Chapter 14 Nitro Compounds I. II.

Introduction ........................................................................................................................309 Reaction Mechanisms ........................................................................................................309 A. Addition-Elimination Reaction .................................................................................309 B. Electron Transfer ......................................................................................................310 C. Photochemical Reaction ...........................................................................................311 III. C-Nitro Carbohydrates .......................................................................................................311 A. Group Replacement ..................................................................................................311 B. Addition Reactions ...................................................................................................312 C. Cyclization Reactions ...............................................................................................313 D. Elimination Reactions ...............................................................................................313 IV. O-Nitro Carbohydrates .......................................................................................................315 A. Intermolecular Hydrogen-Atom Abstraction ............................................................315 B. Epimerization at a Chiral Center ..............................................................................316 C. Intramolecular Hydrogen-Atom Abstraction ............................................................317 D. Carbon–Carbon Bond Cleavage ...............................................................................319 E. Cyclization of Alkoxy Radicals ................................................................................319 V. Reactions of Nitro Compounds with Silanes .....................................................................319 VI. Summary ............................................................................................................................320 VII. References ..........................................................................................................................320

I.

Introduction

Carbohydrates contain two types of nitro groups. The first type has the nitrogen atom in this group attached to a carbon atom in the carbohydrate framework (making a deoxynitro or C-nitro carbohydrate) and the second has the nitrogen atom bonded to an oxygen atom in the carbohydrate structure (making an O-nitro carbohydrate or a carbohydrate nitrate). Radical reactions of nitro compounds are highly dependent upon the atom to which the nitro group is bonded.

II.

Reaction Mechanisms

A. Addition-Elimination Reaction The first step in the reaction of the tri-n-butyltin radical with a nitro compound is the addition of the radical to one of the oxygen atoms in the nitro group. The reaction that takes place after this initial addition depends upon whether the reactant is an O-nitro or a C-nitro compound. O-Nitro carbohydrates fragment to give alkoxy radicals (Scheme 1). C-Nitro carbohydrates have more varied possibilities. The adduct radical either breaks the C–N bond to give a carbon-centered

310

Chapter 14

radical, cleaves an O–N bond to form a nitroso compound, or abstracts a hydrogen atom from an available donor, usually Bu3SnH (Scheme 2). Scheme 1

RONO2

OSnBu3

OSnBu3

Bu3Sn

RO N

RO N O

O h

- NO2

- Bu3SnONO RO

Scheme 2 RNO2 Bu3Sn

- ONOSnBu3

R

OSnBu3

OSnBu3

RN

RN

- Bu3Sn

O

O

Bu3SnH

OSnBu3 RN OH

Bu3SnH

- Bu3Sn

- Bu3SnO

- HOSnBu3

RH

R-N=O R = a carbon-centered,carbohydrate radical

Scheme 3 O RNO2

Bu3Sn - Bu3Sn

- NO2

R N O

R

Bu3SnH - Bu3Sn

RH

R = a carbon-centered, carbohydrate radical

B.

Electron Transfer

Early investigations raised the possibility that reaction of a C-nitro compound with the tri-n-butyltin radical could involve electron transfer (Scheme 3).1–3 Later investigation, however, did not support this possibility because the electron transfer between Bu3Sn· and (CH3)2CHNO2

Nitro Compounds

311

(Scheme 3) was found to be endothermic by at least 12 kcal mol-1 . This endothermic electron transfer was inconsistent with the large rate constant (k = 9.5 x 107 M-1s-1) observed for reaction between this pair [Bu3Sn· and (CH3)2CHNO2].4 The conclusion from this latter study was that the addition-elimination mechanism (Scheme 2)5–8 provided a better explanation for the reaction between Bu3Sn· and a C-nitro compound. The possibility that electron transfer could be involved in reaction of O-nitro compounds (Scheme 4) has not been addressed and, thus, remains open. Scheme 4

RONO2

O

Bu3Sn

RO

- Bu3Sn

- NO2

N

Bu3SnH

RO

- Bu3Sn

O

ROH

RO = an oxygen-centered, carbohydrate radical

C.

