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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5262_Библиотеки_им_академика_М_И_Перельмана.pdf
4 Mechanism Problems from Reactions Give Expected Products258
Experimental Procedure (from Org. Lett., 2014, 16, 3114, Supporting Information)
Representative Procedure for the One-Pot Synthesis of 2H-indazoles:
2-Phenyl-2H-indazole (2): To a 2-dram vial equipped with a stir bar was added
2-nitrobenzldehyde (200 mg, 1.30 mmol) and iPrOH (3.0 mL). Aniline (133 mg,
0.130 mL, 1.43 mmol) was added in one portion and the resulting solution was
heated to 80 °C in a sealed 2-dram vial with stirring for 4 h. The mixture was cooled
to room temperature and tri-n-butylphosphine (790 mg, 0.980 mL, 3.91 mmol) was
added in one portion followed by stirring at 80 °C in a sealed 2-dram vial for 16 h.
The mixture was cooled to room temperature and diluted with EtOAc (25 mL). The
organics were washed with ammonium chloride (15 mL), brine (15 mL), dried over
MgSO
4
, filtered, and concentrated in vacuo. The residue was purified by silica gel
chromatography (0–25% EtOAc/heptane) to afford the desired product 2 (213 mg,
85%) as a white solid. The spectroscopic data obtained for the product matched
previously reported data:
1
HNMR (CDCl
3
, 600 MHz) δ = 8.43 (s, 1H), 7.92 (d, J =
8.8 Hz, 2H), 7.81 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.55 (t, J = 8.2 Hz,
2H), 7.46–7.38 (m, 1H), 7.34 (dd, J = 7.3, 8.5 Hz, 1H), 7.13 (dd, J = 7.0, 8.2 Hz, 1H).
The Mechanism
The tributylphosphine reduces the nitro group sequentially through addition to
the NO bond in both starting material 1 and the assumed intermediate A to give a
nitrene intermediate B. Then cyclization occurs to provide product 2.
Another possible mechanism may be via the N-oxide intermediate C.
N
+
N
Ph
O
−
O
P(n-Bu)
3
N
N
Ph
−
O
O
(n-Bu)
3
P
=
O
(n-Bu)
3
P
=
O
N
N
Ph
O
N
N
Ph
N
N
Ph
O
N
N
Ph
N
N
Ph
B, Nitrene
1
A
2
O
−
P
+
(n-Bu)
3
P(n-Bu)
3
P(n-Bu)
3
P
+
(n-Bu)
3
N
N
Ph
O
N
N
Ph
N
Ph
O
–
N
Ph
N
N
Ph
O
N
N
Ph
–
O
N
N
Ph
O
P(n-Bu)
3
A
C
2
N
+
O
–
N
+
(n-Bu)
3
P
=
O
P(n-Bu)
3
P
+
(n-Bu)
3
4.7 Formation of Bicyclic and Polycyclic Aromatic Heterocycles 259
The product 2 could also be generated via 1,4-addition of tributylphosphane to
the N-oxide C.
Problem 104: Preparation of Indazoles from 2-Methylanilines
Compound 1 is a very active anti-HIV agent [302]. To develop an efficient synthesis
of 1, the key indazole core was prepared from 2-alkylanilines. The reaction from 2 to
3 was reported by Sun’s group [303].
Could you please provide the mechanism for the reaction?
Experimental Procedure (from J. Org. Chem., 1997, 62, 5627)
1-Acetyl-5-(acetoxymethyl)indazole (3). A mixture of 2 (16.58 g, 0.12 mol),
acetic anhydride (34.0 mL, 0.36 mol), and potassium acetate (23.71 g, 0.24 mol) in
240 mL of CHCl
3
was stirred at room temperature for 3 h, refluxed for 2 h, and
stirred at room temperature overnight. Then n-amyl nitrite (32 g, 0.27 mol) and
18-crown-6 (1.59 g, 6.0 mmol) were added and the mixture heated at reflux for 28 h.
