R. Breinbauer Textbooks1-051005 Textbooks of Heterocyclic Chemistry General Textbooks of Organic Chemistry Textbooks of Pharmaceutical Chemistry Textbooks of Heterocyclic Chemistry Reference Books H. Beyer, W. Walter, "Lehrbuch der Organischen Chemie", 23rd ed., S. Hirzel, Stuttgart-Leipzig 1998, 1176 pages. E. Mutschler, G. Geisslinger, H. K. Kroember, M. Schäfer-Korting, "Mutschler-Arzneimittelwirkungen", 8th ed., Wiss. Verlagsgesellschaft, Stuttgart 2001, 1186 pages. "Science of Synthesis", Thieme, Stuttgart 2000-2004, Vol. 9-17. Merck & Co., "The Merck Index", 13th ed., Merck & Co., Inc, Whitehouse Station, NJ 2001, 1818 pages. T. Eicher, S. Hauptmann, "The Chemistry of Heterocycles", Wiley-VCH, Weinheim 2003, 572 pages. T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp. (A very good introductory textbook of heterocyclic chemistry.) (A very well understandable and very well organized introduction into the most important topics of heterocyclic chemistry. Good for learining, less useful for research.) (Although not very helpful when it comes to the description of mechanisms, it is still the only textbook which informs about organic compounds and its properties. Excellent chapters about heterocycles.) (A classic textbook of pharmacology and toxicology which informs well about the structure and properties of drugs.) (A comprehensive reference book of all drugs and most bioactive compounds. The information is very densce. For organic chemists very interesting is a chpater with 446 name reactions.) A. Katritzky (Ed.), "Comprehensive Heterocyclic Chemistry II", 2nd ed., Pergamon, Oxford 1996, Vol. 1-11. (One of the most useful reference works for heterocyclic chemistry. Not textbook but very helpful for research.) (Building on the excellent features of Houben-Weyl this new edition offers very well structured, comprehensive and up-to-date information about heterocyclic compounds. In addition, experimental procedures for the most important reactions are given. This terrific source of reference should be consulted first when studying literature for a research project!) Book Series "Advances in Heterocyclic Chemistry", Elsevier, San Diego 1963-2005, Vol. 1-88. "Progress in Heteroyclic Chemistry", Pergamon, Oxford 1989-2003, Vol. 1-15. (Provides an annual literature update and some review articles) (A series of monographs which contains high quality reviews of very specific topics of heterocyclic chemistry.) J. A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp. (The best and most informative textbook of heterocyclic chemistry. Includes the most recent updates of modern synthetic methods and is very well referenced. This book fulfills all needs both for learning and research.) A. R. Katritzky, A. F. Pozharskii "Handbook of Heterocyclic Chemistry", 2nd ed., Pergamon, Oxford 2000, 734 pp. (A more comprehensive textbook with lots of information but not easy to read. More reference book than text book.) A. Weissberger, E. C. Taylor, P. Wipf (Ed.)"The Chemistry of Heterocyclic Compounds", Wiley-Interscience, London 1970-2004, Vol. 1-62. (Each volume is dedicated to a specific parent class of heterodycles. Very comprehensive in its information content.)
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R. Breinbauer
Textbooks1-051005
Textbooks of Heterocyclic Chemistry
General Textbooks of Organic Chemistry Textbooks of Pharmaceutical Chemistry
Textbooks of Heterocyclic Chemistry
Reference Books
H. Beyer, W. Walter, "Lehrbuch der Organischen Chemie", 23rd ed., S. Hirzel, Stuttgart-Leipzig 1998, 1176 pages.
E. Mutschler, G. Geisslinger, H. K. Kroember, M. Schäfer-Korting, "Mutschler-Arzneimittelwirkungen", 8th ed., Wiss. Verlagsgesellschaft, Stuttgart 2001, 1186 pages.
"Science of Synthesis", Thieme, Stuttgart 2000-2004, Vol. 9-17.
T. Eicher, S. Hauptmann, "The Chemistry of Heterocycles", Wiley-VCH, Weinheim 2003, 572 pages.
T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.
(A very good introductory textbook of heterocyclic chemistry.)
(A very well understandable and very well organized introduction into the most important topics of heterocyclic chemistry. Good for learining, less useful for research.)
(Although not very helpful when it comes to the description of mechanisms, it is still the only textbook which informs about organic compounds and its properties. Excellent chapters about heterocycles.)
(A classic textbook of pharmacology and toxicology which informs well about the structure and properties of drugs.)
(A comprehensive reference book of all drugs and most bioactive compounds. The information is very densce. For organic chemists very interesting is a chpater with 446 name reactions.)
(One of the most useful reference works for heterocyclic chemistry. Not textbook but very helpful for research.)
(Building on the excellent features of Houben-Weyl this new edition offers very well structured, comprehensive and up-to-date information about heterocyclic compounds. In addition, experimental procedures for the most important reactions are given. This terrific source of reference should be consulted first when studying literature for a research project!)
Book Series"Advances in Heterocyclic Chemistry", Elsevier, San Diego 1963-2005, Vol. 1-88.
"Progress in Heteroyclic Chemistry", Pergamon, Oxford 1989-2003, Vol. 1-15.
(Provides an annual literature update and some review articles)
(A series of monographs which contains high quality reviews of very specific topics of heterocyclic chemistry.)
J. A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.
(The best and most informative textbook of heterocyclic chemistry. Includes the most recent updates of modern synthetic methods and is very well referenced. This book fulfills all needs both for learning and research.)
A. R. Katritzky, A. F. Pozharskii "Handbook of Heterocyclic Chemistry", 2nd ed., Pergamon, Oxford 2000, 734 pp.
(A more comprehensive textbook with lots of information but not easy to read. More reference book than text book.)
A. Weissberger, E. C. Taylor, P. Wipf (Ed.)"The Chemistry of Heterocyclic Compounds", Wiley-Interscience, London 1970-2004, Vol. 1-62.
(Each volume is dedicated to a specific parent class of heterodycles. Very comprehensive in its information content.)
R. Breinbauer Monocyclic Hetero Systems with Trivial Names
TrivialHeteroMono-120504
Certain 5- and 6-membered monocyclic hetero systems, both saturated and unsaturated are indexed at trivial names. Presence of a triple bond in addition to the maximum number of noncumulative double bonds is expressed by the subtractive prefix "didehydro".
R. Breinbauer HANTZSCH-WIDMAN - Stems for Monocyclic Hetero Systems
Hantzsch-Widman-120504
No. ofmembers inthe ring
No. ofmembers inthe ring
Unsaturated UnsaturatedSaturated Saturated
Rings Containing Nitrogen Rings Containing No Nitrogen
3
4
5
6
7
8
9
10
3
4
5
6
7
8
9
10
-irine
-ete
-ole
-ine**
-epine
-ocine
-onine
-ecine
-irene
-ete
-ole
-in*
-epin
-ocin
-onin
-ecin
-iridine
-etidine
-olidine
*
*
*
*
*
* Saturation is expressed by detachable prefixes such as "tetrahydro-", "hexahydro", etc. The prefix "perhydro-" is not used.
** When the Hantzsch-Widman prefixes "phospha", "arsa" , or "stiba" are immediately followed by the Hantzsch-Widman stems "-in" or "-ine", they are replaced by the prefixes "phosphor", "arsen" or "stibin", respectively.
