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The Nitro group in organic sysnthesis - Feuer

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8.2

1,3-DIPOLAR CYCLOADDITION 259

NH2

LiAlH4

H2/Raney Ni

NH2

Scheme 8.18.

hydroxymethyl substituents, on the other hand, direct attack of LiAlH4 to the syn face of the C?N double bond to give predominantly threo amino alcohols. Jager and coworkers have used this strategy for synthesis of glycosidase-inhibiting iminopolyols and amino sugars (Eq. 8.61).63b,96 Recently, diastereoselective synthesis of highly substituted 2,5-diaminohexanes via nitrile oxide cycloaddition to an optically active vinylogous amino acid has been shown.96d

		Me	Me	N	O	LiAlH4
Ph C N O		Me	Me			LiAlH4
Ph C N O				Ph	Me
				Ph	Me
					Me
					Me		Me
					Me	Ph + Me		Ph	(8.60)
					OH NH2		OH	NH2
						89% (9:1)
			O		PhNCO	O H		O
O H	+	O2N			PhNCO	O
O H	+	O2N	O		Et3N	O		O
O			O		Et3N		O	O
							O	N
							58%		(8.61)
							HO		(8.61)
LiAlH4		O			O		HO
LiAlH4		O	H		O				O
		O
			OH NH2		O			OH	OMe
			OH NH2						NHAc

The conversion of isoxazolines to β-hydroxy ketones can be carried out by H2 in the presence of Raney Ni under various conditions.97 The reaction proceeds cleanly with complete stereospecificity (Eq. 8.62).

260 CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS

(8.62)

Thus, isoxazolines are converted into γ-amino alcohols and β-hydroxy ketones stereoselectively. However, the intermolecular cycloaddition involving 1,2-unsymmetrically substituted alkenes such as trans-cinnamyl alcohol proceeds nonregioselectively to give a mixture of the two regioisomers (Eq. 8.63).98

(8.63)

Several strategies have been proposed to improve the regioselectivity of nitrile oxide cycloaddition. Kanemasa and coworkers have reported high-rate acceleration and regioselectivity in nitrile oxide cycloadditions to the magnesium alkoxides of allylic and homoallylic alcohols (Eq. 8.64).99

(8.64)

Another strategy to control the regioand stereochemistry of cycloaddition is a silicon-teth- ered reaction, as discussed in the section of nitronates (Section 8.2.3) (Eq. 8.65).100

(8.65)

Isoxazolines are good precursors of α,β-unsaturated ketones.63,94 This transformation is useful for synthesis of polyenes. For example, nitrile oxide cycloaddition chemistry is used to prepare 4-oxo-2-alkenylphosphonates, which are useful to synthesize a long polyethylenic unit via Woodworth-Emmons olefination (Eq. 8.66).101

8.2 1,3-DIPOLAR CYCLOADDITION 261

(8.66)

As a new utility of nitrile oxide in organic synthesis, synthesis of medium and large rings by intramolecular nitrile oxide dimerization is reported (Eq. 8.67).102

(8.67)

Intramolecular 1,3-cycloadditions of nitrile oxides (INOC) provide a useful tool for the construction of fused cyclic ring systems. The stereochemical outcome of this reaction is presumed to be a consequence of reaction through the transition state that minimizes allylic 1,3 strain (Scheme 8.19).103

Kurth and coworkers have reported sequential 1,3-dipolar cycloadditions in the synthesis of bis-isoxazolo-substituted piperidinones (Scheme 8.20).104 The Michael addition of allyl alcohol to nitrostyrene followed by INOC gives a mixture of cisand trans-furanoisooxazoles in 88% yield. The stereoselectivity is much improved by intramolecular silynitronate cycloaddition (ISOC) (see Section 8.2.3). The use of 1,4-phenylene diisocyanate as the dehydrating agent is recommended because the resulting urea polymer can be removed by simple filtration. The introduction of allyl group and formation of the nitroacetoamide provide a precursor of an isoxazoloisooxazoline-containing tetracycle. Finally, INOC of this precursor affords a desired tetracyclic compound stereoselectively.

