Baran Group Meeting
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Commercial available peroxides*
Inorganic peroxides
Na2O2
CaO2
Li2O2
BaO2
Ni2O3
NiO2 xH2O
H2O2(30%)
ZnO2
NaBO3 4H2O
MgO2
TbO2
SrO2
Na2CO3 1.5H2O
sodium
peroxide
$ 109/100g
calcium
peroxide
$ 27/100g
lithium
peroxide
$ 32 /50g
barium
peroxide
$ 146/500g
nickel
peroxide
$ 106/5g
nickel(II)
peroxide
hydrate
$ 40/ 1g
hydrogen
peroxide
$ 350/4L
zinc
peroxide
$ 75/1kg
sodium
perborate
tetrahydrate
$ 94/ 1kg
magnesium
peroxide
complex
$ 40/250g
terbium
peroxide
$ 30/1g
Stronium
peroxide
$ 38/100g
sodium
percarbonate
$ 91/ 2.5kg
(NH4)2S2O8
Na2S2O8
K2S2O8
2K2SO5 KHSO4 K2SO4
5[Bu4N+] SO5] HSO4] SO4]
ammonium
persulfate
$ 39/ 100g
sodium
persulfate
$ 87/ 2.5kg
potassium
persulfate
$ 70/ 500g
Oxone®
monopersulfate
compound
$ 60/ 1kg
OXONE®
tetrabutylammonium salt
$ 156/ 25g
Organic peroxides-1
O
CO3H
tBuOOH
BzOOBz
urea H2O2
tert-Butyl
hydroperoxide
solution (5-6 M)
$ 47/25mL
Benzoyl
peroxide
$ 92/500g
Urea
hydrogen
peroxide
$ 88/ 250g
HOO
O
O
OOH
O
O
Cl
O
Cyclobutane
maloyl
peroxide
$ 100/1g
mCPBA
$ 81/100g
O
tBu
O O
H3C(H2C)9H2C
tBu
O
CH2(CH2)9CH3
O
Lauoyl
peroxide
$ 81/100g
tert-Butyl
peroxide
$ 134/1L
2-Butanone
peroxide
$ 129/500mL
O
Cl
O
Cl
O
O O
Cl
O
2,4-Dichlorobenzoyl Cl
peroxide, 50% in DBP
$ 59/100g
O
O
O
OH
Me
O
O
Me
Me
Ph
Me
O
O
Me
Me
tert-Butyl
peroxybenzoate
$ 86/500mL
Me
tBu
O OtBu
tert-Butyl peracetate solution,
50% in mineral spirits
$ 77/500mL
Me
Me
O
O
Me
Ph
Me
Me
O OtBu
O
tert-Butyl
monoperoxymaleate
$ 75/5g
O
O
O
O
Ph
Me Et
O
O
Et
Me
O
tBu
O
O
O
O
1,1-Bis(tert-amylperoxy)cyclohexane
solution, 80% in mineral spirits
$ 74/500g
O
O
O
O
O O Et
O
Me
tert-Butylperoxy
2-ethylhexyl
carbonate
$ 77/500mL
Dicumyl
peroxide
$ 123/500g
OtBu
OtBu
O
Me
O
Me
O
O
O
O
O
Me Me
O
Me
3,6,9-Triethyl2,4-Pentanedione
1,3-Bis(2-tert-butylperoxyisopropyl) 1,1-Bis(tert-butylperoxy)-3,3,53,6,9-trimethyl-1,4,7-triperoxonane peroxide solution
trimethylcyclohexane
benzene
$ 62/100g
$ 45/500mL
$ 78/500mL
$ 150/250g
* Prices are based on Aldrich Inventory (price from other suppliers will not be noted); any resouce less than 10 mg will not be included
O
2,2-Di(tert-butylperoxy)
butane
$ 86/500mL
Baran Group Meeting
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Hydrogen peroxide based oxidants:
Me
OH
OTMS
Me
H2O2 (NH4)6Mo7O24 4H2O Prep:H2O2 and Mo reagent mixing for the reaction;stable powder
