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.
IX D-1
Mircea Darabantu MASTER
DIAZINES
1. Typical representatives and symbols:
4
4
5
N
N
N
4a
6
N
7
8a
8
N
N2
7
2
6
N
4a
5
4
3
8
7
N
8a
8
1
quinazoline
3
1
2
pyrazi
4
4a
6
2
8a
4
N
pyrimidine
N
1
cinnoline
5
N
5
3
3N
1
6
N
4
6
symbol
2
pyridazine
5
N
1
6
symbol
5
3
N
5
3
6
2
7
N
8
1
quinoxaline
4a
4
3
N
N2
8a
1
phthalazine
benzo[c]pyridazine benzo[d]pyrimidine benzo[b]pyrazine benzo[d]pyridazine
2. Structure:
2.1. Basicity:
N
N
N
N
pKb
13.49
N
12.77
N
10.76
N
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
-0.004
-0.004
+0.077
-0.124 N
+0.047
+0.074
+0.077
-0.124 N
+0.047
+0.074
+0.077
N
-0.195
+0.204
i)
ii)
iii)
+0.077
+0.248
-0.147
N +0.074
+0.074
N
-0.147
+0.296
+0.126
N -0.199
+0.126
+0.155
N
-0.199
-0.009
+0.407
The order is different if relative local π-deficiency (the largest positive charge on any carbon
atom in a molecule) is considered.
The π-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
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
ELUMO (β<0 )
EHOMO (β<0 )
i)
ii)
iii)
N
- 0.576
+ 0.646
N
- 0.527
+ 0.703
N
N
N
- 0.841 - 0.686
+ 1.000 +1.000
N
N
N
N
- 0.871 - 0.727
+ 1.077 + 1.101
N
- 0.781
+ 1.281
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 π-charges:
1H NMR
7.55
+0.050
-0.004
-0.004
7.16
+0.077
8.52
+0.077
N
-0.195
+0.077
-0.124 N
+0.047
-0.124 N
+0.047
N
+0.074
-0.147
N +0.074
8.60
+0.074
+0.074
8.60
+0.126
-0.009
N -0.199
+0.126
+0.155
N
-0.199
N
138.7
7.16
125.6
8.52
149.5
7.52
9.17
N
N
8.60
145.9
8.60
145.9
N
149.5
N
N
145.9
145.9
N
156.9
121.9
N
8.78
7.36
N
8.78
125.6
153.0
130.3
N
130.3
N
153.0
9.17
7.52
N
+0.077
N
-0.147
13C NMR
9.26
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
X
X
N
N
A
N
HN
X X = O : dominant B (minor A)
X = S : exclusive B
X = NH : major A (minor B)
N
HN
+
B
XH
C
-
X
A
C
X
X
N
N
A
B
N
N
H
C
N
NH
XH
N
N
H
X
A
B
C
N
N
H
N+
N
A
XH
X = O : dominant B vs. C
X = S : exclusive B
X = NH : A major (minor B+C)
N
NH
N
N
+
B
N
N
X = O : dominant B (minor A)
X = S : exclusive B
X = NH : exclusive A
N
HN
HN
N
XH
-
N
H
N
X
B
X
X = O : exclusive B identical with C
X = S : exclusive B identical with C
X = NH : A major (minor B+C)
X = O : exclusive B
X = S : exclusive B
- X = NH : exclusive A
X
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
O
OH
NH
N
HO
N
OH
2,4,6-trihydroxypyrimidine
O
N
H
O
pyrimidyn "trione
Barbituric acid
IX D-4
Mircea Darabantu MASTER
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
R1
5
6
1
N
N2
4
R2
3
R1
2
R2
3
1
NH2 F1, F2: functionality (optional H
NH2 R1, R2: H, groups
O
O
hydrazine
4
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
O NH2
R2
N
N
R2
F2
F2
1
2
i) F , F functionality as H:
H
_
_
O
1,4-addition
_Br
O
Br _
- HBr
CH3O
O
OCH3
H
hydrazone of maleic dialdehyde:
R1 = R2 = F1 = F2 = H
2
ii) F , F functionality as OH:
OH
O
N2H4
O
-H2O
O
_
O
O_
