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 4
5 5
N 3
5 3 3N 4
N 1
2
6 1 2 6 1 2
6 N
N N N N

symbol pyridazine pyrimidine pyrazi

5 4 5 5 4
4 5 4
6
4a
6
4a
3
4a N 3
4a 3
3 N 6 6 N
N
7 N2 7 2 7 2 7 N2
N 8a N 8a N 8a N 8a
8 1 8 1 8 8 1
1
symbol cinnoline quinazoline quinoxaline phthalazine
benzo[c]pyridazine benzo[d]pyrimidine benzo[b]pyrazine benzo[d]pyridazine

2. Structure:
2.1. Basicity:
N
N
N
N N N N

pKb 13.49 12.77 10.76 8.7

- 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.

2.2. Aromaticity:
- they all are π-deficient systems as indicated by the Atomic π-charges:

Total π - deficiency

+0.050 +0.077 -0.147 +0.126

-0.004 -0.004 -0.124 N +0.047 +0.074 N +0.074 -0.009 N -0.199
+0.077 +0.077 -0.124 N +0.047 +0.074 +0.074 +0.126 +0.155
N N N
-0.195 +0.077 -0.147 -0.199
+0.204 +0.248 +0.296 +0.407
i) The order is different if relative local π-deficiency (the largest positive charge on any carbon
atom in a molecule) is considered.
ii) The π-acceptor action of heteroatoms in azines is most effective when they are meta-position
each other (pyrimidine).
iii) 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 IX D-2
Important notes:
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 π-acceptor and
less π-donor as revealed by the HMO Energies of Frontier (both decreasing β-values)

N N
N N
N N N N
N N N N

ELUMO (β<0 ) - 0.576 - 0.527 - 0.841 - 0.686 - 0.871 - 0.727 - 0.781

EHOMO (β<0 ) + 0.646 + 0.703 + 1.000 +1.000 + 1.077 + 1.101 + 1.281

i) 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.
ii) nucleophilic substitution becomes successively easier as ELUMO decreases
iii) 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 π-charges:
1H NMR 13C NMR
+0.050 7.55 138.7
-0.004 -0.004 7.16 7.16 125.6 125.6
+0.077 +0.077 8.52 8.52 149.5 149.5
N N N
-0.195

9.17 153.0
+0.077
-0.124 N +0.047 N 7.52 N 130.3
N 7.52 N 130.3
-0.124 N +0.047
9.17 153.0
+0.077

-0.147
N +0.074 N N
+0.074 8.60 8.60 145.9 145.9
+0.074 +0.074 8.60 8.60 145.9 145.9
N N N
-0.147
+0.126 8.78 156.9
-0.009 N -0.199 7.36 N 121.9 N
+0.126 +0.155 8.78 9.26 156.9 158.4
N N N
-0.199
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 X X

N HN N X = O : dominant B (minor A)
X = S : exclusive B
N N HN X = NH : exclusive A
+
A B C
-
XH X X X = O : dominant B (minor A)
N N N
X = S : exclusive B
N HN HN X = NH : major A (minor B)
+
A B C

XH X X

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

N NH N X = O : exclusive B identical with C

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

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 O

N NH

N O N O
HO OH H
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 F1
6 1
R1 5 1 R1 2
N O NH2 F1, F2: functionality (optional H
4
N2 O NH2 R1, R2: H, groups
R2 3 R2 3
4 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 F1
R1 R1
O NH2 N
O NH2 N
R2 R2
F2 F2
1 2
i) F , F functionality as H:

H
_ _ _ _
+
Br2/MeOH MeOH H2O / H O
O 1,4-addition _Br O Br _ - HBr CH3O O OCH3 _ O_
allylic positions
H

hydrazone of maleic dialdehyde: N

R1 = R2 = F1 = F2 = H
N

1 2
ii) F , F functionality as OH:
OH O O
O
N2H4 N NH NH
O N NH
-H2O N

O OH OH O
3,6-dihydroxypyrazine hydrazide of maleic acid:
R1 = R2 = H F1 = F2 = OH
Mircea Darabantu MASTER IX D-5
1 2
iii) F , F functionality as OH and group:

OEt
OH OH O
H3C 3
O H 3C N2H4 H3C H3C
O N 4 NH 2
O
O -H2O N 5 N1
H3C O 6

CH3 CH3 CH3

CH3
2H-4,6-dimethyl-pyridazine-3-one

1 2
iv) F , F functionality as groups:
Ph
Ph Ph
Ph
O Ph N2H4 Ph
O N
O
O -H2O N
H3C O
Ph Ph
Ph

