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1
Synthesis of heterocyclic compounds
Tapio Nevalainen
Drug synthesis II
2010
http://www.scripps.edu/chem/baran/heterocycleshttp://www.scripps.edu/chem/baran/heterocycles/
Heterocyclic compounds
•Heterocycles contain one or more hereroatoms in a ring
Z
X,Y,Z are usually N,O,S
XX X
YY
2
Heterocycles
•Aromatic five‐membered heterocycles
Heterocycles
•Aromatic six‐membered heterocycles
34
34
34
N45
65
65
65
N1
2
3
quinoline
1
N 2
3
isoquinoline
N1
2
N 3
quinazoline
N1
2
3N
quinoxaline
6
78
6
78
6
78
6
78
3
Heterocycles
•Aliphatic heterocycles
Heterocycles•Tautomerism
4
Reactions of heterocyclesFive‐membered heterocycles are good nucleophiles
•Reaction with bromine requires no Lewis acid and leads to substitution at all four free positions.
In Friedel–Crafts reactions the 2the 2‐‐position is more reactive than position is more reactive than the 3the 3‐‐positionpositionpp
Reactions of heterocycles
Vilsmeier reaction (Vilsmeier‐Haack reaction) allows the formylation of heterocyclic and electron‐rich arenes. The formylating agent,
N N
ONH
O
CH3
CH3y g g ,chloroiminium ion, is formed in situ from N,N‐dimethylamide and POCl3
NH
NH1. POCl3 H
2. H2O
5
Reactions of heterocycles
•Aromatic heterocycles undergoes aminoalkylation (Mannich reaction)
•For example N‐methylpyrrole reacts at the 2‐position . Reaction is used in the manufacture of the nonsteroidal anti‐inflammatory compound, tolmetin.compound, tolmetin.
NCH2=O
HNCH3
CH3
H3CN
H3C
N
H3C
CH3
N
CH3
NH3C
CH3
O
H3C
Tolmetin
Mannichreaction
FiveFive‐‐memberedmembered heterocyclesheterocycles act as act as dienesdienes in Dielsin Diels––Alder reactionsAlder reactions
Common building‐blocks for heterocyclic compounds
6
General strategies for heterocycle synthesis
•”1+4” strategy
”1+5” strategy
General General strategiesstrategies for for heterocycleheterocycle synthesissynthesis
”3+3” ”3+3” strategystrategy ”2+3” ”2+3” strategystrategy
ExamplesExamples
H2NX H2N O
HH2N O H2NX
O
O HO
X
O
X = Cl, Br, I
O
O
7
Reactions used in heterocyclic ring synthesis
AldolAldol‐‐typetype reactionsreactions of of enolsenols oror enolateenolate anionsanions withwithelectrophileselectrophiles. .
IImine/enaminemine/enamine formationformation
Reactions used in heterocyclic ring synthesis
•Enamine is tautomeric form of imine. If dialkylamine is used, enamine is formedused, enamine is formed
EnaminesEnamines cancan functionfunction as as enolatesenolates
N
enamine
R2R1
HH N
R2R1
HHO
R3
R3
OH
N
R2R1
H
R3 O
H
- H+
+ H+ H
N
R2R1
H
R3
H
- H2O
H
N
R2R1
H
R3
- H+
H
R4
R4 R4 R4R4
8
Reactions used in heterocyclic ring synthesis
•When the process leads to C‐heteroatom bond formation, then the nucleophile is an appropriate heteroatom.then the nucleophile is an appropriate heteroatom.