H2O / H
allylic positions
1
_
+
MeOH
Br2/MeOH
_
N
N
OH
3,6-dihydroxypyrazine
O
O
NH
NH
NH
N
OH
O
hydrazide of maleic acid:
R1 = R2 = H F1 = F2 = OH
N
N
Mircea Darabantu MASTER
1
IX D-5
2
iii) F , F functionality as OH and group:
OEt
OH
H3C
O
O
H3C
1
H 3C
O
O
O
CH3
CH3
O
OH
N2H4
H3C
N
N
-H2O
3
H3C
NH 2
N1
4
5
6
CH3
CH3
2H-4,6-dimethyl-pyridazine-3-one
2
iv) F , F functionality as groups:
Ph
Ph
Ph
O
Ph
O
Ph
N
N
-H2O
Ph
Ph
1
N2H4
O
O
O
H3C
Ph
Ph
2
v) F , F functionality as amino groups:
NH2
NH
N
N
N
NH
NH
NH2
NH2
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:
→ pyridazines
anhydride → phthalazines
(masked) maleic anhydride
(masked) phthalic
N2H4
O
O
O
OH
O
NH
N
N
NH
O
OH
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
5
R
4
7
N
8
nucleophilic carbon
_
3
6
N2
N N
1
+
Example 1: methodology based on diarylmethane motif to stabilize carbocations of type benzyl
H
+
CH2
+
N
N
X
H
N
N
X
-HX
-
N
N
Example 2: methodology based on nucleophilicity of the termini carbon in a phenylacetylene fragment
and synthetic equivalents
C
N
LG
CH
-H2O
N
+
N
-
LG
O
N
N
OH
CH3
+
N
N X
B) Friedel-Crafts
OH
N
OH
O
- HX
H
H
CH2
+
N
X
+
X
N
N
-
N
methodology: retrosynthetic disconnection as C-4-C-4a
R
5
6
4a
7
8
8a
LG
R
4
should be of interest
3
N
1
N2
N
N
this bond should be
preliminarily formed
N
H
N
4-cinnolone
Mircea Darabantu MASTER
HOOC
IX D-7
COOH
O
ClOC
mesoxalic acid
SOCl2
R
N
H
R
N
H
NH2
N
COOH
R
N
H
COOH
COCl
N
O
COOEt
3-ethoxycarbonyl-4-cinnolone
N
H
C) Intramolecular
N
SN2Ar nucleophilic substitution: retrosynthetic disconnection as C-8a-N-1
5
4a
6
4
3
8a
7
8
N
typical good LG
in SEAr
replacement
R1
R1
R2
R2
N
N2
LG1
1
HOOC
COOH
O
ketomalonic acid
N
NH
LG1
typical good LG
in SN2Ar
replacement
COOH
F
ClOC
COCl
SOCl2
N
N
NHAr
N
NHAr
K2CO3
methyl-ethylketone
COOEt
N
Ar
N
NH
hydrazone as source:
i) electrophile
ii) nucleophile
i) C6H5F
NHAr ii) EtOH
O
O
COOEt
R2
LG2
HOOC
Ar-NH-NH2
R1
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
R4
R2
R3
5
OH
O
4
NH
N3
6
R4
N
2
1
R1: H, Me, Ph, OMe,OH, SMe, SH,
H2N
R1
NH2
R2, R4:H, Me, Ph, OEt
R3: H, Me, Ph, Br, NO, NO2
R1
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
NH2 HCl / EtOH / heat
O
H 3C
H 2N
O
O
N
H 3C
NH2
O
NH2
O
H 2N
S
1H-1,4,6-trimethyl-pyrimidine-2-one
N
O
CH3
N
HCl / EtOH / heat
1H-1-methyl-pyrimidine-2-one
N
O
CH3
NH2 HCl / EtOH / heat
O
O
H 3C
HN
O
CH3
O
N
HCl / EtOH / heat
HN
O
CH3
O
O
CH3
CH3
H 3C
N
H
1H-6-methyl-4-phenyl-pyrimidine-2-one
N
N
H
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
OEt
NH2
O
H 3C
HN
O
N
EtONa / EtOH / heat
t-Bu
H 3C
1H-2-t-butyl-6-methyl-pyrimidine-4-one
t-Bu
N
H
OH
OEt
NH2 EtONa / EtOH / heat
O
O
N
5
N3
4
2
EtO
H 2N
O
NH
O
N
H
NH2
O
6
N1
H
NH2
1H,5H-2-amino-pyrimidine-4,6-dione
O
OEt
NH2 EtONa / EtOH / heat
O
5
6
O
NH
1
4
5
N3
1
C
H2N
N
NH
H 2N
4
N
2
3
NH2
H2N
6
N
H
2
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.