-irane
-etane
-olane
-ane**
-epane
-ocane
-onane
-ecane
* When the Hantzsch-Widman prefixes "phospha", "arsa" , or "stiba" are immediately followed by the Hantzsch-Widman stems "-in" or "-ine", they are replaced by the prefixes "phosphor", "arsen" or "stibin", respectively.
** This stem is not used for saturated hetero systems based on the elements Si, Ge, Sn, or Pb. Saturation of these rings is indicated by detachable prefixes such as "tetrahydro-", "hexahydro", etc. when Hantzsch-Widman names are used. Saturation of 6-membered hetero systems based on the elements B or P is denoted by the stem "-inane".
R. Breinbauer Heterocycles as Parent Rings
Heterocycles1-240504
The following list contains heterocycles which can function as parent rings in ascending order:
Electronpoor 6-membered ring heteroaromatics:- Pyridine- Pyridinium Ion- Pyrylium Ion
Cyclopentadienyl-Ion
Electronrich 5-membered ring heteroaromatices- Pyrrol- Furan- Thiophen
DipolmomentBond LengthsSolubilityBoiling Point
Aromaticity:
T. Eicher, S. Hauptmann, "The Chemistry of Heterocycles", Wiley-VCH, Weinheim 2003, 572 pages.
T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.
(Very good introductory chapter about heteroaromaticity.)
(Good chapter about the nomenclature of heterocycles.)
J. A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.
(Good introduction into heteroaromaticity.)
R. Breinbauer
Lecture2-181005
18.-19.10.2005Heterocyclic Chemistry - Week 2
LiteratureAromaticity:
J. A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.
(Contains an illuminating chapter about general reactivity principles. In addition, for each major structure class a chapter describes the general behaviour of this class in the most reaction types.)
Electrophilic Reaction on Imino-N- Basicity of Nitrogen Heterocycles- Nuleophilicity: Steric and Electronic Influences
Electrophilic Reactions- Reactive Behaviour of 5-Ring and 6-Ring Heterocycles- Activation of Pyridines for SEAr (N-Oxides, EDG-groups)
Nucleophilic Substitution- Reactive Behaviour of 6-Ring Heterocycles (Substituents, Benzofused Rings)- Synthesis of Ciprofloxacin
General Principles of Reactions with Heterocycles:
K. Groebke, J. Hunziker, W. Fraser, L. Peng, U. Diederichsen, K. Zimmermann, A. Holzner, C. Leumann, A. Eschenmoser, "Warum Penotse- und nicht Hexose-Nukleinsäuren, Teil V" Helv. Chim. Acta 1995, 81, 375-474.
(In this landmark publication Eschenmoser discusses within a 2 page long footnote why the C=O bond is so much stronger than the C=C and C=N bond, a fact which is of utmost importance for Watson-Crick base pairing.)
Reactive Behaviour of Different AromaticsResonance Energy1H-NMR Data
NucleobasesTautomers- Iminol vs. Amido- Amin vs. Imino- Thion vs. Thiol
R. Breinbauer
Lecture3-251005
25.-26.10.2005Heterocyclic Chemistry - Week 3
Literature
J. A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.
(Contains an illuminating chapter about general reactivity principles. For each major structure class a chapter describes the general behaviour of this class in the most reaction types.)
(Prof. A. G. Myers at Harvard has made his terrific Chem115 handouts accessbile for the public. A must read for every synthetic chemist. For this course in particular the handouts about Directed Lithiation, Suzuki reaction, and Stille reaction are of special relevance.)
O
n-BuLi
O Li
n-BuLiO LiOEt
H OLi
n-BuLiEt2O
n-BuLiTHF
n-BuLiTHP
t-BuLiTHF
t-BuLiEt2O
s-BuLiTHF
s-BuLiEt2O
R. Breinbauer Stability of Lithium-Reagents in Solution
Li-Stabilitäten1-9.10.2001 P. Stanetty, M. D. Mihovilovic, J. Org. Chem. 1997, 62, 1514-1515.
J. J. Fitt, H. W. Gschwend, J. Org. Chem. 1984, 49, 209-210.
-70 °C -40 °C -20 °C 0 °C +20 °C +35 °C
t-BuLiDME
t-BuLi/TMEDATHF
t-BuLi/TMEDAEt2O
s-BuLiDME
s-BuLi/TMEDATHF
s-BuLi/TMEDAEt2O
n-BuLiDME
n-BuLi/TMEDATHF
n-BuLi/TMEDAEt2O
11 min <2 min
5.6 h 42 min
45 min
stable
8.05 h 61 min "complex"
2 h 2 min
stable 28 min
stable 78 min
stable
19.8 h 2.32 h
1.85 h
55.2 h 5.63 h 38 min
17.3 h 1.78 h
10.1 h
21.0 h 4.63 h
153 h 31 h
Half-Lives of BuLi in Etheral Solvents
P. Stanetty, M. D. Mihovilovic, J. Org. Chem. 1997, 62, 1514-1515.
S. C. Honeycutt, J. Organomet. Chem. 1971, 29, 1-5.
P. Stanetty, H. Koller, M. D. Mihovilovic, J. Org. Chem. 1992, 57, 6833.
Organolithium reagents react with etheral solvents under elimination of ethylene:
> -60 °C
+
+
Kinetic Studies of the decomposition of organolithium reagents
R. Breinbauer
Lecture4-021105
2.11.2005Heterocyclic Chemistry - Week 4
Literature
J. A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.
(Contains a short chapter about synthesis concepts.)
Ring Closures Involving Ionic Cyclizations- C-X Bond Formation- C-C Bond Formation- Application: Hantzsch Dihydropyridine Synthesis
Synthon Selection by Analysis of Oxidation Levels of Ring Atoms
Important Ring Closing Reactions- Heterocycles with 1 Heteroatom- Heterocycles with 2 Adjacent Heteroatoms- Heterocycles with 2 Non-Adjacent Heteroatoms
Mechanistic Understanding of Ring Closures- Nucleophilic Attack on Electrophiles (tet, trig, dig) Bürgi-Dunitz - Trajectorie- Baldwin Rules
General Concepts for the Synthesis of Heterocycles:T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.
(Contains a very long and deep discussion about general principles and strategies for the synthesis of heterocycles.)
R. Breinbauer
Lecture5-081105
8.-9.11.2005Heterocyclic Chemistry - Week 5
Literature
J. A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.
(Contains a short chapter about synthesis concepts.)
Mechanistic Understanding of Ring Closures- Baldwin Rules
Intramolecular Substitution at Saturated C-Atom- Rate Dependence on Ring Size- Thorpe-Ingold Effect, gem-Dimethyl Effect (Activation Entropy)- Feist-Benary- Furan Synthesis (5-exo-tet)
Intramolecular Addition at Carbonyl C-Atom- Combes Quinoline Synthesis (6-exo-trig)
Intramolecular Addition across other Double Bonds- Attack at Electrophilic Nitrogen (Synthesis of Quinoxalinoxide)- Hegedus Indole Synthesis (5-exo-trig)- Activation of Double Bonds through Electrophile- Pictet-Spengler Isoquinoline Synthesis (6-endo-trig)
Cyclisation at Triple Bonds- Attack at Nitrile, Alkyne, Isonitrile- TOSMIC-Reagent
Carbene & Nitrene Cyclisation- Addition across Multiple Bonds- Insertion into CH-Bonds
Electrocyclic Reactions- Woodward-Hoffmann-Rules
General Concept for the Synthesis of Heterocycles:T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.
