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4 Mechanism Problems from Reactions Give Expected Products238
(probably the salt of ethylenediamine and benzoic acid). This mixture could still be
thoroughly stirred with a magnetic stirrer. After cooling to 0 °C, trimethyl phosphite
(3.31 mL, 28.0 mmol, 1.4 equiv) was added, followed by the dropwise addition of
the crude oxime. The oxime container was rinsed with 3-picoline (3.0 mL, 31 mmol,
1.5 equiv), and this solution was also added to the reaction mixture. After stirring
at 0 °C for 0.5 h and at room temperature for 3.5 h, the mixture was heated to 70 °C
for 0.5 h and then cooled to 0 °C. Bromine (2.56 mL, 50.0 mmol, 2.5 equiv) was then
added dropwise within 5 min. The mixture was stirred at 0 °C for 0.5 h and then at
room temperature for 1.5 h. The mixture was cooled to 0 °C and added to an ice-cold
mixture of concentrated aqueous hydrochloric acid (67 mL, 0.70 mol, 35 equiv) and
water (200 mL). After adding sodium bisulfite (3.12 g, 30.0 mmol, 1.5 equiv), the
product was extracted with butyl acetate (3 × 50 mL), and the combined extracts
were washed with brine (100 mL), with a solution of potassium carbonate (15 g,
0.11 mol) in water (100 mL), with brine (100 mL), dried (MgSO
4
), and concentrated
under reduced pressure. The residue was purified by chromatography over silica gel
(30 g; gradient elution with heptane/ethyl acetate). Pyrazine 1 was obtained as an
oil (1.81 g, 40% yield, 99% pure by
1
HNMR content determination with triisobutyl
1
HNMR (CDCl
3
, 400 MHz) δ 8.85 (m, 1H), 8.81
(m, 1H), 4.52 (q, J = 7 Hz, 2H), 1.44 (t, J = 7 Hz, 3H);
13
CNMR (CDCl
3
, 100 MHz)
δ 163.7, 146.3, 145.3, 144.7, 141.6 (q, J = 37 Hz), 120.6 (q, J = 274 Hz), 63.2, 13.9;
19
FNMR (CDCl
3
, 377 MHz) δ − 66.2; DSC (4 K/min) dec onset 173 °C, dec energy
11 J/g.
The Mechanism
The ketooxime 4 isomerizes to the enol form A. Then trimethyl phosphite attacks the
N═O group to give the adduct B. Cyclization of B provides the highly electrophilic
oxazaphosphole C, which is in turn attacked by ethylenediamine (mono-benzoate
form) to generate the ring open intermediate D with elimination of trimethyl phos-
phate and benzoic acid. After D being isomerized to oxime E, recyclization occurs
to yield intermediate 5. Finally bromine-mediated dehydrogenation leads to pyr-
azine 1.
CO
2
Et
CF
3
O
3
BuONO (1.2 eq.)
PhCO
2
H (0.15 eq.)
0 °C, 2 h; 20 °C, 24 h
O
4
N
HO
Add to mixture of
PhCO
2
H (3.5 eq.)
ethyllenediamine (1.3 eq.)
P(OMe)
3
(1.4 eq.) in
3-picoline
0 °C, 0.5 h; rt, 3.5 h;
70 °C, 0.5 h
N
H
N
5
Br
2
0 °C, 0.5 h; rt, 1.5 h
40%
N
N
CF
3
1
N
N
2
N
H
O
F
F
CO
2
Et
CF
3
CO
2
Et
CF
3
CO
2
Et
CF
3
4.6 Formation of Monocyclic Aromatic Heterocycles 239
4.6.12 Triazole
Problem 93: Preparation of [1,2,4]Triazolo[1,5-a]pyridin-2-amine
In 1983, Tisler’s group reported the preparation of a series of heterocyclic com-
pounds [271], including [1,2,4]triazolo[1,5-a]pyridin-2-amine (2) from the thiourea
1. Recently, Tisler triazolopyrimidine cyclization had been applied to the synthesis
of JAK inhibitors CEP-33779 [272, 273], filgotinib [274], VEGFR-2 kinase inhibitor
(3) [275], as well as crop protection agent (4) [276].
Please suggest a mechanism for the reaction from 1 to 2.