Photochemical Reaction

Photolysis of an O-nitrocarbohydrate fragments the N–O bond in the nitro group to produce nitrogen dioxide and the corresponding alkoxy radical (Scheme 1). O

CH2OMMTr O

C 6H 5 O

O

AIBN C 6H 5 Bu3SnH C6 H5 CH3 110o C

NO 2 OH

O O R2

R1 = CH2OMMTr, R2 =H R1 = H, R2 = CH2OMMTr

(1)

R1 OH

60% yield not determined

MMTr = C(C6H5)2(C6H4OMe(p))

III. C-Nitro Carbohydrates A. Group Replacement Since in the reaction of a C-nitro compound the stability of the developing radical (R·) affects the ease of cleavage of the carbon–nitrogen bond (Scheme 2), group replacement occurs more easily for tertiary nitro compounds9–14 than for secondary15–19 and, especially, primary ones.20–22 Reaction of Bu3SnH with a compound containing a tertiary nitro group is given in eq 1.9 If the nitro group in the substrate is secondary, reaction usually follows the same pathway and replaces this group with a hydrogen atom,15–18 but sometimes breaking a C–O bond leading to a nitroso compound (which isomerizes to an oxime) offers significant competition (Schemes 2 and 5).19 When a nitro group is primary, the elimination phase of the reaction is more likely to produce

312

Chapter 14

only the nitroso compound (eq 2),20,21 even though replacement of a primary nitro group with a hydrogen atom has been observed (eq 3).22 Scheme 5 TrOCH2

AIBN TrOCH 2 Bu3 SnH O

B O

TrOCH2

B

+

C6 H6 70o C

NO 2 OEt

H

OEt 7%

O

B O

NO OEt

CH3 NH

B= N

TrOCH2

O

B O

HON

OEt

41%

CH2OAc O CH2NO2 OAc

CH2OAc O CH NOH

AIBN Bu3SnH

OAc

C6 H6 80o C

AcO

(2)

AcO OAc

OAc

90%

O O O2NCH2

O2NCH2

O RN=NR Bu3SnH C6 H5 CH3 110o C

OH CN

O CH3

CH3

(3)

OH

82%

R = C6 H11CH

B.

Addition Reactions

A nitro group in a reactant molecule can be involved in radical addition in several ways. First, denitration can produce a carbon-centered radical that undergoes typical addition to an electron-deficient multiple bond (eq 4).3 In a different role, nitro groups activate multiple bonds toward addition by nucleophilic radicals and affect the regioselectivity of such reactions (eq 5).23

Nitro Compounds

313

Deprotonation of a carbon atom bearing a nitro group creates an unsaturated system to which a carbon-centered radical can add to form a new, C–C bond (Scheme 624).24–26 Finally, the electron-withdrawing character of a nitro group can contribute to turning a normally nucleophilic radical into one that is electrophilic; thus, the philicity of the radical 1, which has both nitro and ethoxycarbonyl groups attached to the radical center, is reflected in its ability to add to the electron-rich double bond in the glycal 2 (Scheme 7).27

CH2OBn O CH2OAc

CN

OBn

Bu3SnH C6 H5 CH3 110o C

NO2 OBn

BnO

CH2OBn O CH2OAc

AIBN

OBn

(4) CH2CH2CN OBn

BnO

45%

O

O O

C 6H 5 O

OMe

O

NO 2

O NO 2 R

C 6H 5

h O

O

OMe

O

three + minor ( 5 ) products

43%

R= O

C.

Cyclization Reactions

A cyclization reaction that begins with a C-nitro carbohydrate is shown in eq 6.28 The high yield of this reaction, which involves a radical centered on a tertiary carbon atom adding to a multiple bond, illustrates that radical addition can be relatively insensitive to steric congestion at the radical center.28,29

D. Elimination Reactions A deoxynitro sugar can undergo an elimination reaction, if a radical center develops on a carbon atom adjacent to that bearing the nitro group.30–32 In the reaction shown in Scheme 8,30 such a radical forms and then eliminates nitrogen dioxide to give an unsaturated compound.

