The Nitro group in organic sysnthesis - Feuer

REFERENCES 69

122. Arai, T., H. Sasai, K. Aoe, K. Okamura, T. Date, and M. Shibasaki. Angew. Chem. Int. Ed. Engl., 35, 104 (1996).

123a. Sasai, H., T. Suzuki, N. Itoh, S. Arai, and M. Shibasaki, Tetrahedron Lett., 34, 2657 (1983). 123b. Sasai, H., N. Itoh, T. Suzuki, and M. Shibasaki. Tetrahedron Lett., 34, 855 (1983).

123c. Sasai, H., Y. M. A. Yamada, T. Suzuki, and M. Shibasaki. Tetrahedron, 50, 12313 (1994).

124.Sasai, H., M. Hiroi, Y. M. A. Yamada, and M. Shibasaki. Tetrahedron Lett., 38, 6031 (1997).

125.Sasai, H., W. S. Kim, T. Suzuki, and M. Shibasaki. Tetrahedron Lett., 33, 6123 (1994).

126.Sasai, H., T. Tokunaga, S. Watanabe, T. Suzuki, N. Itoh, and M. Shibasaki. J. Org. Chem., 60, 7388 (1995).

127.Iseki, K., S. Oishi, H. Sasai, and M. Shibasaki. Tetrahedron Lett., 37, 9081 (1996).

128.Arai, T., Y. M. A. Yamada, N. Yamamoto, H. Sasai, and M. Shibasaki. Chem. Eur. J., 2, 1368 (1996).

129.Hanessian, S., and J. Kloss. Tetrahedron Lett., 26, 1261 (1985).

130.Hanessian, S., and P. V. Devasthale. Tetrahedron Lett., 37, 987 (1996).

131.Corey, E. J., and F. Y. Zhang. Angew. Chem. Int. Ed. Engl., 38, 1931 (1999).

132a. Gasiraghi, G., F. Zanardi, G. Rassu, and P. Spanu. Chem. Rev., 95, 1677 (1995).

132b. Hudlicky, T., D. A. Entwistle, K. K. Pitzer, and A. J. Thorpe. Chem. Rev., 96, 1195 (1996).

133.Wehner, V., and V. Jager. Angew. Chem. Int. Ed. Engl., 29, 1169 (1990).

134.Kiess, F. M., P. Poggendorf, S. Picasso, and V. Jager. Chem. Commun., 119 (1998).

135.Fernandez, R., C. Gasch, A. G. Sanchez, J. E. Vilchez, A. L. Castro, M. J. Dianez, M. D. Estra da, and S. P. Garrido. Carbohydrate Research, 247, 239 (1993).

The Nitro Group in Organic Synthesis. Noboru Ono

Copyright © 2001 Wiley-VCH

ISBNs: 0-471-31611-3 (Hardback); 0-471-22448-0 (Electronic)

4

MICHAEL ADDITION

Conjugate addition of nucleophiles to electron-deficient alkenes is an important tool for the creation of carbon-carbon bond or carbon-heteroatom bond frameworks. This type of reaction is generally called as Michael addition. Because the nitro group is a strong electron-withdraw- ing group, nitroalkenes serve as good Michael acceptors and the anions of nitroalkanes serve as good Michael donors. These reactions proceed under very mild conditions and tolerate various functional groups. Because the nitro group can be converted into various functional groups as discussed in the Chapters 6 and 7, the Michael addition of nitro compounds has been used extensively in organic synthesis. The synthetic utility of the Michael addition of nitro compounds is shown in Scheme 4.1.

4.1 ADDITION TO NITROALKENES

4.1.1 Conjugate Addition of Heteroatom-Centered Nucleophiles

Heteroatom-centered nucleophiles such as oxygen, sulfur, nitrogen, and phosphorous anions are good nucleophiles for the Michael addition to nitroalkenes, which provides a useful method for the introduction of two heteroatoms on vicinal positions. Because this type of reaction may undergo a reverse elimination reaction, the addition products of nitrogen nucleophiles are often unstable. Because the addition products of sulfur and oxygen nucleophiles are more stable, the addition of alcohols and thiols has been frequently used for organic synthesis. In general, the experimental procedure for this addition is very simple. For example, the reaction of thiols with nitroalkenes readily proceeds in the presence of catalytic amounts of base to give β-nitro sulfides in quantitative yields.1 The stereoselectivity of this type of addition is generally low, and two diastereomeric isomers, syn and anti isomers, are formed in about a 1 to 1 ratio (Eq. 4.1).