1 2
v) F , F functionality as amino groups:
NH NH2
N
NH2 NH N
NH2 NH N
N NH2
NH
maleic dinitrile

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 → pyridazines

(masked) phthalic anhydride → phthalazines

OH O
O
N2H4 N NH
O NH
N

O OH O
1,4-dihydroxyphthalazine phthalhydrazide
2,3-dihydrophthalazine-1,4-dione
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 R
5 4
nucleophilic carbon
6 3 _

7 N2 +
8
N N N
1

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

+ H
CH2 -HX
H
+ N
N N
N - N - N
X X

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

and synthetic equivalents
LG OH
CH
C -H2O
+
N N N
N - N N O
LG

-
X N
+ N
O OH OH - HX
H H
4-cinnolone
CH3 CH2 H
+ +
N N N
N - N - N
X X

B) Friedel-Crafts methodology: retrosynthetic disconnection as C-4-C-4a

R LG
5 R should be of interest
4
4a 3
6
this bond should be
7 N2 N preliminarily formed
8
8a N N
1
Mircea Darabantu MASTER IX D-7
HOOC COOH

O ClOC
mesoxalic acid COCl
SOCl2
R R
N COOH N
N N
R H H
NH2 COOH
N
H
O
COOEt
3-ethoxycarbonyl-4-cinnolone
N
N
H

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

typical good LG
R1 R1 in SEAr R1
5 4 R2
replacement R2
4a 3 R2
6 LG2
8a N N
7 N2 NH
N NH LG1
8
1 LG1 typical good LG hydrazone as source:
in SN2Ar i) electrophile
replacement ii) nucleophile

HOOC COOH HOOC COOH ClOC COCl

i) C6H5F
Ar-NH-NH2 SOCl2
O N N
NHAr NHAr ii) EtOH
ketomalonic acid

O O
COOEt K2CO3 COOEt
methyl-ethylketone
N N
F NHAr N
Ar
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
OH
R1: H, Me, Ph, OMe,OH, SMe, SH, NH2
R2 R4 O
4
R2, R4:H, Me, Ph, OEt
R3 5 NH
N3 R3: H, Me, Ph, Br, NO, NO2
6 H2N R1
R4 2
N R1
1 R2 precursor of type amidine
R3
O
precursor of type 1,3-diketone
R4 O

- 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 Ph

O NH2 HCl / EtOH / heat N

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

H 3C O H 2N O H 3C N O
H
CH3 CH3

O NH2 HCl / EtOH / heat N

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

H 3C O HN O H 3C N O
CH3 CH3

O NH2 HCl / EtOH / heat N

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

O HN O N O
CH3 CH3

O NH2 HCl / EtOH / heat N

1H-pyrimidine-2-thione

O H 2N S N S
H

+ +
Obs.: acid catalysis is used to activate >C=O of type carbonyl as >C=OH ↔ >C -OH
Mircea Darabantu MASTER IX D-9
OEt O

O NH2 EtONa / EtOH / heat N

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

H 3C O HN t-Bu H 3C N t-Bu
H
OEt OH O

O NH2 EtONa / EtOH / heat N 5 4 N3

2
EtO O H 2N NH O N NH2 O 6 N1 NH2
H H
1H,5H-2-amino-pyrimidine-4,6-dione

OEt O O
1
O NH2 EtONa / EtOH / heat 5 6 NH 5 4
N3
1
C
H2N NH H 2N 4 N 2 NH2 H2N 6 N 2 NH2
N 3 H
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

Br N Br H2N N CH3

H
H NH H
- NH N H
NH2 -Br-
CH
- H+
Br N Br Br _N Br Br N_ Br N C CH
-

-
N + NH3
N N SN2Ar N
- -NH2- Br N CH3 H2N N CH3
Br N C CH2 Br N CH2

- 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 o-
disubstituted benzene precursor
R1: alkyl
o-amino-alkyl-phenyl-ketone
R1: OEt
anthranilic acid ethyl ester

R1 R1
5 4
4a 3 NH2
6
N O
2
7 O R2
8a N R2 NH2
8
1 simple amide

R1

R1 R1, R2 : H, alkyl N

H2N N R2
O heat
R2 O
- H2O
NH2 X
- H2X R1: OEt; R2 : H, alkyl N
X: O amides - EtOH
X: NH amidines N R2
H
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 disconnection: hydrolytic as N-1-C-2 and N-4-C-5 in the reduced form:

4 4
R1 5 N 3 R2 2H R1 5 N R2 R1 NH2 O R2
3
6
2
R2 6 N 2 R1 R2 N R1 R2 O H2N R1
1 1
2,5-dihydropyrazine α-aminoketones
R1 N=O

R2 O _ _
chemioselective H
R1 NO2 R1 NH2 spontaneous R1 N R2 [O] R1 N R2
reduction dimerization
- 2 H2O - H2O
R2 O _R2 O _ R2 N R1 R2 N R1
H
R1 N3 not isolate or not isolable

R2 O
α-azidoketones
Mircea Darabantu MASTER IX D-11
B) retrosynthetic disconnection: hydrolytic as N-1-C-6 and N-4-C-5 in the reduced form:

4 4
R1 5 N 3 R2 2H R1 5 N R2 R1 O H 2N R2
3
6
2
R1 6 N 2 R2 R1 N R2 R1 O H 2N R2
1 1
2,3-dihydropyrazine 1,2-diaminoalkane
α-diketone
(optionally glyoxal)

H O2
R1 O H2N R2 R1 N R2 optionally R1 N R2
MnO2/EtOH/KOH
R1 O H2N R2 R1 N R2 - H2 O R1 N R2
H
1 2
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
R2 N R2 OO
R2 5 N 3 R2
2H
5 R2 R2
3
6 1
βα NH3
2
R1 6 N 2 R1 R1 N R1 R1 N R1
1 H H
1,2-dihydropyrazine bis(β-acylmethyl)amines

_ _
OO NH O
R2 O O R2 R2 R2 R2 R2
NH3 heat NH3 heat

R1 X X R1 _ R1 N R1 _ R1 N R1
H H
optionally isolable

NH2 O
R2 R2 - H O R2 N R2 R2 N R2
2 [O]

R1 N R1 R1 N R1 R1 N R1
H H H

Notes: the methodology is also known for acetals of the starting α-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 4

6
4a N 3 R1 NH2 O R1
2
7
8
8a N R2 NH2 O R2
1
o-phenylendiamine
α-diketones 2,3-disubstituted quinoxalines
glyoxal quinoxaline
Mircea Darabantu MASTER IX D-12
4. Reactivity:
4.1. Electrophilic substitution:
i) almost non reactive unless resonance donors substituents are present in the molecule
ii) 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 α-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 γ-position
3. from the α-position, inductive effects possessed by the same groups can partially or wholly
cancel the increase of reactivity

Example: N-oxidation
NH2 NH2
2 3 - 2 3 2 2 4 NH2
O 4 NH2
N R-CO-OOH N+ N R-CO-OOH N
N N N - N+
1 1 1 O 1

R R
2 3 2 3
N R-CO-OOH N R: resonance donor and inductive acceptor
N - N
1 O 1
-
O 4 H
N4 N N+
+ R-CO-OOH R-CO-OOH 4
2
strong +
1N Cl
2 N 2 Cl
N Cl acidity
1 1 -
O
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
Nitration:
NH2 NH2
O2N
N N 2,4-diamino-6-chloro-5-nitro-pyrimidine

Cl N NH2 Cl N NH2

OCH3 OCH3
NO2
N N 4-amino-3,6-dimethoxy-5-nitro-pyridazine
N N
NH2 NH2
OCH3 OCH3

OCH3 OCH3 OCH3 OCH3

vigorous NO2 NO2
N N N N
N N N N
CH3 CH3 CH3 CH3
NO2 NO2

O2N
NH heat NH

N O N O

O O
O2N
NH r.t. NH
5-nitro uracil

N O N O
H

Nitrosation:
O O
HONO ON
NH NH
r.t., quantitative yield

H 2N N NH2 H2N N NH2

Halogenation:
N Br
N
(Cl)n
N N
n = 1 - 4, (400oC) 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 π-deficiency
of diazines; accordingly, the σ-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 CH3

N N
[O]
N NaNH2 / NH3 N NH2 N NH2 N
[O] N_ N NH2
N N H
- -
H: + [O] HO
N N NH2

4.2.2. Halogen as leaving group

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

heat
N + POCl3 N + HO-POCl2
N O N Cl
H
(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 Conditions Product