Scheme 8.19.

262 CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS
		Ph					Ph
OK		Ph			OCN		NCO	N
OK					OCN		NCO	N
NO2				NO2			O	O
Ph			O			Et3N
			O			Et3N		H
								H
							88% (ds = 8:1)
Ph						Ph	O
Ph	H					Ph
MgBr	H						N
MgBr	N		O N		CO H		N	NO2
O		O	2		2	O	O
Et2O, –78 ºC				DCC
	H						H
	88%				O		86%
					O
					N
OCN			NCO	Ph	H
OCN			NCO	Ph		O
					N	O
	Et3N				N
	Et3N			O	O

65%

Scheme 8.20.

INOC has been used for the synthesis of tricylic compounds having the taxane A/B ring system with an aromatic C ring (Eq. 8.68).105

			O
O2N		Cl	N
		Cl	N
			N
Cl	NCO		H
Et3N, 70 ºC, 10 h
O O			O O

(8.68)

94%

A potentially useful approach to the marine alkaloid papuamine based on INOC strategy is proposed as shown in Scheme 8.21. In fact, a trans-hydrindane intermediate has been synthe-

sized in racemic form using a model sequence of reactions involving a nitrile oxide cycloaddition as a key step (Eq. 8.69).106

		N	H
H		N	NH2
NO2	H	O	H
PhNCO		LiAlH4	H
Et3N		H	OH
Et3N		H	H H
H			H H
H			(8.69)
			(8.69)
		72%	90%

A diastereoselective synthesis of the model insect antifeedant related to 12-hydroxyazadi- radione starting from α-cyclocitral has been reported. [The key steps involve INOC and a Stille

8.2 1,3-DIPOLAR CYCLOADDITION 263

coupling reaction of a vinyl iodide with a stannylfuran (Eq. 8.70)].107 Many related syntheses by means of INOC have been reported.108

NO2		O N
NO2		H
PhNCO
Et3N
HO	O			O
HO	O	73%
H			HO
H2, Pd/C		9 steps	HO
H2, Pd/C		9 steps	H	(8.70)

H3BO3

80%

Asymmetric synthesis based on INOC using a chiral nitrile oxides is a standard method for obtaining enantiomerically pure compounds. A useful synthesis of enantiomerically pure pyranoand oxepanoisoxazole derivatives by application of INOC is presented in Eq. 8.71.109

O		O N					H	O
		2		O			N		O
		O		O		PhNCO	O		O
O		O			O	PhNCO	O
O		O			O	Et3N
		O			O	Et3N	O	H	O
	HO		O				O	H
							28%		(8.71)

Takahashi and coworkers have used INOC for synthesis of the chiral CD rings paclitaxel, which is an antitumor agent. Synthetic strategy starting from 2-deoxy-D-ribose is demonstrated in Scheme 8.22.110 The precursor of INOC was prepared by 1,2-addition of α,β-unsaturated ester to ketone. INOC and subsequent reductive cleavage by H2/Raney Ni afford the desired CD ring structure.

H H	H H				H		H
N	N				H		H
H			H			NHR RHN
H			H	H		OR RO		H
				H		OR RO		H
H H	H H				H	H	H	H
					H			H
papuamine
	N		N			C N O		O N C
	N		N			H		H
H	O	O		H		H		H
H H			H H			H		H
H H			H H
				NO2	O2N
			H			H
				H	H

Scheme 8.21.

264 CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS

CN X

AcO

EEO

D O

BzHN

OBz

OAc

OR OR

Paclitaxel

Raney Ni

B(OH)3

1) 1,2-addition

OTBS

2) DIBAL

INOC

3) CH =C(OMe)Me,H+

EtO

α +

0 ºC

OR4

4) oxidation

OBn

15min

5) oximation

R1O R2O OR3

R O R2O OR3

6) NaOCl

OBn

R1,R2 = C(CH3)3; R3 = R4 = Bn

1) TBSCl, quant.