Furans
Paal KnorrPaal Knorr
FeistFeist--BenaryBenary
9
Thiophenes PaalPaal KnorrKnorr
•Hinsberg Synthesis of Thiophene Derivatives
GewaldGewald reactionreaction
•Knorr pyrrole synthesis: Condensation of ‐aminoketone and ‐ketoester
PyrrolesPyrroles
PaalPaal--KnorrKnorr PyrrolePyrrole--SynthesisSynthesis: : condensationcondensation amineamine and 1,4and 1,4--ketone ketone
ExampleExample: : SynthesisSynthesis of of atorvastatinatorvastatin ((LipitorLipitor))
10
Pyrroles•Hantzsch pyrrole synthesis: from α‐halomethyl ketones, β‐keto esters and ammonia or amines
A. Hantzsch, Ber. 23, 1474 (1890) Huisgen Pyrrole Synthesis
From Amino acids and alkynes. Example: atorvastatinatorvastatin
1,2‐Azoles
PyrazolesPyrazoles cancan bebe synthesizedsynthesized fromfrom 1,31,3‐‐dicarbonyls dicarbonyls withwith hydrazinehydrazine
Isoxazoles can be made fromfrom 1,31,3--dicarbonyl dicarbonyl compoundscompounds oror ββ--ketoestersketoesters withwith hydroxylaminehydroxylamine
11
1,2‐Azoles Example of pyrazole synthesis: Rimonabant
1,2‐AzolesThe synthesis of sildenafil (Viagra)
RetrosynthesisRetrosynthesis
12
1,2‐AzolesThe synthesis of sildenafil (Viagra)
Bioorg. Med. Chem. Lett. 6, pp. 1819, 1996
1,2‐AzolesThe synthesis of sildenafil (Viagra)
O CH3
O CH3 O CH3
H2NN
NC 3
CH3
H2NCl
O
+pyridine
H2NN
N
CH3
HN
OEt
O
HNN
N3
CH3
N
HNN
N
O CH3
N HN
N
HNN
N
O CH3
N
NaOH
ClSO2OH
OEtEtO
EtO EtO
EtO
Bioorg. Med. Chem. Lett. 6, pp. 1819, 1996
CH3SO O
Cl
NCH3
N
NCH3
CH3SO
O
13
1,2‐Azolessynthesis of isoxazoles
By 1,3By 1,3--cycloaddition cycloaddition fromfrom nitrilenitrile oxidesoxides and and unsaturatedunsaturated compoundscompoundsunsaturatedunsaturated compoundscompounds
NitrileNitrile oxidesoxides cancan bebe preparedprepared byby thethe --eliminationelimination ofof chlorooximeschlorooximes NitrileNitrile oxidesoxides cancan bebe preparedprepared byby the the --eliminationelimination of of chlorooximeschlorooximesoror the the dehydrationdehydration of of nitroalkanesnitroalkanes
1,3‐Azoles
•Oxazoles and thiazoles can be obtained by the Robinson‐Gabriel synthesis from 2‐acylamino‐ketones.
22‐‐acylaminoacylamino‐‐ketones reacts with phosphorus ketones reacts with phosphorus pentasulfide to form pentasulfide to form thiazolesthiazoles
14
1,3‐Azoles
•Oxazoles can be made by Blümlein‐Lewy Synthesis: heating an haloketone with amide
MostMost importantimportant methodmethod for for thiazolesthiazoles is is HantzschHantzsch thiazolethiazole synthesissynthesisfromfrom thioamidesthioamides and and aa‐‐halocarbonylhalocarbonyl compoundscompounds
1,3‐Azoles
ExampleExample: : synthesissynthesis of of nizatidinenizatidine
15
1,3‐Azoles: Synthesis of imidazoles
•From amidines and hydroxy or halocarbonyl compounds
DebusDebus‐‐RadziszewskiRadziszewski imidazoleimidazole synthesissynthesis:: diketonediketoneand ammonia form an diimine, which condenses with and ammonia form an diimine, which condenses with the the aldehydealdehyde
For more imidazole syntheses, look:http://www.scripps.edu/chem/baran/images/grpmtgpdf/Zografos_Feb_04.pdf
1,3‐Azoles: Imidazoles from isocyanides
•The reaction of aldehydes, primary amines and
toluenesulphonylmethyl isocyanide (TOSMIC) yield 1,4,5‐
trisubstituted imidazoles (van Leusen et al. J. Org. Chem. 1977, 42, 1153).