Experimental Procedure (from Monatsh. Chem., 1983, 114, 789)
[1,2,4]Triazolo[1,5-a]pyridin-2-amine (2). 2.25 g of 1 was suspended in 100 mL
of ethanolic solution of free hydroxylamine (prepared from 0.7 g sodium, ethanol
and 3.5 g of hydroxylamine hydrochloride) and the mixture was heated under reflux
CO
2
Et
O
4
N
HO
CF
3
HO
N
O
HO
N
(MeO)
3
+
P
O
N
OH
P
MeO
MeO
MeO
NH
2
H
3
+
N
PhCO
2
−
HN
OH
N
H
PO(OMe)
3
PhCO
2
H
N
OH
N
H
NH
2
N
H
N
5
NH
2
OH
N
N
1
E
N
H
N
H
Br
Br
Br
2
HBr
N
H
N
Br
H
HBr
N
H
N
Br
Br
H
Br
2
HBr
N
H
N
Br
HBr
A
B
C
D
CO
2
Et
P(OMe)
3
CF
3
CO
2
Et
CF
3
O
−
CO
2
Et
CF
3
CO
2
Et
CF
3
CO
2
Et
CF
3
CO
2
Et
CF
3
CO
2
Et
CF
3
CO
2
Et
CF
3
CF
3
CO
2
Et
CO
2
Et
CF
3
CO
2
Et
H
2
N
CF
3
N
N
N
NH
2
F
3
C
N
H
N
H
N OEt
S O
1
NH
2
OH, EtOH
reflux, 2 h
63%
2
[1,2,4]triazolo[1,5-a]pyridin-2-amine
N
N
N
NH
Filgotinib
N
S
O
O
O
N
N
N
NH
CEP-33779
S
N N
O
O
N
O
F
H
N
O
N
N
3, VEGFR-2 inhibitor
N
N
HN
O
N
N
N
N
NH
S
O
O
N
OMe
OMe
MeO
4
4 Mechanism Problems from Reactions Give Expected Products240
for 2 h. During the reaction, hydrogen sulfide was evolved. The solvent was then
evaporated in vacuo and the residue was extracted with CHCl
3
. The oily residue
was crystallized from benzene (0.84 g, 63%), m. p. 110–112 °C (Lit [274]. m. p. 108–
109 °C). MS (m/e): 134 (M
+
). NMR (CDC1
3
): 7.88 (m, H5), 6.50 (m, H6), 7.00 (m, H7
and H8), 4.60 (broad, NH
2
).
The Mechanism
The first step is the thio group replaced by hydroxylamine to give the corresponding
hydroxyimino derivative A, which is subsequently cyclized with the participation
of the ethoxycarbonyl group to form B. Upon heating, with the participation of the
nitrogen in pyridine, elimination of carbon dioxide from B provides the product 2.
As the by-product H
2
S was easily oxidized by air during the reaction, some prod-
ucts contained a certain level of sulfur. The amount of residual sulfur decreased
when the reaction was conducted under N
2
atmosphere [276].
4.6.13 Oxadiazole
Problem 94: Formation of 1,3,4-Oxadiazole
1,3,4-Oxadiazole 3 is an important building block for constructing raltegravir. It was
synthesized from acetonitrile in a three-step sequence [277]. Treatment of acetoni-
trile with NaN
3
in the presence of AlCl
3
provided the tetrazole 1 [278]. Acylation
of tetrazole 1 with ethyl oxalyl chloride afforded intermediate 2, which was heated
at 70 °C to form the oxadiazole ester. Direct KOH-mediated hydrolysis afforded the
corresponding potassium salt 3 as a crystalline solid, in 91% overall yield.
Please propose mechanisms for the synthesis of 3 from acetonitrile.
N
N
N
NH
2
N
H
N
H
N OEt
S
O
1
NH
2
OH, EtOH
reflux, 2 h
63%
2
N
H
N
H
N
OEt
N O
OH
EtOH
N
N
H
N
O
N O
H
H
2
S
CO
2
NH
2
OH
N
H
N
H
N
OEt
HS
O
NOH
A
B
H
NH
2
OH
H
N
N
N
O
OH
H
N
O
F
O
O
N
N
Raltegravir
NaN
3
AlCl
3
CH
3
CN
N
N
N
NH
Cl
CO
2
Et
O
N
N
N
N
O
70 °C
O
N
N
CO
2
K
3
1
2
O
N
N
KOH
91%
from 1
Steps
CO
2
Et
CO
2
Et
4.6 Formation of Monocyclic Aromatic Heterocycles 241
Experimental Procedure (from Org. Process Res. Dev., 2011, 15, 73)
Potassium 5-Methyl-[1,3,4]oxadiazole-2-carboxylate (3). Ethyl oxalyl chloride
(4.01 kg, 29.4 mol) was slowly added to a mixture of methyl tetrazole 1 (2.50 kg,
29.7 mol; while 5-methyl-tetrazole is not rated an explosive material (see: http://www.