Application: 1)[Mo] Among the best catalyst for the epoxidations
Hydrogen peroxide
since it is cheap and easy handling; 2)mono and di-subustituted
ammonium heptamolybdate
alkenes react very slowly
selectively on more hindered alcohol
TBHP, MoO2(acac)2
Me
90%
O
O
Me
Cl
O
2. 96 °C
44%
J. Am. Chem. Soc. 1975, 2281.
TBA, K2CO3, THF, 4d
HO
Me
H2O2 + [Mo]
Me
73%
H
HO
OEt
H
O
O
Cu(ClO4) 6H2O
TBHP
Ph
88%
Prep:70-90% aqueous solution or anhydrous solution in hydrocarbon solvents
(Sharpless'
Aldrich
procedure
to
prepare
anhydrous
TBHP)
Application: 1)oxidation of alkenes to diols; 2) oxidation of allylic or benzylic or
tBu
propargylic positions with SeO2 and TBHP 3)epoxidation widely applied; 4) vicinal
O OH
diol can be cleaved by TBHP with MoO2; 5) alcohol can be oxidized by TBHP with
tbutyl hydroperoxide Se or Cr compound; 6) sulfide can be oxidized to sulfoxide or sulfone; 7)
phosphanes can be oxidized to phphosphine oxide; 8)amine can be oxidized to Noxide or imine; 9) Kharasch reaction; 10) peroxy acetal can be made from
aldehyde or ketone with TBHP; 12) alkyl halide can be converted to alkyl alcohol
from Grignard reagent with TBHP.
TBHP, TMSN3
FeCl3(0.1 eq)
O
R
TBHP, SeO2 (5% mol)
tBuOH
60%
TBHP, VO(acac)2
O
R
R = H, alkyl, aryl
Tetrahedron. Lett. 1976, 3157.
Me
O
sole SeO2 gave oxidation on both sides
Tetrahedron. Lett. 1983, 2321.
DHQ)2Pyr
(3 mol%)
OEt
45%
66%
some noticeable examples
OtBu
O N3
OtBu
O N3
H
O
R
R=H
O
tBuOO
32%, 93% ee
OtBu
OtBu
O
N3
O N3
H
35%, 96% ee 90%, racemic
tBuOOH, AgOTf
Br
Br
CH2Cl2, 0 °C
Me
Br
Me OOH
AgOTf
Me
MeOH
Me
O O
50%
OH
Tetrahedron Lett. 1983, 543-546.
mCPBA and its families:
H
O
Prep:stable in 85% purity, 100% purity is possible, stored in polyethylene
container in fridge
O
Application: 1) epoxidation of alkenes (electron-riched); 2) B-V reaction;
3) Rubottum oxidation; 4) oxidation of sulfide to sulfoxide (tandemed with
meta-chloroperbenzoic acid Mislow-Evans rearrangement); 5) oxidation of selenides and phosphanes
and phosphites;
Cl
CH2Cl2
47% (9% sm)
Ph
NC
O
some noticeable examples
Antilla has chiral Bronsted Acid catalyzed peroxidation of imine on Angew. Chem. Int. Ed. 2010, 6589.
O
TBHP, CrO3 (5%)
OMe
OOtBu
moderate to high ee
30-40% yield
78%
J. Chem. Soc. Perkin. Trans. 1. 1985, 267.
OEt
Me
Org. Lett. 2013, 3832.
O
benzene, 40 °C, 50 h
Me
O
O
J. Org. Chem. 2010, 5065-5071.
OtBu
O N3
CH2Cl2, 0 °C
Me
OH
Me
HO
O
OtBu
H
TBHP:
O
O
CH3CN, 80 °C
without the base, epoxidation can occur
J. Am. Chem. Soc. 1992, 7375.
OH
Me
Cl
1. TBHP, pyridine, CCl4, 0 °C
HO
O
HO
Me
Tetrahedron. Lett. 1981, 2595.
Isr. J. Chem. 1984, 134.
H
O
85%
TBA, K2CO3, THF, 6 d
HO
OH
Me
benzene, CF3CO2H
60 °C, 72 h
Me
O
H2O2 + [Mo]
Me
Baran Group Meeting
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mCPBA, EtOAc
CH2Cl2, Na2CO3 (aq.)