After being cooled to room temperature, the reaction mixture was added to acetic
anhydride (10 mL) and stirred at room temperature overnight. The reaction mixture
was diluted with CH
2
Cl
2
(400 mL), washed with saturated NaHCO
3
(200 mL), water,
and brine, and dried (Na
2
SO
4
) and the solvent evaporated to give a dark brown solid.
Chromatography (silica gel, 15% EtOAc/hexane) gave 3 as a yellow solid (16.98 g,
58%). 3: mp 73–74 °C;
1
HNMR (CDCl
3
) δ 8.44 (d, J = 8.8 Hz, 1 H), 8.13 (d, J =
0.8 Hz, 1 H), 7.75 (d, J = 0.7 Hz, 1H), 7.56 (dd, J = 8.8, 1.5 Hz, 1H), 5.23 (s, 2H), 2.79,
(s, 3H), 2.12 (s, 3H); CIMS (NH
3
) m/z 267 (M + 2 X NH
3
+ H
+
, 100), 250
(
M + NH
4
+
)
.
Anal. Calcd for C
12
H
12
N
2
O
3
: C, 62.06; H, 5.22; N, 12.06. Found: C, 62.07; H, 5.07;
N, 11.91.
N
Ph
O
–
C
P(n-Bu)
3
N
N
Ph
P
N
O
N
Ph
n-Bu
n-Bu
N
N
Ph
2
N
+
P
+
(n-Bu)
3
O
–
n-Bu
(n-Bu)
3
P
=
O
N
N
NH
2
HO
Ac
2
O, KOAc
amylnitrite
18-C-6, CHCl
3
58%
O
AcO
2
3
N
H
N
N
N
N
N
H
O
Bn
HO
Bn
OH
1, anti-HIV active
4 Mechanism Problems from Reactions Give Expected Products260
The Mechanism
This reaction is actually an old one, initially reported by Jacobson and Huber in 1908
[ 304 ]. According to the literature [ 305 , 306 ], the nitroso intermediate A undergoes
isomerization to form the diazoacetate B. This intermediate can then cyclize either
through the formation of the diazonium salt C or via a synergistic reaction to yield
intermediate D. Following isomerization and acetylation of the indazole, the final
product 3 is obtained.
NH
2
HO
2
Ac
2
O
Ac
2
O
N
H
AcO O
O
N
O
Am
AmONO
AmOH
N
AcO
N
O
O
N
OAc
N
AcO
N
N
O
N
N
OAc
3
O
O
H
HOAc
Cyclization
Isomerization
OAc
N
H
N
HOAc
N
+
OAc
N
–
O
H
O
Rearrangement
A
B
D
E
C
HOAc
Problem 105: Synthesis of 7-aza-Indazoles by Diels-Alder/Retro-Diels-Alder
Cascade
A method for synthesizing 7-aza-indazoles by Diels-Alder/retro-Diels-
Alder cascade was developed [ 307 , 308 ]. For example, ethyl 5-fluoro-
1H-pyrrolo[2,3-b]pyridine-3-carboxylate ( 3) was prepared in quantitative yield from
commercially available starting materials 1 and 2. Compound 3 was further con-
verted to compound 4, which is the key intermediate for synthesizing the marketed
drug vericiguat [ 309 ].
Please suggest a mechanism from 1, 2 to 3 .
Experimental Procedure (from J. Am. Chem. Soc., 2019 , 141, 15901, Supporting
Information)
Synthesis of Vericiguat Intermediate 4
Procedure. To a solution of 5-fluoro-2-hydrazinylpyrimidine ( 1, 500 mg,
3.90 mmol, 1.10 equiv.) in THF (0.55 M) were added ethyl 2-oxo-4-(trimethylsilyl)
but-3-ynoate ( 2, 704 mg, 3.55 mmol, 1.00 equiv.) and a catalytic amount of TFA
(0.05 mL, 0.71 mmol, 0.20equiv.) under nitrogen. The reaction mixture was warmed
to 60 °C for 20 min at which point TLC and
1
HNMR analysis of an aliquot dem-
onstrated the total consumption of the starting materials. 3-Pentanone (1.12 mL,
10.64 mmol, 3.00 equiv.) and TFAA (1.48 mL, 10.64 mmol, 3.00 equiv.) were then
added dropwise and stirring was continued for 1 h. TLC and
1
HNMR demonstrated
the total consumption of the trifluoroacetylated hydrazone previously formed.
