DIAZINES

1. Typical representatives and symbols 2. Structure

2.1. Basicity 2.2. Aromaticity 2.3. NMR data 2.4. Prototropic tautomerism

3. Syntheses
3.1. Two aza-atoms in positions 1, 2
3.1.1. Monocyclic rings: pyridazines 3.1.2. Fused rings: phthalazines 3.1.3. Fused rings: cinnolines
a) From o-substituted diazonium salts b) Friedel & Crafts methodology c) Intramolecular SN2Ar nucleophilic substitution

3.2. Two aza-atoms in positions 1, 3

3.2.1. Monocyclic rings: pyrimidines 3.2.2. Fused rings: quinazolines

3.3. Two aza-atoms in positions 1, 4

3.3.1. Monocyclic rings: pyrazines 3.3.2. Fused rings: quinoxalines

4. Reactivity
4.1. Electrophilic substitution
4.1.1. At ring nitrogen 4.1.2. At ring carbon

4.2. Nucleophilic substitution

4.2.1. Hydride ion as leaving group 4.2.2. Halogen as leaving group

4.3. Advanced functionalisation via metallation

Modifications (improvements, additions, corrections, up to dates etc.) are subjected to no notice.

Mircea Darabantu MASTER

IX D-1

DIAZINES
1. Typical representatives and symbols:
4 5 3 1 2 5 6 1 4 3N 2 5 6

N
4 1

3 2

N N symbol
5 6 4a 4

N pyrimidine
4a 4 5 4 4a

N pyrazi
N N
1 5 3 2 8a 8 6 7 8 8a 1 4a 4 3

pyridazine
5 3 6 7 8 8a

N N symbol
7 8 8a

N N
1

6 7

N
1

N2

N N2

cinnoline

quinazoline

quinoxaline

phthalazine

benzo[c]pyridazine benzo[d]pyrimidine benzo[b]pyrazine benzo[d]pyridazine

2. Structure:
2.1. Basicity:
N N pKb
-

N N 12.77 N N N 8.7

13.49

10.76

additional pyridine-like nitrogen strongly decreases basicity (protonation is less tolerated by the previous N-atom); more stabilization of the protonated form is plausible for pyridazine in order to avoid adjacent lone-pair vs. lone pair repulsion in the neutral form. they all are -deficient systems as indicated by the Atomic -charges:

2.2. Aromaticity:
-

Total - deficiency +0.050 -0.004 -0.004 +0.077 +0.077 N -0.195 +0.077 -0.124 N +0.047 -0.124 N +0.047 +0.077 -0.147 N +0.074 +0.074 N -0.147 +0.126 N -0.199 +0.126 +0.155 N -0.199 -0.009

+0.074 +0.074

+0.204
i) ii) iii)

+0.248

+0.296

+0.407

The order is different if relative local -deficiency (the largest positive charge on any carbon atom in a molecule) is considered. The -acceptor action of heteroatoms in azines is most effective when they are meta-position each other (pyrimidine). The ortho-para disposition subjects each carbon atom to two contradicroty forces: a) the strong electron acceptor influence of an ortho-para-nitrogen; b) the weak electron donor influence of a meta-nitrogen.

Mircea Darabantu MASTER Important notes:

IX D-2

1. The resonance energy (ER) decreases as the number of pyridine like nitrogen increases, according to all methods used to evaluate them (calculation, estimation). Benzene > Pyridine > Pyrimidine > Pyrazine > Pyridazine ER (kj/mol) 151 142 138 134 109

2. As the number of pyridine like nitrogen atoms increases, the heterocycle becomes more -acceptor and less -donor as revealed by the HMO Energies of Frontier (both decreasing -values)

N N N - 0.527 + 0.703 N N N

N N

N N N

ELUMO (<0 ) EHOMO (<0 )

i)

