Nitrogen Centered Radicals
Richter
Syntheses Discussed:
H
N
N
H H
Ph
OH
OH
Corey, CBS Ligand
TL, 1989, 5547
H
N
H
N
H
Three types of Nitrogen Radicals:
CO2Me
Fukuyama, Catharanthine
Heterocycles, 2002, 313
O
Grieco, Lycopodine
JACS, 1998, 5128
R
N
R
a. Generation
Zard, 13-Deoxyserratine
ACIEE, 2002, 1783
H Me
N
N
HN
H
Weinreb, Peduncalarine
T, 2001, 8779
Partial List of Transforms Discussed:
Hofmann-Löffler-Freytag Reaction
Ireland-Claisen Rearrangement
Pauson-Khand Reaction
Beckmann Rearrangement
Stieglitz Rearrangement
Relevant or Related Reveiws:
1.
2.
3.
4.
5.
6.
7.
1. Neutral Aminyl Radicals
O
H
1.
2.
3.
4.
5.
Important Note: The term nitrogen centered radical refers
to a species where the initiating radical is localized on
a nitrogen atom, not to transformations that terminate
with a nitrogen radical. Numerous examples of the latter
are known and are not discussed here.
N
H
3/31/04
Group Meeting
Gansäuer, A. Angew. Chem. Int. Ed. Eng. 2003, 42, 5556
Bowman, W.R. J. Chem. Soc. Perkin Trans. 1. 2002, 2747
Friestad, G.K. Tetrahedron. 2001, 57, 5461
Yet, L. Tetrahedron. 1999, 55, 9349
Stella, L. Angew. Chem. Int. Ed. Eng. 1983, 22, 337
Neale, R.S. Synthesis, 1971, 1, 1
Wolff, M.E. Chem. Rev. 1963, 63, 55
R
N
N N
D
or hn
R
R
hn
N Cl
R
b. Reactivity
– Dimerize to form hydrazines, which disproportionate to form imines
and amines
– Abstract allylic hydrogens preferrably
– Can add to styrenes and arenes, if there are no allylic protons
Stella, L. Angew. Chem. Int. Ed. Eng. 1983, 22, 337; Neale, R.S. Synthesis. 1971,1, 1
Nitrogen Centered Radicals
Richter
2. Protonated Aminyl Radicals
3/31/04
Group Meeting
Selected Transformations:
R
N H
1. Hofmann-Löffler-Freytag Reaction:
R
a. Generation
H
hn or FeII
R
N Cl
R
R
1. hn or FeII, H
N
N
2. Base
Cl
H
Mechanism?
TiCl3, MeOH(aq)
N OH
R
H
H
N
H
Cl
b. Reactivity
– Adds to unsaturated hydrocarbons and arenes
– Abstract protons if favorably disposed and activated
3. Aminyl Radicals Complexed to Metal Ions
H
hn or FeII
N
H
Cl
H
H
Cl
N
N
H
R
H
Basic
N MCl
N
Workup
R
2. Synthesis of a-Chloroketones from Alkynes:
a. Generation
CuCl or FeSO4
R
N Cl
R
or TiCl3
R''
R
N H
R''
R
R'
H
R
R'
N
R
Must use neutral conditions to generate, otherwise protonated
aminyl radicals are obtained
b. Reactivity
– Add to dienes, acetylenes, or alkenes
– No acid prevents electrophilic chlorination of the substrate
R''
R''
R'
O
Cl
Stella, L. Angew. Chem. Int. Ed. Eng. 1983, 22, 337; Neale, R.S. Synthesis. 1971,1, 1
H2O
R
H
R'
N
R
Neale, R.S. Synthesis. 1971,1, 1; Wolff, M.E. Chem. Rev. 1961, 63, 55
Cl
Nitrogen Centered Radicals
Richter
3/31/04
Group Meeting
6. Synthesis of g-Lactones or Pyrrolidines:
3. Synthesis of a-Amino Ketones from Alkenes:
Cl
H
hn
N
N
R
N
Cl
R'
N
R
10 min, RT
O
D, 5 min
R'
O
N O
H
H
hn, PhH
BH3•THF
NO
O
H
N
O
H2O
N R'
N
O
R
N OH
NR'
O
R
R
7. Aubé, J. J. Am. Chem. Soc. 1992, 114, 5466:
4. Synthesis of Oximes from Alkenes:
C5H9
Me
hn
H
N
Ph
NO
C5H9
Ph
N
N
CuI
O
N
Ph
CuO
Ph
H
Me
Ph
N O
Me
N
Ph
CuO
CuI
Ph
C5H9
N
NOH
Me
Ph
N
Me
Ph
CuO
Ph
N
Ph
CuO
O
NH
IBX
O
N
THF/DMSO
Ph
Ph
Ph
Me
N
Me
Ph
Neale, R.S. Synthesis. 1971,1, 1; Nicolaou, K.C. Angew. Chem. Int. Ed. Eng. 2001, 40, 202
N
Ph
CuO
5. IBX Reactions:
O
Me
Ph
CuO
N
N
Ph
Neale, R.S. Synthesis. 1971,1, 1; Aubé, J. J. Am. Chem. Soc. 1992, 114, 5466
>95% ee
Nitrogen Centered Radicals
Richter
8. An Alternative to Nitrogen Stitching:
10. Cyclizations involving Nitriles:
Br
N Cl
TiCl3
3/31/04
Group Meeting
CN
N
nBu SnH
3
N
AIBN
AcOH
34%
Mechanism?