2) Swern ox, 89%

OMe

1) m-CPBA

1) HCl/MeOH

Et2O•BF3

2) BnBr, NaH

OBn

2) LiAlH4

OBn

92%

83% (2 steps)

Scheme 8.22.

Evans and coworkers have reported the synthesis and absolute stereochemical assignment of (+)-miyakolide.111 Miyakolide was isolated from a sponge of the genus Polyfibrospongia by Higa et al.112 The elegant synthesis is illustrated in Scheme 8.23, in which the carbon skeleton is assembled in a convergent fashion from three fragments via esterification, [3+2] cycloaddition, and aldol reaction. Here, intermolecular and intramolecular [3+2] cycloadditions of nitrile oxides are used to assemble small components to complex large sized molecules.

1,3-Dipolar cycloaddition of nitrile oxides using chiral alkenes or chiral nitrile oxides has been extensively studied. It has been established that allylic substituents have a strong

influence in determining the π-facial selectivity and that notable high levels of diastereoselectivity (de 56–93%) are observed for cycloaddition to chiral allyl ethers.63c,113 For example,

benzonitrile oxide adds to (S)-isopropylidenebut-3-ene-1,2-diol to afford an 85:15 mixture of the isoxazolines (Eq. 8.72).114 The preferred formation of the adduct (erythro) has been rationalized by Houk et al. in terms of an inside alkoxide effect that involves allylic oxygen (Scheme 8.24).115 The diastereomeric preferences observed in cycloaddition result from the alkoxy group preference for the inside conformation and the alkyl group preference for anti. Examples of the corresponding reactions with chiral allylamine derivatives have also been reported, but, in general, the degree of selectivity is lower and less predictable.116

	N O		N	O
O Ph C N O	Ph	O	Ph		O
O		O	+	O	(8.72)
O		O		O	(8.72)
	85		:	15

Scheme 8.23.

265

266 CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS

Cycloaddition of nitrile oxides to alkenes with various chiral auxiliaries are summarized in Table 8.1, which shows chiral alkenes and differential excess (de).

Compared with the related reactions of nitrones, there have only appeared a few publications of metal-assisted or metal-catalyzed 1,3-dipolar cycloadditions of nitrile oxides. This is due to

Table 8.1. Asymmetric Induction in Nitrile Oxide (PhCNO) Cycloaddition to Optically Active Acrylates

Chiral alkene		de (%)	Ref.
	H
	O	56	117
		56	117
	O
SO2N(C6H11)2
	O
	N	62–90	118
		62–90	118
S	H
O2
	tBu
	O
	N	90	119
	S
	O2
	O H
	N	98	120
	O	98	120
	O
	O Ph
BnO	O
	O
	N	50	121
	N
H	O
	N
		90	122
H
	OEt
	O
	O
O	N	86	123
		86	123

8.2 1,3-DIPOLAR CYCLOADDITION 267

R N

C O

anti (erythro)

Scheme 8.24.

reactivity of nitrile oxides or the requirement of bases such as triethylamine for generation of nitrile oxides. Kanemasa and coworkers have solved some of these problems, as shown in Eq. 8.64.99

It has recently been found that Et2Zn promotes the 1,3-dipolar cycloaddition of nitrile oxides

to allyl alcohol in the presence of catalytic amounts of diisopropyl tartrate (DIPT). By this method, 2-isoxazlines are obtained in good yields and up to 96% ee (Eq. 8.73).124a A positive

nonlinear effect (amplification of ee of the product) has been observed in this reaction. There is an excellent review on positive and negative nonlinear effects in asymmetric induction.124b

				Zn	O
	NOH			Zn	OiPr
			R	N O O	OiPr
OH		DIPT	R	N O O			N O
OH	+	DIPT		Zn			N O
	R Cl	Et2Zn		Zn	OiPr		OH
				O O			OH
				O O			R
R = p-CH3OC6H4					O
	OH				O
	OH
(R, R)-DIPT= iPrO C		CO2iPr				(8.73)
	2