I
CO2Me
Persulfate based peroxide reagents:
OH
5 -20 °C, 1 hour
Application: 1) oxidizing primary and secondary alcohols to aldehyde w/o
oxidizing
cat.(kinatically slow to acid; 2) oxidizing ether to aldehyde
potassium/ammonium aldehyde or ketones to benzoic acid with metal catalysts; 4)oxidizing aliphatic
amines to aldimines or nitriles with Cu(II)/Ni(II) as catalyst; 5)oxidizing
peroxydisulfate
carboxylic acid to peracid under phase transfer condition;
K2S2O8/(NH4)2S2O8
CO2Me
65 - 67%
J. Am. Chem. Soc. 1983, 2908.
Elbs oxidation:
O
H
O
OH
Application: 1) oxidation of alcohol at room
temp for high yield; 2) epoxy ketone can be
HCl
+ Me
Me
N
prepared in one step from allylic alcohol; 3)
Me H Me
forced conditions lead to lactone or ester
meta-chloroperbenzoic acid-2,2,6,6-tetramethylpiperidine from alcohol
hydrochloride
Cl
O
Me
Me
H
O
Me
1. mCPBA, TMPHCl
2. hydrazine
HO
H
Me
MeO
OH
H O
MeO
40%
O
O
OH
flavanol based structure
O
through p-hydroxysulfate ester salts
Chem. Rev. 1951, 49, 91.
Boyland-Sims oxidation:
HO
Me
N
Me
Me
Me
(H4N)O3S O O SO3(NH4)
J. Org. Chem. 1961, 3615.
O
1. K2S2O8
2. NaOH
O
68%
NO2
O
Me
N
O SO3
Me
N
Me
N
Me
OSO3K +
KOH
Characterization:Stable at ambient temperature as white crystal;
Application: epoxidation of alkenes; B-V reaction
o/p = 2/1, 22%
OSO3K
J. Org. Chem. 1992, 2266.
C-H oxidation:
O
Me
p-Nitrobenzoic peroxide
OH
K2S2O8, NaOAc, Cu(II)
PNPBA, CHCl3
MeCN-HOAc, 80 °C
reflux, 23 h
80%
69%
Angew. Chemie. Engl. 1979, 407.
J. Org. Chem. 1986, 3693.
Me
O H
O
O
CO2Me
O
O
tButyl 4-benzoylperbenzoate
epoxidation/B-V
reaction/oxidation
of amine or sulfide
extremely like mCPBA
O
Me
NaOAc-HOAc
reflux
Ph
81%
OOH
Perbenzoic acid
O
K2S2O8, Fe(II)
Me
Prep: from corresponding benzoic acid
with tButyl hydrogperoxide.
Application: low-temperature initiation
(360 nm, compared to reflux of AIBN) of
radical reaction;
CO3H
NH2
NH
p-Methoxyl
carbonylperbenzoic acid
Prep: from ester aldehyde which
was irradiated with 2 kW high
pressure Mercury light with O2, as
stable
as
mCPBA;
Utilization: very similar as mCPBA
Tetrahedron. 1980, 3559.
Oxidation of alkenes:
N
N
N
N
R
K2S2O8
N
N
91%
N
N
R
adenosine
Chem. Pharm. Bull. 1992, 1656.
OH
O
+
EtOH, H2O HOSO2
H2SO4/HOAc
K2S2O8
H2O, 80 °C
Caro's acid
Peroxymonosulfuric acid
80 °C
OH
60%
OH
J. Org. Chem. 1960, 1901.
Baran Group Meeting
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NO2
Oxidation of alcohols:
O
OH
O
S
(NH4)2S2O8, Cu(II)
O
O
O
AcOH, 100 °C
CN
40%
CO3H
Bulll. Acad. Sci. USSR, Div. Chem. Sci. 1984, 2099.
SO3H
C-H oxidation:
o-Sulfoperbenzoic acid
O
R
N
Me
O
Ag
N
Na2S2O8, K2CO3
Me
NO2
Ph
NO2
Ph
X
X = Se, Te, S
OH
isomer distribution
subs.