+	XH	base			NO2
					(4.1)
NO2	X = RS, RO,		X
	R2N, R2P		syn / anti = 1/ 1

70

4.1

ADDITION TO NITROALKENES 71

O

R1

R2

R2

Nef

R1

R2

Nu

+

Nu H+

R1

NO2

NO2

(Chapter 6)

2

Nu

R

Nu

–

–

–

–

R1

= RO

, RS

, RNH ,

NH2

carbanions

R2 = H

Nu

R2 (Chapter 6)

R

1

CNO

R1

H

Nu

Nu

(Chapter 7)

(Chapter 6)

R1

X

1

R1

R

2

X

R2

O

X

+

R

CH2NO2

R2

NO2

R1

X

X= COR, CO2R, CN,

SO2R, etc.

R2 = H

2

R

NH2

R1

R1

X

X

R2

CNO

H

Scheme 4.1.

β-Nitro sulfides are conveniently prepared by simply mixing carbonyl compounds, nitroalkanes, and thiols in the presence of triethylamine.2 β-Nitro sulfide, which is used for synthesis of d-biotin, is prepared by this procedure (Eq. 4.2).3

	O
			+ CH3NO2 + HSCH2CO2H
H			CO2Me
			O

HO O NO2	HN	(4.2)
		NH
	H	H
S	CO2Me	CO2H
	S
		H
		d-biotin

Treatment of β-nitro acetates with thiols in the presence of base is also a simple method for the preparation of β-nitro sulfides (Eq. 4.3).4

72 MICHAEL ADDITION

	OAc	+ PhSH	THF		SPh	(4.3)
O2N				O2N
			Et3N		~100%

β-Nitro sulfides are useful intermediates for the preparation of various heterocycles containing sulfur atoms. Synthetic applications are demonstrated in Schemes 4.25 and 4.3,6 in which biotin is prepared via cycloaddition of nitrile oxides (see Chapter 8).

SH

(CH2)4CO2Me

S (CH2)4CO2Me

+

O2N

O2N

O2N O2N

80%

S

(CH ) CO

Me

S

(CH2)4CO2Me

2 4

2

POCl3

1) Zn/Ag, (CF3CO)2O

HN

NH

N

N

2) Pd/C, H2

O

O

3) COCl2

81%

O

Scheme 4.2.

O2N

N

O

NO2

Ph

N

C

O

EtONa

Et3N

AcS

S

S

HO

O

1) DMSO, Ac2O

N HN C

H2N

H

–

LiAlH4

2) NH2OH

2

1) OH

biotin

3) Beckmann

2) COCl2

S

rearrangement

S

Scheme 4.3.

Synthesis of thiopheno[3,4-c]isoxazoline is shown in Eq. 4.4, in which the Michael addition of allyl thiol to β-nitro enones and subsequent nitrile oxide cyclization are involved.7

O

O

Me

O

Me

Me

Et3N

Me

N

PhNCO

O2N

Me

+

HS

S

NO2

S

O

THF

Et3N

Me

H

99%

82% (ds 71/29)

(4.4)

The base-catalyzed joint reaction of nitroalkenes with thiophenol in the presence of aldehydes gives γ-phenylthio-β-nitro alcohols in one pot (Eq. 4.5).8 The joint reaction of nitroalkenes with thiols and α,β-unsaturated nitriles (or esters) has also been achieved. (Eq. 4.6).9 β-Nitro sulfides thus prepared show unique reactivity toward nucleophiles or tin radicals. The nitro

4.1 ADDITION TO NITROALKENES

73

group can be replaced by various nucleophiles in the presence of Lewis acid.10 The reaction of β-nitro sulfides with tin radical gives alkenes, in which both the nitro and alkylthio groups are eliminated as shown in Eq. 4.7. Details of such substitution and elimination reactions are described in Chapter 7.

