The Nitro group in organic sysnthesis - Feuer

4.1 ADDITION TO NITROALKENES

79

O

NaNO2, AcOH

O N Ph

DMSO, 40 ºC

NO2

O	O				Ph				NH2
	N
					1) Li/NH3				CO2H	(4.30)
				CO2H 2) DOWEX
						50W-X4-400
	51%						62% (96% ee)

An intramolecular Michael type reaction of a nitrogen nucleophile to nitroalkene, as shown in Eq. 4.31, provides a useful method for the preparation of 2,2-dimethyl-1-carbapenam.37

			H
	NSiMe3	KF	N	(4.31)
		0 ºC
			O
	O	NO2		NO2
			78%

The Michael addition of phosphine nucleophiles to nitroalkenes provides novel β-nitro phosphonates, as in Eq. 4.32.38 Yamashita and coworkers have shown that the nucleophilic addition of Ph2POH to chiral nitroalkenes derived from sugars proceeds stereoselectively to the 5-(S)-isomer (Eq. 4.32) in high diastereoselectivity (ds 11:1).

NO2				NO2
		O		O
O	O	Ph2PH	H PPh2		(de = 11:1)	(4.32)
				O
			H	O
MeO	O
				O
			MeO

The base-catalyzed reaction of dialkyl phosphite with nitroalkenes results in the formation of alkenyl phosphonates (Eq. 4.33).39

					O
Ph		Me
				Et3N	(MeO)2P				Me
		+	(MeO)2P(O)H						(4.33)
				THF
H		NO2			Ph				H

72% (E/Z = 3/1)

Combining, in tandem, the nitro-aldol reaction with the Michael addition using thiophenol is a good method for the preparation of β-nitro sulfides as shown in Eqs. 4.2 and 4.3. This reaction is applied to a total synthesis of tuberine. Tuberine is a simple enamide isolated from Streptomyces amakusaensis and has some structural resemblance to erbastatin, an enamide which has received much attention in recent years as an inhibitor of tyrosine-specific kinases. The reaction of p-anisaldehyde and nitromethane in the presence of thiophenol yields the requisite β-nitro sulfide, which is converted into tuberine via reduction, formylation, oxidation, and thermal elimination of

80 MICHAEL ADDITION

the sulfoxide (Eq. 4.34).40 The selective reduction of β-nitrostyrenes to β-aminostyrene derivatives provides a direct method for the preparation of the same enamides, but the reduction of nitroalkenes leads to a formation of complex products involving carbonyl compounds (see Chapter 6).

MeO

CH3NO2, PhSH

CHO

Et3N

MeO

MeO

NO2

1) Zn/HCl

(4.34)

2) HOCOCOCF3

PhS

3) NaIO4

NHCHO

82%

53%

1-Nitro-2,2-bis(methylthio)ethylene is a useful reagent for the preparation of various heterocycles, which is described in Chapter 10.

4.1.2 Conjugate Addition of Heteroatom Nucleophiles and Subsequent Nef

Reaction

Barrett and coworkers have explored hetero-substituted nitroalkenes in organic synthesis. The Michael addition of nucleophiles to 1-alkoxynitroalkenes or 1-phenylthionitroalkenes followed by oxidative Nef reaction (Section 6.1) using ozone gives α-substituted esters or thiol esters, respectively.41 As an alternative to nucleophilic addition to 1-(phenylthio)-nitroalkenes, Jackson and coworkers have used the reaction of nucleophiles with the corresponding epoxides (Scheme 4.4).42 Because the requisite nitroalkenes are readily prepared by the Henry reaction (Chapter 3) of aldehydes with phenylthionitromethane, this process provides a convenient tool for the conversion of aldehydes into α-substituted esters or thiol esters.

1-(Benzyloxy)nitroalkene is useful for the synthesis of bicyclic β-lactam systems and has been applied for the construction of an oxapenam (Eq. 4.35).43 Desilylation and cyclization take place on treatment of N-silylated nitroalkene with Bu4NF to give the nitronate of the bicyclic β-lactam, which is treated with ozone in situ to give the benzyl ester of oxapenam. When (phenylthio)nitromethane is used instead of (benzyloxy)nitromethane, the phenylthio ester of oxapenam is obtained (Eq. 4.36).44

NO2

Nu

Nu

Nu

O3

O

NO2

XR

XR

XR

O

60–80%

X = O, S

N , CH(CO2Me)2

Nu = OMe,

O

NO2

t-BuOOLi

O

Nu

Nu

NO

XR

2

XR

XR

O

Scheme 4.4.