314

Chapter 14 Scheme 6 O

O H

R

H

C N O O OAc

+ AcO

C

R

N

O O

OAc AcO

OMe OAc

OMe OAc

CH2OBn

-e

O R

=

OBn

RCHNO 2 CH2 OH

BnO

O OAc OMe OAc

AcO

Scheme 7 NO2

NO2 CH2

+

CeIV(NH4) 2(NO 3) 6

- HNO3

CH

CeIII(NH4) 2(NO3) 5

+

CO2Et

CO2Et

1 CH2OAc

CH2OAc NO2

O OAc

+

O OAc

CH CO2Et

AcO 2

AcO CHNO 2

1

CO2Et CeIV CeIII

CH2OAc

CH2OAc

O O

AcO EtOC O

C

O

-H

OAc

OAc AcO

N

HC O

EtOC

N

O

O

O

Nitro Compounds

315 ROCH2

B O

NO2

B

ROCH2

AIBN Bu3SnH

O CH2OH

C 6 H5 CH3 100o C

HOCH2 O

(6)

O

CH2C CH

88%

O CH3 NH

R = C(C6H5)2(C6H4OMe(p))

B= N

O

Scheme 8 S

SSnBu3

OCOC6H5 R

OCOC6H5 R

NO2

R

NO2

- C6 H5 OCSSnBu3

Bu3Sn

O

O

NO2

OBn BnO

OMe OBn

BnO

BnO

R

- NO2

CH2OBn BnO R=

O

O

OBn

OBn BnO OBn

OMe OBn

IV. O-Nitro Carbohydrates Reaction of an O-nitro carbohydrate with a tri-n-butyltin radical or with ultraviolet light produces the corresponding alkoxy radical, an intermediate that is reactive enough to abstract a hydrogen atom from most C–H bonds. Also characterizing the reactivity of alkoxy radicals is rapid carbon–carbon bond cleavage to produce both a compound with a carbonyl group and a carbon-centered radical. Examples of these reactions are discussed in the next several sections.

A. Intermolecular Hydrogen-Atom Abstraction Hydrogen-atom abstraction by an alkoxy radical generated from an O-nitro carbohydrate sometimes occurs internally, but often abstraction is from another molecule present in solu-

316

Chapter 14

tion.33-36 In the reaction shown in eq 7, for example, the alkoxy radical produced by photolysis of the carbohydrate nitrate 3 abstracts a hydrogen atom from methanol to give the partially protected sugar 4.33 CH3

CH3 BzO

BzO h CH 3 OH NaHCO3

O

O (7) OMe

OMe OH

ONO 2

4 90%

3

Me2C

O AIBN, Bu3SnH C6 H6, 80 oC

O O

O O O O

CMe2

O

(8)

OH

or h(CH3)2CHOH

O O2NO

Me2C

O

CMe2

Scheme 9

Me2C

O O

OMe H

Me2C

O O

OMe

O

O H

O O

O

O O

CMe2

O

5 dipole-dipole interaction

Me2C

O O

OMe

bond rotation

Me2C

O O

OMe O O

O O

O H

O

CMe2

7

B.

CMe2

H

O O

CMe2

6

Epimerization at a Chiral Center

Hydrogen-atom abstraction by an alkoxy radical has such a large rate constant that few other processes successfully compete with this reaction. One that does is β fragmentation. The β fragmentation that takes place in the reaction shown in eq 8 is followed by epimerization at C-3.34,35 A proposed mechanism for this fragmentation-epimerization process is shown in Scheme 9. This process depends upon ring opening of the alkoxy radical 5 to give the carbon-centered radical 6

Nitro Compounds

317

being faster than hydrogen-atom abstraction from Bu3SnH. Likewise, ring closure of 6 to give the epimerized alkoxy radical 7 also takes place before hydrogen-atom abstraction can intervene (Scheme 9). Ring opening is rapid due to relief of dipole-dipole interactions in the radical 5. The rate of ring closure of the radical 6 also is large due to the close proximity of the radical center to the carbonyl group and the greatly reduced dipole-dipole interaction in the resulting alkoxy radical 7. O2NOCH2CH2

OMe

AIBN Bu3SnD

O

O

HOCH2CH2 D

C6 H6 80o C

O

OMe O (9)

O

CMe2

O CMe2

Scheme 10 CH 2CH2ONO2 O

CH2CH2O Bu3Sn

H

H

O

- Bu3SnNO2

MeO

S

MeO

C 6H 5 O

C 6H 5 O

CH 2CH2OH O

MeO 69%

C.

