Transcript Xanthate Transfer Reactions

Xanthate Transfer Reactions:
Adding Functionality via Reversible,
Degenerate Radical Processes
S
R
R'
S
O
xanthate  dithiocarbonate
Katherine Traynor
McMahon Group
March 8, 2007
General transformation in xanthate transfer
reactions
R
Z
S
S
Z
initiator
OR1
R
S
S
OR1
R = alkyl, acyl, alkoxycarbonyl
- Form new carbon-carbon bond
- Generate new xanthate
2
Why use xanthate transfer reactions?
- Inexpensive:
dilauroyl peroxide (DLP) - $0.17/g
potassium O-ethyl xanthate: - $0.32/g
- Easily scalable: up to 10 g
- Mild, neutral reaction conditions: DLP, (CH2Cl)2, reflux
- Metal-free: no tin
3
Quiclet-Sire, B.; Zard, S.Z. Top. Cur r. Chem. 2006, 264, 201-236.
Retrosynthetic analysis of 10-norparvulenone
and O-methylasparvenone
OH O
HO
OH O
S
MeO
OH
OH O
10-norparvulenone
O
MeO
OH O
radical
addition
and
OPiv cyclization
OEt
S
MeO
PivO
MeO
OH
O-methylasparvenone
4
Vargas, A.C.; Quiclet-Sire, B.; Zard, S.Z. Org. Lett. 2003, 5, 3717-3719.
Overview
5
Barton-McCombie deoxygenation reaction
- Developed for deoxygenation of sterically hindered secondary alcohols
1) NaH, imidazole
2) CS2
R-OH
3) MeI
ergosterol
4) AcOH
HSnBu3,
toluene, 
S
R
O
S
88%
Me
MeSSnBu3
RH
COS
ergosta-5,7,22-triene,
67%
R=
H
6
Barton, D.H.R.; McCombie, S.W. J. Chem. Soc., Perkin Trans. 1, 1975, 1574-1585.
Competition experiment: expected product
S
Me
S
O
R
Bu3SnH
S
S
O
R H
cholestane
R
R=
H
Barton, D.H.R.; Crich, D.; Lobberding, A.; Zard, S.Z. J. Chem. Soc., Chem. Commun. 1985, 646-647.
7
Competition experiment: actual products
S
Me
S
S
O
R
Me
S
O
R
Bu3SnH
S
S
S
O
Bu3Sn
R
S
O
R
- Isopropyl derivative reacts
much faster than methyl
derivative
- Product is propane,
not cholestane!
R=
H
Barton, D.H.R.; Crich, D.; Lobberding, A.; Zard, S.Z. J. Chem. Soc., Chem. Commun. 1985, 646-647.
8
b-scission of C-S vs. C-O bond
Barton, D.H.R.; Crich, D.; Lobberding, A.; Zard, S.Z. J. Chem. Soc., Chem. Commun. 1985, 646-647.
9
Barton-McCombie deoxygenation mechanism
SnBu3
Bu3Sn
S
S
Et
S
Et
O
S
O
S
Bu3SnH
SnBu3
Et
H
- Addition to thiocarbonyl
group is fast and reversible
- Rate-determining step is
b-scission of carbon-oxygen
or carbon-sulfur bond
S
SnBu3
O
COS
Bu3SnSEt
Barton, D.H.R.; Crich, D.; Lobberding, A.; Zard, S.Z. J. Chem. Soc., Chem. Commun. 1985, 646-647. 10
Barton, D.H.R.; Crich, D.; Lobberding, A.; Zard, S.Z. Tetrahedron. 1986, 42, 2329-2338.
Xanthate transfer chain process
11
Quiclet-Sire, B.; Zard, S.Z. Top. Curr. Chem. 2006, 264, 201-236.
Radical Stabilization:
Frontier Molecular Orbital theory
LUMO
LUMO
SOMO
Energy SOMO
HOMO
HOMO
O
R2C NR2
- Stabilization by EDG
R2C
R
- Stabilization by EWG
12
Parsons, A.F. An Introduction to Free Radical Chemistry ; Blackwell Science Ltd, 2000.
