Baran Lab
Group Meeting
Liebigs Annalen
Isabelle Thomé
1. Historical Background
– Liebigs Annalen der Chemie is one of the oldest and historically the most
important journal in the field of Organic Chemistry
– was established 1832 and edited by Justus von Liebig and Fiedrich Wöhler
until the death of Liebig in 1873
– Annalen der Pharmacie, 1832–1839
– Annalen der Chemie und Pharmacie, 1840–1872
– Justus Liebig's Annalen der Chemie und Pharmacie, 1873–1874
– Justus Liebig's Annalen der Chemie, 1875-1944 & 1947–1978
– Liebigs Annalen der Chemie, 1979–1994
– Liebigs Annalen, 1995-1996
– Liebigs Annalen/Recueil, 1997-1998
– in 1998 it was absorbed by European Journal of Organic Chemistry
Justus Freiherr von Liebig, born in 1803 in Darmstadt
died 1873 in Munich
his biggest discoveries
2. Never cited
2.1 Photobromination
Cl
R
R'
Liebigs Ann. Chem. 1979, 905.
R
hv
Cl
NO
R'
NO
R
Cl
R
Br2
R'
R'
Cl
Br
Br
Liebigs Ann. Chem. 1975, 1009.
alpha-nitroso starting material derived from oximes
R
NOH
Cl
R
(CH3)3COCl
(CH3)3COH
NO
R'
R'
2.2 Bischler-Möhlau-Indol-Synthesis
HO
R
HO
H+
R
O
NH2
R
N
R
R
R
O
4
3
R
R
R
R
N
H
N
Liebigs Ann. Chem. 1979, 1503.
2.3 Newman-Kwart-Rearrangment
S
N
Cl
HN
O
N N
Me
O
S
S
O
O
S
N N
Me
N
S
O
S
O
N N
Me
O
S-N-Transcarbazoylation
O
N
N N
Me S
S
Liebigs Ann. Chem. 1991, 405.
1
R
R
2.4 Pyrrol and CO
Liebigs Ann. Chem. 1979, 11.
NaOEt (0.2 eq.), CO (50 bar)
EtOH, 7 days,
during the day: 60 °C,
during the night: rt
N
H
CHO
OH
EtO C
O
H
EtO C
O
EtOH
EtO
X
N
EtO
N
EtOH
CHO
N
H
EtO
MeCNpK
N
BH+
N
≈ 48
N
N
P
N
NMe2 NtBu NMe
2
Me2N P N P N P NMe2
NMe2 NRR' NMe2
MeCNpK
BH+
≈ 28-29
BH+
≈ 38-39
R = R' = Me
R = R' = iPr
NH
Et2O-BF3
R = Ac, R' CCl3, X = NAc
OR
SR''
OR
RO
RO
O
Liebigs Ann. Chem. 1984,
1826.
191 times cited
O
N
Liebigs Ann. Chem. 1984, 1249
209 times cited
3.3 "-amino acids from !#amino acids using Arndt-Eistert reaction
GP
H
N *
R
O
1. activation
2. CH2N2
OH
3.
cat. Ag+/HX
H
N *
GP
R
135 times cited
X
O
Seebach, Podlech
activation: NEt3/ClCOOEt, CH2N2
not suitable for amino acids containing heteroaromatic
cat Ag+: silver benzoate in Et3N
further !#derivatization of "-amino acids with various electrophiles, such aus MeI, BnBr,
Boc-N=N-Boc
DBU
MeCNpK
O
RO
RO
"Phosphazene Bases - exotic record breakers
or useful tolls?"
important features: insensitivity to oxidation,
extreme resistance to hydrolysis
beyond P3 stage no practical procedure for their
liberation (KNH2 in NH3 (lq.)
NtBu
MeCNpK
Liebigs Ann. 1996, 1055.