(Contains a very long and deep discussion about general principles and strategies for the synthesis of heterocycles.)
R. Breinbauer 1,3 - Dipoles
1,3-Dipols1-100102
Type 1 Type 2
ba c b
a cb
a c ba c
NN NR
NN NR
NC NR
NC NR
R R
NO N
NO N
NN CR
NN CRR' R'
NC CR
NC CR
R R
R'R'
NO C
NO CR' R'
Azide
Diazoalkane
Nitrous oxide
Nitrile imine
Nitrile ylide
Nitrile oxide
NC NR
NC NR
R R
OO O
OO O
Azomethine imine
Ozone
R''
R'R'
R''
NO N
NO NAzoxy compound R''
R'R'
R''
OO C
OO C
Carbonyl oxideR
R
R
R
NO C
NO CNitrone R''
R'R'
R''
R'' R''
NC CR
NC CR
R RAzomethine ylide R''
R'R'
R''
R'' R''
Out of 12 thinkable 1,3-dipoles containing C, H, N, and O 9 have been used for [3+2]-cycloadditions.
NN
NX
N
O
NO
NN
N
NN
N
N
N
O
NN
O
NNH
NX
NN
N H
NN
NN O
NN
N
NN
NX
NN
O
N
O
NN
NN S
NS
NO
NN
NX
NN
NN
N
NS
NN
NN
N
NO
NN
NR
NN
S
NN
NN
N
N NN
N
NO
NN
O
R. Breinbauer Heterocycles made by 1,3 - Dipolar Cycloaddition
1,3-Dipol-Cycloaddition-091105
Imidazoles Imidazolidines
Pyrazoles Pyrazolines
Pyrazolidines
1,2,3-Triazoles 1,2,3-Triazolines
1,2,4-Triazoles
X = O, S, NR
1,2,4-Triazolines
1,2,4-Triazolidines
Oxazoles Oxazolines Oxazolidines
Isoxazoles Isoazolines Isoxazolidines
1,2,4-Oxadiazoles 1,2,4-Oxadiazolines
Isothiazoles Isothiazolines 1,2,4-Thiadiazoles
A. R. Katritzky, A. F. Pozharskii "Handbook of Heterocyclic Chemistry", 2nd ed., Pergamon, Oxford 2000.
X = O, S, NR
NO2
R
HH
NH
R
OH
Ph N C O
NCS
N
O
S
RO
NCl
R1 HN R2
N
NN
N
R1R2
NCl
R
OH
NH
O
O
RO
HN Ph
h*ν or ∆
Et3N
Et3N
Et3N
R N S
R1 N NR2
R N O
NCl
Ar
H
R1
R2
NAr
R1 R2
NPhS
R
SiMe3
NR
NH
R1
OH
NR1
OHR3
R2
H
h*ν
Et3N
HgO
F
:CH2
CH2N2
R2 R3
O
h*ν
Ar N CR1
R2
NR3
R2 R1
O
R N CH2
R. Breinbauer Synthesis of 1,3-Dipols I
1,3-Dipol-Synthesis1-091105T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995.
Nitrile Oxides
Nitrile Oxides:
Nitrile Imides:
Nitrile Ylides:
Nitrile Imides
Nitrile Imides:
Nitrile Sulfides
110 - 160 °C
Aromatic Nitrile Ylides
Aliphatic Nitrilmethylide
Nitrones:
Nitrones
NN
RH
R1
O
NH
HN
R2
O
HR3
R1
R2
N R3
R1
R2
NR3
TMSTMSOTf
OTf
N
Ar
RO2C CO2R
ArN
H
CO2R
F
h*ν
NN
R
R1
O
NN
R2
H R3
ArN
H
CO2RH
NAr
RO2C
H
CO2R
H
R1
R2
N CH2
R3
NAr
RO2C
H
H
CO2R
Ar
ArS
Ar
O
OH
N2
CH2N2 SN
N
ArAr
Rh2(OAc)4
Ar
Ar SCH2
OAr
O
R. Breinbauer Synthesis of 1,3-Dipols II
1,3-Dipol-Synthesis2-091105T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995.
Azomethinimides
Azomethinimides:
Azomethin-Ylides:
Carbonyl Ylides:
Base
R = -H, -Ar, -COR, -CO2R Pyridinium N-Imides
Azomethin-Ylides
heat
heat
tautomerism
Carbonyl Ylides
Thiocarbonyl Ylides:
-78 °C -40 °C
- N2
Thiocarbonyl Ylides
R. Breinbauer
Lecture6-151105
15.11.2005Heterocyclic Chemistry - Week 6
Literature
Cycloaddition Reactions
1,3-Dipolar Cycladdtions- 1,3-Dipoles: Types and Synthesis- FMO Considerations
General Concept for the Synthesis of Heterocycles:T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.
(Contains a very long and deep discussion about general principles and strategies for the synthesis of heterocycles.)
R. Breinbauer HUISGEN Azide-Alkyne-Coupling
Azide-Alkyne-Coupling1-091105
Review: R. Breinbauer, M. Köhn, ChemBioChem 2003, 4, 1147-1149.
Azide-Alkyne-Coupling:
Modification of CMV-Virus:
Activity Based Enzyme Profiling:
Challenge in Chemical Biology:
A common problem in Chemical Biology is the attachment of a probe molecule to a biopolymer or the ligation of two entities in a living cell. Such a ligation reaction, should have the following features:
- works smoothly in high yield- works under physiological conditions (water, pH 7, RT, air, atmospheric pressure)- uses bioorthogonal functional groups- works without addtional reagents
CuSO4
NN
N R2
R1
HR1
NN
N R2
R1 CuLn
CuLnR1
R2NNN
[CuLn]
ligand (L)reducing agent
+
-+
[N3]60
NH DYE
OH
OHO O
COOH
NH
OH
NH DYE
OH NN
N
Ph
N
NNN N
H
O
DYE60
117 eq
pH 8
phosphate buffer / 5% tBuOH
50 eq CuSO4100 eq 2
100 eq TCEP
16 h / 4 °C
:Ligand:
3
2
N3 (CH2)6 OSO2Ph
H RHODAMINE
Nu
(CH2)6NNN
RHODAMINE
(CH2)6N3
pH 8 phosphate buffer / 5% tBuOH
CuSO4(1 mM )Ligand (2 mM )TCEP (1 mM )
1 h / Rt
(2.5µM)
(20 µM)
3
4
Protein Extract
V. V. Rostovtsef, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem. 2002, 114, 2708-2711.
C. W. Tornoe, C. Christensen, M. Meldal, J. Org. Chem. 2002, 67, 3057-3064.
Cu(I) catalysis allows to run this process at room temperature instead of >130°C typical for the uncatalyzed version:
Q. Wang, T. R. Chan, R. Hilgraf, V. V. Fokin, K. B. Sharpless, M. G. Finn, J. Am. Chem. Soc. 2002, 124, 14397-14402.
A. E. Speers, G. C. Adam, B. F. Cravatt, J. Am. Chem. Soc. 2003, 125, 4686-4687.
R. Breinbauer
Lecture7-221105
22.-23.11.2005Heterocyclic Chemistry - Week 7
Literature
Cycloaddition Reactions
1,3-Dipolar Cycladdtions- 1,3-Dipoles: Types and Synthesis- FMO Considerations- Heterocycles Produced by 1,3-Dipolar Cycloadditions- Huisgen Azide-Alkyne Coupling
Hetero Diels-Alder Reaction- Jacobi-Reaction- Enantioselecitve Hetero-Diels-Alder-Reaction: "Mighty Fist"- Cr-salen catalyst- Synthesis of 1,4-Aminoalcohols- Diels-Alder-Reaction with Inverse Electron Demand
[2+2]-Cycloaddition- Synthesis of β-Lactams- Synthesis of Oxetanes: Paterno-Büchi-Reaction
General Concept for the Synthesis of Heterocycles:T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.