4.7 Formation of Bicyclic and Polycyclic Aromatic Heterocycles 261
The reaction mixture was cooled to room temperature, diluted with EtOAc and
washed twice with an aqueous saturated solution of Na
2
CO
3
. The organic layer was
dried over MgSO
4
, filtered, and the solvent evaporated under vacuum. The crude
residue was directly engaged in the desilylation step. To a 0 °C solution of the crude
residue in THF (0.25 M) under nitrogen was added dropwise TBAF (3.55 mL, 1 M
in THF, 3.55 mmol, 1.10 equiv.). After 2 hours, TLC showed total conversion of
the intermediate. The mixture was diluted with EtOAc and washed with water.
The organic layer was dried over MgSO
4
, filtered, and the solvent evaporated under
vacuum. The crude residue was directly engaged in the protection step. To a solution
of the residue in DMF (0.22 M) at room temperature was added cesium carbonate
(873 mg, 4.05 mmol, 1.10 equiv.) followed by 1-(bromomethyl)-2-fluorobenzene
(0.49 mL, 4.05 mmol, 1.10 equiv.). After 1 h, the solution was dissolved with EtOAc
and washed with water. The organic layer was dried over MgSO
4
, filtered, and the
solvent was evaporated under vacuum. The crude product was analyzed by
1
HNMR
and consisted of a clean mixture of two isomers resulting from the N-benzylation
reaction (N1/N2 = 60 : 40). After purification on silica gel chromatography, ethyl
5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (494.2 mg)
and ethyl 5-fluoro-2-(2-fluorobenzyl)-2H-indazole-3-carboxylate (330.5 mg) were
isolated as colorless oils (67% combined yield).
Characterization. Ethyl 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-
3-carboxylate (4).
1
HNMR (CDCl
3
, 500 MHz, ppm): δ 8.42 (q, J = 1.0 Hz, 1H), 8.06
(dd, J = 8.0 Hz, J = 3.0 Hz, 1H), 7.19–7.14 (m, 1H), 7.09–7.06 (m, 1H), 7.00–6.93
(m, 2H), 5.81 (s, 2H), 4.46 (q, J = 7.0 Hz, 2H), 1.41 (t, J = 7.0 Hz, 3H); These data
are in agreement with the reported
1
HNMR for this compound.
13
CNMR (CDCl
3
,
125 MHz, ppm): δ 161.6, 160.3 (d, J = 248.2 Hz, 1C), 156.5 (d, J = 250.1 Hz, 1C),
147.9, 139.8 (d, J = 38.3 Hz, 1C), 134.5 (d, J = 6.5 Hz, 1C), 129.8 (d, J = 10.1 Hz, 1C),
129.8 (d, J = 4.3 Hz, 1C), 124.2 (d, J = 4.5 Hz, 1C), 122.9 (d, J = 18.1 Hz, 1C), 115.6
(d, J = 26.8 Hz, 1C), 115.5, 115.4 (d, J = 26.3 Hz, 1C), 61.4, 45.3 (d, J = 6.0 Hz, 1C),
14.4;
19
FNMR (CDCl
3
, 471 MHz, ppm): δ − 117.8, 133.6.
