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The Nitro Group in Organic Synthesis

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The Nitro Group in Organic Synthesis. Noboru Ono

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

CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS

Nitro compounds have been converted into various cyclic compounds via cycloaddition reactions. In particular, nitroalkenes have proved to be useful in Diels-Alder reactions. Under thermal conditions, they behave as electron-deficient alkenes and react with dienes to yield 3-nitrocy- clohexenes. Nitroalkenes can also act as heterodienes and react with olefins in the presence of Lewis acids to yield cyclic alkyl nitronates, which undergo [3+2] cycloaddition. Nitro compounds are precursors for nitrile oxides, alkyl nitronates, and trialkylsilyl nitronates, which undergo [3+2]cycloaddition reactions. Thus, nitro compounds play important roles in the chemistry of cycloaddition reactions. In this chapter, recent developments of cycloaddition chemistry of nitro compounds and their derivatives are summarized.

8.1 DIELS-ALDER REACTIONS

Diels-Alder reactions are one of the most fundamental and useful reactions in synthetic organic chemistry. Various dienes and dienophiles have been employed for this useful reaction.1 Nitroalkenes take part in a host of Diels-Alder reactions in various ways, as outlined in Scheme 8.1. Various substituted nitroalkenes and dienes have been employed for this reaction without any substantial improvement in the original discovery of Alder and coworkers.2 Nitrodienes can also serve as 4π-components for reverse electron demand in Diels-Alder reactions. Because the nitro group is converted into various functional groups, as discussed in Chapters 6 and 7, the Diels-Alder reaction of nitroalkenes has been frequently used in synthesis of complex natural products. Recently, Denmark and coworkers have developed [4+2] cycloaddition using nitroalkenes as heterodienes; it provides an excellent method for the preparation of heterocyclic compounds, including pyrrolizidine alkaloids. This is discussed in Section 8.3.

8.1.1 Nitroalkenes Using Dienophiles

Nitroethene undergoes rapid cycloaddition to 1,3-dienes; the subsequent Nef reaction gives cyclohexenones, which are formally produced by the Diels-Alder reaction of ketene with

231

232 CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS
			Nef		R
			Nef
			reaction
				X	O
		R	Al/Hg		R
			Al/Hg
X	X	NO2		X	NH2
X
					R
R			Bu3SnH
NO2			AIBN	X
NO2
	A					O A
	O O	A	MeO2C		O	O A
B	N		MeO2C	MeO2C	O	N
B
	H	B [2+3]				B
	H	B [2+3]				B
	R		cycloaddition			R
	R					R
				H2/Raney Ni
	O	A				A
	N		B	MeO2C		N
	HO		B			B
		R		HO
		R				R

Scheme 8.1.

1,3-dienes (Eq. 8.1).3 This strategy has been used for the synthesis of prostaglandins by Corey and coworkers.4 Another synthesis of prostaglandin based on the Diels-Alder reaction of nitroalkenes is presented in Scheme 8.2, in which the nitro group is reduced to an amino group.5 A total synthesis of antheridium-inducing factor of the fern Anemia phyllitidis uses the Diels-Alder reaction of nitroethylene followed by the Nef reaction.6

CH2OCH2Ph	PhCH2O
PhCH2O	PhCH2O
–20 ºC	Nef reaction
+	O
NO2	O
NO2	71% (8.1)

The Diels-Alder reaction of nitroalkenes followed by the Nef reaction is frequently used in natural product synthesis.7 For example, Scheme 8.3 shows an elegant synthesis of dl-mesem- brane starting from the Diels-Alder reaction of 1-arylnitroethene with 1,3-butadiene.7a

Ono and coworkers have developed a new strategy using nitroalkenes as alkene equivalents in Diels-Alder reactions. When unsymmetrical dienes are used, the nitro group controls the regiochemistry of the Diels-Alder reaction, as shown in Eq. 8.2. The nitro group in cycloadducts is removed by radical denitration (see Chapter 7); therefore, nitroalkenes can be regarded as reactive dienophilic alkene equivalents.8 Vinyl sulfones have similar utility in organic synthesis.9 In general, nitroalkenes are more reactive and selective than the corresponding sulfones, but the latter are more readily available than nitroalkenes.