Overview
13
Preparation of xanthates
- Nucleophilic displacement
F
S
EtO
S
K
Br
S
CH3OH
CO2Et
1.5 h, RT
EtO
($0.32/g)
F
S
CO2Et
80%
S
O
MeO
S
Cl
N
H
CO2Et
K
S
CH2Cl2
OEt
O
S
OEt
20 min, RT
MeO
N
H
CO2Et
70%
Jean-Baptiste, L.; Yemets, S.; Legay, R.; Lequeux, T. J. Org. Chem., 2006, 71, 2352-2359.
Udding, J.H.; Hiemstra, H.; Speckamp, W.N. J. Org. Chem., 1994, 59, 3721-3725.
14
Preparation of tertiary xanthates
- Radical decarbonylation of acyl radicals
O
O
S
Cl
EtO
S
acetone
S
Na
S
h
S
-35 °C, 1 h
OEt
benzene,
reflux, 14 h
S
OEt
81%
>99%
- Reaction of bis-xanthates with azo compounds
S
EtO
S
S
CN
OEt
S
N N
NC
S
conditions
A or B
EtO
CN
S
AIBN
(1.5 equiv)
A: EtOAc, reflux, 18 h
B: cyclohexane, reflux, 3-4 h
Thang, S. et al. T etrahedron Lett . 1999, 40, 2435-2438.
Barton, D.H.R.; George, M.V.; Tomoeda, M. J. Chem. Soc. 1962, 1967-1974.
94%
87%
15
Formation of quaternary centers
16
Binot, G.; Quiclet-Sire, B.; Saleh, T.; Zard. S.Z. Synlett. 2003, 3, 382-386.
Reductive cleavage of the C-S bond
S
R
S
S
O
Me
CH3(CH2)9CH2
R
CH3(CH2)9CH2
S
O
OH
O
CH3(CH2)10
O
O
(CH2)10CH3
O
OH
RH
- Force hydrogen abstraction from an
inexpensive hydrogen donor
- Use peroxide in stoichiometric amounts
- Most efficient with secondary xanthates
Liard, A.; Quiclet-Sire, B.; Zard, S.Z. Tetrahedron Lett. 1996, 37, 5877-5880.
OH
O
17
Me
Reduction of C-S bond
with phosphorus reagents
18
Boivin, J.; Jrad, R.; Juge, S.; Nguyen, V.T. Org. Lett. 2003, 5, 1645-1648.
Access to synthetic equivalents
of propargyl radicals
19
Zard, S.Z.; Boutillier, P. Chem. Commun. 2001, 1304-1305.
Radical-polar crossover reactions
Zard, S.Z.; Boutillier, P. Chem. Commun. 2001, 1304-1305.
Quiclet-Sire, B.; Zard, S.Z. T op. Curr. Chem. 2006, 264, 201-236.
20
Intermolecular oxidative radical alkylation
21
Osornio, Y. M. et al. Chem. Commun. 2003, 2316-2317.
Radical alkylation of different
heteroaromatic systems
O
O
O
H
H3C
Ph
N
O
CH
3
74%
EtO
86%
N
H
EtO
O
65%
O
H
S
N
H
O
46%
OEt
60%
CH3
N
CH2Ph 44%
O
O
Ph
Ph
MeO
O
CHO
O
O
O
EtO
CH3
MeO
S
O
75%
N
O
H
81%
22
Osornio, Y. M. et al. Chem. Commun. 2003, 2316-2317.
Origin of regioselectivity
4
O
3
5
N
H
EtO
4
O
5
EtO
N
H
O
Position
HOMO
LUMO
3
0.0920
0.1048
3
O
O
HO
4
0.1483
0.0013
N
H
5
0.3347
0.0904
tolmetin
O
- SOMO of electron-deficient radical reacts with HOMO
of heterocycle
Artis, D.R.; Cho, I.; Muchowski, J.M. Can. J. Chem. 1992, 70, 1838-1842.
Baciocchi, E.; Muraglia, E.; Sleiter, G. J. Org. Chem. 1992, 57, 6817-6820.