S

CH2CH2OH O

- C 6 H 5 SO

MeO

S

C 6H 5 O

Intramolecular Hydrogen-Atom Abstraction

Alkoxy radicals are so effective at hydrogen-atom abstraction from C–H bonds that internal reaction is likely whenever the oxygen atom bearing the radical center closely approaches a hydrogen atom in the radical.37–41 (This approach occurs most readily when the interacting atoms are 1,6-related and the molecular structure does not prevent such contact.) Internal reaction leads to a carbon-centered radical that typically will not abstract a hydrogen atom from a carbon– hydrogen bond but will abstract such an atom from tri-n-butyltin hydride. Internal hydrogen-atom abstraction by an alkoxy radical often is not detectable unless a donor such as Bu3SnD replaces Bu3SnH as a reactant and a deuterium atom is incorporated in to the product (eq 9).37 Other

318

Chapter 14

indications that internal hydrogen-atom abstraction to form a carbon-centered radical has taken place include loss of a group from a neighboring carbon atom (Scheme 10)38 and addition of the radical produced by hydrogen-atom abstraction to a compound with a carbon–carbon multiple bond (Scheme 11).42,43 [The stereoselectivity of addition of the radical 8 (Scheme 11) is determined by approach of acrylonitrile to the less-hindered face of this radical.] Scheme 11 HH

H

H

O ONO2

H

O

O

O

O

Bu3Sn

O

O

Bu3SnNO 2

TsO

OH

TsO

TsO

OTs

OTs

OTs 8 CN

CH2CH2CN H O

CH2CHCN H O

O

O

Bu3SnH

OH

- Bu3Sn

TsO

OH TsO

OTs

OTs

78%

Scheme 12 CH2OR OH OAc H AcO

OH H

Bu3Sn

ONO 2 OAc

- Bu3SnONO

OAc Bu3SnH

OAc RO

ROCH2 OAc

OAc

- Bu3Sn

O

OCH OAc H

=

H O

O OAc

R = SiMe2 t-Bu

HCO

O H

H

AcO

O

OAc 9

Nitro Compounds

319

D. Carbon–Carbon Bond Cleavage Alkoxy radicals fragment readily to give carbonyl compounds and carbon-centered radicals. In cyclic structures this fragmentation usually results in ring opening. Such reaction produces open-chain products44,45 unless rapid closure reforms the ring system. Ring closure takes place in the reaction pictured in eq 8 and described mechanistically in Scheme 9. In contrast, the product isolated from the reaction shown in Scheme 12 is the ring-open structure 9.44 One explanation for the difference in ring reformation in these two reactions is that they are reflecting the generally more rapid radical cyclization to give a five-membered ring when compared to that producing a six-membered ring. 44–46

C 6H 5

C 6H 5

O O

O

Bu3SnH

O O

O

( 10 )

OMe

OMe CH3

O2NO

E.

O

Cyclization of Alkoxy Radicals

An example of a cyclization reaction involving an alkoxy radical adding to a double bond is shown in eq 10.47 This type of reaction is rare because in most instances alkoxy radicals undergo either hydrogen-atom abstraction or radical fragmentation. A significant factor in the cyclization shown in eq 10 is having the alkoxy radical held in close proximity to the double bond. Scheme 13 OSi(SiMe3) 3 RNO2

+ Si(SiMe3) 3

RN

OSi(SiMe3) 3 RN

O

O

- ONOSi(SiMe3) 3 R

RN O +

OSi(SiMe3)3

complex mixture

V. Reactions of Nitro Compounds with Silanes Concerns with the toxicity of tri-n-butyltin hydride and the purification problems that accompany its use have spawned a variety of attempts to replace this reagent with a less troublesome one (see Appendix I). Tris(trimethylsilyl)silane normally is an attractive alternative to Bu3SnH, but it fails completely in this role in group replacement reactions in nitro compounds. The reason