- 0.576 + 0.646

- 0.841 - 0.686 + 1.000 +1.000

- 0.871 - 0.727 + 1.077 + 1.101

- 0.781 + 1.281

ii) iii)

electrophilic substitution become successively more difficult as EHOMO decreases both at nitrogen (weakened basicity) and on ring carbon atoms: no reaction at all without activating substituents. nucleophilic substitution becomes successively easier as ELUMO decreases successive introduction of nitrogen atoms causes a gradual reduction in aromatic stabilisation in both nucleophilic and electrophilic substitution

2.3. NMR data:

- they are in agreement with the Atomic -charges:

1H NMR +0.050 -0.004 -0.004 +0.077 +0.077 N -0.195 7.55 7.16 8.52 N 7.16 8.52 125.6 149.5

13C NMR 138.7 125.6 N 149.5

+0.077 -0.124 N +0.047 -0.124 N +0.047 +0.077 -0.147 N +0.074 N -0.147 +0.074

9.17 7.52 N N 7.52 9.17

153.0 130.3 N 130.3 N 153.0

+0.074 +0.074

8.60 8.60

N N

8.60 8.60

145.9 145.9

N N

145.9 145.9

+0.126 -0.009 N -0.199 +0.126 +0.155 N -0.199

8.78 7.36 N 8.78 N 9.26

156.9 121.9 N 156.9 N 158.4

Mircea Darabantu MASTER -

IX D-3

2.4. Prototropic tautomerism:

relevance is found in hydroxy-, mercapto- and amino-derivatives (in aq. solution, at r.t.):

XH N N HN N

X N HN

X = O : dominant B (minor A) X = S : exclusive B X = NH : exclusive A

A
N N XH N HN

B
X

C
X X = O : dominant B (minor A) X = S : exclusive B X = NH : major A (minor B)

N HN

A
XH N N N X

+
X

NH N H

X = O : dominant B vs. C X = S : exclusive B X = NH : A major (minor B+C)

A
N N XH

B
NH N X N H

C
N X X = O : exclusive B identical with C X = S : exclusive B identical with C X = NH : A major (minor B+C)

A
N N XH

B
N N H X

C
H N+ N X = O : exclusive B X = S : exclusive B - X = NH : exclusive A X

Notes: i) for amino derivatives, aromatic tautomeric forms are favored ii) tautomerism involving proton transfer to a ring carbon atom is not known if but one XH group is present iii) tautomerism involving proton transfer to a ring carbon atom is important if more than two XH group are present

OH N HO N OH O

O NH N H O

2,4,6-trihydroxypyrimidine

pyrimidyn "trione Barbituric acid

Mircea Darabantu MASTER

IX D-4

3. Synthesis:
3.1. Two aza-atoms in positions 1,2
3.1.1. Monocyclic rings: pyridazines
- retrosynthesis: simple hydrolytic disconnection N-1-C-6 and N-2-C-3

F1 R1
4 5 6

F1 N N2
1

R1 R2

R2

O O
4

NH2 F1, F2: functionality (optional H NH2 R1, R2: H, groups

hydrazine

F2

F2
2,3-non saturated 1,4-dicarbonyl compound

- C-1, -4 functionality as H, OH in the starting compound is crucial for the functionality of the subsequent pyridazine system:

F1 R1 R2 F2
i) F , F functionality as H:
1 2

F1 O NH2 O NH2 R1 R2 F2 N N

_
Br2/MeOH

H _
MeOH H2O / H
+

_
- HBr

_ O O_ H

1,4-addition

_Br

Br _

CH3O

OCH3

allylic positions

hydrazone of maleic dialdehyde: R1 = R2 = F1 = F2 = H

1 2

N N

ii) F , F functionality as OH:

O
N2H4

OH N N OH
3,6-dihydroxypyrazine

O NH N OH

O NH NH O
hydrazide of maleic acid: R1 = R2 = H F1 = F2 = OH

O
-H2O

Mircea Darabantu MASTER

1 2

IX D-5

iii) F , F functionality as OH and group:

OEt H3C O H3C OH O O CH3

iv) F , F functionality as groups:
1 2

OH
N2H4 -H2O

O H3C
4 5 6 3

H 3C

O O CH3

H3C

N N CH3

NH 2 N1 CH3

2H-4,6-dimethyl-pyridazine-3-one

Ph Ph O H3C Ph
v) F , F functionality as amino groups:
1 2

Ph O O Ph O O Ph
N2H4 -H2O

Ph Ph N N Ph

NH N NH2 NH2 N
maleic dinitrile

NH2 N N NH2

NH NH NH

Notes: - the appropriate cis (Z) disposal of the 1,4-dicarbonyl-2,3-non saturated precursor is ensured (and originates) by the stereochemistry of the (masked) maleic anhydride - other appropriate precursors of are not E-Z stereoisomers

3.1.2. Fused rings: phthalazines

- the appropriate disposal of the carbonyl groups is ensured by their ortho linkage at the benzene ring: (masked) maleic anhydride (masked) phthalic

pyridazines anhydride phthalazines

OH O NH NH O
phthalhydrazide 2,3-dihydrophthalazine-1,4-dione

O
N2H4

O O

N N OH

1,4-dihydroxyphthalazine

Mircea Darabantu MASTER

IX D-6

3.1.3. Fused rings: cinnolines

A) From o-substituted

diazonium salts: retrosynthetic disconnection as N-2-C-3

R
5 6 7 8 4 3

R _ N N
+

nucleophilic carbon

N
1

N2

Example 1: methodology based on diarylmethane motif to stabilize carbocations of type benzyl

+
CH2 + N N X N N

H H X
-HX

Example 2: methodology based on nucleophilicity of the termini carbon in a phenylacetylene fragment and synthetic equivalents

C N

CH N
+

LG
-H2O

OH

LG

N
-

O CH3 + N N X

OH CH2 + N X
-

OH

- HX

H H N N

N H

4-cinnolone

B) Friedel-Crafts

methodology: retrosynthetic disconnection as C-4-C-4a

R
5 6 7 8 8a 4a 4 3

LG

R N

should be of interest this bond should be preliminarily formed

N
1

N2

Mircea Darabantu MASTER

IX D-7

HOOC O

COOH ClOC R
SOCl2

mesoxalic acid

COCl N

R N H

N H NH2 O COOEt

COOH COOH

R N H

3-ethoxycarbonyl-4-cinnolone

N H

C) Intramolecular
R1
5 6 7 8 4a 8a 4 3

SN2Ar nucleophilic substitution: retrosynthetic disconnection as C-8a-N-1

typical good LG in SEAr replacement

R1 R2 N LG1 R2 NH

R1 R2 N NH

LG2 LG1
typical good LG in SN2Ar replacement

N
1

N2

hydrazone as source: i) electrophile ii) nucleophile

HOOC O

COOH

HOOC
Ar-NH-NH2

COOH N NHAr

ClOC
SOCl2

COCl N

i) C6H5F

ketomalonic acid

NHAr ii) EtOH

O COOEt F N NHAr
K2CO3 methyl-ethylketone

O COOEt N Ar N

Mircea Darabantu MASTER

IX D-8

3.2. Two aza-atoms in positions 1,3

3.2.1. Monocyclic rings: pyrimidines
- general retrosynthesis: double hydrolytic disconnection as N-3-C-4 and N-1-C-6 is the most useful.

R2 R3 R2 R3 R4
5 6 4

OH O NH H2N R1

R1: H, Me, Ph, OMe,OH, SMe, SH, R2, R4:H, Me, Ph, OEt R3: H, Me, Ph, Br, NO, NO2

NH2

R4 N3

N
1

R1 R3 R4

R2 precursor of type amidine O

precursor of type 1,3-diketone

in bold: groups which afford tautomeric (thi)one- or imine forms general conditions: basic (NaOH, EtONa) to activate amidine precursor acidic conditions are also used to activate 1,3-diketone precursor.

