	R = NH2		H2, Raney Ni
	R = NH2
O	O	O
O
O		O O
		O O
			O
HN				O O
O		O
		O		O
				O
	HN			O
	HN			NH
		O		NH
		O		H
		H		N
		N

O		O
		NH
O
	O
NH

	O	O

O		O

O O

	O	O	NH HN
		O				O
		O				O
		O O	O			O
			O			O
		O O	O			O
		O O	O	O	O	R = NO2
				O
								H2, Raney Ni
						R = NH2		H2, Raney Ni
						R = NH2
		Scheme 4.24.
	1) n-BuLi, THF, –78 ºC					PhH2C
	1) n-BuLi, THF, –78 ºC					NH
NO2	2) PhCH2N=CHPh					Ph	Et	(4.121)
NO2	3) THF, AcOH, –78 to 0 ºC					Ph		(4.121)
	3) THF, AcOH, –78 to 0 ºC					NO2
						NO2
					95% (anti/syn = 10/1)

4.3 MICHAEL ADDITION OF NITROALKANES

111

The sequence of the Michael addition of nitroalkanes and denitration provides a general method for conjugate addition of primary and secondary alkyl groups to electron deficient alkenes (Eq. 4.122).168

	O	O2N	Me	CO2Me		CO2Me
MeNO2	O		Me	CO2Me		Me
MeNO2					O2N	Me
		O			O2N	O
						O
	PhO2S	CO2Me		Bu3SnH	PhO2S	CO2Me
SO2Ph				Bu3SnH
SO2Ph		Me		AIBN		Me
DBU		Me		benzene		Me
DBU	O2N			benzene		H
	O2N			80 ºC		H
		O		80 ºC		O
		O				O

(4.122)

					NO2
TBDMSO	CHO	1) MeONa, MeNO2,		TBDMSO
		1) MeONa, MeNO2,		TBDMSO
	Me	MeOH, RT, 2 h			Me
		2) MsCl, Et3N, CH2Cl2			Me
		2) MsCl, Et3N, CH2Cl2
Me		0 ºC, 1 h		Me
Me

				62%
		NO2
1) NaBH4, CHCl3/i-PrOH,				amberlyst A-21, Et2O,
RT, 40 min		RO		amberlyst A-21, Et2O,
2) CH3CN/H2O, HF,			Me	RT, 2 h
2) CH3CN/H2O, HF,			Me
RT, 24 h				O	OTBDMS
3) (S)-2-methylbutyric		Me		O	OTBDMS
anhydride, DMAP,		Me
anhydride, DMAP,		59%
40 ºC, 20 min		59%
40 ºC, 20 min
		O
	O	OTBDMS
	O
		n-Bu3SnH, AIBN
	O	NO2	toluene
	Me	Me	toluene
	Me	Me	reflux, 30 min
			reflux, 30 min
	Me
		70%
	O				HO	O
O	OTBDMS			O		O
O	OTBDMS			O
O					O
Me	Me			Me		Me
Me				Me
	55%			(+)-dihydromevinolin

Scheme 4.25.

112 MICHAEL ADDITION

Hanessian and coworkers have used this strategy for a total synthesis of (+)-dihydromevi- nolin (Scheme 4.25).169

Ballini and coworkers have developed a new strategy for alkenylation of carbonyl compounds based on the Michael addition followed by elimination of HNO2 (see Section 7.3). A variety of 2-alkylidene 1,4-dioles have been conveniently prepared, in two steps, by the Michael addition of a nitroalkane to the appropriate enedione derivatives under basic conditions, followed by chemoselective reduction with LiAlH4 (Eq. 4.123).170

Me	NO2	CO2Me		Me	CO2Me		Me	OH
			DBU			LiAlH4		OH
		+
Me	H		MeCN Me		CO2Me		Me
		CO2Me						82%
					94%

(4.123)

The synthesis of 2,3,5-trialkylpyrroles can be easily achieved by conjugate addition of nitroalkanes to 2-alken-1,4-dione (prepared by oxidative cleavage of 2,5-dialkylfuran) with DBU in acetonitrile, followed by chemoselective hydrogenation (10% Pd/C as catalyst) of the C-C- double bond of the enones obtained by elimination of HNO2 from the Michael adduct. The Paal-Knorr reaction (Chapter 10) gives 2,3,5-trialkylpyrroles (Eq. 4.124).171

DBU

PhCH2CH2NO2

MeCN

CH2Ph

77%

Pd/C

PhCH2NH2 Me

(4.124)