320

Chapter 14

for failure is that the radical formed by addition of (Me3Si)3Si· to a nitro group does not break the carbon–nitrogen bond required for group replacement but rather cleaves a nitrogen–oxygen bond to begin a sequence of reactions leading to a complex reaction mixture (Scheme 13).48 RNO2 + Bu3SnH

Bu3SnONO + C6H5SiH3

RH + Bu3SnONO ( 11 )

Bu3SnH + C6H5SiH2ONO

( 12 )

A more effective procedure for reducing the amount of tri-n-butyltin hydride needed for nitro-group replacement with a hydrogen atom consists of regenerating Bu3SnH from the Bu3SnNO2 formed during the substitution process. A pair of reactions that achieve group replacement and regenerate Bu3SnH are given in equations 11 and 12. This alternative method requires only 10% of the tri-n-butyltin hydride needed in the standard procedure.49

VI. Summary The type of radical produced by reaction of a nitro group in a carbohydrate depends upon whether this group is bonded to a carbon or an oxygen atom. A nitro group bonded to an oxygen atom invariably fragments to produce an alkoxy radical, but a nitro group attached to a carbon atom either fragments to generate a carbon-centered radical, expels an oxygen-centered radical to form a nitroso compound, or abstracts a hydrogen atom. The alkoxy radicals produced from O-nitro carbohydrates rapidly abstract hydrogen atoms either internally or from molecules present in solution. Competing with or, in some instances, superseding hydrogen-atom abstraction is carbon–carbon bond cleavage to give a carbonyl group and a carbon-centered radical. The carbon-centered radicals derived from reaction of C-nitro carbohydrates form most readily if the radical being produced is tertiary. These radicals undergo typical replacement, addition, and cyclization reactions. Primary radicals are much less likely to form from C-nitro carbohydrates; instead, these carbohydrate derivatives usually produce nitroso compounds.

VII. References 1. 2. 3. 4. 5.

Tanner, D. D.; Blackburn, E. V.; Diaz, G. E. J. Am. Chem. Soc. 1981, 103, 1557. Ono, N.; Miyake, H.; Tamura, R.; Kaji, A. Tetrahedron Lett. 1981, 22, 1705. Dupuis, J.; Giese, B.; Hartung, J.; Leising, M. J. Am. Chem. Soc. 1985, 107, 4332. Tanner, D. D.; Harrison, D. J.; Chen, J.; Kharrat, A.; Wayner, D. D. M.; Griller, D.; McPhee, D. J. J. Org. Chem. 1990, 55, 3321. Ono, N.; Kaji, A. Synthesis 1986, 693.

Nitro Compounds 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38.