NO2

TMG

NO2 OH

+ PhSH + HCHO

(4.5)

TMG: tetramethylguanidine

SPh

88%

MeO

NO2

SEt

EtSH

MeO

NO2

Et3N

MeO

MeO

SEt

CN

MeO

CN

(4.6)

(Me2CH)2NH MeO

NO2

80% (ds 1:1)

SR

SR

Bu3SnH

Me3SiX

(4.7)

AIBN

TiCl4

X

NO2

X = H, CN,CH2=CHCH2

Ono and Kamimura have found a very simple method for the stereo-control of the Michael addition of thiols, selenols, or alcohols. The Michael addition of thiolate anions to nitroalkenes followed by protonation at –78 °C gives anti-β-nitro sulfides (Eq. 4.8).11 This procedure can be extended to the preparation of anti-β-nitro selenides (Eq. 4.9)12 and anti-β-nitro ethers (Eq. 4.10).13 The addition products of benzyl alcohol are converted into β-amino alcohols with the retention of the configuration, which is a useful method for anti-β-amino alcohols. This is an alternative method of stereoselective nitro-aldol reactions (Section 3.3). The anti selectivity of these reactions is explained on the basis of stereoselective protonation to nitronate anion intermediates. The high stereoselectivity requires heteroatom substituents on the β-position of the nitro group. The computational calculation exhibits that the heteroatom covers one site of the plane of the nitronate anion.14

Me Me

+

Reagent and condition

Yield (%) anti/syn

NO2

NO2

PhSLi, –78 ºC, AcOH

71

91/9

NO2

Me

+

Me

PhSH, Et3N, RT

88

40/60

Me

Me

SPh

SPh

(4.8)

74 MICHAEL ADDITION

NO2

Me

AcOH

Me

Me

(4.9)

Me

+

PhSeNa

–78 ºC

NO2

SePh

68% (syn/anti = 91/9)

NO2

NH2

Ph

PhCH2ONa

Me

Ph

Pd/C, H2

Me

Ph

Me

AcOH

EtOH, HCl

NO2

OCH2Ph

OH

–78 ºC

73% (syn/anti = 91/9)

72% (syn/anti = 91/9)

(4.10)

Enantioselective synthesis of β-amino alcohols is also reported by the application of the oxa-Michael addition to nitroalkenes (Eq. 4.11). The sodium salt derived from (1R,2S)-N- formylnorephedrin and NaH reacts with nitroalkenes at –78 °C with high diastereoselectivity (de: 93–98%) in good yields. Virtually diastereomerically pure compounds can be obtained by using column chromatography. After the reduction of the nitro group to the amino group, the cleavage of the ether with sodium in liquid NH3 at –78 °C leads to amino alcohols without racemization.15

Ph

Ph

Me

O

NHCHO

H

1) NaH, –78 ºC

H N

OH

+

Me

NO2

2) AcOH

Me

O

Me

NO2

66% (de 94%)

1) NaBH4, Pd/C

Na/ NH3

OH

OR

OH

NHBoc

Me

2) Boc2O

–78 ºC

→ NHBoc)

75% (ee 96%)

80% (NO2

(4.11) The Michael addition of alkoxides to nitroalkenes gives generally a complex mixture of products due to the polymerization of nitroalkenes.16 The effect of cations of alkoxides has been examined carefully, and potassiumor sodium-alkoxides give pure β-nitro-ethers in 78–100% isolated yield (Eqs. 4.12 and 4.13).17 When lithium-alkoxides are employed, the yields are

decreased to 20–40%.