- o Diazinones
HO hydroxy NaOH / H2O, 150 C
- o Alcoxydiazines
RO alcoxy RONa / ROH / 65 C
- PHONa / EtOH Phenoxydiazines
PhO phenoxy
- KSH / propylene glycol Diazinthiones
HS mercapto
- o Methylmercaptodiazines
MeS methylmercapto NaSMe / MeOH, 65 C
o Amino-, methylamino-
NH3 (amino), Me2NH (dimethylamino), NH3/H2O etc.100 – 200 C
hydrazinodiazines
N2H4 (hydrazine)
- Diazine sulfonic acids
HSO3 NaHSO3 / H2O
I2 HI Iododiazines
- KF, HF (heat) Fluorodiazines
F
Mircea Darabantu MASTER IX D-15
- typical examples for the nucleophiles listed in Table:
Cl
N
N
N
N Cl
3-chloropyridazine 2-chloropyrazine

Selective nucleophilic substitution – general rules and conditions:

Nu:-
X
4
N X: halogen
Aminolysis: F 60 - 200 times faster than Cl, Br, I
Positions 4 (6): up to 10 times more reactive than
(X)H 6 N 2 X

- 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< N< N<

N fast N slower N slow N

Cl N Cl Cl N Cl >N N Cl >N N 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 Nu:- almost exclusively

Cl Cl
4 4
Cl
N 3

2
N
N Cl N

- the better regioselectivity in the above dichloro-benzodiazines series might be explained by the more
aromatic character of the intermediate σ-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 + 0.72 furane
ortho + 0.55 benzene
Metallating DoMG
Group + 0.14 pyridine
N deprotonation
DoMG N Li DESIRED
- 0.23
N R-Li diazines
N - 0.32
DoMG
N nucleophilic addition
H - 0.68
TO AVOID
N benzodiazines
R - 0.90
Li

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
3 5
R-Li CH3 CH3
H3C 2 CH3
1 6

R: n-Bu, sec-Bu, t-Bu H 3C N CH3 H 3C N CH3

Li Li
pKa: 45 - 50
LDA LTMP
lithium diisopropyl amide lithium 2,2,6,6-tetramethyl-pyperidyl amid
pKa: 35.7 pKa: 37.3

Generation in situ:
(i-Pr)2NH LDA
n-BuLi
0oC, min.
H3C CH3 quantitative LTMP
yield
H 3C N CH3
H

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
DoMG Directing ortho-Metallating Group, structural unit with crucial role:

i) kinetic role:
MORE
increased acidity increased acidity
H H
N,N N,N Li.......B
DoMG DoMG chelation of Li
in the transition state
(- I) (- I)
INCREASED

ii) thermodynamic role:

Li Li N Li N
N N s e e n as
N DoMG N DoMG N DoMG N DoMG
stabilisation stabilisation stabilisation
as complexed carbanion by the (-I) of DoMG 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:
Li +
E
H R2NLi k1 E
N,N N,N
N,N
k-1 DoMG DoMG
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 Functionalisations as:

Halogens: F, Cl, Br, I Halogen: F, Cl, Br, I

Oxygenated Groups: OCH3, OCH2OCH3 Carbonated: C(OH)R1R2, COOH, COR,

OCONEt2 etc. CHO, CH3, CONR2 etc.

Carbonyl: CONH-t-Bu, CONEt2, CF3 etc. Nitrogen: NH2 (via N3)

Nitrogen: NH-CO-t-Bu, NH-COO-t-Bu Others: SiR3, SnR3 etc.

Sulfur: SCH3, SOR, SO2R, SO3R, SO2NHR

Note: in the absence of DoMG, yields and regioselectivities much decrease: no synthetic importance
Mircea Darabantu, P-6, ianuarie 2004

P–6
1. Propuneti un mecanism de reactie pentru transformarea de mai jos :

COOEt

COOEt
NaOEt / EtOH COOEt
N N
COOEt
2. Propuneti un mecanism de reactie pentru transformarea de mai jos :
Ph

CH3
Ph-CH=O

Ac2O / AcOH
N N

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

S
O H2N
C CH-CN
OEt N
H3C SOCl2 m-Cl-C6H4-CO3H H
A B C D
H 3C O

4. Realizati transformarea :

OCH3 OCH3 C6H4-OMe-p

O
N CO-NH-Ph N
O
5. Identificati compusii A – E din schema de obtinere a alcaloidului de mai jos :

H3CO CH=O
p-MeO-C6H4-CH2-CO-Cl
A B C D
H3CO
HO
E
NH
HO

OH