321

Ono, N.; Miyake, H.; Kamimura, A.; Hamamoto, I.; Tamura, R.; Kaji, A. Tetrahedron 1985, 41, 4013. Kamimura, A.; Ono, N. Bull. Chem. Soc. Jpn. 1988, 61, 3629. Korth, H.-G.; Sustmann, R.; Dupuis, J.; Giese, B. Chem. Ber. 1987, 120, 1197. Hossain, N.; van Halbeek, H.; De Clercq, E.; Herdewijn, P. Tetrahedron 1998, 54, 2209. Otani, S.; Hashimoto, S.; Bull. Chem. Soc. Jpn. 1987, 60, 1826. Garg, N.; Plavec, J.; Chattopadhyaya, J. Tetrahedron 1993, 49, 5189. Brakta, M.; Lhoste, P.; Sinou, D. J. Org. Chem. 1989, 54, 1890. Begley, M. J.; Fletcher, R. J.; Murphy, J. A.; Sherburn, M. S. J. Chem. Soc., Chem. Commun. 1993, 1723. Baumberger, F.; Vasella, A. Helv. Chim. Acta 1983, 66, 2210. Martin, O. R.; Lai, W. J. Org. Chem. 1993, 58, 176. Gurjar, M. K.; Nagaprasad, R.; Ramana, C. V. Tetrahedron Lett. 2002, 43, 7577. Spak, S. J.; Martin, O. R. Tetrahedron 2000, 56, 217. Witczak, Z. J.; Chhabra, R.; Chojnacki, J. Tetrahedron Lett. 1997, 38, 2215. Hossain, N.; Papchikhin, A.; Garg, N.; Fedorov, I.; Chattopadhyaya, J. Nucleosides Nucleotides 1993, 12, 499. Pham-Huu, D.-P.; Petrušová, M.; BeMiller, J. N.; Petruš, L. Synlett 1998, 1319. Pham-Huu, D.-P.; Petrušová, M.; BeMiller, J. N.; Petruš, L. J. Carbohydr. Chem. 2000, 93. Witczak, Z. J.; Li, Y. Tetrahedron Lett. 1995, 36, 2595. Sakakibara, T.; Takaide, A.; Seta, A.; Carbohydr. Res. 1992, 226, 271. Martin, O. R.; Xie, F.; Kakarla, R.; Benhamza, R. Synlett 1993, 165. Aebischer, B.; Meuwly, R.; Vasella, A. Helv. Chim. Acta 1984, 67, 2236. Branchaud, B. P.; Yu, G.-X. Tetrahedron Lett. 1991, 32, 3639. Sommermann, T.; Kim, B. G.; Peters, K.; Peters, E.-M.; Linker, T. Chem. Commun. 2004, 2624. Garg, N.; Hossain, N.; Chattopadhyaya, J. Tetrahedron 1994, 50, 5273. Kancharla, P. K.; Vankar, Y. D. J. Org. Chem. 2010, 75, 8457. Kobertz, W. R.; Bertozzi, C. R.; Bednarski, M. D. J. Org. Chem. 1996, 61, 1894. Barton, D. H. R.; Dorchak, J.; Jaszberenyi, J. Cs. Tetrahedron Lett. 34, 8051. Hossain, N.; Garg, N.; Chattopadhyaya, J. Tetrahedron 1993, 49, 10061. Binkley, R. W.; Abdulaziz, M. A. J. Org. Chem. 1987, 52, 4713. a) Binkley, R. W.; Koholic, D. J. J. Carbohydr. Chem. 1984, 3, 85; b) Binkley, R. W.; Koholic, D. J. J. Org. Chem. 1979, 44, 2047. Vite, G. D.; Fraser-Reid, B. Synthetic Commun. 1988, 18, 1339. Walton, R.; Fraser-Reid, B. J. Am. Chem. Soc. 1991, 113, 5791. Guo, Z.; Samano, M. C.; Krzykawski, J. W.; Wnuk, S. F.; Ewing, G. J.; Robins, M. J. Tetrahedron 1999, 55, 5705. Robins, M. J.; Ewing, G. J. J. Am. Chem. Soc. 1999, 121, 5823.

322 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49.

Chapter 14 Robins, M. J.; Guo, Z.; Wnuk, S. F. J. Am. Chem. Soc. 1997, 119, 3637. Robins, M. J.; Guo, Z.; Samano, M. C.; Wnuk, S. F. J. Am. Chem. Soc. 1999, 121, 1425. Robins, M. J. Nucleosides Nucleotides 1999, 18, 779. Lopez, J. C.; Alonso, R.; Fraser-Reid, B. J. Am. Chem. Soc. 1989, 111, 6471. Lopez, J. C.; Fraser-Reid, B. Chem. Commun. 1997, 2251. Francisco, C. G.; León, E. I.; Moreno, P.; Suárez, E. Tetrahedron: Asymmetry 1998, 9, 2975. Francisco, C. G.; León, E. I.; Martín, A.; Moreno, P.; Rodríguez, M. S.; Suárez, E. J. Org. Chem. 2001, 66, 6967. Batsanov, A. S.; Begley, M. J.; Fletcher, R. J.; Murphy, J. A. J. Chem. Soc., Perkin Trans. 1 1995, 1281. Fraser-Reid, B.; Vite, G. D.; Yeung, B.-W. A.; Tsang, R. Tetrahedron Lett. 1988, 29, 1645. Ballestri, M.; Chatgilialoglu, C.; Lucarini, M.; Pedulli, G. F. J. Org. Chem. 1992, 57, 948. Tormo, J.; Hays, D. S.; Fu, G. C. J. Org. Chem. 1998, 63, 5296.