			8.1 DIELS-ALDER REACTIONS			233
C5H11
S S	R	C5H11		R	C5H11
	R	C5H11		R	C5H11
+		S S	Al/Hg	S	S
+	O2N			H2N
R	O2N			H2N
R		(major)		90%
NO2				90%
R = (CH2)6CN				O
R = (CH2)6CN	H2N	R C5H11 O		(CH ) CO		H
	H2N	R C5H11 O		(CH ) CO		H
1) OsO4				2 6	2
1) OsO4
2) Pb(OAc)4		O		HO
3) HgCl2	CHO	O		HO

HO OH	OH
HO OH
	Scheme 8.2.

NO2	O2N	O
	O2N	O
		Nef reaction

MeO

	MeO			MeO
MeO	MeO			MeO
	MeO			MeO
O		MeO2C
		HN
RhCl3	1) LiAlH
	4
MeO	2) CH3C(O)NCO	MeO
	3) Tf2O	MeO
	3) Tf2O
MeO		MeO
85%		MeO		OMe
85%
	O
	O			OMe
	Cl3C			OMe
	Cl3C
CCl3COCl	N	CuCl (bipy)	Cl	ClCl
	MeO2C		Cl
	MeO2C
	MeO			O
	MeO			N
				N
	MeO			CO2Me
	MeO			88%
				88%
OMe		OMe
OMe			OMe
	OMe		OMe
	OMe

Bu3SnH

AIBN

O N

CO2Me

dl-Mesembrane

Scheme 8.3.

234 CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS
	NO2			C H	9
O2N C4H9	C4H9			4	9
O2N C4H9	C4H9	Bu SnH
		3
Me		AIBN	Me
Me			80%
	72%		80%
	72%
Me	NO2
O2N		Bu3SnH
Me	C4H9	Bu3SnH	Me	C4H9
Me	C4H9	AIBN	Me	C4H9
C4H9	70%		52%	(8.2)
	70%		52%	(8.2)

The Diels-Alder reaction of morphinan-6,8-dienes with nitroethene affords a novel type of opium alkaloids (Eq. 8.3).10a High reactivity of nitroethylene is demonstrated for the Diels-Alder reaction with thermally unstable dienes, and this is used for synthesis of polycyclic kopsane-like alkaloids.10b

MeO

	O2N	benzene	O
O	+	reflux	N
O
	N
	N		CHO
	CHO		NO2
			NO2

63% (8.3)

Functionalized nitroalkenes are important dienophiles in the Diels-Alder reaction. For example, (E)-methyl β-nitroacrylate is an important reagent in organic synthesis. The nitro group can be readily eliminated; the Diels-Alder reaction of β-nitroacrylate is equivalent to that of ethyl propiolate with an inverse regiochemistry (Eq. 8.4).11

	CO2Et
H	CO2Et
	55%
	NO2
	CO2Et	DBU		CO2Et
O2N	CO Et
	2
	91%		60%	(8.4)
	91%			(8.4)

Another example is presented in Eq. 8.5, in which the nitro group is more effective in controlling the direction of addition than the carbonyl group.12

	O	O	O
		O

+			DBU
+
O2N		NO2

83% (8.5)

8.1 DIELS-ALDER REACTIONS 235

Various dienes substituted with heteroatoms such as 1-oxabuta-1,3-dienes have been used in organic synthesis, as shown in Eq. 8.613 and Eq. 8.7.14

		O2N				CO2Me
		O2N		benzene
	+			benzene		NO2	(8.6)
		CO2Me		RT, 3 h		NO2
NHBoc		CO2Me				NHBoc
NHBoc					63%
					63%
		O2N					NO2
		O2N	1) benzene, RT, 42 h				(8.7)
	+		1) benzene, RT, 42 h				(8.7)
						O	CO2Me
Me3SiO		CO2Me	2) AcOH
			2) AcOH
					72%
					72%

Nitroethene substituted with the Me3Si group is used in a Diels-Alder reaction (Eq. 8.8).15a An example of the reaction with 1-nitro-2-(trialkylsilyl)acetylenes has also been published.15b