(Contains a very long and deep discussion about general principles and strategies for the synthesis of heterocycles.)
R. Breinbauer, M. Köhn, "Azide-Alkyne-Coupling: A Powerful Ligation Reaction for Bioconjugate Chemistry", ChemBioChem 2003, 4, 1147-1149.
R. Breinbauer
Lecture8-291105
29.-30.11.2005Heterocyclic Chemistry - Week 8
Literature
Epoxides:
Synthesis:- Direct Oxidation (Ethylene, Butadiene)- Preparation of Propyleneoxide- Prileschajew-Oxidation with Peracid- Corey-Chaykovsky-Reaction with Sulphur-Ylides: Synthesis of Fluconazole- Becker-Adler-Oxidation- Sharpless Asymmetric Epoxidation- Jacobsen Asymmetric Epoxidation: Synthesis of Indinavir- Shi Asymmetric Epoxidation: Synthesis of Glabroscol- Jacobsen Hydrolytic Kinetic Resolution (HKR)
Reactions:- Reactions with External Nucleophiles- Payne-Rearrangement- Conversion of Epoxides to Thiiranes
Oxaziridines:
Synthesis:- Photoisomerization of Nitrones- Amination of Carbonyl Compounds- Oxidation of Imines with Peroxyacids
Reactions:- DAVIS- Oxaziridine
Synthesis, Reactivity, and Use of Heterocycles:
3-Ring-Systems: T. Eicher, S. Hauptmann, "The Chemistry of Heterocycles", Wiley-VCH, Weinheim 2003, 572 pages.
T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.
(Descrption of ring systems not very well structured but nevertheless insightful.)
(Excellent chapters about ring systems.)
J. A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.
(The chapters about small rings are not as comprehensive and terrific as for 5- and 6-membered rings, but nevertheless worth reading.)
N
OH
MeO
MeOOMe
Boc
TosMIC
N
O
Ph
O O
N
O
N
O
MeOO
N
O
O
OH
H
O
OTBS
N
O
N
O
MeO
N
O
O
OH
O
TBSO
O
H
O O
N
O
O
MeO
N
O
O
OH
O
OO
O
O
O
AcO
(H2O)
NMeO
MeOOMe
OMeO
NMeO
MeOOMe
Boc
N O
NMeO
MeOOMe
O
(-)-Teubrevin GI. Efremov, L. A. Paquette, J. Am. Chem. Soc. 2000, 122, 9324-9325.
P. A. Jacobi, T. A. Craig, D. G. Walker, B. A. Arrick, R. F. Frechette, J. Am. Chem. Soc. 1984, 106, 5585.B. Liu, A. Padwa, Tetrahedron Lett. 1999, 40, 1645.
R. Breinbauer JACOBI - Reaction
Jacobi1-080301
P. A. Jacobi, D. G. Walker, J. Am. Chem. Soc. 1981, 103, 4611.P. A. Jacobi, D. G. Walker, I. M. A. Odeh, J. Org. Chem. 1981, 46, 2065.
First example for a highly selective intermolecular cycloaddition-retrofragmentation
tetralin, 205 °C
52 % (at 90% conv.)
exclusive regioisomer
P. A. Jacobi, K. Lee, J. Am. Chem. Soc. 1997, 119, 3409-3410.
(rac)-Stemoamide
1) NaBH42) MeOH, H+
3) CH3CCSnBu3, BF3
64 % (3 steps)
diethylbenzene182 °C
53 %
NiCl2, NaBH4
MeOH, -30 °C
73 %
in situepimerization
- MeCN
J. C. Lee, J. K. Cha, J. Am. Chem. Soc. 2001, 123, 3243-3246.Imerubrine
o-dichlorobenzenereflux
90 %
82 %
Examples:
O
N
O R'
RR''
R
R'
R
OR'
ON
Ph SO2Ph
O
O O TBSO
O
O
O
OO
O
Ph
ONPh SO2Ph
O
O O TBSO
O
O
O
OO
O
Ph
OH
R
OR'
OH
HOOH OH
OH
OH OHOH
OH
OH
CO2Et
O
OH
OO
OO
CMe3
H OMe
OMe
CO2Et
O
OH
OH
OO
OO
CMe3
OHOMe
OMe
O
OO
OO
OHO
HO
Me HO H
CMe3
H
R. Breinbauer DAVIS - Oxaziridine
Davis-Oxaziridine1-9.4.2001
F. A. Davis, L. C. Vishwakarma, J. M. Billmers, J. Finn, J. Org. Chem. 1984, 49, 3241-3243.
P. A. Wender, N. F. Badham, S. P. Conway, P. E. Floreancig, T. E. Glass, C. Gränicher, J. B. Houze, J. Jänichen, D. Lee, D. G. Marquess, P. L. McGrane, W. Meng, T. P. Mucciaro, M. Mühlebach, M. G. Natchus, H. Paulsen, D. B. Rawlins, J. Satkofsky, A. J. Shuker, J. C. Sutton, R. E. Taylor, J. Tomooka, J. Am. Chem. Soc. 1997, 119, 2755-2756.
1 eq. KHMDS2 eq Davis oxaziridine
-78 °C to -20 °C / THF
97 % @ 57 % conv.Taxol
F. A. Davis, A. C. Sheppard, Tetrahedron. 1989, 45, 5703.
J. D. White, H. Shin, T.-S. Kim, N. S. Cutshall, J. Am. Chem. Soc. 1997, 119, 2404-2419.
Euonyminol
1) 1.5 eq KHMDSTHF, -78 °C
2) 1.5 eq
THF, -78 °C, 45 min
83 %
M. T. Crimmins, J. M. Pace, P. G. Nantermet, A. S. Kim-Meade, J. B. Thomas, S. H. Watterson, A. S. Wagman, J. Am. Chem. Soc. 2000, 122, 8453-8463.
