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4 Mechanism Problems from Reactions Give Expected Products208
followed by the addition of Na
2
CO
3
(2.0 equiv) and NaCN (2.0 equiv). The vial was
sealed and aged at room temperature with rapid stirring for 1 h. For cases where
assay yields were determined, the entire reaction mixture was diluted in a volu-
metric flask with 3:1 MeCN: 0.1% aqueous H
3
PO
4
and the resulting solution was ana-
lyzed on an HPLC instrument calibrated to the product standard. The concentration
of the 2-cyanopyridine product was determined and used to calculate the yield of
the product. For cases where the product was isolated, the reaction mixture was
diluted with isopropyl acetate, and washed twice with water and once with brine.
The organic solution was dried over MgSO
4
, and the product was purified by silica
gel chromatography using a TeleDyne Isco CombiFlash purification system.
2-cyano-4-phenylpyridine (3). The compound was prepared using the standard
procedure on 0.5 mmol scale. The product was purified on silica gel with a gradient
of 0–50% EtOAc in hexanes, and obtained as a white solid in 84% yield.
1
HNMR
(500 MHz, Acetonitrile-d
3
) δ 8.72 (dd, J = 5.2 and 0.6 Hz, 1H), 8.11 (dd, J = 1.8
and 0.7 Hz, 1H), 7.86 (dd, J = 5.2 and 1.9 Hz, 1H), 7.79 – 7.72 (m, 2H), 7.59 – 7.48
(m, 3H).
13
CNMR (126 MHz, Acetonitrile-d
3
) δ 152.55, 150.31, 136.85, 135.08,
131.12, 130.38, 128.10, 127.63, 125.83.
The Mechanism
Compound 1 functions as a bifunctional reagent, playing a dual role in the reaction
mechanism. Initially, it acts as an electrophilic activator, promoting nucleophilic
addition to the pyridine ring. Subsequently, in the presence of a base, compound
1 serves as a two-electron oxidant, facilitating the re-aromatization of the dihy-
dropyridine intermediate (C). However, it was observed that the formation of the
intermediate pyridinium chloride salt (A) was thermodynamically unfavorable,
with the reaction equilibrium heavily favoring the starting materials. To address this,
a stoichiometric amount of NaOTf was introduced, which enhanced the conversion
to the pyridinium salt (B) by driving the precipitation of NaCl, thereby shifting the
equilibrium toward the desired product.
N
O
S
Cl
O O
1
+
N
Ph
2
1. TfONa (1.2 eq.)
CH
3
CN, 80 °C
2. NaCN (2 eq.)
Na
2
CO
3
, DMF
rt, 1 h
N
Ph
3 (84%)
CN
O
O
N
H
H
O
O
N
H
H
CN
4
80%
5, 2.5:1 two isomers
4.6 Formation of Monocyclic Aromatic Heterocycles 209
Pyridine substrates bearing 3-halogen and oxygen substituents predominantly
yielded 2-cyano-3-substituted pyridines, with a selectivity ratio of 2-cyanation to
6-cyanation exceeding 95:5. In the case of isoquinolines, cyanation exclusively pro-
duced 1-cyano products. These findings align with the mechanism of nucleophilic
addition occurring at the most electrophilic carbon of the pyridinium intermediate
[207]. Substrates with bulkier or less polar groups at the C-3 position resulted in
mixtures of two isomers. Notably, 4-cyanopyridine products were not detected
under any conditions.
Problem 75: Synthesis of 2-Arylpyridines from Acetophenones
Vismodegib is a medication for treatment of basal-cell carcinoma. In a man-
ufacturing production of vismodegib, 2-(2-chloro-5-nitrophenyl)pyridine (3)
is a key building block. One of the large-scale (e.g., 128 kg) synthesis of 3 is the
reaction of 1-(2-chloro-5-nitrophenyl)ethan-1-one (1) with 1,3-dimethyl-2-oxo-
2,3-dihydropyrimidin-1-ium chloride (2a) and NH
4
OAc in acetic acid [208].
1,3-Dimethyl-2-oxo-2,3-dihydropyrimidin-1-ium hydrogen sulfate (2b) was also
applied for preparation of 3 [209]. Neither articles mentioned the mechanism of
this pyridine build-up reaction.
Please provide a mechanism for this reaction.