chemicalbook.com/ChemicalProductProperty_EN_CB4290179.htm), it is an irri-
tant and highly flammable. It should be handled only after all hazard data has been
reviewed and proper PPE obtained) and triethylamine (3.03 kg, 30.0 mol) in tol-
uene (32 L) at 0 °C at such a rate that the temperature stayed below 5 °C at all times.
(Caution: 2 is a potentially explosive intermediate that will quickly generate nitrogen
gas at <50 °C. Conduct this chemistry only after training for handling explosive com-
pounds, and conduct the heating only behind a shield.) The slurry was stirred for
1 h at 0–5 °C. The triethylamine hydrogen chloride salt was filtered off. The solid
was washed with 27 L of cold toluene (5 °C). The combined filtrates were kept at
0 °C at all times and were slowly added to a hot solution of toluene (50 °C, 15 L) over
40–50 min. (Caution: N
2
gas evolves. Use the same precautions during heating as
above.) Most of the intermediate 2 had been converted to the corresponding non-
explosive oxadiazole ester at this moment. The solution was continually stirred at
70 °C for 1 h. After cooling to 20 °C, the toluene solution was washed with 5 L of
10% brine, and solvent was switched to ethanol. EtOH was added to adjust the final
volume to approximately 40 L. The solution was cooled to 10 °C and aqueous KOH
(8.0 L) was added over 30 min. The resulting thick slurry was then stirred for 40 min
at room temperature while the oxadiazole K salt crystallized. The solid was collected
by filtration and washed with EtOH (11 L) and MTBE (15 L). The crystalline solid
was dried overnight under vacuum at 20 °C with nitrogen sweep to give oxadiazole K
salt 3 (4.48 kg) in 91% yield, mp 258.3 °C dec.
1
HNMR (400 MHz, CD
3
OD/D
2
O) 2:1)
δ: 2.62 (S, 3H);
13
CNMR (100 MHz, CD
3
OD/D
2
O) 2:1) δ: 165.8, 161.8, 158.3, 9.8. MS
(FAB) m/z 129 (corresponding to free acid, M + H, 100%).
The Mechanism
The first stage is a [3+2] cycloaddition. The acylated intermediate 2 was heated to
release one molecule of N
2
, followed by recyclization to afford the oxadiazole ester.
Problem 95: Preparation of 1,2,4-Oxadiazole
1,2,4-Oxadiazole is an important subunit in some drugs such as opicapone, a medi-
cation for Parkinson’s disease. In a patent application [279], 5-(2-nitrophenyl)-1,2,4
-oxadiazole (2) was prepared from 2-nitrobenzamide (1) by the following reactions.
Please provide mechanisms for the transformation from 1 to 2.
N
N Na
AlCl
3
N
N
N
NH
1
Then aq.
workup
Cl
O
N
N
N
N
O
2
N
2
N
O CO
2
Et
+
O
N
N
O
N
N
3
KOH
AlCl
3
−
N N
+
N
–
CO
2
Et
CO
2
Et
CO
2
Et
CO
2
K
4 Mechanism Problems from Reactions Give Expected Products242
Experimental Procedure (from WO2018/144620, 2018, A1)
N-[(E)-(dimethylamino)methylidene]-2-nitrobenzamide (A). 2-Nitrobenzamide
(1, 1.00 g, 6.02 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (4.0 mL,
30 mmol) were stirred at 100 °C for 1 h. The mixture was filtered, washed with hexane,
and dried under reduced pressure at 50 °C to give 1.03 g (A, 100% purity, 78% yield) of
the target compound, which was used without further purification. LCMS (Method 2):
R
t
= 0.76 min; MS (ESIpos): m/z = 222 [M + H]
+
.
1
H-NMR (400 MHz, DMSO-d
6
): δ
[ppm] = 3.03 (d, 3H), 3.20 (s, 3H), 7.63–7.73 (m, 2H), 7.78–7.82 (m, 1H), 7.92 (dd, 1H),
8.58 (t, 1 H).