N
O
O
S2O82-
R
2-OAc 3-OAc 4-OAc
68
21
95
100
0
100
0.6
0
5
0
0
0
31
79
0
100
0
yield(%)
63
18
63
35
35
63
Symmetric peroxide reagents:
R = OH
O
[Ag]
O
76%
Ph
HOAc/KOAc
anisole
biphenyl
Bis(2,2'-bipyridyl)silver(II) peroxydisulfate
naphthalene
4-bromoanisole
one electron oxidant of electron-rich aromatic compounds 4-fluoroanisole
can be also in catalytic version with K2S2O8
4-t-Butylanisole
N
H2O, 100 °C
R = OMe
N
N
R=H
CONHMe
X
under dimethyldioxirine item
2+
O
O
2KHSO5 KHSO4 K2SO4
oxone
R
H2O, 100 °C
R=H
86%
S
J. Org. Chem. 1990, 1267.
J. Org. Chem. 1991, 1014.
experiments suggested a radical
Potassium
o-Nitrobenzeneperoxysulfonate
K2S2O8
O
ONs
Preparation: insu with KO2 and sulfonyl chloride
Application: epoxidation of alkenes (basic condition epoxidation);
oxidation of benzylic position (few case); oxidative desulfurization of
thiocarbonyl compounds (sulfuryl urea to urea)
O
O
S
O OK
NO2
H
O
X
around 60%
Preparation: o-sulfobenzoic anhydride and 30% H2O2 in acetone, stable in
acetone;
Utilization: epoxidation and hydroxylation have been reported; sometimes the B-V
reaction gave better result compared to peracetic acid-Boron Etherate
O
Ag(I), Cu(II),
MeCN, 80 °C
56%
S
X
X = OR, NR2
O
Na2S2O8
Tetrahedron. Lett. 1985, 2525.
O
O
O
CN H2O, 60 °C
Me
O
(ArSO3)2
Application: Pseudohalogen reagent whose reactivity is comparable to that of chlorine;
-hydroxy ketone can be made from enol derivatives (OTMS, OAc, NR2)
OH
Na2S2O8
O
S
p-Nitrobenzenesulfonyl peroxide
J. Org. Chem. 1983, 4914.
CO2H
O
O2N
96%
OH
O
O
(ArSO3)2
Ph
X
O
O
S
Ar
MeOH
16-98%
XPh
O O
OMe
Ph
O
J. Am. Chem. Soc. 1979, 5687.
m-Nitrobenzenesulfonyl peroxide
Preparation:potassium carbonate, sulfonyl chloride and hydrogen peroxide;
Application: moderate aromatic substitution to give aryl sulfonates, which can be hydrolyzed to phenols
dibenzoyl peroxide
Alternate name: DBP; relative unstable;
Application: 1) widely used as radical initiator; classic anti-Markovnikov
reaction;Minisci reaction of radical from alkyl halides, dioxane, DMF and even
cyclohexane to protonated heteroaromatic compounds; used as benzoyloxylation
of aromatics; used in hydroxylation of enolate
Baran Group Meeting
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DMDO and TFDO: (it is worthy to give another group meeting on these two reagents!)
O O
Me
Preparation: recent easy Organic Synthesis procedure;
Application: Epoxidation of kinds of alkenes! C-H activation of alkanes with the
retention of the stereochemistry; readily oxidize amines and sulfide.
Me
H2O2
MeO2C
Dimethyldioxirane
oxidation of vincinal diols:
OH
OH
1.2 eq DMDO
O
1. H2O2, BF3 OEt2, CH2Cl2
masked during
oxidation
MeO
OH
OH
> 98% ee
98%
Tetrahedron. Lett. 1993, 4559.
96%
O
Me
CF3
methyl(trifluoromethyl)dioxirane
OH
J. Am. Chem. Soc. 1992, 1375.
O
NH2
J. Org. Chem. 1993, 3600.
O
O O
N
MeO
HO
> 98% ee
HN
2. TMSNCO
N
H
acetone, 0 °C
acetone, 0 °C
OH
MeO2C
HN
1.2 eq DMDO
HO
Utilization: B-V reaction using 90% H2O2 and BF3 Et2O, much
stronger condition; moderate hydroxylation of arenes with HF as
additive
BF3 Et2O
hydrogen peroxide-Boron trifluoride
Preparation: Guillaume's procedure, stable in fridge for a week;
Utilization: epoxidaton of extreme inert alkenes such as CF3
substituted alkenes;oxidation of hindered phenols such as 2,6-di-t-butyl
phenol; some magic C-H oxidation
O
O OH
OH and
O OH
O-
O
O
OH
1 eq. TFDO
monoperoxyphthalic acid
H
+
0 °C, 7 min
tBuMe2SiOOH
H
Hg(OTf)2
soluable in most solvent, mercury, toxic!
hydroperoxide - mercury triflate
H
86%
Mg2+ 6H2O
O
Preparation: phthalic anhydride and H2O2 in
the presence of NaOH or MgO
Utilization:epoxidation of alkenes, B-V rxns;
and oxidation of amine, sulfide and selenium
13%
1. peroxide, Hg*
BrHg
Tetrahedron. Lett. 1992, 7929.