(rac)-Ginkgolide B
1.5 eq tBuLi0.2 eq Et2NHTHF, -78 °C, 1 h
then 10 eq Davis oxaziridine-78 °C to 0 °C, 1 h
60 %
1) Base
2)
O
OMe
H2N
N NH
O
NH2O
OMeO
OMe
H2N
N NH
ONH2
O
OMe[H]
OH
OHMe
H2N
N NH2
ONH2
O
A
OH
OHMe
H2N
N
ONH2
O
NH2
:DNA
OH
H
ON
O
O
O
NH2OH
NH
FR-900482
OH
N NH
ONH2
O
H
O
OH
NNH2
DNA
DNA
H
O
:DNA
OH
OHMe
H2N
N
ONH2
O
NH2
DNA
OH
OHMe
H2N
N NH
ONH2
O
OH
OHMe
H2N
N NH
ONH2
O
OMe
H A
H-A
H-A
OH
OHMe
H2N
NNH2
DNA
DNA
OH
OHMe
H2N
NNH2
DNA
OH
OHMe
H2N
N NH
ONH2
O
OMeH
OH
OHMe
H2N
N NH
ONH2
O
H
:DNA
A
R. Breinbauer
Mitomycin-021105
Mitomycin C
Mitomycin C
- isolated from Streptomyces caespitosus
Inhibition of Replication
Bioreductive Activation and Biological Action:
- marketed as an anti-cancer drug ("Mutamycin", Bristol-Myers-Squibb)
inside cell
Apoptosis
Compound with similar properties:
+ 2 e , +2 H
- H2O
R1 O
X
R4
OR1
O
R2 R3
EWG
O R2
Na2CO3
O R4
R3R2
R1
O R2
EWGR1
R1 OH
R2 O
OR1
R2 R3
BrPPh3
EtO
NaH
R1
O
R2
OR1 R2
R' R'
N
OR1 R2
R
R' R'
R1
O R2OR1 R2
O
R2
R1 R3
O
R2
R1
R. Breinbauer
Furan-Synthesis1-301105
Synthesis of Furans
FEIST-BENARY - Synthesis:
+
PAAL-KNORR - Synthesis:
ZnCl2 or PPA
from α-Hydroxy ketones
JACOBI - Synthesis:
or conc. H2SO4
X = Br, Cl
(works especially well for intramolecular reactions)
+
- R-CN
via DIELS-ALDER
R' = EWG, TMS, R3Sn
+
from Allenyl ketones
Ag, Pd
from Alkynyl ketones
Pd (0)or
R4
OR1
O
R2 R3
O
R1 R2
O
SRO2C CO2RS
R1 R2
RO2C CO2R
RONa
R2 O
R1
EWG
CN
S8
EtOH
S R4
R3R2
R1
S NH2
EWGR2
R1
S
R1 R2
R1 O
R2
R1 O
R2 HCO2R
R R
R1
R2O
H
Cl
R1
R2O
H
O
RO2C
R1
NaOH
HS EWG
HS EWG
HS EWG
SR R
S EWG
R2
R1
S EWG
OH
R1
S EWG
R2 R1
R. Breinbauer
Thiophen-Synthesis1-301105
Thiophens
HINSBERG - Synthesis:
GEWALD - Synthesis:
+
1) NaOH
2) H3O
3) ∆
+Morpholin
PAAL - Synthesis:
H2S or P4S10
FIESSELMANN - Syntheses:
PiperidinPyridin
DMF/POCl3
VILSMEIER-HAACK
(instead of -CO2R other EWGs can be used as well)
Starting from conjugated diynes:
R = alkyl, aryl
H2S or Na2S
or LAWESSON reagent
:S
H
HO O
HN
HO O
HN
NHOO
H
THIP
HN NS
HN
HN
NN
OS
HN
HN
NO
O
N
S NS
HN
HN
NO
O
N
O
O H
O
N OHH
N
N NN
H
N
N
O
HO
R. Breinbauer
Bioisosterism1-041205
Bioisosterism I
Definitions: GABA agonists:
Bioisosteres are compounds which fit the broadest definition of isosteres and have the same type of biological activity.
Reviews:
G. A. Patani, E. J. LaVoie "Bioisosterism: A Rational Approach in Drug Design", Chem. Rev. 1996, 96, 3147-3176.
P. H. Olesen "The use of bioisosteric groups in lead optimization", Chem. Rev. 1996, 96, 3147-3176.
Isosterism: Replacement of an atom or a group of atoms in an active molecule by another one, presenting a comparable electronic and steric arrangement.
C. G. Wermuth in C. G. Wermuth (Ed.), The Practice of Medicinal Chemistry, Elsevier, London (2003).
C. G. Wermuth in C. G. Wermuth (Ed.), The Practice of Medicinal Chemistry, Elsevier, London (2003), 189-214.
Key parameters of GABAA receptor agonists are an acidic (pKa: ca 4) and a basic (protonated nitrogen) functions with a ca. 5.1 Angsstrom interchange distance.
3H-Diazirines:Synthesis:- Oxidation of Diaziridines
Application:- Photoaffinity Labelling
Aziridines:Polyethylenimine (PEI)Reduced Pyrimidal Inversion of N, Bearing EWG Groups
Synthesis:- Cyclisation of β-Substituted Amines (GABRIEL-Synthesis, WENKER-Synthesis)- Cyloaddition of Nitrenes to Olefins- N2-Extrusion of Triazolines
Reactions:- Ring Opening Reactions with Nucleophiles- Thermal /Photochemical Preparation of 1,3-Dipoles
Application:Chemotherapy: DNA Cross-Linking through N-Lost and Mitomycin
Synthesis, Reactivity, and Use of Heterocycles:
3-Ring-Systems:
T. Eicher, S. Hauptmann, "The Chemistry of Heterocycles", Wiley-VCH, Weinheim 2003, 572 pages.
T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.
(Description of ring systems not very well structured but nevertheless insightful.)
(Excellent chapters about ring systems.)
J. A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.
(The chapters about small rings are not as comprehensive and terrific as for 5- and 6-membered rings, but nevertheless worth reading.)
(A video showing the first minutes of R. B. Woodward's recorded lecture at the Technion in Haifa 1966 about the Synthesis of Cephalosporin C.)
4-Ring-Systems:
Azetidines
Azetidinones (β-Lactams):Synthesis:- Reaction between Imines and Ketenes (STAUDINGER-Reaction)- [2+2]-Cycloaddition between Olefins and Chlorosulfonylisocyanate
Achmatowicz-Rearrangement1-30.5.2001 P. A. Wender, K. D. Rice, M. E. Schnute J. Am. Chem. Soc. 1997, 119, 7897-7898.
E. F. Ullman, J. E. Milks, J. Am. Chem. Soc. 1962, 84, 1315.
Review: P. G. Sammes, Gazz. Chim. Ital. 1986, 116, 109-114.
88 %
Phorbol
1) VO(acac)2tBuOOH, DCM
2) Ac2O,pyr, DMAP
2:1 C6-epimers
P. A. Wender, C. D. Jesudason, H. Nakahira, N. Tamaura, A. L. Tebbe, Y. Ueno, J. Am. Chem. Soc. 1997, 119, 12976-12977.
(+)-Resiniferatoxin
96 % (3 steps)
2) mCPBA, THF, 0 °C3) Ac2O,pyr, DMAP
C6-epimers
1) NaBH4, MeOH, 0 °C
O. Achmatowicz Jr., P. Bukowski, B. Szechner, Z. Zwierzchowska, A. Zamojski, Tetrahedron 1970, 27, 1973-1996.
Br2, MeOH, -35 °Cthen NH3(g)
92 %
2% H2SO4, 90 min, RT
99 %
The pyranulose products allow the generation of 3-oxidopyryllium species, which undergo cycloaddition reactions.