O
thermodynamical product
R'
cat. NaH
OR
3.1 extremely strong, uncharged polyaminophosphazenes, 178 times cited
P
X
R'
kinetical product
K2CO3 !:" = 1:10
3. Most cited publications
N
X = OR
O
RO
RO
or
R'CN
X
R''SH
Et2O-BF3
R = Ac
H
C
O
N
N
N
NR
N P
N P N P N P N
N
N
N
N
NH
O
X
N
H
EtO C
O
O#M+
OR
O
RO
RO
EtOH
N
H
O
RO
RO
base
OR
EtO C
O
220 times cited
OR
O
RO
RO
mechanism:
CO
Liebigs Ann. Chem. 1984, 1343.
3.2 O-! und O-" Glycosylimidates
OR
N
H
EtO
Baran Lab
Group Meeting
Liebigs Annalen
Isabelle Thomé
BH+
≈ 24-25
Liebigs Ann. Chem. 1995, 1217.
2
4. Flash Vaccum Pyrolysis
5. Regioselective Monometalation of 2,5Pyridinedicarboxamide using TMPMgCl
4.1 Naphthothiete
CH2OH
R6
FVP
750 °C, 10-3 Torr
N
R5
N
Liebigs Ann. 1995, 2221.
FVP
O
OCH2R2
OH
O
H
O
3
4
37%
36%
49%
43%
---
49%
11%
7%
1
R1
R2
2
a
H
b
c
H
H
CH3
CH3
CH3
O
H
R3/R4
tBu/H
tBu/H
tBu/H
tBu/H
R5/R6
tBu/H
Me/H
Ph/H
iPr/iPr
R6
R5
N
O
a,b,c
5
O
N
PMT Mg
c
!R2CH3
O R1
CHR1
H
O
7
8
O
O
Ph
H
4
O
R3
O
b
R
O
hv
OTMS
R1
R
OTMS
Ph
OH
H2
[Pd(OH)2]
Ph
HO R
R1
Hydrogenolyses with Pearlman's catalyst allows reductive cleavage of acid-sensitive substrates
Liebigs Ann. 1995, 441.
2•10-3 Torr
N
R3
O
750 °C
R4
N
Liebigs Ann. 1995, 1441.
OH
O
O
Schering AG and Johann Mulzer
N
R1
O
1
O
O
a
Fixation of the amide group at C-2 by complexation
Mg Cl
3
!CO
N
OH
6. Early Thorsten Bach work as habilitand
O
6
N R3
TMP
Cl
2
CH2
3-/4-selectivity
3.9/1.0
1.0/3.0
3-selective
3-selective
OH
O
R5
a/b
70/18
22/65
50/0
90/0
R5
N
Mg Cl
O
!R1CH2R2
R3
N
O
---
R6
1. TMPMgCl (8 equiv)
2. NFNMP (8.5 equiv)
3. H+ (pH 2-3)
O
H
R1
R4
N
O
S
50%
SH
OCH2
Baran Lab
Group Meeting
Liebigs Annalen
Isabelle Thomé
Ph
H2
O
[Pd(OH)2]
64%
HO
Bn
O
(81%)
Liebigs Ann. 1995, 1045
3
7. Fluorine-Chemistry
CH3CN
3 LiF
2a
1
1a
X
F
R
(CH3)2CH
Cl
(CH3)2CH
R2N!SiR'Cl2
2 LiF
R2N!SiF3
1
Br
R = C3H7, R' = CH3
3a
(R2N)2SiCl2
2 LiF
CH3CN
R = C2H5, n-C3H7
4a
4b
2a
2
F
F
CH3CHC2H5
(CH3)2CH
R2N!SiR'F2
3
2 LiCl
(R2N)2SiF2
5
2 LiCl
CH3CHC2H5
Liebigs Ann. Chem. 1980, 223.