						4.1	ADDITION TO NITROALKENES 81
			O		NO2	1) Bu4NF, THF, O3				O
				OCH2Ph					N
		N					O				(4.35)
O			Si			2) DBU				CO2CH2Ph
								52%

	O	NO2			O
	N	SPh	Bu4NF, O3	O	N
			THF
O	Si				(4.36)
					COSPh
					64%

Stereocontrolled total syntheses of penicillanic acid S,S-dioxide and 6-aminopenicillanic acid from (S)-asparatic acid and (R,R)-tartaric acid, respectively, have been reported (Eq. 4.37).45

Si O

N

O

			HO	H
S	NO2	Bu4NF, O3
	OCH2Ph			N
		THF	O
Si

S

CO2CH2Ph

1)CF3SO2Cl

2)LiN3

3)H2, Pd/C

		H	80%
	H3N		S
	O	N	(4.37)
			CO2

A stereospecific total synthesis of polyoxin C and related nucleosides is reported, in which the reaction of 1-(phenylthio)-1-nitroalkenes with nucleophiles and subsequent ozonolysis are key reactions. Addition of potassium trimethylsilanoate to 1-(phenylthio)-nitroalkenes derived from D-ribose followed by ozonolysis gives the α-hydroxy thioester, which is formed with excellent diastereoselectivity (Scheme 4.5).46 This conformation meets the stereo-electronic requirements for antiperiplanar addition of the nucleophile with the result of high 5-(S) stereochemical bias in the reactions.

However, not all nucleophiles show the same bias as shown in Scheme 4.5 on addition to the nitroalkene. The product of the addition of potassium phthalimide has 5(R) stereochemistry (Eq. 4.38).47 This stereoselective addition is applied for the synthesis of other related antibiotics, such as nikkomycine B.48

		O	O
O2N SPh	1)	NK		COSPh
				O	OMe
O			N
	OMe
		O		H
H
	2) O3		O	O	O
O O
			80% (ds 15:1)		(4.38)

82	MICHAEL ADDITION
O	O	OMe
H			1) PhSCH2NO2, t-BuOK
	O O		2) MsCl, i-Pr2NEt
O2N	SPh						OTMS
	O	OMe			O2N		H
	H		1) KOTMS, DMF, 0 ºC					O
			2) O3, MeOH, –78 ºC
	O	O			PhS			O
							O
	83%							OMe
			COSPh					OH
		HO	O	OMe				O
					CO2
			H
						O
			O O		H3N		N	NH
					H			O
					HO		OH
		94% (ds 50:1)

Scheme 4.5.

Diastereoselective conjugate addition of oxygen and nitrogencentered nucleophiles to nitroalkenes derived from (+)-camphorsulfonic acid and ozonolysis give α-hydroxy and α-amino thiol acid derivatives (Eq. 4.39). In all cases, the (R)-diasteromer is formed as the major component.49

		O
	1)	NK , –40 ºC		O
	S	O	S	N
			(R)
	2) O3	SO	NiPr O
	NO2			O
		2	2
	SO2NiPr2		61% (de 71%) (4.39)

1-(Phenylthio)nitroalkenes are also excellent intermediates for the synthesis of other heterocyclic ring systems. For example, tetrahydropyran carboxylic acid derivatives are formed by the intramolecular addition of oxygen nucleophile to 1-(phenylthio)nitroalkene predominantly as the cis-isomer (9.1:1) (see Eq. 4.40). The reaction may proceed via the chair-like transition state with two pseudo-equatorial substituents.50

HF, pyridine

SPh

SiO Ph

NO2

			SPh
Ph	O		t-BuOK, O3
			NO2H
	H
		H	Ph O COSPh (4.40)

4.1

ADDITION TO NITROALKENES 83

O

O

STol

NH3

O

O

O

t-BuOOLi

NO2

O

STol

O STol

–78 ºC

syn 12:1

NH2

O

Ph3COOK

NO2

–78ºC

O

O

STol

NH3

O

O

O

NO2

O

STol

anti 15:1

NH2

Scheme 4.6.

Jackson and coworkers have used a new approach to the synthesis of β-hydroxy-α-amino acids using (arylthio)nitrooxiranes. D-Isopropylideneglyceraldehyde is converted into the corresponding 1-arylthio-1-nitroalkene, which is a key material for stereoselective synthesis of β,γ-dihydroxyamino acids (Scheme 4.6). The key step is stereoselective nucleophilic epoxidation of the 1-arylthio-1-nitroalkene. Syn and anti epoxides are selectively obtained by appropriate choice of epoxidation reagent.51

The rationalization of stereoselectivity is based on two assumptions. (1) The 1-arylthio- 1-nitroalkenes adopt a reactive conformation in which the allylic hydrogen occupies the inside position, minimizing 1,3-allylic strain. (2) The epoxidation reagent can then either coordinate to the allylic oxygen (in the case of Li), which results in preferential syn epoxidation or in the absence of appropriate cation capable of strong coordination (in the case of K); steric and electronic effects play a large part, which results in preferential anti epoxidation (Scheme 4.7).52