J. B. Hedrickson, J. S. Farina, J. Org. Chem. 1980, 45, 3359.
Y. Lefebvre, Tetrahedron Lett. 1972, 13, 133-136.
mCPBA
65 %
OHN
X
O
OR1
HN R2
N
O
OH
X
O
H
N
OR1
R2
OH
OHN
X
O
MeOOMe
OHN
X
O
MeOOMe
ONHTs
OCH3
NHO
HHN3 O
NO
HHHN
O
iBuO
O
OMe
NHO
HHN3 O OMe
MeO
ONHTs
OCH3
NH
OH
OH
HOOH
NHO
HHHN O OMe
MeO
O
iBuO
NHOTs
O
OCH3
NHO
HHH2N O OMe
MeO
R. Breinbauer Aza - ACHMATOWICZ - Rearrangement
Achmatowicz-Rearrangement2-27.9.2001
M. A. Ciufolini, C. Y. W. Hermann, Q. Dong, T. Shimizu, S. Swaminathan, N. Xi, Synlett 1998, 105-114.Review:
Ox
This direct oxidation route, is only amenable if R2 = SO2R, otherwise 3-pyridinols form by aromatization. Hydrogenation of the double bond before the rearrangement prevents the substrate from aromatization.
M. A. Ciufolini, C. Wood, Tetrahedron Lett. 1986, 27, 5085.
X = CH2, O
Br2, MeOH, Et2O, -40 °Cthen NH3(g)
85 - 95 %
Raney-NiH2, 1500 psi
50 °C95 - 99 %
15 mol-% TfOH2 eq H2OTHF, RT
80 - 91 %
Br2, MeOH, -20 °Cthen NH3
95 %
Raney-NiH2, 1500 psi
50 °C
99 %
iBuOOCClsatd. NaHCO3
0 °C
85 %
10 % TFACHCl3, 0 °C
99 %
M. A. Ciufolini, Q. Dong, J. Chem. Soc., Chem. Commun. 1996, 881.
Y.-M. Xu, W.-S. Zhou, Tetrahedron Lett. 1996, 37, 1461-1462.
Deoxymannojirimycin
+
Ti(OiPr)4, L-(+)-DIPTTBHP, silica gel, CaH2
DCM, RT, 5 d
40 %
(from 2-furaldehyde)
R4
OR1
O
R2 R3
R1 O
X EWG
O R2
AcOHOCH3O OCH3
R1 R4
R2 R3
R1 O
R2 NH2
EWG
O R3
O
R3
R1 O
R2
H2N CO2R
AcOH N R4
R3R2
R1
R
N R4
R3R2
R1
R
N R2
EWG
R
R1
NH
R3
EWG
R2
R1
NH
CO2R
R3
R1
R2
Tos N C
(isocyanoacetate)
RO2C N C
(TosMIC)
N
OR2
R1
O
EWGR3
N NRO2C CO2R
R1 R2
R1 EWG
R1 NO2
R2
HN
OO
R1
R2
NaH
DBU
Zn/AcOH
NH
R1 EWG
NH
R1 R2
RO2C
NH
CO2R
R2
RO2C
R1
NH
R1
EWG
R2
R3
R. Breinbauer
Pyrrole-Synthesis1-061205
Synthesis of Pyrroles I
HANTZSCH - Synthesis:
+
PAAL-KNORR - Synthesis:
NH3 or R-NH2
VAN LEUSEN - Synthesis:
X = Br, Cl
+
BARTON-ZARD - Synthesis:
NH3 or R-NH2
NH3 or R-NH2
KNORR - Synthesis:
+
(can be producedby in-situ-reduction
of α-oximinoketones)
+
from 1,3-Dicarbonyls and Glycine Esters
+
Ring Contraction of Pyridazines:
(from Hetero--Diels-Alder-reaction)
HUISGEN - Synthesis
+
(azlactone)
R1
OR2
NH2
CN
H2N
R1
OR2
X
NH2
HN R2
R1 O
R2 OH
O
R1 O
R2
O R3
H
(cyanamide)
H2NO
H
2 NH3
(isothiocyanate)
R1
OR2
NH2
NC
R3
SN
NH
SR1
R2 R3
N
NH
R3R1
R2
N
NH
R2
R1
N
NH
NH2R1
R2
N
NH
R3R1
R2
R1 N
HR2
Tos N C
(TosMIC) K2CO3 N
NR1
R2
R. Breinbauer
Imidazole-Synthesis1-071205
Synthesis of Imidazoles
from Amidines:
+
MARCKWALD - Synthesis: VAN LEUSEN - Synthesis:
X = Br, Cl, OH
+
BREDERECK - Synthesis:
+
from 1,2-Dicarbonyls:
+
2
+
+
(2-unsubstituted imidazoles)
by Dehydrogenation:
N
NH
R3R1
R2MnO2or CuBr2/Base or BrCCl3/DBUNH
NH
R3R1
R2
(from 1,2- diamines and aldehydes)
NN
SPr
N
OH
N
NNN
PrS
F
OH
F
N
SO2
C
K2CO3
NH2
OH
NN
SPr
H
O
N
NNN
MeO
F
OH
3 N HCl
NN
SPr
OMe
OMe
N
N
CO2Me
Cl
Cl
N
HN
S
F
NH
O
H
SO2
F
N
SO2
C
THF, RT
piperazine
DMF
K2CO3
N
SO2Tol
CS
Cl
N
SO2Tol
C
Cl
F
N
N
H
O
H
H
O
H
NH4OH
HCONH2
H2N CO2Me
TMSCl
F
H
O
O
H
HO
O
O
H
R. Breinbauer TosMIC - Imidazol-Synthesis
TOSMIC-Imidazol-221002
J. Sisko, M. Mellinger, Pure Appl. Chem. 2002, 74, 1349-1357.
J. Sisko, M. Mellinger, P. W. Sheldrake, N. H. Baine, Org. Synth. 2000, 77, 198-205.
Large Scale Preparation of Aryl-substituted TosMIC:
J. Sisko, M. Mellinger, P. W. Sheldrake, N. H. Baine, Tetrahedron Lett. 1996, 37, 8113-8116.
50 °CPhMe/CH3CN
TolSO2H50 °C
93 %
2 eq POCl3
THF, 0 °C
ex Et3N
>500 kg scale
+
DMF, RT
60 % (one pot)
1) OxoneMeOH, H2O
2) NaOH
90 %
p38 Kinase Inhibitor
J. Sisko, M. Mellinger, Pure Appl. Chem. 2002, 74, 1349-1357.
Process by GlaxoSmithKline:
+ +
87 %
(98 % ee)