N
NaNH2 / NH3 (l)
Br
N
H
NH2
Br
N
Br
N
H
Br
H2N
Br
NH H
_N
-
N H
CH
Br
N_
Br
N C CH
-
+ NH3
N
Br
CH3
NH
-Br- H+
Br
N
N C CH2
Br
N
CH2
-
-NH2-
N
Br
N
N
SN2Ar
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
H2N
N
CH3
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
R1
5
6
4a
4
N
3
NH2
O
2
7
8a
8
N
R2
O
NH2
R2
1
simple amide
R1
N
R1, R2 : H, alkyl
R1
O
H2N
R2
X
NH2
R2
N
heat
O
- H2O
- H2X
R1: OEt; R2 : H, alkyl
X: O amides
X: NH amidines
N
- EtOH
R2
N
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
R1
R2
O
O
R2
H2N
R1
3
6
R2
R1
N=O
R2
R1
O
NO2
R2
R1
O
N3
R2
O
α-azidoketones
6
N
1
2
R2
R1
N
2
1
α-aminoketones
2,5-dihydropyrazine
chemioselective
reduction
_
_
R1
NH2
_R2
O _
spontaneous
dimerization
- 2 H2O
not isolate or not isolable
R1
R2
H
N
R2 [O] R1
N
R1
H
- H2O
R2
N
R2
N
R1
Mircea Darabantu MASTER
B) retrosynthetic
IX D-11
disconnection: hydrolytic as N-1-C-6 and N-4-C-5 in the reduced form:
4
4
R1
N
5
3
R2 2H
R1
R2
R1
5
N
R2
R1
O
H 2N
R2
R2
R1
O
H 2N
R2
3
6
6
R1
N
2
1
2
N
1
1,2-diaminoalkane
α-diketone
(optionally glyoxal)
2,3-dihydropyrazine
R1
O
H2N
R2
R1
N
R1
O
H2N
R2
R1
N
1
H
H
R2
O2
optionally
MnO2/EtOH/KOH
R1
N
R2
R2
- H2 O
R1
N
R2
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 5
N
3 R2
R2
2H
5
6
N
2
R2
R1
R1
1
N
H
1
2
_
R1
R1
R2
O O
R2
R2
R1
X X
_ R1
R1 _
N
H
NH3
R1
bis(β-acylmethyl)amines
NH3 heat
NH3 heat
R1
N
H
_
OO
R2
βα
1,2-dihydropyrazine
R2
OO
3
6
R1
R2
N
R2
R1
NH
O
N
H
R2
R1
optionally isolable
R2
NH2 O
R1
N
H
R2 - H O
2
R2
N
R2
R1
R1
N
R1
H H
[O]
R2
N
R2
R1
N
R1
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
6
4
4a
N
3
R1
NH2
O
R1
R2
NH2
O
R2
2
7
8
8a
N
1
o-phenylendiamine
α-diketones
glyoxal
2,3-disubstituted quinoxalines
quinoxaline
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 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
-
3
2
N
N
R-CO-OOH
NH2
O
1
3
2
N+
N
N
N
1
1
R
4
NH2
2
R-CO-OOH
-
O
N
N+
4
NH2
1
R
3
2
2
3
2
N
N
R-CO-OOH
-
1
O
N
N
R: resonance donor and inductive acceptor
1
-
O
R-CO-OOH
+
N
H
N+
4
N4
2
Cl
1
N
N
1
2
R-CO-OOH
4
strong
acidity
+
Cl
1N
2
-
Cl
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
Cl
N
N
Cl
NH2
N
OCH3
N
N
N
N
2,4-diamino-6-chloro-5-nitro-pyrimidine
NH2
OCH3
NO2
4-amino-3,6-dimethoxy-5-nitro-pyridazine
NH2
NH2
OCH3
OCH3
OCH3
OCH3
vigorous
N
N
N
N
CH3
CH3
NO2
N
N
CH3
NO2
N
O2N
heat
NH
OCH3
OCH3
NO2
N
N
CH3
NO2
NH
N
O
O
O
O
N
H
O2N
r.t.