Ph O H 3C O CH3 O H 3C O NH2 HN O CH3 O O NH2 HN O CH3 NH2 HCl / EtOH / heat H 2N S

HCl / EtOH / heat

Ph NH2 HCl / EtOH / heat H 2N O H 3C N H CH3 N H 3C

1H-1,4,6-trimethyl-pyrimidine-2-one

1H-6-methyl-4-phenyl-pyrimidine-2-one

N O CH3 N

HCl / EtOH / heat

1H-1-methyl-pyrimidine-2-one

N O CH3 N N H

O O

1H-pyrimidine-2-thione

S
+ +

Obs.: acid catalysis is used to activate >C=O of type carbonyl as >C=OH

>C -OH

Mircea Darabantu MASTER

IX D-9
O
EtONa / EtOH / heat

OEt O H 3C O OEt O EtO O H 2N NH2 EtONa / EtOH / heat NH O HN NH2

N H 3C N H OH N N H

1H-2-t-butyl-6-methyl-pyrimidine-4-one

t-Bu

t-Bu O
5 4

N3
2

NH2

N1 H

NH2

1H,5H-2-amino-pyrimidine-4,6-dione

OEt O C N H2N NH2 EtONa / EtOH / heat NH H 2N

5 4

O
6

O NH
2 1 5 4 1

N3
2

N
3

NH2

H2N

N H

NH2

1H-2,4-diamino-pyrimidine-6-one 1H-2,6-diamino-pyrimidine-4-on

Obs.: in basic conditions NH2 is activated against carbonyl groups of type ester and nitrile. Equilibrium might occur. EtOH should be continuously removed from the reaction mixture.

Synthesis via the A N R O R C mechanism

Definition: the ANRORC (Addition of Nucleophile, Ring Opening, Ring Closure) reaction involves the initial
addition of a nucleophile to a ring carbon not carrying a halogen atom, followed by electrocyclic ring opening when the halogen atom is removed.

NaNH2 / NH3 (l)

N H2N N CH3

Br H NH2 Br N N Br

Br

Br

NH H
-Br- H+

NH CH Br N_ Br

N H
-

_N

Br

N C CH

N
+ NH3

N Br N

SN2Ar

N H2N N CH3

Br
-

N C CH2

Br

CH2

-NH2-

CH3

the method is general and of synthetic interest halogen should be a good LG. note conditions for the nucleophilic displacement of the second bromine atom

Mircea Darabantu MASTER

IX D-10

3.2.2. Fused rings: quinazolines

retrosynthetic disconnection: hydrolytic (N1-C-2 and N-3-C-4) because of the availability of the odisubstituted benzene precursor
R1: alkyl o-amino-alkyl-phenyl-ketone R1: OEt anthranilic acid ethyl ester

R1
5 6 7 8a 8 4a 4

R1 N
3

O NH2 O

NH2 R2

N
1

R2

simple amide

R1 R1 O NH2 H2N R2 X
heat R1, R2 : H, alkyl

N N O R2

- H2O - H2X

R1: OEt; R2 : H, alkyl - EtOH

N N H R2

X: O amides X: NH amidines

4-quinazolone

Obs.: note the similitude with pyrimidines / pyrimidinones synthesis

3.3. Two aza-atoms in positions 1,4

3.3.1. Monocyclic rings: pyrazines

A) retrosynthetic
R1 R2 R1 R2 R1 R2 R1 R2 N=O O NO2 O N3 O

disconnection: hydrolytic as N-1-C-2 and N-4-C-5 in the reduced form:

4 5 4 3

N N
1

R2 2H R1

R1
6

N
3

R2
2

R1 R2

NH2 O

O H2N

R2 R1

R2

N
1

R1

2,5-dihydropyrazine

-aminoketones

chemioselective reduction

_ R1 _R2

NH2 O _

spontaneous dimerization - 2 H2O

R1 R2

N N

R2 [O] R1 R1
- H2O

N N

R2 R1

R2

not isolate or not isolable

-azidoketones

Mircea Darabantu MASTER

IX D-11
4

B) retrosynthetic
4

disconnection: hydrolytic as N-1-C-6 and N-4-C-5 in the reduced form:

3

R1 R1

N N
1

R2 2H R2

R1
6

N
3

R2
2

R1 R1

O O

H 2N H 2N

R2 R2

R1

N
1

R2

2,3-dihydropyrazine

1,2-diaminoalkane -diketone (optionally glyoxal)