5-(2-Nitrophenyl)-l,2,4-oxadiazole (2). To a solution of hydroxylamine hydro-
chloride (0.98 g, 14.1 mmol, 1.3 equiv.) in sodium hydroxide (5 M, 2.8 mL, 1.3
equiv.) was added (E)-N-(dimethylaminomethylene)-2-nitrobenzamide (A, 2.4 g,
10.8 mmol, 1.0 equiv.) portionwise over 5 minutes at 20 °C and the mixture stirred
at 20 °C for 0.5 hours. The mixture was diluted with water (10 mL) and extracted
with DCM (10 mL × 3). The organic layer was dried and concentrated under
reduced pressure to give (E)-N-((hydroxyamino)methylene)-2-nitrobenzamide (B,
1.20 g) which was used directly without further purification. A mixture of (E)-N-
((hydroxyamino)methylene)-2-nitrobenzamide (B, 0.9 g, 4.30 mmol, 1.0 equiv.) in
acetic acid (7 mL) and dioxane (7 mL) was stirred at 90 °C for 2 hours. The mix-
ture was concentrated under reduced pressure and the residue was purified by silica
gel chromatography (petroleum ether-ethyl acetate 10: 1 to 5: 1) to give the desired
product as a light yellow solid (0.4 g, 49%);
1
HNMR (DMSO-d
6
, 400 MHz) δ 9.25
(s, 1H), 8.23–8.21 (m, 1H), 8.13–7.11 (m, 1H), 7.99–7.95 (m, 2H).
The Mechanism
Step 1. Formation of (E)-N-((dimethylamino)methylene)-2-nitrobenzamide (A)
Step 2. Hydroxylamine replaced dimethylamine, formation of (E)-N-
((hydroxyamino)methylene)-2-nitrobenzamide (B)
Step 3. Cyclization and dehydration to form 5-(2-nitrophenyl)-1,2,4-oxadiazole (2)
N
N
O
2
ONO
2
1
DMF-DMA
N
O
N
A
N
O
B
N
H
OH
NH
2
NO
2
NH
2
OH
NO
2
NO
2
O
N
N
NH
2
O
1. DMF-DMA, 120 °C, 2 h
2. NH
2
OH.HCl, 5 N NaOH
20 °C, 0.5 h
NO
2
3. HOAc, 90 °C, 2 h
1
2
O
N
N
N
+
HO
HO
O
2
N
Cl
Cl
Opicapone
NO
2
O
–
NH
2
ONO
2
1
OMe
N
MeO
DMF-DMA
MeOH
N
O
N
OMe
H
MeOH
N
O
N
A
NO
2
NO
2
4.6 Formation of Monocyclic Aromatic Heterocycles 243
4.6.14 Thiadiazole
Problem 96: Formation of 1,2,4-Thiadiazole
Z-Isomer of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetic acid (1) is a
side chain of cephem antibiotics such as SCE2787 [280]. Tatsuta’s group reported
the synthesis of the key intermediate (2) from malononitrile (3) by the following
reaction sequence [281].
Please provide reaction mechanisms from 3 to 2.
Experimental Procedure (from Bull. Chem. Soc. Jpn., 1994, 76, 1701)
3,3-Dimethoxyacrylonitrile (4). To a stirred solution of malononitrile (3, 12.0 g,
182 mmol) and methanol (7.35 mL, 182 mmol) in dry ether (240 mL) was bubbled
hydrogen chloride gas (8.5 g, 230 mmol) during 1 h at 5 °C. After stirring at the
same temperature for 1 h and at room temperature for 6 h, the formed crystals were
filtered off, washed with ether, and dried in vacuo to give methyl cyanoacetimidate
hydrochloride (23.8 g, 98%).