N
N
F
NHNH
2
+
TMS
CO
2
Et
O
1
2
1. TFA (20 mol%)
THF, 60 °C, 20 min
2. TFAA, 3-pentanone
THF, 60 °C, 1 h
3. Bu
4
NF, THF, 0 °C, 2 h
N
F
3 (quant. crude)
N
H
N
CO
2
Et
2-F-BnBr, Cs
2
CO
3
DMF, 20 °C, 1 h
N
F
N
N
F
4
6 steps
N
F
N
N
F
Vericiguat
N
N
HN
CO
2
Me
CO
2
Et
4 Mechanism Problems from Reactions Give Expected Products262
The Mechanism
The first reaction is a condensation of the hydrazine 1 with the ketone 2 to form
intermediate A. An intramolecular Diels-Alder reaction then occurs between the
triple bond and the pyrimidine to give the bridged intermediate B. Subsequently, a
retro Diels-Alder reaction occurs with the elimination of HCN to yield intermediate
C. The HCN could be trapped by 3-pentanone. Finally, desilylation of C by TBAF
leads to the product 3.
Problem 106: Synthesis of Indazole by Davis-Beirut Reaction
BI-0282 (1) is a very potent inhibitor of the MDM2-p53 interaction [310]. The final
step of the synthesis of 1 incorporates a Davis-Beirut reaction [311] as shown below.
Please suggest a mechanism for this transformation.
Experimental Procedure (from Org. Process Res. Dev., 2022, 26, 2526)
Compound 1. Intermediate rac-2 (28.8 g, 44.8 mmol) is dissolved in isopropanol
(300 mL) and a solution of KOH (39.0 g, 694.9 mmol) in water (95 mL) is slowly
added. After stirring for 16 h at ambient temperature, the solvents are partially
removed under reduced pressure. The residue is diluted with ethyl acetate and
treated with a diluted aqueous solution of citric acid. After extraction of the aqueous
layer with ethyl acetate, the organic layers are combined, dried with sodium sulfate,
N
N
F
N
H
TMS
CO
2
Et
O
1
2
NH
2
H
2
O
TMS
N
N
H
N
N
F
D-A
HN
N
N
N
TMS
F
HCN
N
F
N
H
N
retro-
D-A
3-pentanone
HO CN
Si
N
F
3
N
H
N
H
F
–
TMSF + Bu
3
N
+ BuOH
A
B
C
Bu
4
NF
then aq. work up
CO
2
Et
CO
2
Et
CO
2
Et
CO
2
Et
N
H
NH
HN
F
Cl
CO
2
Me
O
2
N
OH
O
Cl
Rac-2
Aq. KOH
i-PrOH, rt, 16 h
70%
N
H
NH
F
Cl
O
Cl
Rac-1
BI-0282
O
N
N
HO
2
C
4.7 Formation of Bicyclic and Polycyclic Aromatic Heterocycles 263
and the solvent is removed under reduced pressure. Purification by normal phase
column chromatography using DCM and methanol as solvents yields rac-1 (25.8 g,
43.5 mmol) in 70% yield as an amorphous white solid.
1
HNMR (500 MHz, DMSO-d
6
): δ 12.64 (br s, 1H), 10.29 (s, 1H), 7.67 (s, 1H), 7.47
(d, J = 8.83 Hz, 2H), 7.297.36 (m, 1H), 7.26 (d, J = 7.88 Hz, 1H), 7.21 (dd, J = 1.26,
8.83 Hz, 1H), 7.12 (t, J = 8.04 Hz, 1H), 6.92 (dd, J = 1.89, 7.88 Hz, 1H), 6.48 (d, J =
1.89 Hz, 1H), 5.86 (t, J = 9.14 Hz, 1H), 4.594.68 (m, 1H), 4.52 (dd, J = 7.88, 11.35 Hz,
1H), 4.234.32 (m, 1H), 4.20 (d, J = 10.09 Hz, 1H), 2.27 (dd, J = 7.57, 13.08 Hz, 1H),
2.13 (dd, J = 5.83, 13.08 Hz, 1H), 0.470.62 (m, 1H), 0.260.37 (m, 1H), 0.110.20
(m, 1H), 0.04 to 0.04 (m, 1H), 0.25 (s, 1H).