R1NH2 +
R1 N R2
CH3
S
O
ON
R3
N R2
R3
TOSMIC
NTsR3
NR3
S
O
- H2O
Base
CH
O
R2
N TsC
R1
Base
H
http://www.organic-chemistry.org/Highlights/2005/05May.shtm
R1
NR1
N R2+
H3C
SOH
Base
R2
H
16
1,3‐Azoles: Imidazoles from isocyanides
•Substituted tosylmethyl isocyanides (TosMICs) are synthesized from tosylmethyl formamides and p‐methylphenylsulphinic acid.
•Synthesis of the GSK p38 kinase inhibitor
1,3‐Azoles
Synthesis of 2-Butyl-4-chloro-5-hydroxymethyl-1H-imidazole
HN
N
CH3HO
H2N
HN
CH3HO
O
OHNHO
Cl
HNN
NN
N CH3
H2N
HN
CH3
HN
N
CH3HO
HN CH3
HO
HNOH
HO
O
OH+
1. Me3SiCl,2.Chlorosuccinimide3. Zn, AcOH
NH3, MeOH
Cl
N
CH3HO
Cl
Losartan
NHO
Cl
Synthetic Communications (1993), 23(18), 2623-30.
2-Butyl-4-chloro-5-hydroxy-methyl-1H-imidazole
17
Dihydroimidazoles
Clonidine (anti-hypertensive agent)
Oxymetazoline (topical decongestant)
CH3HOCH3HOCH3HOCH3HOH2N
Oxymetazoline
HN
NCH3
3
CH3
CN3
CH3
Cl3
CH3
CH2O/HCl H2N
235°C, N2
KCN
1,4‐Dihydropyridines
• Hantzsch Dihydropyridine (Pyridine) Synthesis
4-Aryl-1,4-dihydropyridines (e.g. nifedipine) are calcium channel p )modulators for the treatment of cardiovascular diseases such as hypertension, cardiac arrhythmias, or angina.
18
Pyridines
•Pyridoxine, vitamin B6, has been synthesised by Guareschi ring synthesis
Glutarimides
TThalidomide
NHN
O
O
O
O
O
O
O
NH2
N
OO
OH
NH2
H2N
O
O
OHAc2O
A i l t thi idA i l t thi id
ThalidomideOOO OO
Tetrahedron Letters (1999), 40(19), 3697-3698.
N
O
O
CO2H
CO2H
2-phthalimido-D-glutaric acid
NHN
O
O
O
O
(R)-Thalidomide
O
NH2HOBt = N-hydroxybenzotriazole
EDCCl = N-(3-dimethylamino)propyl-N'-ethylcarbodiimide hydrochloride
EDCCI NN
N
OH
C NNH3C NH+
CH3
CH3Cl-
HOBt
F3C
AminoglutethimideAminoglutethimide
19
Pyrimidines
• Pinner pyrimidine sythesis: from 1,3-dicarbonyl compounds and amidines
NHH2N
R4NN
R4
R1 R3
NHN
O
R1 R3NH2H2N
O
Instead of amidines, pyrimidines are obtained also by using guanidine, urea and thiourea
R2
O
R3
OR2
R1
R2
NN
NH2
R1 R3
R2
R2
NHN
S
R1 R3
NHH2N
NH2
NH2H2N
S
Pyrimidines
•Example: trimethoprim (bacteriostatic antibiotic)
NN
NH
NH2
NHH2N
NH2guanidine
FGI
OO
OEt
OO
OEtEtO EtO
OMe
NH2
OMe
NH2
OO
H
FGI
OMe
OMe
BrMeO
MeO MeO
MeO
MeO
MeO
MeO
MeO
20
Pyrimidines
•Biginelli Reaction: acid‐catalyzed, reaction between an aldehyde, a,ß‐ketoester and urea constitutes a rapid and facile
synthesis of tetrahydropyrimidones.