NO2		SiMe
+	110 ºC, 8h	3
	110 ºC, 8h	(8.8)
		(8.8)
Me3Si		NO2
		61%

Recently, enhanced endo selectivity has been reported in the Diels-Alder reaction of (E)-1-acetoxybuta-1,3-dienes with methyl β-nitroacrylate. The selectivity is compared with that of the reaction using 1-methoxybuta-1,3-dienes and 1-trimethylsilyloxybuta-1,3-di- enes.16 The degree of electron richness of a diene is an important consideration in endo:exo selectivity issues. In particular, electron-rich dienes favor the formation of exo-nitrocycload- ducts (Eq. 8.9).

CO2Me		CH2	Cl2
CO2Me		CH2	Cl2		R	endo	exo	Yield (%)
+					R	endo	exo	Yield (%)
+		RT
O2N
					Me	67	33	67

OR
MeO2C	MeO2C				SiMe3
+						68	32
						68	32

O2N		O2N			COMe	95	5	71
OR				OR	COMe	95	5	71
OR		exo		OR
endo
endo

(8.9)

Node and co-workers have found that the Diels-Alder reaction of nitroalkenes with 1- methoxy-3-trimethylsilyloxy-1,3-butadiene (Danishefsky’s dienes) exhibit abnormal exo-se- lectivity. Electrostatic repulsion between the nitro and the silyloxy group of the diene induces this abnormal exo-selectivity (Eq. 8.10).17 This selective reaction has been used for the asymmetric synthesis of various natural products as shown in Scheme 8.6.

236 CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS

NO2	OMe
	1) benzene, reflux

2)HCl

R		OSiMe3			R	exo	endo	Yield (%)
		OSiMe3
	O			O
					Ph	87	13	60
R		OMe	+		n-C5H11	66	34	71
			R		OMe
			R		OMe
		NO2			NO2
	exo			endo				(8.10)

Total synthesis of epibatidine, a potent analgesic compound isolated from the Ecuadorian poison frog Epopedibates tricolor has been accomplished as shown in Scheme 8.4. Here the Diels-Alder reaction of 5-(2-nitrovinyl)-2-chloropyridine with 2-trimethylsilyloxy-1,3-butadi- ene is used as a key step.18 This alkaloid is prepared by using polymer-supported reagents and sequencing agents in a successive manner. The key steps are similar to those in Scheme 8.4, but no chromatographic purification steps are required to afford the product in >90% purity.19

The Diels-Alder reaction of nitroalkenes with Danishefsky’s dienes is applied to synthesis of truncated carbocyclic analogues of a potent neuraminidase inhibitor 4-guanidino-Neu4Ac2en (see Scheme 8.5).20 Carbocyclic analogs are found to retain interesting levels of antiviral activity comparable to those shown by their oxygen-containing compounds in Scheme 8.5.

	δ-		OMe			OMe
	δ-		OMe			δ-
	Me3Si O					δ-	SiMe3
						O
	steric		O			O
	steric	R	N			O	electrostatic
	repulsion		N		R	N
	repulsion		O		R	N
			O			O	repulsion
			H			O
						H
	exo					endo
	NO2		O	N				O2N
			2
Cl N	1) 120 ºC				O	1) L-selectride		OMs
	+					2) MsCl
	2) CF3CO2H					2) MsCl	Cl	N
	2) CF3CO2H		Cl N
	OSiMe3		Cl N
				68%				53%
			HO					MsO
	1) NaOMe, O3							MsO
	1) NaOMe, O3				1) NaN3, DMF
	–78 ºC			OMs	1) NaN3, DMF			N3
	2) NaBH4			OMs	2) MsCl, Et3N
	2) NaBH4				2) MsCl, Et3N
	Cl		N				Cl	N
			80%				Cl	N
			80%					63%
								63%
		MsO						Cl
		MsO					H
	SnCl2					∆	H	N
	SnCl2			NH2		∆	N	N
	MeOH-THF			NH2
	25 ºC	N
	Cl	N						84%
			80%					84%
			80%

Scheme 8.4.