OOtBu
2. KBr, H2O-CH2Cl2
3 eq. TFDO
H
H
O
I2, CH2Cl2
OOtBu
H
O
J. Org. Chem. 1992, 5052.
H
OH
I
OOtBuAgOTf, CH2Cl2 O
O
+
H
CH2Cl2, 0 C, 3h
85%
H
I
>45%
63%
NaI, acetone
50%
used in peroxy-mercuration to epoxidation (by Corey)
J. Chem. Soc. Perkin. Trans. 1. 1991, 1923.
Metal-based peroxides:
NaBO3 4H2O
sodium perborate
oxidizing agent for a variety of functional groups; cheap/safe/convenient alternative
Ce(OH)3O2H
to oxidants such as H2O2, MeCO3H or mCPBA; In general, not good for
dihydroxylation, B-V reaction though which was reported before; industry level viable cerium(IV) trihydroxide hydroperoxide
alternative to hydrogen peroxide for the oxidative decomposition of
organophsphorus ester wastes
NaBO3 4H2O
Ac2O, H2SO4, reflux
OAc
Prepared in situ with LiOH and H2O2;
Utlization: cleavage of different kinds of amide ligands, such as Evan's
lithium hydroperoxide oxazolidones, Davis' sultam auxiliary, and Myer's pseudoephenamine auxiliary;
ester can be also cleaved.
LiOOH
OH
relative harsh condition
59%
Synth. Comm. 1988, 937.
readily available, stable red solid. mild oxidizing reagent for
functional groups such as alcohol (aldehyde), phenol(to
quinone) and amine (to azo compound)
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R
O
Se
OOH
Application:major for B-V reaction; and oxidizing agent for multiple
functional groups such as hydrazyl imine to cyano groups
R = H or NO2
R
F3 C
m. p. 52 °C w/ detonation;
Preparation: diphenyl diselenide with 30% H2O2
Benzeneperoxyseleninic acid
Me
Me
CHO H2O2, DNPDS
O
O
palladium t-Butyl Peroxide
Trifluoroacetate
TfO
Me
OCHO
R
+
R
F3 C
O
O
MeOH
94%, suitable for phenol with EDG groups
Nickel(II) Peroxide
O
oxydiperoxymolybdenum (Py)-HMPA
Me
R
O
Ph
O
[Pd], tBuOOH, benzene
O
Me
O
50 °C, 12 h
Ph
Me
Me
OH
O
71%
J. Chem. Soc. Chem. Comm. 1983, 1245.
OH
O O
O
O
Mo
O O
Ph
O O
N O
O Mo O N
Ph
O O
Oxoperoxobis(N-phenylbenzohydroxamato)molybdenum(VI)
Me2N
Oxidation of primary and secondary alcohols
epoxydation of alkenic alcohols (not common)
NC
Ph
NC
Ph
TMS
Me
86%
Peroxylbis(triphenylphosphine)palladium
Preparation: Pd(PPh3)4 and O2
Utilization: Mild oxidation of alkenes,
sulfur compouns and oxime
The sole peroxide which can be generated in situ (industral favored)
Electrophilic reagent capable of reacting with many functional groups; prepared in situ in
industry for epoxidation of vegetable oil and fatty acid esters; broad range of epoxides
O
peracetic acid formation when carrying no acid sensitive groups;(terminal alkenes are sluggish); in
some cases, different regioselectivities can be observed comparing to mCPBA; oxidation
of arenes to phenols in low yield; B-V reaction;amine to nitroso, sulfide to sulfone
O
Me
not sensitive to equilibration
compared to Davis' reagent
PPh3
O
Pd
O
PPh3
O
tBu
Pd O
+ R
Peracid series:
Preparation: MoO3, 30% hydrogen peroxide with HMPA, freeflowing yellow crystal
Application: common reagent for hydroxylation of enolates;
oxidation N, S, P.