8.2.3 Nitronates

Alkyl and silyl nitronates are, in principle, N-alkoxy and N-silyloxynitrones, and they can react with alkenes in 1,3-dipolar cycloadditions to form N-alkoxy- or N-silyloxyisoxazolidine (see Scheme 8.25). The alkoxy and silyloxy groups can be eliminated from the adduct on heating or by acid treatment to form 2-isoxazolines. It should be noticed that isoxazolines are also obtained by the reaction of nitrile oxides with alkenes; thus, nitronates can be considered as synthetic equivalents of nitrile oxides. Since the pioneering work by Torssell et al. on the development of silyl nitronates, this type of reaction has become a useful synthetic tool. Recent development for generation of cyclic nitronates by hetero Diels-Alder reactions of nitroalkenes is discussed in Section 8.3.

A series of 3-substituted-2-isoxazoles are prepared by the following simple procedure; in situ conversion of nitroalkane to the silyl nitronate is followed by 1,3-dipolar cycloaddition to produce the adduct, which undergoes thermal elimination during distillation to furnish the isoxazole (Eq. 8.74).125 Isoxazoles are useful synthetic intermediates (discussed in the chapter on nitrile oxides Section 8.2.2). Furthermore, the nucleophilic addition to the C?N bond leads to new heterocyclic systems. For example, the addition of diallyl zinc to 5-aryl-4,5-dihydroi- soxazole occurs with high diastereoselectivity (Eq. 8.75).126 Numerous synthetic applications of 1,3-dipolar cycloaddition of nitronates are summarized in work by Torssell and coworker.63a

CH3NO2	Me3SiCl	N	Ph		N		∆	Ph	N
	Et3N			Ph		OSiMe3			O
		O OSiMe3			O
									51%

(8.74)

268 CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS
	N	+	Zn	THF		NH
Ph				–78 ºC	Ph		(8.75)
			2
	O					O

72% (ds = 6.9:1)

Eguchi and Ohno have used silyl nitronate induced 1,3-dipolar cycloaddition for function-

alization of fullerene C60 (Eq. 8.76).127a Nitrile oxides also undergo 1,3-dipolar cycloaddition

to C60.127b

C60	MeNO2	N OSiMe	TsOH	N
	Me3SiCl	3		O
	Me3SiCl	O		O

Et3N

42% (8.76)

Nitroethane undergoes base-catalyzed addition to C60 to give 2-hydroxy-1,2-dihydrofulleryl ketoxime by way of a unique intramolecular redox process, which is not observed in normal electron deficient alkenes (Eq. 8.77).128 (See Section 4.3 Michael addition of nitroalkanes).

		Me
C60	EtNO2	NOH	(8.77)
C60	Et3N	OH	(8.77)
	Et3N	OH
		46%

Denmark and coworkers have developed an elegant method for generating cyclic nitronates using nitroalkenes as heterodienes in the Diels-Alder reaction (Eq. 8.78). The synthetic utility of this reaction is discussed in Section 8.3.

O	O	[2 + 4]	O O
			N
+	N			(8.78)

Lewis acid

Recently, Kanemasa and coworkers found a new method for preparing cyclic nitronates. ω-Halo-α-nitropropane and -butane are cyclized with base to form cyclic nitronates which are labile 1,3-dipoles. They can be trapped by a variety of monosubstituted ethenes to give the corresponding adducts (Eq. 8.79).129a The N–O bonds in adducts are cleaved on treatment with acid to give functionalized isoxazeles. Cyclic nitronates are also prepared by intramolecular O-alkylation of ω-nitro alcohols via Mitsunobu condensation using triphenylphosphine and diethyl azodicarboxylate.128b

Another approach to cyclic nitronates has been developed by Rosini et al. in which nitro-aldol and subsequent cyclization is used as a key step. For example, 2,3-epoxy aldehydes react with ethyl nitroacetate on alumina surface in the absence of solvent to give 4-hydroxyisoxazoline 2-oxides in good yields (Eq. 8.80).130

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