8.1 DIELS-ALDER REACTIONS 237

PhCH2O H OCH2Ph OTMS

toluene

+ O2N O 110 ºC

O2N

OMe

MeO

PhCH2O

58%

1) Ac2O, pyridine

PhCH2O

1) H+, HO

DMAP

H2N

2) HCl

2) NaBH4, CoCl2

AcHN

MeO

72%

66%

PhCH2O

Me3S+I-

NaN3

AcHN

n-BuLi

AcHN

CO2H

NH2

NHAcH

Drug for influenza A and B

Scheme 8.5.

1-Nitrodiene systems such as 3-(2-nitrovinyl)indoles21 and 2-(2-nitrovinyl)furans22 are reactive enough as dienes for the Diels-Alder reaction, as shown in Eqs. 8.11 and 8.12. Elimination of HNO2 and dehydrogenation take place spontaneously to give aromatized products, respectively.

NO2		O	O
			O
	+		140 ºC	(8.11)
	+		N	(8.11)
N			H
N			O
H		O	O
H			50–60%


			CO2Me
NO2	+	CO2Me	140 ºC
O	+			(8.12)
			O	(8.12)


			53%

Reactions of 2-(2-nitrovinyl)-1,4-benzoquinone with furans, indoles, and endocyclic enol ethers form angular, fused heterocyclic quinoid ring systems (see Eq. 8.13).23

238 CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS
	O	O2N
	O
O2N	heat	OH
	+	(8.13)
	O	O
	O	HO

87%

Aromatization is often observed during the Diels-Alder reaction using nitroalkenes. Jung24 and Ono25 have reported that 2-phenylsulfinyl-1-nitroalkenes act as nitroacetylene equivalents in Diels-Alder reactions to give aromatic compounds, as shown in Eqs. 8.14 and 8.15, respectively.

		Me		Me	Me
Ph	NO2	Me			(8.14)
			benzene		(8.14)
			benzene
S	+	OSiMe3			NO2
	+	OSiMe3	reflux		NO2
O	Me		reflux		OH
O		OMe			OH
		OMe			32%
					32%
		OMe			Me
Ph	NO2		toluene		(8.15)
S	+		110 ºC, 2 h	HO	(8.15)
O			110 ºC, 2 h	HO
O		Me3SiO			51%
		Me3SiO			51%

Another example of the preparing of aromatic compounds via the Diels-Alder reaction of nitroalkenes is presented in Eq. 8.16.26 Cycloaddition of methyl propiolate affords a high yield of the isomeric product.

		OMe
	CO2Me
OMe	O2N		CO2Me
	HO		CO2Me
OMe	1) 0–25 ºC	80%
OMe	2) DBU	80%	(8.16)
	2) DBU		(8.16)
Me3SiO		OMe
	CO2Me		CO2Me

Node and coworkers have used this aromatization strategy for the synthesis of (–) aphanorphine.27 The Diels-Alder reaction of chiral nitroalkene, prepared by the asymmetric nitroolefination reaction of α-methyl-δ-valerolactone, with the Danishefsky’s diene followed by aromatization is used as a key step for this total synthesis, as shown in Scheme 8.6.

Nitrodienes are conveniently prepared by elimination of benzoic acid from β-nitro-β-1-cy- clopentenyl-α-benzoyloxyethane. They undergo the Diels-Alder reaction with methyl acrylate (Eq. 8.17).28

O2N		O2N
OC(O)Ph	AcONa
+	AcONa
+	CO Me benzene, 120 ºC	CO2Me
	CO Me benzene, 120 ºC	CO2Me
	2

47% (8.17)

			8.1	DIELS-ALDER REACTIONS		239
			OMe		O	O
	O				O
	O				Me
	Me		1) benzene, reflux		O
O		+	1) benzene, reflux

	(R)		2) HCl
	(R)		2) HCl
	NO2	Me3SiO			NO2	OMe
					30% (overall)
			OMe
	p-TsOH, MeOH		Me	1) (COCl)2, DMSO
			MeO2C	2) BF3•OEt2
			OH
			74%
					NMe
	MeO			MeO
		Me CO2Me			Me
		41%		(–) - aphanorphine

Scheme 8.6.