N
ONO
2
N
A
H
2
N
OH
N
O
N
HN
OH
H
OH
Me
2
NH
N
O
B
N
H
OH
H
2
N
NO
2
NO
2
N
ONO
2
B, E-form
N
H
OH
Isomerization
N
O
B, Z-form
NH
O
H
N
N
O
OH
H
H
2
O
N
N
O
2
O
2
N
NO
2
NO
2
1
N
S
N
N
MeO
2
N
S
N
MeO
2
C
H
N
O
O
N
N
3
1. HCl, MeOH
2. MeOH
3. 225 °C
MeO
MeO
CN
4
NH
2
OH.HCl
EtOH-H
2
O
O
N
MeO
5
O NCS
O
CH
3
CN
Steps
SCE2787
N
S
N
HO
2
C
H
N
N
MeO
N
N
+
N
O
CO
2
–
Steps
HO
2
C
NH
2
NH
2
4 Mechanism Problems from Reactions Give Expected Products244
A suspension of methyl cyanoacetimidate hydrochloride (23.8 g, 177 mmol) in
methanol (177 mL) was stirred at room temperature for 12 h and the reaction mix-
ture was concentrated to a residue, which was dissolved in EtOAc. The solution
was washed with saturated aqueous Na
2
CO
3
and saturated NaCl, dried, and concen-
trated. The crude syrup obtained was purified by distillation under reduced pressure
to give 3,3,3-trimethoxypropionitrile (22.1 g, 86%) as a syrup: Bp 110–112 °C/2533
Pa;
1
HNMR δ = 2.87 (2H, s, CH
2
) and 3.36 (9H, s, 3 Me).
A syrup of 3,3,3-trimethoxypropionitrile (22.1 g, 153 mmol) was stirred at 222–
225 °C for 7 min. The reactant was distilled under reduced pressure to give 4 as a
syrup (14.2 g, 70% from 3): Bp 112–115 °C/2533 Pa;
1
HNMR δ = 3.50 (1H, s, H-2)
3.74 (3H, s, OMe), and 3.80 (3H, s, OMe). Found: C, 52.91; H, 6.10; N, 12.04%. Calcd
for C
5
H
7
NO
2
: C, 53.09; H, 6.24; N, 12.38%.
3-Amino-5-methoxyisoxazole (5). To a stirred solution of hydroxylamine
hydrochloride (1.55 g, 22.3 mmol) in water (3.41 mL) was added 8 M NaOH solution
(3.35 mL, 26.8 mmol) at room temperature. After the solution warmed to 45 °C, a
solution of 4 (2.27 g, 20.1 mmol) in methanol (5.50 mL) was added dropwise during
30 min, and the resulting mixture was stirred at the same temperature for 1 h. After
the consumption of 4 was completed, 8 M NaOH solution (1.25 mL, 10.1 mmol) was
added at 45 °C, and the reaction mixture was stirred at 60 °C for 6 h and then con-
centrated until precipitates of inorganic compound separated out. The mixture was
extracted with EtOAc and then the extracts were dried and evaporated to a residue.
Recrystallization from hexane-EtOAc gave 5 as colorless crystals (1.71 g, 75%): Mp
82–83 °C; IR (CHCl
3
) 3840, 1628, and 1487 cm
1
;
1
HNMR (CDCl
3
+ D
2
O) δ = 3.93
(3H, s, OMe), and 4.83 (1H, s, H-4). Found: C, 41.74; H, 5.06; N, 24.35%. Calcd for
C
4
H
6
N
2
O
2
: C, 42.11; H, 5.30; N, 24.55%.
Methyl 2-(5-methoxycarbonylamino-1,2,4-thiadiazol-3-yl)acetate (2). A
suspension of methyl chloroformate (0.927 mL, 12 mmol) and potassium thiocy-
anate (KSCN) (1.26 g, 13 mmol) in MeCN (10 mL) was stirred at 70 °C for 30 min
and, after ice-cooling, 5 (1.14 g, 10 mmol) was added under stirring. The reaction
mixture was further stirred at 5 °C for 10 min and at room temperature for 15 min,
and poured into ice water (18 mL). The formed precipitates were filtered off, washed
successively with water and ether, and dried in vacuo. Recrystallization from MeOH
gave 2 as colorless crystals (1.98 g, 86%): Mp 167–169 °C; IR (CHCl
3
) 3406, 1736, and
1549 cm
1
;
1
HNMR δ = 3.73 (3H, s, COOMe), 3.95 (NCOOMe), 3.97 (2H, s, CH
2
),
and 10.50 (1H, br s, NH). Found C, 36.40; H, 3.94; N, 18.11%. Calcd for C
7
H
9
N
3
O
4
S:
C, 36.36; H, 3.92; N, 18.17%.