also never cited
7.2 Fluor-Silicium-Nitrogen-Compounds B
NH2R + 3SiF4 + 2NR3
Diazotization agent:
t-BuONO, SiF4, DCM, 69%
NaNO2, SiF4, DCM, 0%
n-BuONO, SiF4, DCM, 2%
t-BuONO, SiF4, Et2O, 0%
t-BuONO, SiF4, n-hexane, 0%
t-BuONO, SiF4, CH3CN, 34%
time
temperature
NH2Me
LiAlH4
B2H6
LiAlH4
10
260 °C
175 °C
300 °C
2
12
product
(SiF3)2NMe, 9%
(SiF3)2NMe, 14%
(SiF3)2NPh, 6%
J. Chem. Soc., Dalton Trans. 1973, 2675.
R
Py•HF
this work
Schiemann
o-Me
m-Me
p-Me
p-CN
p-NO2
p-Cl
o-Cl
m-Cl
p-CH3O
69
60
60
56
43
60
40
50
49
45-65
69-87
70
0
35-58
63
6-65
83
47-73
99
98
98
14
92
92
72
98
71
p-CH3OCO
61
0
0
t-BuONO
ArNHNO
!t-BuOH
1/n (SiF2NR)n + 2NHR3 + SiF5
agent
F
R
possible reaction route:
ArNH2
amine
NH2Me
NH2Ph
NH2 SiF , RONO
4
R
3 LiX
2
1b
CH3CN
Eur. J. Org. Chem. 1998, 725.
7.4 Deaminative fluorination of anilines with SiF4
7.1 Fluor-Silicium-Nitrogen-Compounds A
R2N!SiX3
1a
Baran Lab
Group Meeting
Liebigs Annalen
Isabelle Thomé
4 ArN=N!OH
+ 3 SiF4
2 (ArN2+)2SiF62-
ArN=N!OH
2 (ArN2+)2SiF62-
+ SiO2 + 2 H2O
2 ArF
!N2, SiF4
7.5 Dediazoniation under solvolytic conditions
SF5
SF5
Eur. J. Org. Chem. 2014, 1630.
SF5
7.3 O-Difluoromethylation of Monosaccharids
HO
O
O
O
O
ZnBrCF3 • 2CH2CN
DCM, rt, 6-8 h
O
TFE
Liebigs Ann. 1995, 1717.
F2HCO
O
O
O
59%
O
O
N2BF4
F
1
2
1
Preparation of ZnBrCF3• 2 solvent:
CBrF3 + Zn
DMF, I2
ZnBrCF3 • DMF + ICl
J. Flourine Chem. 1994, 67, 91.
CBrF3 pressure: 3.5-4 bar
ZnBrCF3 • 2 DMF
crystalline solid
CF3I
SM
7 days at rt: 2:4:94
4 h at 70 °C 39:56:3
1
TfOH
1 month
50 °C
OCH2CF3
3
3 (100%)
SF5
SF5
SF5
MeOH
1
50 days
rt
65%
5%
OMe
OH
30%
<1%
4
7.6 [18F]-Flouride Ion
Eur. J. Org. Chem. 2008, 2853.
Baltz-Schiemann Reaction for the preparation of carrier-added [18F]fluoroaneres
N2+ BF4"
R
7.8 Decarboxylative Julia-Kocienski gem-difluoro-olefination
SO2CF2CO2" K+
18F/F
N2+ [18F]BF4"
18F"
3/BF3
+ N2
N=N"N
SO2CF2CO2
18F
18F"
R
N
R
K+
18F
18F",
K.2.2.2-K+
F F
18F
18F
O
H+/NO2"
[H]
N
DMSO
7.7 vic-difluorination of fluoroalkenes with XeF2
R1
R4
R2
R3
F
XeF2, SiF4
rt
R1=R2=R3=R4= H, 63%
R1= EtO, R2=R3=R4= H, 0%
R1= Br, R2=R3=R4= H, 93%
F
R4
3
R
R1
R2
F
F
H
H
H
R
F
!+
Xe
R
H
F"
!-
SiF4
F
H
1
H
R
H
H
H
F"Xe
H
R
F
H
H
H
H
"H+
R
H
1
SiF5
R
Eur. J. Org. Chem. 1999, 3151.