						Ph
	OH		1)	Ph	NO2	NO2	(4.12)
		KH, THF				O
		RT	2) 1 N-HCl
						80%
						NO2
	OH	NaH, THF	1)	NO2		O
							(4.13)
		RT	2) 1 N-HCl

94%

4.1 ADDITION TO NITROALKENES

75

The Michael addition of oxygen-nucleophiles followed by subsequent cyclization or cycloaddition provides an important method for the preparation of oxygen-heterocycles such as tetrahydrofurans. For example, 3-nitro-2H-chromenes bearing various substituents are prepared by the reaction of substituted salicylaldehydes with nitroalkenes (Eq. 4.14).18a The reaction with nitroethanol in the presence of di-n-butylammmonium chloride in refluxing isopentyl acetate gives 2-unsubstituted 3-nitro-2H-chromene in 50% yield.18b Some 3-nitro-2H-chromenes display efficient optical second harmonic generation for nonlinear optical applications.19

R1

CHO

Ar

R

1

NO2

OH

+

1) Et3N, RT

(4.14)

NO2

O Ar

R2

2) Al2O3

2

R

	R1, R2 = H, Cl, OMe	70–84%
	Ar = Ph, p-MeOC6H4, 2-thienyl

The Michael addition of allyl alcohols to nitroalkenes followed by intramolecular silyl

nitronate olefin cycloaddition (Section 8.2) leads to functionalized tetrahydrofurans (Eq. 4.15).20

Me

+

HO

t-BuOK

Me

NO2

Me3SiCl

–98 ºC

NO2

O

OSiMe3

Me

OSiMe

Me

N

Me

N

3

Bu4NF

N

O

O

O

O

O

O

74%

(tandem reaction)

(4.15)

Recently, tandem (domino) Michael addition initiated by oxygen nucleophiles has received much attention for the construction of octahydrobenzo[b]furans. The reaction of 1-nitrocyclo- hexene with 4-hydroxy-2-butynoates, catalyzed by t-BuOK at 0 °C, gives the desired furan in 90–100% yield (Eq. 4.16).21 Similarly, 4-chlorobut-2-yn-1-ols (Eq. 4.17)22 or prop-2-ynyl alcohols (Eq. 4.18)23 react with nitroalkenes in the presence of t-BuOK to give the furans. Anionic domino transformations induced by the addition of alkoxides to nitroalkenes proceed with high diastereoselectivity due to allylic 1.3-strain.22 The reduction of the nitro group in the products of Eq. 4.18 with SmI2 affords 3,6-dihydro-1,2-oxazines (Eq. 4.19). The cleavage of the N-O bond of the product generates 1,4-bifunctional groups.24a The [2,3]sigmatropic rearrangement of the allylic nitro compounds is also possible.24b Such anionic domino transformations have been reviewed.25

				CO2Me
NO2				O2N
	+	HO	t-BuOK
				(4.16)
		CO2Me	0 ºC
				O
				H

100%

76 MICHAEL ADDITION

NO2	+	HO					t-BuOK
						Cl	0 ºC

NO2	+					t-BuOK
						0 ºC
		HO

	O2N	•
		SmI2
	H	O

		O2N	•
			(4.17)
		H	O
		70–78%
O2N			O2N
			+
H	O		O
			H

78% (5-exo/6-endo = 1.7/1) (4.18)

O

HN

(4.19)

O

H

60–90%

The addition-elimination reaction of hetero-atom-substituted nitroalkenes provides functionalized derivatives of unsaturated nitro compounds.26 Nitroenamines are generally prepared from α-nitro ketones and amines (see Chapter 5 regarding acylation of nitro compounds).26

The addition of alkoxides to 2-nitro-1-phenylthio-1-alkenes affords β-nitro-aldehyde acetals.27d The reaction of the same nitroalkenes with amines gives nitroenamines.27c They are important intermediates for organic synthesis and are generally prepared by the reaction of nitroalkanes with triethylorthoformate in the presence of alcohols or secondary amines.27a–c The methods of Eqs. 4.20 and 4.21 havesomemeritsover theconventionalmethods,forvariouslysubstitutedβ-nitro-aldehydes acetals or nitroenamines are readily prepared by these methods.