13
C
{
1
H
}
NMR (125 MHz, DMSO-d
6
): δ
177.5, 168.1, 156.1 (d,
1
J
C,F
= 248.7 Hz), 146.3, 145.3, 144.0, 134.1, 130.3, 129.7, 129.5,
126.8, 126.7, 125.4 (d,
3
J
C,F
= 4.4 Hz), 123.5 (d,
2
J
C,F
= 13.2 Hz), 122.5, 120.0, 119.9,
119.7 (d,
2
J
C,F
= 18.3 Hz), 118.7, 110.0, 107.3, 76.4, 69.2, 57.5, 56.8, 54.2, 51.2, 11.6,
5.5, 4.1. HRMS (ESI) m/z: [M + H]
+
calcd for C
30
H
24
Cl
2
FN
4
O
4
, 593.1153; found,
593.1165.
The Mechanism
The mechanism of Davis-Beirut reaction was first published in 2005 by Kurth,
Olmstead, and Haddadin (see below) [312]. The reaction begins with the base
deprotonation of benzylic hydrogen adjacent to the secondary amine group, cre-
ating a carbanion. The carbanion then extracts an oxygen from the nitro group.
That mechanism is widely cited in some online sources such as Wikipedia,
YouTube, and Google. However, I do not agree with that mechanism since the neg-
ative oxygen on nitro group is almost impossible as an electrophile attacked by a
carbanion nucleophile.
In this context, I propose an alternative mechanism. As expected, the methyl
ester undergoes facile hydrolysis to yield the corresponding carboxylic acid. In the
presence of KOH, this acid is converted into its potassium salt. The Davis-Beirut
reaction initiates with the amine acting as a nucleophile, attacking the nitrogen
atom within the nitro group to form intermediate A. Under strongly basic condi-
tions, a molecule of water is eliminated, resulting in intermediate B. Subsequently,
N
+
O
O
–
NHBn
NaOH
H
HO
–
O
NHBn
–
N
O
OH
NBn
H
2
O
H
N
O
NBn
MeO
–
N
N
OMe
Bn
OH
H
N
N
OMe
Bn
NaOH
MeOH, heat
Unreasonable
N
+
O
–
H
2
O
4 Mechanism Problems from Reactions Give Expected Products264
the hydroxyl group of the primary alcohol adds to the indazole N-oxide, leading to
the formation of the N-hydroxy dihydroindazole C. Under the same strongly basic
conditions, another molecule of water is eliminated, ultimately producing product 1.
Upon revisiting the mechanism proposed by Kurth, Olmstead, and Haddadin [312],
a slight modification leads to a plausible pathway. The carbanion in intermediate I
attacks the nitro group from the oxygen side of the N═O double bond, resulting in
the formation of the benzoisoxazole intermediate II. Subsequent ring opening of
the oxazole generates the nitroso intermediate IIIa/IIIb. Elimination of water from
IIIb then produces the nitroso imine IV. The remaining steps align with the mech-
anism originally proposed by Kurth et al.
The following mechanism is also reasonable.
N
H
NH
HN
Ar
CO
2
Me
N
+
OH
O
Cl
Rac-2
Aq. KOH
Me ester
hydrolysis
amine
attacks
nitro
O
N
H
NH
N
Ar
CO
2
K
OH
O
Cl
HO
H
O
−
H
Catalyzed
by HO
−
N
H
NH
N
Ar
O
O
Cl
H
H
O
H
Catalyzed
by HO
−
N
H
NH
N
Ar
O
O
Cl
NHO
H
H
3
+
O
N
H
NH
F
Cl
O
Cl
Rac-1
BI-0282
O
N
N
HO
2
C
A
B
C
−
O
−
O
N
+
N
+
−
O
O
−
H
CO
2
K
CO
2
K
O
−
H
Catalyzed
by HO
−
H
2
O
H
2
O
O
NHBn
NaOH
H
HO
−
O
NHBn
–
N
N
O
NHBn
MeO
−
N
N
OMe
Bn
OH
H
N
N
OMe
Bn
Reasonable
O
NHBn
N
O
NBn
I
II
IIIa
IV
V
H
2
O
NaOH
N
O
NBn
OH
H
IIIb
O
−
Na
+
O
−
N
+
N
+
Na
+
O
−
O
−
Na
+
H
2
O
H
2
O
H
2
O
4.7 Formation of Bicyclic and Polycyclic Aromatic Heterocycles 265
4.7.5 Quinazoline
Problem 107: Synthesis of Quinazolines
Quinazoline is an important structural motif occurring in several marketed drugs
such as anticancer medication vandetanib. Yu’s group reported a preparation of
quinazolines (2o) by the following reaction [312].