62%
Cl
Br
N
TiCl3
Cl
N
N
N
AcOH
60%
N Cl
N
N
Cl
N
TiCl3
AcOH
N
N
46%
Cl
9. Aryl Amination:
H2SO4
Cl
N
11. Synthesis of a Twistane:
FeII
N
R
81%
R
H
1. TFA, hn
NCl
H2SO4
Cl
Me
90%
N
hn
Me
Stella, L. Angew. Chem. Int. Ed. Eng. 1983, 22, 337
N
2. Na, iPrOH
H
N
Bowman, W.R. Tetrahedron Lett. 2000,41, 8989; Heusler, K. Tetrahedron Lett. 1970, 11, 97
Nitrogen Centered Radicals
Richter
Syntheses:
3/31/04
Group Meeting
2. (±)-13-Deoxyserratine
Zard, S.Z. Angew. Chem. Int. Ed. Eng. 2002, 41, 1783:
1. A Chemzymatic Ligand
Corey, E.J. Tetrahedron Lett. 1989, 30, 5547:
O
1. (COCl)2,
DCM, DMF
HO
BnHN
2. BnNH2,
TEA, 80%
O
OTBS
1. LAH, THF,
D, 93%
1.
1. nBuLi
2. TBSOTf,
2,6-Lut, 96%
2. NBS, Et2O,
0 oC
O
MgBr
2. HMPA, 83%
THPO
OTBS
OTBS
H
CuBr (cat),
NBr
Ph
N
Bn H
0 oC, 85%
Name?
Br
1. Co2(CO)8
DME, D
THPO
2. NMO•H2O
DCM/THF, 89%
Stereochemistry?
30:1
1. (COCl)2, DMSO,
–78 oC; TEA, 93%
2. PhLi, THF, –78 oC, 93%
H
N
Bn H
OH
3. 10% PdOH/C, H2,
MeOH, AcOH, 99%
H
LiOH
THPO
O
Name?
H
OTBS
N
H H
Ph
OH
OTBS
1. iBuO2CCl, TEA
2.
Cl
H
NHOH
H
Cl
TEA
3. BzCl, TEA, 81%
HO2C
Synthesis of Chiral Starting Material Using a CBS Reduction.
O
BzON
O
Br
2. Ac2O, Py
O
Br
AcO H
2. TBDMSCl, D
Name?
HO
OTBS
OH
O
H
N
O
O
1. TBSOTf,
TEA, 83%
2. LAH
3. TBAF, 58%
nBu SnH
3
ACCN
O
1. nBu3SnH
1. CBS Reduction
Jones
H
N
O
13-Deoxyserratine
Br
Nitrogen Centered Radicals
Richter
3. (±)-Catharanthine
Fukuyama, T. Heterocycles. 2002, 56, 313:
Bn
N
1. BnBr,
0 oC to RT
N
3/31/04
Group Meeting
4. (±)-Lycopodine
Grieco, P.A. J. Am. Chem. Soc. 1998, 120, 5128:
1. CbzCl, PhH,
80 oC, 62%
OMe
OMe
2. NaBH4,
EtOH, 0 oC
Mechanism?