The Mechanism
The process begins with the addition of methanol to the acid-activated nitrile
group in malononitrile (3), forming acetimidate A. A second methanol addition
to A yields 3-amino-3,3-dimethoxypropanenitrile (B), which is then converted to
3,3,3-trimethoxypropionitrile (C) by replacing the amino group with a methoxy
group. At elevated temperatures, the elimination of one molecule of methanol from
C produces 3,3-dimethoxyacrylonitrile (4).
4.6 Formation of Monocyclic Aromatic Heterocycles 245
Next, hydroxylamine reacts with the nitrile group in 4 to form imidamide D. An
intramolecular Michael addition of the hydroxyl group to the C═C double bond
results in the formation of dihydroisoxazole E. Following the elimination of another
methanol molecule, 5-methoxyisoxazol-3-amine (5) is generated.
The final step involves the reaction of the amino group in 5 with O-methyl car-
bonisothiocyanatidate (F), leading to the formation of thiourea H via intermediate
G. Subsequently, the thio group attacks the isoxazole ring, forming 1,2,4-thiadiazole
I, which readily tautomerizes to yield the final product 2.
Direct elimination of NH
3
in the presence of HCl from intermediate C will also
generate intermediate 4.
Intermediate F is generated in situ from methyl chloroformate and KSCN.
4.6.15 Triazine
Problem 97: Synthesis of 1,2,3-Triazines
Methoxatin is a natural product and shows the ability to reduce damage in
ischemia-reperfusion injury of a heart attack or stroke. 1,2,3-Triazines (6) is applied
in the synthesis of methoxatin. Boger’s group reported the preparation of a series
of 1,2,3-triazines (6) by the following reactions [282, 283]. One of the reported
NN
H
+
O
H
CNHN
MeO
H
+
Cl
–
O
H
CNH
2
N
MeO
MeO
MeO
MeO
3
4
MeOH
HCl
NH
4
Cl
NH
2
OH HCl
OH
NH
2
N
OMe
MeO
C
NH
O
N
OMe
MeO
H
O
N
NH
2
MeO
5
N
CO
2
Me
C
S
O
N
H
N
MeO
N
C
S
H
O
N
N
MeO
NH
S
H
2
N
S
N
NH
N
S
N
NH
O
H
MeO
N
HO
H
MeOH
A
B
D
E
G
H
I
O
H
CNMeO
MeO
MeO
C
H
MeOH
F
H
+
Cl
–
NH
2
CO
2
Me
CO
2
Me
CO
2
Me
CO
2
Me
CO
2
Me
CNH
2
N
MeO
MeO
NH
4
Cl
B
CNMeO
MeO
4
H
+
Cl
–
H
HCl
Cl OMe
O
KS N
KCl
N
CO
2
Me
C
S
F
4 Mechanism Problems from Reactions Give Expected Products246
preparations of compound 3 in 95% yield is achieved just by heating both starting
materials (1 and 2) neat at 80 °C for 30 minutes [284].
Please provide mechanisms stepwise for the synthesis from starting materials
(1 and 2) to 3 and 6.
Experimental Procedure (from Org. Lett., 2014, 16, 5084, Supporting Information)
Diethyl 1-amino-1H-pyrazole-3,5-dicarboxylate (5). A solution of t-BuOK
(775 mg, 6.91 mmol) in N-methyl-2-pyrrolidone (NMP) (6.9 mL) was added to a
stirred solution of 3,5-dicarboethoxypyrazole (3, 1.33g, 6.28 mmol) in NMP (8.1 mL).
The reaction mixture was stirred for 20 min at room temperature and then a solu-
tion of O-4-nitrobenzoylhydroxylamine (4, 1.14 g, 6.28 mmol) in NMP (4.3 mL) was
added dropwise while keeping the internal reaction temperature below 25 °C. The
reaction mixture was stirred at room temperature for 1 h. After 1 h, 10% aqueous
NaCl (25 mL) and EtOAc (25 mL) were added to the reaction mixture. The organic
layer was separated and the aqueous layer was extracted with EtOAc (25 mL). The
combined organic extracts were washed with 5% aqueous NaHCO
3
(15 mL) and
H
2
O (3 × 15 mL), dried over Na
2
SO
4
, and concentrated on a rotary evaporator. Flash
chromatography (SiO
2
30% EtOAc/hexanes) provided the title compound (1.22 g,
86%) as an off-white solid: mp 6364 °C;
1
HNMR (CDCl
3
, 600 MHz) δ 7.18 (s, 1H),
6.84 (bs, 2H), 4.33 (q, J = 7.2 Hz, 2H), 4.31 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H),
1.31 (t, J = 7.2 Hz, 3H);
13
CNMR (CDCl
3
, 100 MHz) δ 161.2, 159.8, 137.4, 127.54,
127.49, 111.89, 111.84, 61.8, 61.2, 14.3, 14.1; IR (film) v
max
1714, 1532, 1270, 1218,
1200, 1160, 1109, 1078, 998, 960, 926, 853, 757, 718 cm
1
; HRESI-TOF m/z 228.0980
(C
9
H
13
N
3
O
4
+ H
+
requires 228.0979).