Please provide a mechanism for the reaction.
Experimental Procedure (from J. Org. Chem., 2016, 81, 9924)
General Procedure for the Synthesis of Products (2). A mixture of iodine
(244 mg, 0.96 mmol) and KI (160 mg, 0.96 mmol) in DMSO (2.5 mL) was stirred
at room temperature for 10 min and then treated with substrate 1 (0.40 mmol), fol-
lowed by addition of K
2
CO
3
(139 mg, 1 mmol) and a further 2.5 mL of DMSO. The
reaction was heated to 100 °C until TLC indicated the conversion was complete.
After cooling to room temperature, it was quenched with 5% Na
2
S
2
O
3
(15 mL) and
then extracted with EtOAc (15 mL × 3). The combined organic layer was dried over
anhydrous Na
2
SO
4
, concentrated, and then purified through silica gel column chro-
matography to afford the desired product 2.
6-Methyl-2-phenyl-4-(pyridin-4-yl)quinazoline (2o). 3.5 h; eluent: EtOAc/PE
80:20; yield: 117 mg, 99%; brown solid, mp 134136 °C;
1
HNMR (400 MHz, CDCl
3
)
δ 8.88 (d, J = 5.6 Hz, 2H), 8.668.63 (m, 2H), 8.09 (d, J = 9.2 Hz, 1H), 7.787.57
(m, 4H), 7.557.50 (m, 3H), 2.54 (s, 3H);
13
CNMR (100 MHz, CDCl
3
) δ 164.9, 159.7,
150.7, 150.0, 145.5, 138.0, 137.9, 136.4, 130.6, 129.2, 128.6, 128.5, 124.6, 124.4, 121.2,
22.0; HRMS (m/z) [M + H]
+
calcd for C
20
H
16
N
3
, 298.1339, found 298.1337.
N
+
O
O
–
NHBn
NaOH
H
HO
–
N
O
Reasonable
O
NHBn
II
H
2
O
OH
NHBn
H
VI
N
N
OMe
Bn
N
O
NBn
OH
H
IIIb
N
+
O
–
HN
N
Ph
I
2
, KI, K
2
CO
3
DMSO, 100 °C
N
N
Ph
99%
1o
2o
N
N
NH
OMe
O
N
FBr
N
N
Vandetanib
4 Mechanism Problems from Reactions Give Expected Products266
The Mechanism
The initial step involves the oxidation (dehydrogenation) of phenylbenzimidamide
(1) using I₂ in the presence of a base. This is followed by an oxidative cyclization
facilitated by I₂ and the base.
Problem 108: Carbon Dioxide Mediated Synthesis of Quinazoline-2,4(1H,3H)-
dione
Quinazoline-2,4(1H,3H)-diones, such as compound 2, is an important pharmaco-
phore in several drugs such as alfuzosin, prazosin, and doxazosin. Recently, Rasal
and Yadav developed a process for preparation of quinazoline-2,4(1H,3H)-diones
from 2-aminobenzonitriles mediated by CO
2
with DMF in water. When an electron
withdrawing group (F, Cl, NO
2
) attached on the benzene ring, some side products
were also obtained [313].
Please suggest a mechanism for the reaction.