OH
O
Ph
O
O X
Me
Black hydrous powder
Utilization: oxidation of primary alcohols to carboxylic acid in aqueous media, or
oxidize allylic, benzylic alcohol to aldehyde in organic solvent; oxidize phenols to
polymeric mixtures and quinones; oxidize alcohol or aldehyde to amide in ammonia
solution; oxidize amine to cyano or diazo compounds; dehydrogenation of
unsaturated hertocycles
HMPA
O
O
Mo
O
O
N
Ph
Pd
H2O2 can be used as oxidant for this transformation:
Varation: Pd(PPh3)4 + aq. H2O2
Tetrahedron. 1987, 2853.
NiO2
R
key intermediate
different from Wacker
oxidation
general mechnism:
Pd OTf
OCHO KOH
CH2Cl2, 20 °C
Preparation: yellow crystal from Palladium(II) acetate and
trifluoroacetic acid and TBHP
Utlization: alkenes to methyl ketone
O
tBu
Pd O
Me
THF, 0 °C
72%
L
Pd
L
NC
NC
J. Organo. Met. 1975, 115.
O
Et
O
Me
Et
OO
Chem. Lett. 1983, 1771.
3
-butenolides, mCPBA is compared worse for this reaction
H
OAc
Me
O
CH2Cl2, 7 °C
TMS
78%
H
O
molybdenum (VI)
Application: enantioselective epoxidatioin
of unfunctionalized simple alkenes
(PPh3)2PdO2
NaOAc, MeCO3H
23-50 °C
Ph
95%
Ph
TFA
O
Ph
NC
NC
Ph
OH
MeCN/H2O/CH2Cl2
MeO2C
55%
L
Pd O
L
NC
NC
OAc
RuCl3, MeCO3H
MeO2C
O
J. Org. Chem. 1993, 2929.
OTBS
Me
NaOAc, AcOH, EtOAc, rt
NH
O
OTBS
RuCl3, MeCO3H
99%
OAc
Me
NH
O
Baran Group Mee
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Changxia Yuan
O
Preparation: in situ with Tf2O and 90% H2O2 or Urea H2O2;
Application: the strongest organic peroxy acid; very powerful
epoxidation reagents, more than mCPBA; diols are the subsquently
hydrolysis by TFA; B-V reaction is facile; various of heteroatoms can be
oxidized
H
O
F3 C
O
Trifluoroperacetic acid
O
H
H
CO2H
Peroxymaleic acid
CH2Cl2, 23-0 °C
76%
Me
Ph
OMe
Me
J. Org. Chem. 1983, 5199.
Br N N
Miscellaneous peroxides:
EtO
O
H 2N
OOH
O-ethylperoxycarbonic acid
H
H O
N
O
H
H
hydrogen peroxide-urea
Preparation: not stable to store; ethyl
chloroformate with hydrogen peroxide in situ
Utilization: epoxidation of alkenes on biphase
condition, cheap and evironmentally benign
Ph
OOH
pyrazolyl peroxide
O
stable white powder; utilized as anhydrous
"hydrogen peroxide" in organic solvent for the
standard reactions such as epoxidation, B-V
reactions and oxidation reactions
stable at -30 °C for years
Et3SiOOOH
triethylsilyl Hydrotrioxide
F3 C
O2H
OH
2-Hydroperoxyhexafluoro-2-propanol
N H
O
O
R
O
R = Ph or Me
better leaving group than HO-OH Me3SiO S O
Preparation: hexafluoroacetone with 30% or 90% H2O2 Peroxyacetimidic acid (Payne oxidation)
O OSiMe3
Utilization:epoxidation; oxidize aldehyde to acid without
weak reactivity for epoxidation, to
touching alcohol;oxidize sulfide to sulfoxide and sulfones
Bis(trimethylsilyl)
show acetonitrile as solvent can help
monoperoxysulfate
epoxidation using other peroxides
Ph3COOH
triphenylmethyl
Hydroperoxide
H
oxidant useful for enantioselective metalcatalyed epoxidation of allylic alcohols and
enantioselective oxidation of sulfides to
sulfoxides (moderate to poor result)
O
O
Me
O
NO2
Peroxyacety nitrate
exist in polluted air, easy to
generate peroxy radical; not
useful comparing to mCPBA
and H2O2
N H
O
O
Cl3C
Trichloroperoxyacetamidic acid
Prepared with trichloroacetonitrile
and 30% H2O2; most of the time
which can be substituted by
common reagents for epoxidation
Prepared from the tetralin and O
Utilization: for epoxidation, usua
mCPBA or TBHP/Mo is superior;
oxidation of aromatics to give ph
low yield
prepared from diphenylpyrazole, 90% hydrogen peroide (caution!)