23
Alkylation of 3,4-dihydro-2H-pyran
24
Torres-Murro, J.; Quintero, L.; Sartillo-Piscil, F. Tetrahedron Lett. 2005, 46, 7691-7694.
Attempted trapping of oxocarbenium ion
25
Torres-Murro, J.; Quintero, L.; Sartillo-Piscil, F. Tetrahedron Lett. 2005, 46, 7691-7694.
Synthesis of functionalized boronates
O
S
R
S
n
B
O
O
O
OEt
n
nB
B
O
DLP
R
R
O
O
O
O
Me
NC
B
Me
EtO(S)CS
50%
63%
B O
O
O
SC(S)OEt
O
SC(S)OEt
B
85%
O
SC(S)OEt
Bn
N
O
B
S
68%
O
SC(S)OEt
N N
O
B
N N
70%
O
SC(S)OEt
26
Lopez-Ruiz, H.; Zard, S.Z. Chem. Commun. 2001, 2618-2619.
Construction of the a-tetralone subunit of
10-norparvulenone and O-methylasparvenone
1) Ac2O, pyridine, RT
2)
OPiv
OH O
MeO
11 mol % DLP,
Ac2O, (CH2)2Cl2,
reflux
OH O
KSC(S)OEt
Br acetone, 0 °C
SC(S)OEt
3) DLP, (CH2)2Cl2,
reflux
4) NH4 OH,
MeOH, RT
MeO
>99%
OH O
OAc O
O
Cl
MeO
EtO(S)CS
MeO
OPiv
OPiv
OH O
Cl
TiCl4, CH2Cl2
-10 C - r.t.
36%
O
MeO
96%
OPiv
27
Vargas, A.C.; Quiclet-Sire, B.; Zard, S.Z. Org. Lett. 2003, 5, 3717-3719.
Construction of the a-tetralone subunit of
10-norparvulenone and O-methylasparvenone
OH O
1) NaBH3CN
MeOH, 0 °C
O
MeO
OPiv
2) NaOH,
MeOH, 50 °C
OH O
HO
MeO
68%
OH
10-norparvulenone
CH3BrPPh3,
n-BuLi,
THF
OH O
OH O
MeO
39%
OPiv
1) H2 , 10% Pd/C
EtOAc, RT
2) NaOH
MeOH, 50 °C
MeO
84%
OH
O-methylasparvenone
28
Vargas, A.C.; Quiclet-Sire, B.; Zard, S.Z. Org. Lett. 2003, 5, 3717-3719.
Stereocontrolled carboazidation in the total
synthesis of Hyacinthacine A1 and epi-3Hyacinthacine A1
PhMe2Si
PhMe2Si
EtO2C
S
OEt
S
(Bu3 Sn)2
O
4 steps
O
N3 OAc
84%
85:15, syn:anti
HO
O
HO
O
O
EtO2C
t-BuON=NOt-Bu
Benzene, 60 °C
PyrSO2N3
OAc
PhMe2Si
EtO2C
O
O
N3 OAc
O
7 steps
EtO2C
N3
H OH
H OH
N
7 steps
OH
OH
3-epi-hyacinthacine A1
N
OH
OH
hyacinthacine A1
29
Chabaud, L.; Landais, Y.; Renaud, P. Org. Lett. 2005, 7, 2587-2590.
Mechanism of Carboazidation
30
Ollivier, C.; Renaud, P. J. Am. Chem. Soc. 2001, 123, 4717-4727.
Reversible Addition Fragmentation
chain Transfer process
Initiation
monomer
I
P1
Transfer to xanthate
I
=
S
Pn
S
CO2Et
Pn
S
S
CO2 Et
Pn
S
OZ
OZ
S
CO2Et
OZ
Chain-to-chain transfer
Pn
S
S
OZ
Pm
Pn
S
S
OZ
Pm
S
S
Pm
OZ
Pn
- Fast chain transfer allows for formation of polymers
with narrow distribution in molecular weight
Stenzel, M.H. et al. Macromol. Chem. Phys. 2003, 204, 1160-1168.