CH2Ph

H CH2Ph

95%

92%

The Michael addition of cyclic α-nitro ketones to acrolein or methyl vinyl ketone followed by reduction of the carbonyl group and treatment with base results in the ring expansion (Eq. 4.125).172 Hesse and coworkers have used this strategy for the preparation of various macrolides.173 For example, Michael addition of 2-nitrocyclodecanone methyl vinyl ketone followed by reduction with (S)-alpine-hydride gives the nitrolactone in 72% yield. Radical

denitration of the nitrolactone with Bu3SnH gives (+)-(S)-tetradecan-13-olide in 44% yield (Eq. 4.126).173c

	O		(H2C)n	O
C)			(H2C)n
2 n		CHO
		CHO
	n NO2				CHO
		PPh3		NO2	CHO
		PPh3		NO2
n = 0, 1, 2, 6				84–93%
			O	84–93%		O
			O			O
		(H2C)n				O
	NaBH4			OH		(H2C)n
	NaBH4			OH	NaH
			NO2		DME
			90–95%			NO2
			90–95%			75–81% (4.125)
						75–81% (4.125)

		4.3 MICHAEL ADDITION OF NITROALKANES 113
O	O	O	O
O		O	O
	NO2
	PPh3		NO2
	O	Me	O	Me
	(S)-alpine		Bu3SnH
	hydride		Bu3SnH
		NO2	AIBN
				(4.126)
		72%		44%

The Michael addition of α-nitro ketones to α,β-unsaturated ketones followed by radical denitration provides a useful strategy for the preparation of 1,4-diketones.134b 1-Phenylheptane-

1,5-dione, isolated from the decayed heart wood of aspens, is prepared by this strategy (Eq. 4.127).174

							O	O
	O		+		PPh3		Ph
		NO2			PPh3		Ph

Ph			O					NO2
Ph			O					NO2
				O		O		71%
				O		O
			Bu3SnH	Ph				(4.127)
			AIBN	Ph
			AIBN
				70%

The Michael addition of nitro compounds to α,β-unsaturated ketones or esters followed by reduction of the nitro to amino group is useful for the preparation of various heterocycles. This is presented in Chapter 10 (Synthesis of Heterocycles).

4.3.2 Intramolecular Addition

Intramolecular Michael addition of nitro compounds proceeds in a stereoselective way to give various types of cyclic nitro compounds with high stereoselectivity. The Michael addition of 1-acetylcyclohexene to nitrostyrene followed by treatment with MeONa in MeOH gives 4-nitro-3-phenyldecalone with high stereoselectivity (Eq. 4.128).175

O			O Ph
O				NO2
	1) LDA			NO2
	2) Ph	NO2
		NO2	75%
			75%
			O	O
			H	H
	MeONa-MeOH		+	(4.128)
			+	(4.128)
	RT		Ph	Ph
	RT		H	H
			NO2	NO2
			45% (7:93)

114 MICHAEL ADDITION

Double Michael additions of nitro compounds bearing tethered acidic carbons to 3-butyn- 2-one under NaH catalysis give nitrocyclohexanes with high stereoselectivity. The products are transformed into trans-fused bicyclic compounds via the Dickmann reaction on treatment with base. (Eq. 4.129).176

	O	CN			Me	CNO
CN		Me	CO2Et	NaOEt	Me
	Me		CO2Et	NaOEt
	CO2Et NaH, THF		Me
NO	CO2Et NaH, THF	O2N		O	N
Me	2		O	2		OEt
		58%				80%

(4.129)

The intramolecular Michael addition is used as a key step for synthesis of epibatidine (Scheme 4.26).177 Epibatidine is an analgesic, operating by a nonopioid mechanism, it is several hundred times more potent than morphine.

O2N

1) NaBH4/EtOH

KF/Al2O3

2) MeSO2Cl

THF, RT

CH2Cl2, py

NO2

59%

OMs

SnCl2•2H2O

toluene

NO2

EtOH

NH2

R = H (67%)

R = Ms (91%)

80%

R = CO-menthyl

t-BuOK

t-BuOH

50%

60%

Scheme 4.26.