and dibromo- 5,5'-dimethylhydantoin
1 fast rate 2 mild reaction 3 stable reagent
Utilization: oxygen transfer reagents; heteroatom and alkene oxida
faster N, S oxidation compared to (same magnitude) flavin hydrope
and (two orders) acyclic azo hydroperoxides and 105 more than H2O
Prepared from triethylsilane and O3, stable for a few minutes at -78
Reactivity: very like the combo of ozone (oxidative cleavage of alke
Et3SiH (reduction to alcohol or aldehyde)
H
O
Et3SiO3H
H
O
-Tetralyl Hydroperoxide
O
MeO
CF3
HO
Prepared from 90% hydrogen
peroxide and maleic anhydride
Utilization: for epoxidation; B-V
reaction (most common) no buffer
needed; oxidize amine to nitro group
unusually stable peroxide but still need
cautions; for epoxidation, it is faster
Ph
comparing to TBHP and higher yield; a
reliable reagent for enantioselective
cumyl hydroperoxide sulfoxide formation with Ti(OiPr)4 and
diethyl tartrate
TFPAA, H2O2
OMe
O
H
O
Me
OOH
Me
N
N
O
CH2Cl2
TBSOTf
O
Me
O
48%
OMe
O
O
O
OMe
Tetrahedron. Lett. 1985, 4485.
Preparation: from SO3 and TMSOOTMS using as crude at -30 °C
decompose (explose) at rt! Use immediately.
Application: strong oxidant; B-V oxidant in nonprotic solvent;
alkenes to ketones; sulfides to sulfoxides, pyridine to pyridine-oxide
Me peroxide
CH2Cl2, -30 °C
high yield
J. Org. Chem. 1990, 93.
Me
O
Baran Group Meeting
4/5/2014
Changxia Yuan
Some peroxides contained natural products:
Me
Me
OH
Me
HO
H
O O
Me
Me
first studied naturally
occurring organic peroxide
C16H33
O
O
HO
Me
Me
O
Chondrillin
H
S
Plakorin
O
H O
O
OMe
HO
O
Prostaglandin G2 OOH
O O
O
Gracilioether A
key intermediates in prostaglandin's
biosynthesis from arachidonic acid
within a big family of prostaglandin
show considerable antimalarial activity
Mycangimycin
selectively inhibits the beetle's fungal antagonist
HO2C
HO HO
O
OH
H
O O
O
O
N
O
N
N
MeO
H
O
H
Me
Me
Terpenic peroxide
O O
Me
Verruculogen
moderate antimalarial activity
produces severe tremors and acute toxicity
Me
CO2Me
O O
CO2H
O
The first isolated five-membered ring peroxide
which has a big family on the side chain; remarkable
cytotoxicity against fungal and cancer cell lines
MeO
CO2Me
O O
H
S
1,2,4-trioxane core, artemisinin and its derivatives
are a group of drugs that possess the most rapid
action of all current drugs against falciparum malaria
HO2C
Plakinic acid A
R
first cyclic peroxide to be
isolated from marine sources
HO
O O
C16H33
H
S
MeO
H
Me
O
Qinghaosu
or
Artemisinin
Yingzhaosu C
Yingzhaosus A and C both contain a 1,2-dioxane core
structure. These compounds have been extensively
studied for their potential antimalarial activity
Me
O
Me
Me
Yingzhaosu A
Ascaridole
H
O
O
Me
O
O
Me
Me
Me
Me
O
CO2H
O
Plakortide G
Et
O O
Plakortide E
O O
S
N
N
S
O O
Me
H
H
O
OH
H
Dioxetanone
H
Et
O
CO2H
Me
Trunculin B
O
O
OAc
Me
Me
Talaperoxides A
collected on the coastal saltmarsh
of the South China Sea
Baran Group Meeting
4/5/2014
Changxia Yuan
Semi-synthesis of Artemisinin-Qinghaosu in industry:
Brief History:
Malaria is a disease that affects millions of people; Discovery by Keasling of a biosynthetic pathway for artemisinic acid; Initial chemistry path discovered by Amyris;
An industrial process was fully implanted to produce 60t in 2014.