Destarac, M. Macromol. Rapid Commun. 2002, 23, 1049-1054.
31
Overview
- Development of xanthate transfer reactions
- Preparation of xanthates
- Xanthate transfer reactions
- Limitations
- Conclusions
32
Limitations
- Not broadly stereospecific
- Kinetics not fully understood
- Must achieve a delicate balance in stability of radicals
for successful chain process
- Although a transfer process is tin-free, reductive cleavage
of xanthate often involves tin
33
Conclusions
- Can generate many different types of radicals and
radical equivalents
- New ways to think about retrosynthetic disconnections
- Variety of synthetic applications
- Potential for heteroatom-based radicals
34
Acknowledgements
- Professor Bob McMahon
- McMahon Group
Phillip Thomas
Caroline Pharr
Nikki Burrmann
Jessica Menke
- Practice Talk Attendees
Maren Buck
Lauren Boyle
Julee Byram
Alex Clemens
Richard Grant
Mike Kinsinger
Margie Mattmann
Claire Poppe
Becca Splain
Matt Windsor
35
36
Stereocontrolled Carboazidation
Chabaud, L.; James, P.; Landais, Y. Eur. J. Org. Chem. 2004, 3173-3199.
37
Requirements for radical chain reactions
- specific generation of initiator radicals
Y
R
R
Bu3SnX
- selectivities of the radicals involved
in the chain have to differ from
each other
- reaction between
radicals and
Y
non-radicals must be
faster than radical
Bu3SnH recombination rates
- reasonable termination steps to
produce innocuous by-products
that do not disturb the chain
Bu3Sn
RX
R
Y
Giese, B. Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds; Pergamon 38
Press, 1986.
Xanthates and related derivatives
S
R
S
O
R'
xanthate  dithiocarbonate
other dithiocarbonyl derivatives:
S
R
S
R'
S
N
dithiocarbamate
R
S
R'
dithioester
S
R
R'
S
S
trithiocarbonate
39
Competing mechanisms
Barton, D.H.R.; McCombie, S.W. J. Chem. Soc., Perkin T rans. 1, 1975, 1574-1585.
Barker, P.J.; Beckwith, L.G. J. Chem. Soc., Chem. Commun., 1984, 683-684.
40
Potential for intermolecular addition to
unactivated olefins
- extended lifetime of R in medium due to reversible,
degenerate process
- no longer restricted to general pairing of nucleophilic
radical with electron-poor olefin
- very few radical reactions allow addition to
unactivated olefins, with exception of allylation using
allyl stannanes
41
Intramolecular variant yields polycyclic
structures
O
EtOC(S)S
O
Me
O
Me
Bu3SnH, AIBN
benzene, reflux
DLP
DCE, reflux
R
Me
Ph
R
SCSOEt
R=Ph, 71%, 9:1 dr
R=i-Pr, 80%, 9:1 dr
R=Ph, 71%
R=i-Pr, 80%
- compound with pendant isopropyl group exhibits the
structural core of many terpenes
OH
O
Me
Me
Me
Me
Me
O
DLP
DCE, reflux
Me
Me
Me Me R
SCSOEt
89%
Me
Bu3SnH, AIBN
benzene, reflux
R=SCSOEt, 39%
R=H, 75%
O
Me
Me
Me Me
stemodinone
- 6-exo-ring closure on cyclohexene
- formation of cyclohexane with geminal dimethyl synthesis:
another common terpene motif
42
Binot, G.; Quiclet-Sire, B.; Saleh, T.; Zard. S.Z. Synlett. 2003, 3, 382-386.