NH
NH
N
O
5-nitro uracil
O
Nitrosation:
O
O
H 2N
N
ON
HONO
NH
NH2
NH
H2N
N
r.t., quantitative yield
NH2
Halogenation:
N
Br
N
(Cl)n
N
n = 1 - 4, (400oC)
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 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
N
N
NaNH2 / NH3
[O]
NH2
N
N
N
N_
NH2
[O]
N
H
-
N
NH2
-
H: + [O]
N
N
HO
NH2
4.2.2. Halogen as leaving group
the most useful: chlorine since it is easier to introduce in a classic variant:
-
N
N
H
+ POCl3
O
heat
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
Product
Diazinones
o
RONa / ROH / 65 C
PHONa / EtOH
Alcoxydiazines
KSH / propylene glycol
Diazinthiones
Phenoxydiazines
o
Methylmercaptodiazines
NaSMe / MeOH, 65 C
o
NH3/H2O etc.100 – 200 C
Amino-, methylaminohydrazinodiazines
NaHSO3 / H2O
HI
Diazine sulfonic acids
KF, HF (heat)
Fluorodiazines
Iododiazines
Mircea Darabantu MASTER
IX D-15
- typical examples for the nucleophiles listed in Table:
Cl
N
N
N
N
3-chloropyridazine
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
N
N
fast
N
Cl
N<
N<
Cl
Cl
Cl
N
N
slower
Cl
>N
N<
N
slow
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
Cl
Nu:- almost exclusively
Cl
4
4
N
N
2
Cl
3
Cl
N
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
ortho
Metallating
Group
+ 0.72 furane
+ 0.55 benzene
DoMG
N
DoMG
N
+ 0.14 pyridine
deprotonation
N
DESIRED
Li
- 0.23
R-Li
diazines
N
- 0.32
DoMG
N
H
N
Li
nucleophilic addition
- 0.68
TO AVOID
benzodiazines
R
- 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
CH3 CH3
R-Li
R: n-Bu, sec-Bu, t-Bu
pKa: 45 - 50
5
3
H3C
2
1 6
CH3
N
N
CH3
H 3C
CH3
Li
Li
LTMP
LDA
lithium diisopropyl amide lithium 2,2,6,6-tetramethyl-pyperidyl amid
H 3C
pKa: 37.3
pKa: 35.7
Generation in situ:
(i-Pr)2NH
LDA
n-BuLi
H3C
H 3C
CH3
N
H
CH3
0oC, min.
quantitative
yield
LTMP
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
Li.......B
N,N
N,N
chelation of Li
DoMG
in the transition state
(- I)
DoMG
(- I)
INCREASED
ii) thermodynamic role:
Li
N
N
N
Li
Li
s e e n as
N
DoMG
stabilisation
as complexed carbanion
N
N
N
DoMG
stabilisation
by the (-I) of DoMG
DoMG
N
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
E
E
+
N,N
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
OCONEt2 etc.
Carbonated: C(OH)R1R2, COOH, COR,
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
N
COOEt
N
COOEt
2. Propuneti un mecanism de reactie pentru transformarea de mai jos :
Ph
CH3
Ph-CH=O
N
Ac2O / AcOH
N
3. Identificati compusii A, B, C, D din schema de mai jos :
S
O
H2N
CH-CN
C
OEt
H 3C
H3C
A
SOCl2
B
m-Cl-C6H4-CO3H
C
N
H
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
A
B
p-MeO-C6H4-CH2-CO-Cl
H3CO
HO
E
HO
NH
OH
C
D
D