+ +
78 %
J. Sisko, M. Mellinger, Pure Appl. Chem. 2002, 74, 1349-1357.
50 % aqueous
R1
HN
R2
O OR3
N2
R1 O
R2
CR3
N
(α-(acylimino)ketones)
R1O
R2
O OR3
NH3
R1 O
XR2
NH2
O R3
Rh2(OAc)4
N
O R3R1
R2
N
O R3R1
R2
N
O R3R1
R2
O
N R3R1
R2
R1 O
H
R1 O
ClLi N C
R2
Tos N C
(TosMIC)
(α-metallated isonitrile
K2CO3
N
OR1
R2
N
OR1
R. Breinbauer
Oxazole-Synthesis1-071205
Synthesis of Oxazoles
from α-(Acyloxy)ketones:
+
ROBINSON-GABRIEL - Synthesis: VAN LEUSEN - Synthesis:
X = Br, Cl, OH
+
+
H2SO4 or PPA
BLÜMLEIN-LEWY - Synthesis:
SCHÖLLKOPF - Synthesis:
+
from α-Diazocarbonyl Compounds:
(via carbene intermediate)
by Dehydrogenation:
N
O R3R1
R2MnO2or CuBr2/Base or BrCCl3/DBUNH
O R3R1
R2
(from β-aminoalcohols and aldehydes)
P. Wipf, S. Lim, J. Am. Chem. Soc. 1995, 117, 558.
R. Breinbauer WIPF - Oxazole Synthesis
Wipf-Oxazol-101205
NH
O
NHCO2Me
OH
CO2Me
N
NHCO2Me
O
CO2Me
N
NHCO2Me
O
OH
K. R. Hornberger, C. L. Hamblett, J. L. Leighton, J. Am. Chem. Soc. 2000, 122, 12894-12895.
DAST, DCM, -20 °CBrCCl3, DBU, 0 °C
64 %
HN O
MeO2C
N3
OH
DCM
N O
MeO2C
N3
OO
N O
NH
O
MeO
CN
OHOMe
NMe2OH
OH OH
O
OH
POHO
HO
(+)-Calyculin A
A. B. Smith III, G. K. Friestad, J. Barbosa, E. Bertounesque, K. G. Hall, M. Iwashima, Y. Qiu, B. A. Salvatore, P. G. Spoors, J. J.-W. Duan, J. Am. Chem. Soc. 1999, 121, 10478-10486.
20
25
1) MeO2CNSO2NEt3THF, 55 °C
84 %
2) CuBr2, HMTA, DBU
80 %
In the Smith Calyculin Synthesis the Wipf method proved out to be superior to other methods, which all led to empimerization at the α-methyl group:
A. J. Phillips, Y. Uto, P. Wipf, M. J. Reno, D. R. Williams, Organic Lett. 2000, 2, 1165-1168.
Application:
One-Pot method:
O
PMBO
O
HOOTBDPS
H2N
N
O Me
O
O
OH
BocMe
OTESMe
O
PMBO
OO
OTBDPS
N
N
O Me
OBocMe
OTESMe
Phorboxazole A
C. J. Forsyth, F. Ahmed, R. D. Cink, C. S. Lee, J. Am. Chem. Soc. 1998, 120, 5597-5598.
+
1) EDC*MeI, HOBt, DCM87 %
2) Dess-Martin-periodinane3) a) (BrCCl2)2, Ph3P, DCM
Thiophens:Synthesis:- Mechanism of GEWALD-Synthesis
Application:-Bioisosterism
Pyrroles:Synthesis:
Application:- Neurotoxicity of n-Hexanes- Wound Healing of Caulerpa taxifolia
Synthesis, Reactivity, and Use of Heterocycles:
5-Ring-Systems: T. Eicher, S. Hauptmann, "The Chemistry of Heterocycles", Wiley-VCH, Weinheim 2003, 572 pages.
T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.
(Descrption of ring systems not very well structured but nevertheless insightful.)
(Excellent chapters about ring systems.)
J. A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.
(The chapters about small rings are not as comprehensive and terrific as for 5- and 6-membered rings, but nevertheless worth reading.)
G. Pohnert, "Wundverschlüsse durch Biopolymerisation", Nachrichten Chemie 2005, Heft 6, 638ff.
(Descrption of the green algae Caulerpa taxifolia and how it spread through the mediterrean sea.)
N
HN
O
Cl
NH
N
NH3C NH
O S
FN
NH O
ON
CF3
CF3CH3
N
N
N
H3C O
NH
O HN
O
F
F
N
NO
HN
N
ON
F3C
HN
NN N
NR
N
NR
R
CH3 OH OCH3 Cl HN CH3 NH2
OH
O
F S OOH CH3
O
ONO2
R. Breinbauer
PrivilegedStructures1-111202
Privileged Structures
Definition: Privileged Structures:
Privileged structures are defined as a single molecular framework able to provide ligands for diverse protein receptors.
B. E. Evans, K. E. Rittle, M. G. Bock, R. M. DiPrado, R. M. Freidinger, W. L. Whitter, G. F. Lundell, D. F. Veber, P. S. Anderson, R. S. L. Chang, V. J. Lotti, D. J. Cerino, T. B. Chen, P. J. Kling, K. A. Kunkel, J. P. Springer, J. Hirshfield, J. Med. Chem. 1988, 31, 2235-2246.
Benzodiazepines:
"...judicious modification of such structures could be a viable alternative in the search for new receptor agonists and antagonists"
Synthesis:- from 1,3-Dicarbonyl Compounds- by [3+2]-Cycloaddition- Isothiazoles by Oxidation of β-Iminothiones
Synthesis, Reactivity, and Use of Heterocycles:5-Ring-Systems:
T. Eicher, S. Hauptmann, "The Chemistry of Heterocycles", Wiley-VCH, Weinheim 2003, 572 pages.
T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.
(Description of ring systems not very well structured but nevertheless insightful.)
(Excellent chapters about ring systems.)
J. A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.
(The chapters about small rings are not as comprehensive and terrific as for 5- and 6-membered rings, but nevertheless worth reading.)
J. W. Yang, M. H. Fonseca, Ni. Vignola, B. List, "Metal-Free, Organocatalytic Asymmetric Transfer Hydrogenation of α,β-Unsaturated Aldehydes", Angew. Chem. 2005, 117, 110-112.
O
BrMe
OTBS
Me
Me
MeO
Me
Me
O
O
CO2Me
O
Me
Me
OHMeOH
OPMB
OO
H
O
MeO
Me
Me
O
O
CO2Me
O
Me
Me
OMeMe
OXp
OTES
OPMB
NO
O
O2NMe
OH
Me
Me
MeO
Me
Me
O
O
CO2MeMe
Me
OHO
OH
HMe
OH
OHO
O
O2NMe
O
Me
Me
O
O
CO2Me
O
Me
Me
OMeMe
OXp
OTES
OPMB
D. A. Evans, D. H. B. Ripin, D. P. Halstead, K. R. Campos, J. Am. Chem. Soc. 1999, 121, 6816-6826.
R. Breinbauer Isoxazol - Coupling
Isoxazol-coupling1-15.3.2001
N. Kornblum, H. E. Ungnade, Org. Synth. 1963, Coll Vol. IV, 724-727.
Isoxazoles are a synthon for 1,3-diketones.