Synthesis of 2,3-trans disubstituted
tetrahydrofurans
S
X
R1
O
S
X
R2
X
SC(S)OR1
R2
R2
Entry
X
R1
R2
method
yield
dr
1
O
Et
CHFCO 2Et
A
79
>98:2
B
67
>98:2
A
81
>98:2
B
73
>98:2
A
30
>98:2
B
52
>98:2
B
55
9:1
2
3
4
BnO
O
CH2
CH2
CH2
DLP (0.3 equiv)
DCE, reflux, 5 h
BnO
Ph(CH2 )2
CHFCO 2Et
CF3
Et
CH2CN
Et
BnO
O
BnO
SC(S)OEt
CHFCO2Et
57%
SC(S)OR1
O
NH
AgOTf, silylated thymine
toluene, 0 °C, 3 h
O
RO
RO
N
O
CHFCO2Et
R=Bn 61%
R=H 98%
43
Jean-Baptiste, L.; Yemets, S.; Legay, R.; Lequeux, T. J. Org. Chem., 2006, 71, 2352-2359.
Synthesis of 2-sulfolenes:
precursors to 1,3-dienes
O
O
O
SC(S)OEt
R1
R3
peroxide
R2
mCPBA R1
R3
R1
R2
SC(S)OEt
O
S
R2
Yield
Yield
(b-ketoxanthate) (2-sulfolene)
Entry
R1
R2
R3
1
Ph
H
C6H13
84
79
2
Ph
H
CH2SiMe3
72
70
3
2-MeC6H4
H
C6H13
68
62
4
4-MeOC6H4
H
C6H13
92
77
5
4-MeOC6H4
H
80
60
6
4-BrC6H4
H
C6H13
84
81
7
tBu
H
(CH2)9OAc
74
72
C6H13
43
48
8
R3
44
Lusinchi, M.; Stanbury, T.V.; Zard, S.Z. Chem. Commun. 2002, 1532-1533.
Xanthate transfer chain process
45
Quiclet-Sire, B.; Zard, S.Z. Top. Curr. Chem. 2006, 264, 201-236.
Construction of a-amino acid derivatives
MeO
O
HN
S
OEt
MeO
O
S
HN
MeO
S
R
MeO
O
HN
H
MeO
O
O
HN
MeO
S
S
R
MeO
O
HN
MeO
EtO
S
O
di-tBu peroxide
benzene
NH
CO2 Me
O
OEt
R
O
OEt CO2Me
MeO
MeO
SMe
R
O
O
OMe
S
NH
O
MeO
O
HN
S
MeO
S
OEt
O
OMe
46
Udding, J.H.; Hiemstra, H.; Speckamp, W.N. J. Org. Chem., 1994, 59, 3721-3725.
C-alkylation of small peptides
O
BzHN
N
H
NC
O
Ph
BzHN
OMe
NC
O
50%
Me3Si
O
BzHN
N
H
OMe
O
37%
O
OMe
BzHN
N
NC
CN O
H
N
O
20%
BzHN
N
H
O
14%
O
43%
Ph
O
BzHN
O
N
H
OMe
N
H
CN
OMe
O
23%
OMe
Ph
47
Blaksjaer, P.; Pedersen, L.; Skrydstrup, T. J. Chem. Soc., Perkin Trans. 1. 2001, 910-915.
C-allylation of small peptides
O
BzHN
S
O
H
N
O
S
EtO
SEt
N
H
OEt
H
N
O
O
N
H
OMe
O
Ph
17%
N
H
SO2Et
S
O
H
N
Ph
O
BzHN
N
H
OMe
O
57%
Et
SO2
H
N
EtSO2
O
O
N
H
O
BzHN
N
H
OMe
O
33%
48
Blaksjaer, P.; Pedersen, L.; Skrydstrup, T. J. Chem. Soc., Perkin Trans. 1. 2001, 910-915.
Radical-polar crossover reactions
49
Quiclet-Sire, B.; Zard, S.Z. T op. Curr. Chem. 2006, 264, 201-236.
Construction of a-tetralone by Bos et al
OCH3
CH3O
BuLi
CO2
H3CO
OH
CH3O
O
O
O
LDA
OBu
H3CO
55%
O
O
OBu
H3CO
OH
50%
50
Effect of –Z on polydispersity
S
H3CH2 CO2 C
S
O
Z
xanthate
CTA
Z
Mw/M n
X1
-CH2CH3
2.01
X2
-CH2CF3
1.57
X3
-CH[P(O)(OCH2 CH3)2]CF3
1.15
51