Barco and coworkers have reported a more elegant synthesis of the nitrocyclohexanone via the double Michael addition of nitromethane with enones. (Eq. 4.130).178

		O
TolSO2	MeNO2
O	MeNO2	(4.130)
O	KF
	KF
Cl N	Cl	NO2
	Cl	N

4.4 ASYMMETRIC MICHAEL ADDITION

115

The sequential process consisting of palladium-catalyzed alkylation and the intramolecular Michael addition of nitro compound provides a nitrocyclohaxane derivative, which is a good precursor for synthesis of Erythrina alkaloids (Eq. 4.131).179

O	O- Li+		AcO	Pd(PPh3)4, PPh3
	N		+	THF
O	N	O-		THF
O		O-	MeO2C
			MeO2C
O				O
	NO2			O
O	NO2			D	C
O			CO2Me	O	N	(4.131)
	1	H	CO2Me	O	B	(4.131)
		H			A 6
	H2C			3	A 6
	H2C			MeO
	57%			MeO
	57%

4.4 ASYMMETRIC MICHAEL ADDITION

4.4.1 Chiral Alkenes and Chiral Nitro Compounds

Diastereoselective conjugate addition of nucleophiles to enones, enals, and enoates occurs with high stereocontrol and constitutes a powerful method in stereoselective synthesis.185

The conjugate addition of nucleophiles to optically pure γ-oxygenated substrates is of special interest in the enantioselective synthesis of natural products. Highly syn-selectivity is observed in the conjugate addition of ammonia,186 alkoxides,187 and alkyllithium derivatives.188 High anti-selective addition is observed in the addition of metal enolates and cuprates.189 The Michael addition of nitromethane to enoates derived from glyceraldehyde acetonide leads to syn-adducts with high diastereoselectivity (de 76–90%) (Eq. 4.132).190 Primary and secondary nitroalkanes afford syn-adducts diastereoselectively in the Bu4NFor DBU-catalyzed Michael addition to the same enoates of Eq. 4.132.191

	O				O
	O		Bu4NF·3H2O	O		OEt
		+ MeNO2	Bu4NF·3H2O	O		OEt
O	OEt					(4.132)
O	OEt		THF			(4.132)
			THF			O
						O
	O				O2N

70% (syn/anti = 95/5)

Syn-selectivity of the DBU-catalyzed Michael addition of nitromethane to chiral γ-oxygen- ated enones is quite general, as shown in Scheme 4.27.192

Feringa and coworkers have used the optical active furanone or pyranone as an acceptor for the diastereoselective Michael reactions (Eq. 4.133).193

								O
	O	O H					O	O H
O		O H	Me	CHNO		2			(4.133)
			2			2	O2N		(4.133)
	O				N		O2N	O	O
	O	O	N		N		Me	Me
		O	N		N		76% (90% de)
					H		76% (90% de)

116 MICHAEL ADDITION
					O	N
	O	N		MeNO2	O		S
O		S		DBU		O
		S		DBU	O2N	O
	O				O2N
	O				92% (88% de)
					92% (88% de)
						NO2
	O	O			O	O
	O	O		MeNO2	O		S
O			S	MeNO2	O		S
O			S	DBU
				DBU		OBn	N
	OBn	N				OBn	N
	OBn	N			94% (83% de)
					94% (83% de)
							O	O	NO2
	O	O		O			O	O	O
	O	O		O	MeNO2	ButMe2SiO			S
t	Me2SiO			S	MeNO2	ButMe2SiO			S
Bu	Me2SiO			S	DBU
					DBU		O	O	N
		O	O	N			O	O	N
		O	O	N

92% (86% de)

Scheme 4.27.

Krief and coworkers have found that 2-lithio-2-sulfonylpropane and 2-lithio-2-nitropropane behave differently in the addition to dimethyl alkylidenemalonate. Thus, 2-lithio-2-sulfonyl- propane reacts with it almost exclusively on the (Si)-face and leads to the anti-adduct, whereas 2-lithio-2-nitropropane reacts under similar reaction conditions, exclusively on the (Re)-face, providing the syn-product (Eq. 4.134).194

		Me SO2Ph		Me	SO2Ph
		Me SO2Ph		Me	CO2Me
		Me	Li	O
				O	CO2Me
	CO2Me	THF			CO2Me
	CO2Me	THF		O
O				O
O	CO2Me	Me NO2		72% (92% de)		(4.134)
	CO2Me			Me	NO2
O
		Me	Li
		Me	Li	Me	CO2Me
				Me	CO2Me
		THF		O	CO2Me
					CO2Me

71% (100% de)

The Michael addition of nitromethane to vinylogous esters of N-protected amino acids proceeds with good yields and with good diastereoselectivity (Eq. 4.135).195

				NHBoc
NHBoc		MeNO2	EtO		Me

EtO
	Me		O	(4.135)
		DBU

O			O2N
			95% (60% de)

Levoglucosenone, a cellulose-derived α,β-unsaturated ketone, is an interesting material because it is both chiral and contains an activated double bond. This compound has been used