N. Kornblum, B. Taub, H. E. Ungnade, J. Am. Chem. Soc. 1954, 76, 3209-3211.
Preparation of nitro compunds from bromides
1) AgNO2, Et2O
2) HF.pyr, pyr/THF
78 %
85 %
Macrolactonization via intramolecular [3+2] cycloaddition:
S. S. Ko, P. N. Confalone, Tetrahedron 1985, 41, 3511-3518.
3-ClPhNCO, DIPEAbenzene, 90 °C
20 h addition of substrate
68 %
1) pH 10 buffer95 %
2) DDQ, H2O, DCM77 %
(+)-Miyakolide
T. Mukaiyama, T. Hoshino, J. Am. Chem. Soc. 1960, 82, 5339-5342.
Preparation of Nitrile Oxides from Nitroalkanes:
O
MeO
Me
Me
O
O
CO2Me
O
Me
Me
OHMe
OXp
OTES
OPMB
NO
A: Mo(CO)6
B:Me
O
Me
Me
O
O
CO2Me
O
Me
Me
OHMeOH
OPMB
NO
HH
D. A. Evans, D. H. B. Ripin, D. P. Halstead, K. R. Campos, J. Am. Chem. Soc. 1999, 121, 6816-6826.
H2O, MeCN, 70 °C69 %
orW-2 Raney-Ni
1 atm H2EtOAc/AcOH
74 %
R3
R1
R1
NO2
CH3
NH
NH2
NH
CH3O
R2
N
R3O
R3
R2
NMe2MeO
MeO
R1
R2
O
H
H
R1
NaNH2
NO2
NMe2
R1
R3
NR3
R2
R3
NH
R2
R1
NH
R2
R1
NH
R1
R1
O
O
NO2
CH3
NH
I
R
O
OR2R2O
O
CO2RR1
NH2
R1NO2
R3
R2
R1
DMF
NO2
CO2R2
O
MgBr
R1 R1
R1
NH
R1HO
CO2R
R1
NHR1
NR2
R
R3
NH
CO2R2
R. Breinbauer
Indole-Synthesis1-110106
Synthesis of Indoles
FISCHER - Indole Synthesis:
+
or Lewis-acid
works best if R3 = EDG
BATCHO-LEIMGRUBER - Synthesis:
H2/Pd
MADELUNG - Synthesis:
250 °C
due to harsh reaction conditions is limited to R2 = alkyl
BISCHLER - Synthesis:
REISSERT - Synthesis:
H2/Pd
NENITZESCU - Synthesis:
+
LAROCK - Synthesis:
+
cat. Pd(OAc)2Base
BARTOLI - Synthesis:
3 eq
ortho-substituted nitrobenzenes
MeO NO2
NO2MeO
Me
R4
R5NO2
NO2R3R2
R1
AcOH
AcOH
PhCH2ONO2
NO2PhCH2O AcOH
NO2
NO2O
O
AcOH
NH
O
O
R4
R5NH
R3R2
R1
MeO NH
MeOMe
PhCH2ONH
PhCH2O
OMeOMe
NO2
NO2
MeOOMe
NH
N
N
MeOMeMeO
OO
H
R. Breinbauer
Borchardt-Indole-Synthesis1-2.6.2001
BORCHARDT - Indole -Synthesis
F. He, Y. Bo, J. D. Altom, E. J. Corey, J. Am. Chem. Soc. 1999, 121, 6771-6772.
Aspidophytine
excess Fe-powdersilica gel
AcOH/toluene
71 %
reflux, 15 min
A. K. Sinhababu, R. T. Borchardt, J. Org. Chem. 1983, 48, 3347.
The reductive cyclization of 2,β-dinitrostyrenes is the most convenient method for the synthesis of N-unsubstituted alkoxyindoles. The usually moderate yields (30-50 %) can be increased by the addition of silica following the modificaton by Borchardt.
excess Fe-powdersilica gel
reflux, 1 h
benzene/cyclohexaneor
toluene
Examples:
excess Fe-powdersilica gel
reflux, 1 hbenzene/cyclohexane = 1:3
93 %
excess Fe-powdersilica gel
reflux, 1 htoluene
excess Fe-powdersilica gel
reflux, 1 hbenzene/cyclohexane = 1:3
91 %
75 %
R
NH
R'S
R
NH
R'S
R
NH
R'SSnBu3
R
N R'
.SnBu3
NH
Br
OTHP
NH
OAc
NH
OTHP
NTBS
O
NH
R'
R
NH
R'
R
NH
R'
RH
SSnBu3
NH
OH
R. Breinbauer FUKUYAMA - Synthesis of 2,3-disubstituted Indoles
Fukuyama-Indol-Synthesis1-100703
H. Tokuyama, T. Yamashita, M. T. Reding, Y. Kaburagi, T. Fukuyama, J. Am. Chem. Soc. 1999, 121, 3791-3792.
S. Kobayashi, G. Peng, T. Fukuyama, Tetrahedron Lett. 1999, 40, 1519-1522.
Mechanism:
- HSSnBu3
1-2 eq Bu3SnH
0.1 eq Et3B
toluene, RT, 5-40 min
Examples:
81 % yield 89 % yield 71 % yield93 % yield
Alternative method starting from phenyl isonitriles:
R2
HO NH3
NH
EWG EWG
R1 R1
R2 H
N
EWG EWG
R1 R1
R2
NH2R1
R2
O R4
R3
EWG
OR1
EWG
R1O
EWG
OR1
R2EWG
R3H2N NH
EWG EWG
R1 R3
R2 H
N
EWG EWG
R1 R3
R2
R1 R2O O NR1 R2
HH2NOH
NOH
R1 R2
H
R1
R1 R2O O
NH3
NR1 R2
O
R3
OR1
R2
R4H2N
EWG
N
EWG
R1 R4
R3
R2
R1
NNMe2
EWG
EWG
NN
N
R2
R1
R4N
R3
HN
R1 O
N
R3O
R2 NH4OAc
AcOH
N R1
NR1 R3
R2
NR1
R2R3
R4
N
R2 R4
R1
R3
N
R1 EWG
EWG
R. Breinbauer
Pyridine-Synthesis1-110106
Synthesis of Pyridines
HANTZSCH - Synthesis:
Synthesis via Cycloaddition:
Synthesis via 1,5-Dicarbonyl Compounds:
BÖNNEMANN - Synthesis:
+ +oxidation
+oxidation
CpCo(I)-complex
Synthesis via 1,3-Dicarbonyl Compounds:
+
BOHLMANN-RAHTZ - Synthesis:
+
+
+ - N2-
- HNMe2
KRÖHNKE - Reaction:
+
NH2
O
R2
O
R3
R4
NH
O
O
R1
O
R2
R3KOH
NH2
O
COO
H
R1
NH2
R1
R2
O
R3O NH
R3
OR2
R1H
R1
R1
R1
N
R3
R4
R2
N
R2
R3
CO2H
N R3
R2
R1
R1
NH2
NH
O
R2
O
R3
R2
R4
DMF
POCl3R1
R1
NH
O
R2
NCl
NH
R4
OR2
R3 H
As2O5
R1
R1
N
R2
R3
R4
N
R2
Cl
R. Breinbauer
Quinoline-Synthesis1-110106
Synthesis of Quinolines
PFITZINGER - Synthesis:
FRIEDLÄNDER - Synthesis:
COMBES - Synthesis:
+- H2O
1)
2)
isatin isatic acid
+
DOEBNER-MILLER - Synthesis:
+
(oxidant)
SKRAUP - Synthesis: involves in situ-preparation of acrolein from glycerin/H2SO4
METH-COHN - Synthesis:
(is best synthesis for quinolines unsubstituted on the hetero-ring)