R1 R1
1

O O
2

H2N H2N

R2 R2

R1 R1

N N

R2 R2

O2 optionally MnO2/EtOH/KOH - H2 O

R1 R1

N N

R2 R2

Note: if R = R = H, pyrazine itself is prepared

C) retrosynthetic

disconnection: hydrolytic as N-4-C-3 (or N-4-C-5) in the reduced form:

4 4 3 R2

R2 5 R1
6

N N
1

2H

R2
6

N
3 1

R2
2

R2 R1

OO N H

R2 NH3 R1

R1

R1

N H

R1

1,2-dihydropyrazine

bis(-acylmethyl)amines

_ R2 R1 O O X X R2
NH3 heat

R2 _ R1

OO

_ R2 R1 _
NH3 heat

R2 R1

NH

R2 R1

R1

N H

N H

optionally isolable

R2 R1

NH2 O

R2 - H O 2 R1

R2 R1

R2

[O]

R2 R1

N N

R2 R1

N H

N R1 H H

Notes: the methodology is also known for acetals of the starting -cloro carbonylic compounds

3.3.2. Fused rings: quinoxalines

retrosynthetic disconnection: hydrolytic as double hydrazone (N-1-C-2 and N-4-C-3)
5 6 7 8 8a 4 4a

N N
1

3 2

R1 R2

NH2 NH2
o-phenylendiamine

O O

R1 R2
2,3-disubstituted quinoxalines quinoxaline

-diketones glyoxal

Mircea Darabantu MASTER

IX D-12

4. Reactivity:
4.1. Electrophilic substitution:
i) ii) almost non reactive unless resonance donors substituents are present in the molecule almost all substituents linked a priori in the precursors are resonance donors

4.1.1. At ring nitrogen - less important, according to lower basicity, in comparison with pyridines; significance is given to
substituted pyridazines (the more basic). - rules: 1. strongly withdrawing substituents (NO2, COR, Cl) are very effective in -position vs. nitrogen ring atom since the effect is largely inductive 2. strongly electron donating substituents (NH2, OR) operate by mesomeric effects and is strongest from the -position 3. from the -position, inductive effects possessed by the same groups can partially or wholly cancel the increase of reactivity

Example: N-oxidation
NH2
2 3

R-CO-OOH

NH2 O
2 3 2

N N
1

N+ N
1

N N
1

NH2

R-CO-OOH

N N+
1

NH2

R
2 3 2

R
3

N N
1

R-CO-OOH

O
+

N N
1

R: resonance donor and inductive acceptor

4 R-CO-OOH
2

N4 N
1

N
R-CO-OOH

H N+
4
2

Cl

N
1

Cl

strong acidity

+
1N

Cl

Note: similar reactivity is found for N-alkylation, especially with MeI to afford quaternary salts

4.1.2. At carbon ring

General: reactivity can be predicted from a knowledge of benzene chemistry. 1. The poor reactivity of diazines is exacerbated by the protonation at ring nitrogen in strong acidic media (however, this protonation, including other electrophilic substitution, is often reversible). 2. Diazines without strongly activating substituents (NH2, OR), do not react. 3. Diazines with a single strongly activating substituent and diazinones undergo nitration and sulfonation with difficulty (ca. m-dinitrobenzene). 4. Diazines with two strongly activating substituents readily undergo nitration, sulfonation and halogenation (ca. benzene). 5. Diazines with three strongly activating substituents are very reactive towards electrophilic substitution. 6. Alkyl groups and halogen atoms behave normally, as weakly activating and deactivating substituents respectively.

Mircea Darabantu MASTER

IX D-13
NH2 O2N N N NH2
2,4-diamino-6-chloro-5-nitro-pyrimidine

Nitration:

NH2 N Cl N NH2

Cl

OCH3 N N N N NH2 OCH3 OCH3 N N

vigorous

OCH3 NO2
4-amino-3,6-dimethoxy-5-nitro-pyridazine

NH2 OCH3 OCH3 OCH3 N N NO2 CH3 N N NO2 OCH3 NO2 CH3

N N NO2

CH3

CH3

NH N O NH N H Nitrosation: O O

heat

O2N N O

NH O

r.t.