Experimental Procedure (from Org. Process Res. Dev., 2016, 20, 2067)
Reaction Procedure. All reactions were carried out in a 100 mL autoclave as dis-
cussed in our recent report. In a typical experiment, 10 mmol of 2-aminobenzonitrile
(ABN) (or another substrate) and 5 equiv of DMF in 30 mL of water were taken
in the reactor. The reactor was flushed two to three times with CO
2
to remove
unwanted air. The temperature was increased to the desired value (150 °C), and
5 MPa of CO
2
was then introduced in the reactor and maintained for 5 h. After com-
pletion of the reaction, the reactor was cooled naturally to room temperature and
N
N
Py
Ph
H
I I IK
Base
N
N
Py
Ph
I
H
Base
N
N
Py
Ph
K
2
CO
3
, I
2
I
I
N
N
Py
Ph
I
H
N
N
Py
Ph
I
H
Base
N
NPh
1
2
N
Base
KHCO
3
KI
K
2
CO
3
IK
I
KHCO
3
KI
K
2
CO
3
I
2
K
2
CO
3
KHCO
3
KI
K
2
CO
3
KHCO
3
KI
+
−
CN
DMF (5 eq.), CO
2
(5 MPa)
H
2
O, 150 °C, 5 h
N
H
NH
O
O
1
2 (85–99%)
N
N
N
Prazosin
O
N
O
O
N
N
NH
2
N
Alfuzosin
O
O N
H
O
O
N
N
N
Doxazosin
O
O
N
O
O
O
R
R
N
H
N
O
3 (3–10%, R
=
F, Cl, NO
2
)
R
NH
2
NH
2
NH
2
O
4.7 Formation of Bicyclic and Polycyclic Aromatic Heterocycles 267
then CO
2
was released. The product was separated from the reaction mass by simple
filtration. Then, recrystallization of the product was done in water, and the product
was weighed to obtain the yield of the reaction. The product was analyzed by HPLC
(area normalization method) and characterized by mass and NMR.
6,7-Dimethoxy Quinazoline-2,4(1H,3H)-dione (2).
1
HNMR (500 MHz,
DMSO-d
6
) δ 11.09 (s, 1H), 10.94 (s, 1H), 7.21 (d, J = 6.1 Hz, 1H), 6.66 (s, 1H), 3.81
(s, 3H), 3.76 (s, 3H);
13
CNMR (126 MHz, DMSO-d
6
) δ 162.86, 155.31, 150.88, 145.44,
136.95, 107.52, 106.6, 98.17, 56.17.
The Mechanism
A plausible mechanism was initially proposed by the authors in the literature [314].
However, several inaccuracies were identified in the published mechanism, which
does not meet the criteria for a well-defined mechanism. Below is my interpreta-
tion of the authors’ proposed pathway. Under high-pressure conditions (5 MPa) in
water, CO
₂
is partially converted into carbonic acid, which exhibits greater electro-
philicity compared to CO
₂
. Subsequently, carbonic acid is attacked by DMF, forming
an activated species A, analogous to the Vilsmeier–Haack reagent. This activated
species is then attacked by the -NH₂ group in ABN, 1, followed by the elimination of
Me₂NH, yielding the formylated intermediate B. Intermediate B undergoes hydro-
lysis in a mild acidic medium (H₂CO₃) to produce intermediate C. The hydrolyzed
product then cyclizes to form the hydroxyl intermediate D. Further oxidation of
hydroxyl intermediate D leads to the formation of quinazoline-2,4(1H,3H)-dione
(2). Dehydration of D could result in the side product quinazolin-4(3H)-one (3). In
this mechanism for the formation of 2, DMF serves as the carbon source, while CO₂
primarily acts as an activator.
CO
2
+
H
2
O
HO OH
O
O
N
DMF
O N
+
HO
O
HO
HCO
–
3
A
H
2
N
NC
R
1
H
N
NC
R
N
O
H
2
CO
3
H
H
N
R
Me
2
NH
O
N
OH
2
N
R
HN
OH
O
H
HN
H
N
R
O
O
2
B
C
H
HN
H
N
R
HO
O
D
Oxidation
HN
N
R
O
Dehydration
H
2
O
3
HO
–
N
+