Extension of this strategy enables syntheses of both protected D-threonine and L-allo- threonine, in which reagent-controlled stereoselective epoxidation of a common intermediate is the key step (Scheme 4.8).53

The stereoselective synthesis of anti-β-amino-α-hydroxy acid derivatives using nucleophilic epoxidation of 1-arytlthio-1-nitroalkenes has been reported (Eq. 4.41).54

O
t-BuO	NH STol			LiOOBut
				–78 ºC
Ph		NO2					O
		O
	t-BuO		NH O STol			HN		O
								(4.41)
		Ph		NO2		Ph		COSTol
							43%
	t-BuO				O2N	O
	O Li							O
	O2N		O	O	TolS	H
	TolS	H				Ph3COO K
		syn				anti

Scheme 4.7.

84 MICHAEL ADDITION

Si

Si

Si

O

O

O

STol

Ph3CO2K

O STol

NH3

NO2

THF, –78 ºC

O

NO2

STol

NH2

BF3•Et2O

82% (ds 20:1)

86%

OH

STol

Ph3CO2Li

OH

STol

O

NO2

THF, –78 ºC

NO2

65% (ds 100%)

Si

Si

TBSOTf

NH3

O O

O

STol

O

NO2

STol

NH2

82% (ds 20:1)

65%

Scheme 4.8.

An elegant synthesis of (5R, 6S, 8R)-6-(α-hydroxyethyl)-2-(hydroxymethyl)penem-3-car- boxylic acid has been accomplished by the strategy based on the Michael addition and Nef reaction (Scheme 4.9).55

Si		1) KS	Si
				O
O		KS NO2
				S		NO2
	OC(O)Ph
		2) Me2SO4	Me
Me					SMe
				NH
	NH
O				O
				76%
1) O		Si
		O
Cl	CO2PNB	S	NO2	LiN(SiMe3)2
		Me	SMe
2) P(OMe)3		N
		O
		CO2PNB
		1) 75%, 2) 90%
Si	O			OH
Me	S SMe			Me	S	OCONH2
	N	NO2		O	N
	O				CO2Me
	60%

Scheme 4.9.

4.1 ADDITION TO NITROALKENES

85

4.1.3 Conjugate Addition of Carbon-Centered Nucleophiles

4.1.3a Active Methylene Compounds Nitroalkenes are powerful Michael acceptors that can serve as synthons of the type +C-C-NH2 and +C-(C=O)R. Classically, the reactions of nitroalkenes with carbon-centered nucleophiles have been limited to reactions carried out under mildly basic conditions using relatively acidic reaction partners such as malonate derivatives and 1,3-diketones.56 The Michael addition of such active methylene compounds to nitroalkenes is catalyzed by various bases, including ROM (M = metal), triton B, and triethylamine. For example, the reaction of acetyl acetone or ethyl acetate with nitrostyrene proceeds in the presence of catalytic amounts of triethylamine at room temperature to give the adduct in 98% or 78% yield, respectively. The addition products are useful intermediates for the preparation of furans or pyrroles.57 Metal complex catalysts such as Ni(acac)2 are also effective to induce the Michael addition of acetyl acetone to nitrostyrene.58 Yoshikoshi and coworkers have found that the potassium fluoride-catalyzed addition of 1,3-dicarbonyl compounds to nitroalkenes leads to the formation of furans (Eq. 4.42) or Michael adducts and their Nef products (Eqs. 4.43 and 4.44), depending on substrates and conditions.59

O

O

Me

KF, xylene

+

(4.42)

Me

reflux

O

Me

NO2

O

Me

Me

52%

O

O

Me

Me

Me

Me

KF, xylene

+

(4.43)

NO2

reflux

O

O

O

96%

O

Me

KF, xylene

CO2Et

+

reflux

NO2

O

O

CO2Et

CO2Et

Me

+

Me

(4.44)

O

NO2

20%

47%

The Michael addition of nitroalkanes to nitroalkenes is catalyzed by triethylamine to give 1,3-dinitro compounds (Eq. 4.45).60 In some cases, the intramolecular displacement of the nitro group takes place to give cyclic nitronates (Eq. 4.46).61

					R2
R2		Et N or K CO		O2N	NO2
R1	+ R3 NO2	3	2 3		(4.45)
NO2				R1	R3
				51-98%

86 MICHAEL ADDITION
					Ph	CO2Et
Me	NO	CO2Et	KF/Al O
	2		2	3
	+ Ph				Me	N	O	(4.46)
Me		NO2	MeCN
	H				Me	O
						70%

The asymmetric Michael addition of 1,3-dicarbonyl compounds to nitrostyrene is promoted by chiral alkaloid catalysts to give the addition products in good chemical yield, but the enantioselectivity is rather low (Eq. 4.47).62