O2N N

NH O

5-nitro uracil

O NH H 2N N NH2
HONO

O ON H2N N NH NH2
r.t., quantitative yield

Halogenation: N (Cl)n N
n = 1 - 4, (400oC)

Br N

ca. 200oC (62 - 88% yield

Note: for synthetic interest, nucleophilic chlorination is preferred

Mircea Darabantu MASTER

IX D-14

4.2. Nucleophilic substitution:

General:
crucial to enlarge functionality of diazines. of particular importance: H (Chichibabin methodology) and halogens much more facilitated than in pyridine series because of the additional ring nitrogen (e.g. the LUMO level, as acceptor, decreases).

4.2.1. Hydride ion as leaving group

- reaction is made in liquid ammonia with sodamide as nucleophile because of the increased -deficiency of diazines; accordingly, the -complex, as intermediate, has less tendency for re-aromatization; combined with the poor ability of hydride ion to be a good LG, an oxidant is needed to push the reaction (KNO3, KMnO4), even ammonia itself.

CH3 N N N N
NaNH2 / NH3 [O]

CH3 N N N N NH2 NH2 N N_ NH2 H

[O]

N N HO NH2

H: + [O]

4.2.2. Halogen as leaving group

the most useful: chlorine since it is easier to introduce in a classic variant:
heat

N N H
-

+ POCl3 O

N N

+ HO-POCl2 Cl

(benzo)diazinone

the general decreasing order of reactivity, according to halogen (exceptions make the rule !!): F > I > Br > Cl in agreement with a SN2Ar (SAE) mechanism

nucleophilic reagents, as general decreasing of reactivity: Nucleophile

-

HO hydroxy RO alcoxy PhO phenoxy HS mercapto MeS methylmercapto NH3 (amino), Me2NH (dimethylamino), N2H4 (hydrazine) HSO3 I2 F
-

Conditions o NaOH / H2O, 150 C RONa / ROH / 65 C PHONa / EtOH KSH / propylene glycol NaSMe / MeOH, 65 C NH3/H2O etc.100 200 C NaHSO3 / H2O HI KF, HF (heat)
o o o

Product Diazinones Alcoxydiazines Phenoxydiazines Diazinthiones Methylmercaptodiazines Amino-, methylaminohydrazinodiazines Diazine sulfonic acids Iododiazines Fluorodiazines

Mircea Darabantu MASTER

IX D-15
Cl N N
3-chloropyridazine

- typical examples for the nucleophiles listed in Table:

N N Cl

2-chloropyrazine

Selective nucleophilic substitution general rules and conditions:

Nu:X
4

N (X)H 6 N 2 X

X: halogen
Aminolysis: F 60 - 200 times faster than Cl, Br, I Positions 4 (6): up to 10 times more reactive than

- as in benzene chemistry: electron donating substituents (Me, Ph, OMe, NH2, NMe2, etc.) decrease the rate of nucleophilic substitution, whereas electron-withdrawing substituents (Cl, CF3, NO2, etc.) have opposite effect

Cl N Cl N Cl
fast

N< N Cl N
slower

N< N N Cl
slow

N< N >N N N<

Cl

>N

- comparison of (poly)chloro-derivatives of diazine type as masked imidoyl chlorides is more pertinent than in pyridine series. in benzodiazine series:

Nu:- almost exclusively Cl

4

Nu:- almost exclusively Cl

4

N N
2

Cl
3

Cl

- the better regioselectivity in the above dichloro-benzodiazines series might be explained by the more aromatic character of the intermediate -complex following the attack at C-4 than at C-2 (-3).

Mircea Darabantu MASTER

IX D-16

4.3. Advanced functionalization via metallation:

Overview:
- diazines, possessing two nitrogen atoms, are very sensitive to nucleophilic additions at the carbon ring. the LUMO (diazines) << LUMO (pyridines) hydrogen atoms linked to the ring are more acidic than in the pyridine series.