PhS	+					THF			N	(4.20)
NO2			N			RT, 2 h
										NO2
			H							85%
						MeO			NO2
PhS		MeONa				MeO				(4.21)
NO2		RT, 24 h					H
							78%

Interesting push-pull dienes, 1-dialkylamino-4-nitro-1,3-butadienes, are prepared by the application of this addition-elimination reaction. (Eq. 4.22).28

	PhS	+		CH2Cl2	N
			N	RT		(4.22)
		NO2			NO2
			H		80%

A new synthesis of β-nitroenamines by amination of nitroalkenes with methoxyamine in the presence of base is reported (Eq. 4.23).29

		4.1		ADDITION TO NITROALKENES					77
		H2NOMe		Ph				H
Ph	NO2			H N				NO	(4.23)
		t-BuOK
				2	2
				94%

The Michael addition of a nitrogen-centered nucleophile to nitroalkenes affords compounds that may serve as precursors of vicinal diamines, since the nitro group can be reduced to an amino function by reduction. The very convenient method for the preparation of 1,2-diamines is developed by the addition of O-ethylhydroxylamines to nitroalkenes followed by reduction with H2 in the presence of Pd/C (Eq. 4.24).30

						NH2
1			NO2	1) EtONH2•HCl, NaHCO3, THF	R1	NH2
R						(4.24)
			2	2) H2, Pd/C, EtOH		R2
	R
						54–90%

The conjugate addition of chiral-nitrogen nucleophiles to nitroalkenes provides access to chiral compounds having nitrogen functionalities on vicinal carbon atoms. Various natural products belong to this class of compounds such as biotin, penicillin, and several amino acids that are components of the peptide antibiotics. Chiral nitrogen nucleophiles, (S)-2-methoxymethylpyrrolidine (SMP) and its enantiomer (RMP) have been used for this process.30 Fuji and Node developed an elegant method for asymmetric synthesis using (S)-2-methoxymethylpyrrolidine and nitro enamines,118 which is discussed in Section 4.2 (Eq. 4.25).

			OMe
O N	+	THF	(4.25)
NO2	N	RT	N
	H OMe
			NO2

Amino alcohols like (S)-prolinol react with nitroalkenes very rapidly with very high facial selectivity.31 Rapid and stereoselective reduction of the nitro function is essential for the conversion of the products to 1,2-diamine derivatives with the retention of the configuration. Samarium diiodide is recommended in the stereoselective reduction of thermally unstable 2-aminonitroalkanes to give a range of useful 1,2-diamines (Eq. 4.26).32

NO2

+

OH

CH2Cl2, RT

N

30 min

H

OH

OH

NO2

NH2

N

SmI2

N

(4.26)

MeOH-THF

95% (trans/cis = 99/1

90%

facial selectivity = 97/3)

78 MICHAEL ADDITION

The asymmetric synthesis of 1,2-diamines using (2S,3R,4R,5S)-1-amino-3,4-dimethoxy- 2,5-bis(methoxymethyl)pyrrolidine with high enantiomeric excess (93–96% ee) has been developed, as in Eq. 4.27.33

MeO	OMe
MeO		Me	NO2
	OMe
N		–78ºC→20ºC
NH2
	MeO	OMe
MeO			NH2	(4.27)
	N H		Raney Ni, H2	NH2
MeO		N	Me
		NO2	70% (ee 96%)
	Me
	75%

The conjugate addition of (R)- or (S)-4-phenyl-2-oxazolidinone to nitroalkenes is catalyzed by t-BuOK at –78 °C to give the addition product with excellent diastereoselectivity, the products are converted into vicinal diamines (Eq. 4.28).34

O

O

Ph

O

NO2

N

O

N

Ph

+

t-BuOK, THF

NO2

–78 ºC, 15 min

H

NHAc

75% (ds 98%)

1) HCO2NH4, Pd/C

NHAc

(4.28)

2) Li/NH3

3) AcCl

46%

An alternative method for the stereoselective preparation of 1,2-diamines is shown in Eq. 4.29, in which the addition of nitroalkanes to imines is used as a key reaction.35

Ph

1) n-BuLi, –78 ºC, THF

EtCH2NO2 +

N

OMe

2) AcOH

MeO

1) SmI2

(4.29)

NH

NH

THF-MeOH

2

Ph

Ph

2) CAN

NH2

NO2

MeCN-H2O

anti/syn = 10/1	RT

The products of the conjugate addition of (R)-4-phenyl-2-oxazolidinone to nitroalkenes are converted into D-α-amino acids with high enantiomeric purity (Eq. 4.30).36