•Synthesis of rac‐Monastrol (Mitosis blocker by kinase Eg5 inhibition)
Tetrazoles Carboxylic acid isostereCarboxylic acid isostere
SynthesisSynthesis
SynthesisSynthesis of of LosartanLosartan ((antihypertensiveantihypertensive))
21
Indoles Fischer Indole Synthesis:
The The conversionconversion of of arylaryl hydrazoneshydrazones to to indolesindoles; ; requiresrequires elevatedelevated temperaturestemperaturesand the and the additionaddition of of BrønstedBrønsted oror Lewis Lewis acidsacids
Synthesis of Sumatriptany p
((Daniel Daniel LednicerLednicer:: StrategiesStrategies for for OrganicOrganic DrugDrug SynthesisSynthesis and Design)and Design)
Quinolines
QuinolineQuinoline nucleusnucleus is is usuallyusually formedformed in in oneone of of twotwowaysways
•Skraup‐reaction
MechanismMechanism::OH O
H2CNH2H+
O
OHHOH2C
H N
NH N
[O]
- 2 H2O
HH
NH
O
NH
OH
- H2O
H
22
Quinolines•Doebner‐Miller –reaction: ‐unsaturated ketone or aldehyde can beused instead of glycerol to form a quinoline
ConradConrad‐‐Limpach reactionLimpach reaction: Synthesis of 4: Synthesis of 4‐‐oxyquinolines by oxyquinolines by condensation of esters of betacondensation of esters of beta‐‐keto acids with aromatic amines keto acids with aromatic amines
Quinolines
•Friedländer‐quinoline synthesis
23
Isoquinolines
The general synthetic routes to isoquinolines The general synthetic routes to isoquinolines involve the following skeletal types:involve the following skeletal types:g ypg yp
Isoquinolines
•Bischler‐Napieralski Reaction:
--PhenylethylaminePhenylethylamine is is acylatedacylatedthen then cyclodehydratedcyclodehydrated using using phosphorylphosphoryl chloride, phosphorous chloride, phosphorous pentoxidepentoxide or other or other lewislewis acids. This acids. This gives the gives the dihydroisoquinolinedihydroisoquinoline, , which can be aromatised by which can be aromatised by dehydrogenation with palladium. dehydrogenation with palladium. E.g. in the synthesis of E.g. in the synthesis of papaverinepapaverine
24
Isoquinolines
•Pictet‐Spengler synthesis: β‐Arylethylamine is heated in the presence of an aldehyde and acid.
•A special case of the Mannich reaction.
SynthesisSynthesis of of TadalafilTadalafil
Isoquinolines
•Pomeranz‐FritschReaction NH2
EtO OEt
R
ON
OEt
OEt
R
N
O
R
C Pomeranz Monatsh 14 116 (1893)
+- H2O H3O
+
R
N
R
N
OH
- H2O
C. Pomeranz, Monatsh. 14, 116 (1893)P. Fritsch, Ber. 26, 419 (1893)
SchlittlerSchlittler--MüllerMüllerü eü e
ReactionReaction
25
Quinolones•Retrosynthesis
Synthesis
Thiadiazoles•Synthesis of Timolol (‐blocker)
26
Benzodiazepines The The retrosynthesisretrosynthesis of of diazepamdiazepam
The The synthesissynthesis of of diazepamdiazepam (Sternbach et al, 1961).
Cl
NH
CH3
Cl
N
O
CH3
C
O
ClPh
AlCl3Cl
N
O
CH3
ONaOH, H2O
Cl
NH
O
CH3
OCHCH
Ac2O
ClCl
Cl
N
O
CH3O
ClNH3
Cl N
NO
CH3
Diazepam
Benzodiazepines
Ugi Reaction (Ugi, I., et. al. Angew. Chem. 1959, 71, 386)
Concise synthesis of benzodiazepines with UgiReaction (Hulme, C., et. al. J. Org. Chem. 1998, 63, 8021)