Jul.

5, 2003 Se-Ho Kim

Tandem Polar/Radical Crossover Sequences for the Formation of Fused and Bridged Bicyclic Nitrogen Heterocycles Involing Radical Ionic Chain Reactions, and Alkene Radical Cation Intermediates, Performed under Reduing Conditions: Scope and Limitations
EtO EtO P R -(Phosphatoxy)alkyl Radical O O

Rearrangement Substitution

Organic Sythesis

(Tandem Polar/Radical Crossover Sequence)

David Crich; Krishnakumar Ranganathan; Santhosh Neelamkavil; Xianhai Huang, J. Am. Chem. Soc. 2003, 125, 7942

Mechanism for the rearrangement of Barton ester

PhO O Ph O P OPh O R R O N Ph S R = CH2Ph PhO O PhO O P OPh + O Ph Ph Ph Ph Ph SSIP P OPh O CIP PhO O Ph P OPh O Ph Ph Ph OPh P O Ph

PhO HO P

OPh O Ph Ph

PhO O

Ph

PhO O Ph P

OPh Ph Ph

Solvent Ph

Free ions

 -(Acyloxy)alkyl Rearrangement
O OAc + EtO O CN EtO CN OAc EtO O CN

O EtO H O EtO CN OAc CN H

OAc

Surzur, J. -M.; Teissier, D. C. R. Acad. Sci. Fr. Ser. C. 1967, 264, 1981. Surzur, J. -M.; Teissier, D. Bull. Soc. Chim. Fr. 1970, 3060. Ph O 3' rearrangement ? 2 2,3-shift O Ph O O Ph O

2' 1'O 1

1,2-shift

Mechanism for the rearrangement of Barton ester

PhO HO PhO O Ar Ar O O N S Ar = 4-MeOC6H4 PhO O PhO O P OPh + O Ar Ph SSIP P OPh O P OPh O PhO O P OPh O Ar CIP Ar PhO O P OPh O PhO O P Ar P

OPh O

OPh O

Solvent

Free ions

Detection of Radical Cations

S N O OPO(OPh) OMe OPO(OPh) t-Bu OMe k23 9 x 106 s-1 (acetonitrile) t-Bu ArN + MeO ArN t-Bu MeO
2

t-Bu MeO

OPO(OPh)

O t-Bu

MeO MeO

OAc

H2O, H+ k20 106 s-1

MeO MeO

OAc

ESR observable

General Mechanistic Scheme

O X O R X O O R CIP O R SSIP X O R + O X O

Free ions

X R

R Fragmentation Products

Rearranged Products X = CR; P(OR)2, NO, SOR

Rearrangements of o-(Acyloxy) Radicals

O O O C8H17 O

C8H17 AcO AcO H C8H17 Bu 3SnH, AIBN C6H6, AcO AcO 59% Br O O Ph Br Bu 3SnH, AIBN C6H6, Ph O O AcO H H

C8H17

OAc

Rearrangements and their Applications in Synthesis

OAc AcO AcO Ac O O Br Bu3SnH, AIBN benzene, reflux 92% OAc AcO AcO O OAc

OAc AcO AcO

OAc O Br

Bu3SnH, AIBN benzene, reflux

OAc AcO AcO O OAc

BzO

O Br

TTMSS, AIBN benzene, reflux 86%

2

BzO

O OP(O)(OPh) BzO
2

BzO OP(O)(OPh)

OAc O AcO AcO O (PhO) 2P Br O

Bu3SnH, AIBN THF, h AcO AcO

OAc O O HO BnO Mg(ClO 4)2 OBn (PhO) 2P O O OBn OMe 72% AcO AcO

OAc O BnO O BnO

OMe OBn O

/ = 1/1

Intermolecular Formation of a Tetrahydrofuran

PhO O Ph Ph O O N PhO S ? Ph CIP Ph t-BuSH O Ph 80% O O P OPh O OH Ph O P OPh O h PhO O P OPh O

S O Ph O O P OPh O OPh h Ph

O P OPh O

OPh

ispo and cine Substitutions Nu R R' Nu ipso R X R' Nu cine Nu R R'