LUMO (ev) Directing ortho Metallating Group DoMG N N N N Li

R-Li

+ 0.72 furane + 0.55 benzene DoMG N N Li DoMG H R

nucleophilic addition deprotonation

+ 0.14 pyridine - 0.23 diazines - 0.32

DESIRED

TO AVOID

- 0.68 benzodiazines - 0.90

Remarks: - the metallating reagent should be less nucleophilic (e.g. by intrinsic steric hindrance) - the metallating reagent can be less basic (since diazines are more acidic) - alkyllithium reagenats (e.g. n-BuLi) should be avoided in diazine series.
4

R-Li R: n-Bu, sec-Bu, t-Bu pKa: 45 - 50 H 3C

CH3 CH3

5 2 1 6

H3C

CH3

N N CH3 H 3C CH3 Li Li LTMP LDA lithium diisopropyl amide lithium 2,2,6,6-tetramethyl-pyperidyl amid pKa: 35.7 Generation in situ: (i-Pr)2NH
n-BuLi

pKa: 37.3

LDA CH3
0oC, min. quantitative yield

H3C H 3C N H

LTMP

CH3

DoMG Directing ortho-Metallating Group, structural unit with crucial role: - kinetic and thermodynamic - useful structure to develop multi step synthesis - it should be not Methyl group, in order to avoid the deprotonation at this site.

Mircea Darabantu MASTER

IX D-17
Group, structural unit with crucial role:
MORE increased acidity

DoMG Directing ortho-Metallating

i) kinetic role:
increased acidity

H N,N DoMG (- I) N,N

H Li.......B
chelation of Li DoMG in the transition state (- I) INCREASED

ii) thermodynamic role:

Li N N DoMG
stabilisation as complexed carbanion

Li N N DoMG

N N

Li s e e n as DoMG

N N DoMG

stabilisation by the (-I) of DoMG

stabilisation against vicinal repulsion

Note: the DoMG must be simple enough, easily to introduce in the diazine motif or, even better, present before the ring closure. General mechanism:

H N,N DoMG

R2NLi k1 k-1

Li N,N DoMG

E N,N DoMG

a) k1 >>> k-1: trivial case; deutherated species detectable b) k1 <<< k-1: metallation in equilibirum; "trapping in situ" methodology; no deutherated species detectable no reaction between R2NLi and E+

Directing ortho-Metallating Groups Halogens: F, Cl, Br, I Oxygenated Groups: OCH3, OCH2OCH3 OCONEt2 etc. Carbonyl: CONH-t-Bu, CONEt2, CF3 etc. Nitrogen: NH-CO-t-Bu, NH-COO-t-Bu Sulfur: SCH3, SOR, SO2R, SO3R, SO2NHR

Functionalisations as: Halogen: F, Cl, Br, I Carbonated: C(OH)R1R2, COOH, COR, CHO, CH3, CONR2 etc. Nitrogen: NH2 (via N3) Others: SiR3, SnR3 etc.

Note: in the absence of DoMG, yields and regioselectivities much decrease: no synthetic importance

Mircea Darabantu, P-6, ianuarie 2004

P6
1. Propuneti un mecanism de reactie pentru transformarea de mai jos :
COOEt COOEt

NaOEt / EtOH

COOEt COOEt

2. Propuneti un mecanism de reactie pentru transformarea de mai jos :

Ph CH3
Ph-CH=O

Ac2O / AcOH

3. Identificati compusii A, B, C, D din schema de mai jos :

S

O OEt H 3C O

H2N C H3C CH-CN

SOCl2

m-Cl-C6H4-CO3H

N H

4. Realizati transformarea :

OCH3

OCH3 C6H4-OMe-p O

CO-NH-Ph

N O

5. Identificati compusii A E din schema de obtinere a alcaloidului de mai jos :

H3CO H3CO

CH=O

A
HO

p-MeO-C6H4-CH2-CO-Cl

E
HO

NH

OH