Diethyl 1,2,3-Triazine-4,6-dicarboxylate (6). Diethyl 1-amino-1H-pyrazole-
3,5-dicarboxylate (5, 340 mg, 1.50 mmol) was dissolved in CH
2
Cl
2
20% aqueous
KHCO
3
(15 mL, 1:1), cooled in an ice bath, and stirred while I
2
(570 mg, 2.25 mmol)
in CH
2
Cl
2
(15 mL) was added by an addition funnel. The reaction mixture was
stirred at room temperature for 1 h. After 1 h, saturated aqueous Na
2
SO
3
was added
to quench the reaction mixture and the organic layer was separated. The aqueous
layer was extracted with CH
2
Cl
2
(2 × 25 mL). The combined organic layers were
HN
Methoxatin
N
HO
2
C
O
O
N
N
N
I
2
, KHCO
3
DCM, H
2
O
46%
N
N
H
2
N
O
2
N
O
O
NH
2
t-BuOK, NMP, rt, 1 h
86%
CO
2
Et
EtO
2
C
+
Neat, 80 °C
30 min
95%
HN
N
6
5
1
2
3
4
Steps
N
2
EtO
2
C
CO
2
Et
CO
2
H
HO
2
C
CO
2
Et
EtO
2
C
EtO
2
C CO
2
Et
4.6 Formation of Monocyclic Aromatic Heterocycles 247
washed with H
2
O (25 mL), dried over Na
2
SO
4
, and concentrated on a rotary evap-
orator. Flash chromatography (SiO
2
, 3% acetone/toluene) provided 6 (142 mg, 42%;
40–46%) as a yellow solid: mp 85 °C (hexanes);
1
HNMR (CDCl
3
, 400 MHz) δ 8.55
(s, 1H), 4.61 (q, J = 7.2 Hz, 4H), 1.51 (t, J = 7.2 Hz, 6H);
13
CNMR (CDCl
3
, 100 MHz)
δ 162.6, 151.4, 117.7, 64.3, 14.6; IR (film) v
max
1721, 1384, 1368, 1351, 1263, 1092,
1014, 957, 857, 803, 761, 718 cm
1
; HRESI-TOF m/z 226.0822 (C
9
H
11
N
3
O
4
+ H
+
requires 226.0822).
The Mechanism
The formation of 3 is a [3+2] cycloaddition.
The formation of 5 is an amination of the pyrazole 3 by the reagent 4 under
strong base.
Possible mechanism A. The mechanism for the formation of 1,2,4-triazines (6) from
N-aminopyrazoles is proposed in the literature [285]. The amino nitrogen is inserted
between the two nitrogens in the pyrazole via nitrene transition state. Iodine plays
the oxidant role.
The following mechanism is also reasonable.
Possible mechanism B.
Possible mechanism C.
CO
2
Et
EtO
2
C
N
–
[3+2]
N
N
H
H
+
Isomerization
HN
N
1
2
3
CO
2
Et
CO
2
Et
EtO
2
C
CO
2
Et
N
+
NO
2
O
O
H
2
N
N
N
EtO
2
C
CO
2
Et
3
H
t-BuO
−
N
−
–N
t-BuOH
O
2
N
CO
2
–
N
N
H
2
N
5
4
EtO
2
C
t-BuO
−
CO
2
Et
EtO
2
C
CO
2
Et
N
N
NH
2
EtO
2
C
CO
2
Et
I
I
N
N
N
I
HI
H
Base
H
+
N
N
I
N
Nitrene
N
N
I
5
EtO
2
C
CO
2
Et
EtO
2
C
CO
2
Et
EtO
2
C
N
–
I
–
I
–
N
–
N
+
CO
2
Et
N
N
N
6
CO
2
Et
EtO
2
C
CO
2
Et
N
–
EtO
2
C