4.4 ASYMMETRIC MICHAEL ADDITION

117

as a chiral starting material for synthesis of a variety of natural compounds such as alkaloids or antibiotics.196 The Michael addition of nitro compounds to levoglucosenone provides a useful tool for the synthesis of various chiral compounds. Nitromethane undergoes TMG-catalyzed addition to levoglucosenone, affording 2:1 and 1:2 adducts in high yield (95%); the products result from initial Michel addition exclusively at the exo-face of the alkene anti to the 1,6-anhydro bridge (Eq. 4.136).197 If nitromethane is used as a solvent, the 2:1 adduct is obtained. A reaction is carried out by stirring a mixture of nitromethane and levoglucosenone (2:1 ratio) in CH2Cl2 in the presence of catalytic amounts of TMG to give a 1:2 adduct.

			O	O
O	MeNO2	O	MeNO2	O
O	TMG		TMG	NO2
O		O2N	O	OH
O	MeNO2	O2N		O2N
	TMG		O
			O
		O	OH	(4.136)
			OH

O2N O

O O

A variety of important synthetic reactions can be promoted by electrogenerated bases (EGB). The Michael addition and alkylation of compounds with activated hydrogen atoms are two examples in which using EGB has been very successful. The electrochemical method is very successful for functionalization of levoglucosenone as shown in Scheme 4.28.198

	O			O
	O			O
		O		O
EtO		OEt	Me	OEt
	NO2	O	O2N	O
	O	O		O
O		EtO2CCH(NO2)CH2CH2CO2Et	MeCH(NO2)CO2Et			O
						O
						O
O						O
O
	O	O	O2NCH2CO2Et			O
	O
						OEt
		Me2CHNO2		O2N		OEt
Me NO		O		O2N
Me	2					O
Me			O


		cyclo-C5H9NO2	CH3NO2
	O					O
	O
	O	O2NCH2CO2Et	CH2(NO2)2		O	OH
	O	CH2=CHCH2Br				OH
	O	CH2=CHCH2Br
O2N		O	O	O2N		O
		O	O	O		O
		O	O	O		O
			O
			O
	EtO		O
	EtO
		NO2	O2N NO2
		O	O2N NO2

Scheme 4.28.

118 MICHAEL ADDITION

4.4.2 Chiral Catalysts

Catalytic enantioselective nucleophilic addition of nitroalkanes to electron-deficient alkenes is a challenging area in organic synthesis. The use of cinchona alkaloids as chiral catalysts has been studied for many years. Asymmetric induction in the Michael addition of nitroalkanes to enones has been carried out with various chiral bases. Wynberg and coworkers have used various alkaloids and their derivatives, but the enantiomeric excess (ee) is generally low (up to 20%).199 The Michael addition of methyl vinyl ketone to

2-nitrocycloalkanes catalyzed by the cinchona alkaloid cinchonine affords adducts in high yields in up to 60% ee (Eq. 4.137).200

			N
		HO
		H	H	O
O			O	O
O		O
	NO2	O	N
	NO2	+	N	(4.137)
		+	NO2	(4.137)
		CCl4, –20 ºC, 60 h

84% (54.6% ee)

Matsumoto and coworkers have introduced a new strategy for asymmetric induction under high pressure. The Michael addition of nitromethane to chalcone is performed at 10 kbar in the presence of a catalytic amount of chiral alkaloids. The extent of asymmetric induction reaches up to 50% ee with quinidine in toluene.201

Chiral monoaza-crown ethers containing glucose units have been applied as phase-transfer

catalysts in the Michael addition of 2-nitropropane to a chalcone to give the corresponding adduct in up to 90% ee. (Eq. 4.138).202

O							O
Me	Me	NaOtBu, toluene
+		NaOtBu, toluene					*
+	NO2						*
H	NO2	MeO		H		O
				H	O	O	O2N Me
		O			O
		O				N R
						N R	Me
				H O			Me
	1	1	O	H O		O	82% (90% ee)
	R	O R	O

(4.138)

Yamaguchi and coworkers have found that proline rubidium salts catalyze the asymmetric Michael addition of nitroalkanes to prochiral acceptors. When (2S)-L-prolines are used, acyclic (E)-enones give (S)-adducts. Cyclic (Z)-enones give (R)-adducts predominantly (Eq. 4.139).203 Recently, Hanessian has reported that L-proline (3 ~ 7% mol equiv) and 2,5-dimethylpiperazine are more effective to induce catalytic asymmetric conjugate addition of nitroalkanes to cycloalkanones.204

O	NO2	N CO2Rb	O

		H
	+	(5–10 mol%)	(4.139)
		20 h
			O2N

			84% (84% ee)

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