				Me	Ph
O	O	Ph	(–)-quinine	O	NO2
	+	NO2			(4.47)
Me	Me			O	Me

89% (16% ee)

Recently, very effective asymmetric conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes has been reported, as shown in Scheme 4.10. The reaction of ethyl acetoacetate with nitrostyrene is carried out in the presence of 5 mol% of the preformed complex of magnesium triflate and chiral bis(oxazoline) ligands and a small amount of N-methylmorpholine (NMM) to give the adduct with selectivity of 91%. The selectivity depends on ligands. The effect of ligands is presented in Scheme 4.10.63

	O	O		ligand (5.5 mol%)			O	Ph	ligand:	R	R
				Mg(OTf)2 (5 mol%)						O	O
	Me	OEt		NMM (6 mol%)				NO2
					CHCl3, sieves		Me			N	N
	Ph						CO2Et
		NO2			RT, 3 h
	Entry	Ligand			Selectivity (%)		Conversion (%)				1
										R R
	1	1a			95		96			O	O
	2	1b			65		33			R2	R2
	3	1c			77		44			N	N
										R1	R1
	4	2c			58		9
										2: R1 = Ph, R2 = H
	5	3c			0		7
										3: R1 = CMe3, R2 = H
	6	4c			76		15
	7	4a			82		99			4: R1 = R2 = Ph

a: R = -CH2CH2-; b: R = H, c: R = Me

Scheme 4.10.

4.1.3b Enolates Derived From Ketones and Esters and Carbanions Stabilized by Sulfur In recent years, a variety of procedures for the successful addition of simple ketones or esters to nitroalkenes have been developed. Seebach and coworkers have reported

4.1 ADDITION TO NITROALKENES

87

the Michael-type addition of lithium enolates, sulfur-substituted organolithium reagents, and

other reactive carbanions to nitroalkenes. Some typical examples are presented in Eqs. 4.48 and 4.49.64a

OLi					NO2
	O	NO2
+			THF	O
						(4.48)
			–78 ºC
	O			O	O
					93%
S		Me	NO2		S
	LDA			O2N	S
						(4.49)
	THF, –78ºC
S					Me
					65%

Dianions or trianions derived from 1,3-dicarbonyl compounds react with nitroalkenes at low temperature to give the adduct, which undergoes a nitro-aldol type cyclization (Eq. 4.50).64c

Nitroethylene is extremely reactive and sensitive to strong basic conditions, but various ketone and ester enolates undergo alkylation with nitroethylene at low temperature (Eq. 4.5165 and Table 4.1).

		OMe
O O			OMe
1) LDA, THF, –78 ºC
2) MeO	O	O
			NO2
MeO	NO2
	NO2
	HO	OMe
		OMe	(4.50)
	O
	68%
O		O
			NO2
1) LDA, THF, –78 ºC
			(4.51)

2)NO2

74%

Nitroalkenes react with lithium dianions of carboxylic acids or with lithium enolates at –100 °C, and subsequent treatment of the Michael adducts with aqueous acid gives γ-keto acids or esters in a one-pot operation, respectively (Eq. 4.52).66 The sequence of Michael addition to nitroalkenes and Nef reaction (Section 6.1) provides a useful tool for organic synthesis. For example, the addition of carbanions derived from sulfones to nitroalkenes followed by the Nef reaction and elimination of the sulfonyl group gives α,β-unsaturated ketones (Eq. 4.53).67

88	MICHAEL ADDITION
Table 4.1. Michael Addition to Nitroalkenes
R-H			Base	Nitroalkene		Product		Yield (%)	Reference
	O		LDA		NO2	O		81	65
	Ph	Me				Ph	NO2
	O					O	NO2
					NO2
			LDA					72	65
		O				O2N	O
			LDA		NO2			62	71
	N					N
	CH2Ph					CH2Ph
	O					O	NO2 57
	BuO		LDA		NO2	BuO			65
		Me				Me
	O					O
						MeO	NO2
			LDA		NO2			94	65
MeO
PhO2S			LDA	Me			NO2	90	72
					NO2	PhO S	Me
						2
							NO2
O		SPh LDA			NO2	O	CO Et	85	73
	OEt CO Et
						OEt SPh 2
		2
Ph	N CO2Et					Ph	NO2
			LDA	Ph	NO2	Ph		66	74
	Ph					Ph N	CO Et
							2

			O	SPh
		1) LDA, THF, –78 ºC			(4.52)
	PhS CO2H 2)			CO2H
		NO2		80%
		3) H+

1)LDA

2)Et

SO2Ph	NO2	(4.53)
+	O
3) H

82% (E/Z = 2/1)

4) DBU