H
Me
H
Me
RhCl(PPh3)3 cat.
S/C 2000/1
Me
toluene, H2/25bar Me
25 °C
H
HOOC
99%
Artemisinic acid
+
Me
H
HOOC
Me
H
H
Me
H
Me
H
SOCl2, NEt3
MeOH
Htoluene,
25 °C
H
HOOC
Me
Me
85%
Dihydroartemisinic acid (DHAA)
H
MeO2C
H
Me
+
Me
Me
Arbry
decomposition
H
Me
H2O2, Na2MoO4
H
MeO2C
H
Me
Me
O
HO
MeO2C
1,2-butanediol
Dihydroartemisinic acid methyl ester (DHAM)
H
DOWEX resin
Cu(OSO2Ph)2
air
Me
CH2Cl2
H
isolation by
Me chromatography
Linear peroxide of DHAM
23%
Me
O
O
O
HO
H
Me
O
Artimisinin
90:10
Diastereoselective hydrogenation
problems
NiBH4 gives 3:2 d.r. ratio
Willkinson cat. is good solely
based on inherent diastereoselectivity of artemisinic acid,
Rh is too expensive
S/C is 2000/1
Photooxidation of artemisinin
solution
problems
RuCl2[(R)-DTBM-Segphos](DMF) n is catalyst that is
favor of inherent diastereoselectivity of artemisinic
acid (AA) with an appropriately matched chiral ligand,
Ru is much more affordable
solution
Mechanism: Schenck ene reaction/Hock cleavage/subsequent oxygenation/cyclization
41% yield from the lead by Amyris with significant impurities
solvent is initially switched to CH2Cl2 because 1) safety concern: nonhalogenated solvent is forbidden in oxygenation reaction; 2) CH2Cl2 can be
recycled
Aubry reaction is to avoid photochemical equipment
sensitizer was changed to tetraphenylporphyrin (TPP) since it is cheap and
highly efficent for photosensitizer
S/C is 8000/1, with more time, 16000/1
but the d.r. is not perfect with extensive screen
reaction performed at 15 °C showed accumulation of the hydroperoxide,
one-pot procedure was needed, therefore the ester was ochestrated to
more activated anhydride ester
The first generation of peroxide is dangeous
Mechanism of photooxidation of artemisinin
H
Me
H
O2,h
Me
EtO
O
O
H
Me
RuCl2[(R)-dtbm-Segphos](DMF) 2
S/C >8000/1
MeOH, Et3N, 22bar / 5-6h
Me
Me
H
HOOC
Artemisinic acid
tworkup by evaporation of
MeOH, extraction using
aq. HCl/CH2Cl2
H
H
HOOC
Me
H
TFA
H
O
H
+
Me
H
H
Me
HOOC
O
Me
O
H
EtOCOCl
K2CO3
CH2Cl2, Me
H
20 °C EtO
Me water wash
Dihydroartemisinic acid (DHAA)
Me
O
quant.
O
O
3
O
H
Me
95:5
99%
H2O O
EtO
H
Hock
Me
cleavage
Me
O
Me
H2O
Me
H
O
O
HO O
O
O
H
O
EtO
O2
Me
EtO
O
Me
H
H
O
Me
N. P.
H
Me
O
Me
H
Hg vapor lamp
TPP / air
+
Me
H
EtO
Me
O
O
H
2Cl2, THF
H CH-10
°C
Me
O
Dihydroartemisinic acid methyl ester (DHAM)
Me
OOH
EtO
O
O
Me
concentration
of steps
Hock cleavage
cyclization
NaHCO3/H2O
Me
washes
isolation by
H
solvent switch
Me with heptane/EtOH
O
55% in all total
H
Me
O
O
O
HO
H
Me
O
Mixed anhydride linear peroxide steps including Artimisinin
crystalization of
the final product
Org. Process Res. Dev. 2014, 18, 417-422