H
F
R
R
H
H
H
H
S
O
H R
H
F
R
K+
N
O O
F
F
S
R
N "
H
O
K+
O
"
H
F F
K+
O" H+
O
NH H R
S
O
Me
1. C3H5Si(CH3)3
2. (NH4)2Ce(NO3)6/H2O
SO2Ph
Fe(CO)4
Me
R
F
H
F
SO2Ph
H2C
BF4
99%ee
Synthesis, see
Angew. Chem. Int. Ed. 1994, 33, 1949
F"
O"
8. Synthesis of (R)-(")-10-Methyltridecan-2-one
by iron-mediated chirality transfer
H
F
H
H
R
F
F
Me
O
O
Me
nBuLi, THF, HMPA
4
Me
Pd/C, H2
SO2Ph
O
4
1. Na(Hg), Na2HPO4, MeOH
2. THF/H2O, HCl, heat
3. O3, DCM, H2O2
H
SO2Ph
Me
O
Br
O
F
H
H
F
Eur. J. Org. Chem. 2014, 928.
N2+
NH2
NO2
NO2
SO2CF2
"
"CO2
radiosyntheses of [18F]p-fluoroaniline and -diazonium ion
NO2
H
proposed mechanism:
Wallach reaction yields [18F]fluoroaneres by acidic decomposition of a triazene precursor
R
O
N
R
R
[18F]BF
R
Baran Lab
Group Meeting
Liebigs Annalen
Isabelle Thomé
99%ee
Me
polymerization
SO2Ph
Fe(CO)4
Me
2
3
1
BF4
Enders, Jandeleit, Liebigs
Ann. 1995, 1173.
d1/a3-butyl synthon
5
Baran Lab
Group Meeting
Liebigs Annalen
Isabelle Thomé
9. Authors with the most publication
11. Oximes
Walter Ried, German, University of Frankfurt, 215 publications
11.1 Tricycles in domino reactions of alkenal oximes
Z
N
N
N
N
R1
N
H
NH2
X
X = Cl, Y = Cl, OPh,
Z = O, S (Y = Cl)
Y
N
or
CN
MeS
CN
N
R1
N
H
Z
HO
S
HO
SH
S
1+2
N
OH
S
N
SH
N
H
R
S
N
3
O
Liebigs Ann. 1990, 207.
MeS
SH
N
2
or
MeS
HO
1
N
N
MeS
SH
O
N
Liebigs Ann. 1995, 1649.
S
6
O
5
4
N
CN
Hans Fischer, German, Nobel Prize for the synthesis of haemin, 158 publications
S H
Ulrich Schöllkopf, German, amino acid synthesis, doctoral student of Wittig, 98 publications
Georg Wittig, German, Nobel Prize, wittig reaction, 94 publications
N
3+1
10. Number of Publications over time
R
O
R
H
S
N
O
H
R = H, CO2Et
S
8
7
400
S
H
intramolecular cycloaddition
350
300
250
N
OH R1
200
150
Series1
X
9, X = NR2
10, X = O
S H
100
50
1901
1906
1911
1916
1921
1926
1931
1936
1941
1947
1952
1957
1962
1967
1972
1977
1982
1987
1992
1997
0
1
H
9 or 10
H
H
N
O
H
R1
X
11, 12
H
S
N
O
H
X
H
R1
13
6
Baran Lab
Group Meeting
Liebigs Annalen
Isabelle Thomé
11.2 Ozonolyses of O-methyloximes
Griesbaum, research from Karlsruhe, origin of Criegee
12. ASAP's from European Journal of Organic Chemistry
12.1 Fluorinated Sulfoximines " Review
(CH2)n
NOCH3
C=NOCH3
CF3
O
R
O
OR
(CH2)n
O O
O O
CF3
C
C
OR
O
CN
carbonyl trapping agents
electron withdrawing !-substituents
activate carbonyl of ester for cycloaddition with carbonyl oxides
CF3
OR
O
O
R = CH2CF3, p-C6H4NO2, Ph
via
NOCH3
O
H
O
NC
Liebigs Ann. 1995, 1571.