In intramolecular Diels-Alder reactions, two rings are formed in one step. The reaction has been used to synthesize a number of interesting ring systems.29 The intramolecular cyclization of (E)-1-nitrodeca-1,6,8-triene at 80 °C affords an endo cycloadduct with the trans ring fusion preferentially, as shown in Eq. 8.18. In contrast, (Z)-nitroalkenes produce a nearly 1:1 mixture of cisand trans-fused cycloadducts.30

		H		H
		80 ºC	+
			+
		Me		Me
O2N		H		H
		NO2		NO2
		89	:	11	(8.18)
		H		H	(8.18)
		H		H
		25 ºC	+
			+
		Me		Me
		H		H
O	N	NO2		NO2
2		1	:	1
		1	:	1

Although Lewis acid-catalyzed-Diels-Alder reactions of enones are common, there are few reports on the catalysis of Diels-Alder reaction of nitroalkenes. The reaction of nitroalkenes with alkenes in the presence of Lewis acids undergoes a different course of reaction to give cyclic nitronates (see Section 8.3). Knochel reported an enhanced reactivity and selectivity of the intramolecular Diels-Alder reaction using silica gel as Lewis acid in hexane (Eq. 8.19).31

	H
Silica gel	(8.19)
	(8.19)
hexane	Me
hexane	H
O N	NO2
2	85% (single diastereoisomer)
	85% (single diastereoisomer)

240 CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS

A concentrated solution of LiClO4 in diethyl ether has also been shown to activate the intramolecular Diels-Alder reactions (Eq. 8.20).32 The reaction proceeds at room temperature to give the adduct in good yield, whereas noncatalyzed reaction proceeds very slowly even at 80 °C (yield was 22% for 65 h).

EtO2C	CO2Et	CO2Et
O2N	LiClO4	CO2Et (8.20)
O2N	Et2O	CO2Et (8.20)
	Et2O	O2N
		70%

Intramolecular Diels-Alder cyclizations of (E)-1-nitro-1,7,9-decatrienes under thermal conditions and Lewis acid conditions lead to the formation of decalin ring systems with excellent endo selectivity (Eq. 8.21). This strategy is used for preparing of the AB ring system of norzoanthamine.33

		O2N
		H
MOMO		OMOM
MOMO	NO2
	NO2
H3C	H3C	H CH	(8.21)
CH3	benzene	3
CH3	benzene
	85 ºC, 65 h

OPMB	OPMB

Oppolzer and Robbiani have reported highly stereoselective total syntheses of alkaloids such as chelidonine by an intramolecular o-quinodimethene/nitrostyrene-cycloaddition (Scheme 8.7).34 (Benzocyclobutane is used as a source of quinodimethene). The high regioand stereoselectivity in the intramolecular cycloaddition is remarkable; a strong preference for transition state, exo-NO2, over transition state, endo-NO2, is responsible for the stereoselectivity.

It has been known that aromatic heterocycles such as furan, thiophene, and pyrrole undergo Diels-Alder reactions despite their aromaticity and hence expected inertness. Furans have been especially used efficiently as dienes due to their electron-rich properties. Thiophenes and pyrroles are less reactive as dienes than furans. But pyrroles with N-electron-withdrawing substituents are efficient dienes. There exists a limited number of examples of five-membered, aromatic heterocycles acting as dienophiles in Diels-Alder reactions. Some nitro heteroaromatics serve as dienophiles in the Diels-Alder reactions. Heating a mixture of 1-(phenylsulfonyl)- 3-nitropyrrole and isoprene at 175 °C followed by oxidation results in the formation of indoles (see Eq. 8.22).35a N-Tosyl-3-nitroindole undergoes high-yielding Diels-Alder reactions with

NO2		O	N		Me		O2N
		2
+						+		Me
+	Me					+	N H
N	Me		N	H			N H
SO Ph				H			SO2Ph
SO Ph			SO		Ph		SO2Ph
2			SO		Ph
				2
		Me
1) base		+					Me	(8.22)
2) DDQ	N				N			(8.22)
2) DDQ	N				N
	SO2Ph				SO2Ph
		91% (3:1)

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