(3 steps)
2. Br2, DCM, 97%
2. LAH
MeO
Cbz
N
2. 100 oC,
O
EtO2C
CO2Et
iBuO
HO
HO2C
O
O
1. Ac2O, Py,
74% (2 steps)
2. Zn, AcOH, DCM
3. CH2N2, Et2O,
83% (2 steps)
Mechanism?
AcO
O
AcO
Cbz
O
N
CO2Me
N
CO2Me
1. Lawesson's Reagent,
Py, Tol, 110 oC, 86%
CHO
H
9, THF, 0
to RT; NaOH
OTBDPS
–78 oC to RT,
68%
Mechanism?
N
H
CO2Me
Catharanthine
9
iBuO
H
B
S
TMS
Ph
Mechanism?
Synthesis of 9?
OTBDPS
1. HCl, THF
2. K2CO3, MeOH
H
LiClO4•OEt2,
OTBDPS
OTBS
SPh
H
H
H
H
Li
iBuO
OTBDPS
TFA, 66%
Mechanism?
SPh
THF, –78 oC,
SPh
HO
TBSO
N
O
oC
H
2. AIBN, H3PO2, TEA,
nPrOH, 90 oC, 40-50%
Mechanism?
1. K2CO3, MeOH
2. MsCl, TEA, DCM,
82% (2 steps)
3. Et3SiH, Pd(OAc)2,
EtOH, EtOAc, 96%
H
OH
O
iBuO
N
H
Cbz
N
H
O
NH2
O
iBuO
tBuOMgBr,
THF; ADDP,
I
N
N
H
OH
H
ICH2CH2CH2OTMS,
3. K2CO3, MeOH, 66%
OH
H
Cbz
WSCD,
TEA, DCM,
I
O
1. TBDPSCl, imid.
2. LDA, THF, –78 oC;
2. I2, NaHCO3,
H20, 67% (4 steps)
CO2Et
Cbz
70%
1. KOH, EtOH, 80 oC
EtO
N
CO2H
OH
N
Br
EtO2C
iBuOH,
MeO
Cbz
1. DABCO,
MeCN, 80 oC
Br
conc. H2SO4,
1. Birch
MeO
H
iBuO
TBSO
OTBDPS
3. o-NBSeCN, Bu3P,
THF; H2O2, 60%
Nitrogen Centered Radicals
Richter
4. (±)-Lycopodine (Continued)
Grieco, P.A. J. Am. Chem. Soc. 1998, 120, 5128:
SPh
H
H
SPh
H
1. TBAF, THF
2. MsCl, TEA, DCM;
H
H
O
NaI, acetone, 80%
3. nBu3SnH, AIBN, 65%
H
H
O
H
OTBDPS
5. Peduncularine (Formal)
Weinreb, S.M. Tetrahedron 2001, 57, 8779
Hiemstra, H. J. Am. Chem. Soc. 1989, 111, 2588
1. Li(tBuO)3AlH,
0 oC to RT, 90%
2. Ac2O, DMAP
H
O
H
H
H
AcO
H H
H
3. NaI, HgCl2,
TMSCl, H20,
MeCN, 70%
OH
Me
H H
H
O
Me
H
1. AgBF4
H
H
1. H2O2, DCM,
0 oC to RT, 90%
2. BBr3, DCM,
–78 to –20 oC, 83%
O
H
1. (COCl)2, DMSO,
DCM, –60 oC
N
2. TEA, RT, 96%
3. Ph3PMeBr, nBuLi,
THF, 85%
O
Intercepted
Intermediate
2. NCS; TPAP, 50%
Me
1. Lawesson's
Reagent
Cl H
N
H
1. Red-Al, 80%
–50 oC to RT,
(EtO)2PCl, 70%
Mechanism?
OH
N
H
iPr NEt,
2
(PhSe)2DCM,
N
RT, 65%
HO
H
SePh
H
AcO
DCM, 12Kbar,
Me
2. SOCl2, dioxane
Name?
OMe O
N
H H
N
1. NH2OH, EtOH,
NaOAc, 100%
H
O
OMe
MeO
O
3/31/04
Group Meeting
2. NaCNBH3,
MeOH, 46%
Mechanism?
Name?
N
1. DCM, THF,
–78 to 0 to 20 oC,
N
N
O
2. MeI, Et2O
H
O
MeS
H
O
H Me
Lycopodine
N
PhNHNH2,
O
O
H
(ca 1:1)
H2SO4
44%
MgBr
O
2. NaCNBH3, AcOH
N
HN
H
Peduncalarine