Intramolecular Hydrogen Abstraction/cine Substitution Sequence

O (PhO) 2P O Ph O O N O Ph 3Sn Ph O (PhO) 2P O O O (PhO) 2P O Ph OH

O (PhO) 2P O Ph OH

Ph

Ph 3SnH 95%

Ph

Effects of Substituents on Yield

O (EtO) 2P O Ph O O N O

PhSnH, AIBN benzene, reflux 60%

Ph

O (EtO) 2P O Ph

O O N O

PhSnH, AIBN benzene, reflux 90%

Ph

O (EtO) 2P O Ph

O O N O

PhSnH, AIBN benzene, reflux 90%

Ph

Hoffmann-Loeffler-Freytag Reaction
NHRCl -Cl NHRCl NHR NH 2R

base N R

Cl

NH 2R

Intermolecular Formation of a Tetrahydrofuran

O P(OPh) NO 2 O P(OPh) O P(OPh)

O Ph

Bu 3SnH Ph

O Ph

OH

Ph

Ph

Cyclization Leading to a Lactone

OTHP NO 2 CO 2Me DBU, 80% OTHP NO 2 CO 2Me 1. TsOH 2. (PhO)2POCl 3. LiOH

Ph

Ph

Ph

O OP(OPh) 2 NO 2 CO 2H

Bu 3SnH Ph

A cine-exo/exo-Mode Tandem Cylization

OTHP NO 2 OH O OP(OPh) 2 NO 2 N Boc 1. PPh3, I2 2. NH 2 3. Boc2O 83% Ph OTHP NO 2 N Boc O OP(OPh) 2 NO 2 N H 1. TsOH 2. (PhO)2POCl

Ph

TMSOTf

Ph

Ph

Bu 3SnH 85%

Transistion States of Formation of Products

N Ph 2.7 N N Ph 1.6 N N Ph 1 N N Ph 1 N

Ph

Ph

Ph

Ph

Precusor Synthesis and a ipso exo/exo-Mode Tandem Cylization Leading to Pyrrolizidine and Indolizidine Skeletons
O O NH 2 OH O N H O O2N P(OPh) O O
2

1. LAH 2. Boc2O 3. PCC

O N Boc

NO 2

ButOK

O2N TMSOTf lutidine

P(OPh) O N H

N Boc

Bu 3SnH H N N H

75%

Precusor Synthesis for a ipso endo/exo-Mode Tandem Cylization Leading to Bridged Systems
O O

RNH 2 O NHR OH O 1. LAH 2. Boc2O OH Boc NR 1. CBr4, PPh3 2. NaNO2 O NO 2 Boc NR H N NH 2

1. NaOMe, CH2O 2. (PhO)2POCl 3. TMSOTf n = 1, R = Bn n = 1, R = allyl n = 2, R = ally O R N n

(PhO) 2P O

NO 2

Boc

ipso endo/exo-Mode Tandem Cylization Leading to Bridged Systems

Bn N Bn HN Bn N

NO 2

O O

P(OPh)

90%

NO 2

H N

Bn N

O O

P(OPh)

78%

17%

NO 2

H N n=2

Bn N

Bn N 58%

O O

P(OPh)

ipso -endo/exo-dig-Mode Tandem Cylizations

O O2N P(OPh) O
2

Ph Ph

H N

N Ph H

N H H N

60%, E:Z = 5.7:1

O O2N

P(OPh) O H N

Ph

Ph

No cyclization

Formation of a Tetrahydropyran
O NO 2 Ph OH O P(OPh) O
2

Bu 3SnH AIBN Ph C6H6/CH3CN = 1/1

O + 30% Ph

P O

(OPh) 2

OH 60%

Conclusion
O O2N P(OPh) O N H H N n =1, 2 O O P(OPh)
2 2

Nitrogen Containg Heterocycles

NO 2

References Beckwith, A. L. J.; Crich, D.; Duggan, P. J.; Yau, Q. Chem. Rev. 1997, 97, 3273. Merph, J. A. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH; Weinheim, 2001; Vol 1, p298. Crich, D. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH; Weinheim, 2001; Vol 2, p188.