O
O
OCH2
O
R
Ph
LiB(C2H5)3H
O
O
O
HN
NH2
R
1) nBuLi, THF, "78 °C
2) NFSI, "78 °C
O NH
Me3OBF4
S
Ph
CHF2 K2CO3
Et3N, DCM
O NMe
S
Ph
CHF2
O
O
CO2R
O
NC
Ph
CN
R
R2
N
HN
NaOH, H2O2
MeOH/H2O
NTs
reflux, 2 h
S
Ph
CH2F
O NH
S
Ph
CH2F
O NH
S
Ph
CH2F
Fluorinated Sulfoximines as fluoroalkylating agents
O O
NaBH3CN
R=
Chloramine-T•3H2O
N-benzyl-N,N-diethylethanaminium chloride
DCM, reflux, 3 d
N
S
J. Org. Chem. 2004, 69, 6470.
R1
n
O
1. MeOTf
2. KPF6 (aq)
S
Ph
N
PF6
CHF2
BF4
O
CF3
base, DCM, rt, 1 h
amine +
NaBH(OAc)3 or
O O
R=
OH
CH2F MeCN, 50 °C, 24 h
O NTBS
S
Ph
CH3
(COCl)2, DMSO
O
O NH
S
Ph
CH2F
PhI=NTs, Cu(OTf)2
Fkuorination of Sulfoximine
O3
O O
O NH
S
Ph
CF3
CF3
PhSCH2F
4, R = tbutyl,
cis : trans > 20:1
3, R = Ph,
cis : trans > 20:1
5, R = p-C6H4OAc, cis : trans > 20:1
6, R = COOEt
cis : trans
5:1
LiBH4
O
S
NaN3
oleum 20%
1,3-dipolar cycloaddtion
of carbonyl oxide with carbonyl
compound gives ozonide
O O
6
O
S
Oxidation of fluorinated sulfilimine
R
11.3 Application of the Griesbaum coozonolysis
N
Ph
Ph
R'
Eur. J. Org. Chem. 2014,
DOI:10.1002/ejoc.201402086
Preparation by imination of sulfoxide
O N
S
Ph
CF3
CF3
CO2R
NC
BF4
base, DCM, rt, 1 h
CN
CF3
R2
R1
n
7
Baran Lab
Group Meeting
Liebigs Annalen
Isabelle Thomé
12.2 One-Pot Transformation of Methylarenes into Aromatic Aldehydes under
Electrophilic difluoromethylation
NNa
N CF2H
Metal-Free Conditions
O NTs
S
Ph
CF2H
Ar
RSNa
R
S
NMO (4 equiv)
CF2H
Ar!CH2X
Method A: DBDMH (0.55 equiv)
AIBN (0.1 equiv)
CH3CN (4.0 mL), reflux
Li
Ar!CH3
Ar
Ts
N
S
O
NMO (4.0 equiv)
mechanism:
Nu!CF2H
Ar!CH3
Ph
:CF2
Nu!
O NTs
S
Ph
CHF2
Nu!
Ar!CHO
CH3CH2CN (10 mL)
rt (2 h) to reflux
" 2nd step"
O NTs
S
Ph
CHF2
NuH
evaporation
Method B: NBS (1.1 equiv), W-h"
CCl4 (1.0 mL), 30 °C
"1st step"
CF2H
proposed difluorocarbene mechanism for the reaction of S-, N- or C-nucleophiles with sulfoximine
Nu!
Ar!CHO
THF (10 mL), reflux
NuH
Nu!CF2D
Ar!CH2Br
O Me
N
O
Nu!CF2!
Wohl-Ziegler reaction
SN2
N Me
O
Me
Ar!HC
H O N
Ar!CHO
!NM•Br
O
D2O
Eur. J. Org. Chem. 2014, DOI: 10.1002/ejoc.201402015
8
Isabelle Thomé
Baran Lab
Group Meeting
Liebigs Annalen
13. The Strychnine Ghost and how Justus von Liebig conjured the ghost
Chemie in unserer Zeit 1990, 24, 1.
9