N
O
S
Cl
O O
1
N
R
N
+
R
N
OMs
TfONa
NaCl
(R=4-Ph)
R
N
OMs
TfO
–
NaCN
–
CN
TfONa
N
R
N
OMs
CN
H
N
Ph
3
CN
Na
2
CO
3
+
NaHCO
3
+
MsONa
+
CH
3
CN
A
B
C
2
CI
–
N
+
–
OCO
2
Na
N
O
Cl
–
N
O Cl
NO
2
+
1
2a
NH
4
OAc
HOAc
110–115 °C, 6 h
Cl
NO
2
3
78%
N
Cl
HN O
Cl
S
O
O
Vismodegib
Steps
N N
+
O
HSO
4
–
2b
NH
4
OAc
HOAc, 115 °C, 7 h
88%
3
N
+
4 Mechanism Problems from Reactions Give Expected Products210
Experimental Procedure (from Org. Process Res. Dev., 2016 , 20, 1509, Supporting
Information)
2-(2-chloro-5-nitrophenyl)pyridine 3: 1-(2-Chloro-5-nitrophenyl)ethan-1-one 1
(140.0 kg, 1.0 molar equiv), 1,3-dimethyl-2-oxo-2,3-dihydropyrimidin-1-ium chlo-
ride ( 2, 140.0 kg, 1.2 molar equiv) and ammonium acetate (360 kg) were added to
a 3000 L reactor containing acetic acid (1000 kg), and the mixture was heated to
110–115 °C for 6 hours (IPC, 1 < 5 A% by HPLC). Then water (700 L) was added with
cooling to 0–10 °C and stirred for at least 1 hour. The suspension was centrifuged,
washed with a mixture of methanol (150 L) and water (150 L), and finally with
water (480 L). The crude wet product was dissolved in warmed acetone (2000 L) at
40–50 °C, and the hot solution was polish filtered. After rinsing the used-line with
acetone (50 L), water (660 L) was added dropwise into the filtrate. The mixture was
then cooled to 0–10 °C and stirred for at least 1 hour. The solids were isolated by
centrifugation and washed with a ~5 °C cooled mixture of acetone (75 L) and water
(75 L). The cake was dried under vacuum at 50 °C for about 24 hours to give 3 as a
pale yellow powder (128.4 kg, 78.0% yield, 99.9A% purity by HPLC). MP: 151.3 °C.
1
HNMR* (400 MHz, CDCl
3
) δ 8.77 (1H, ddd, J = 4.8, 1.6, and 1.2 Hz), 8.52 (1H, d,
J = 2.8 Hz), 8.20 (1H, dd, J = 8.8 and 2.8 Hz), 7.83 (1H, td, J = 8.0 and 2.0 Hz), 7.70
(1H, dt, J = 7.6 and 1.2 Hz), 7.66 (1H, d, J = 8.4 Hz), 7.38 (1H, ddd, J = 7.6, 4.8, and
1.2 Hz).
* The
1
HNMR data is interpreted by the author of this book according to the spectrum provided in the
Supporting Information.
The Mechanism
The first stage is an addition (condensation) of the enol form of 1 to 2 to give
intermediate A, followed by ring opening to generate B. Nucleophilic addition
O Cl
NO
2
1
=
Ar
HOAc
Ar
O
H
N
N
+
O
Cl
–
2
2
N
N
O
Ar
O
HCl
H
N
O
NH
Ar
O
NH
3
Ar
O
N
H
O
N
H
HOAc
H
2
N
H
2
O
N
3
Ring
opening
Elimination
urea
Cyclization
dehydration
N
O
NH
Ar
O
NH
2
H
acid activation
“NH
3
” addition
A
B
C
1
NH
4
OAc
Cl
O
2
N
+
H
4.6 Formation of Monocyclic Aromatic Heterocycles 211
of NH
3
, from NH
4
OAc, to the acid-activated B followed by elimination of
1,3-dimethylurea yields the keto-enamine C. Final cyclization and dehydration of C
leads to the pyridine product 3.
Problem 76: Preparation of penta-substituted Pyridone
Chemists form Takeda and Millennium developed a one-pot process for
penta-substituted pyridone (2) from dimethyl-ɑ-flouromalonate (1) [210]. Pyridone
2 is a key intermediate for synthesis of TAK-733, a new MEK inhibitor. In Fochon
Pharma, we also employed this chemistry to build-up our MEK inhibitors, such as
FCN-159, which was recently approved in China [211].
Please provide stepwise mechanisms for the process.
Experimental Procedure (from Org. Process Res. Dev., 2012, 16, 1652)
2-Amino-5-fluoro-4-hydroxy-1-methyl-6-oxo-1,6-dihydropyridine-3-
carbonitrile (2). Dimethyl α-fluoro malonate (1, 3.00 kg, 20.0 mol) and malono-
nitrile (1.32 kg, 20.0 mol) were dissolved in THF (15 L) and cooled to 25 ± 5 °C.
DBU (6.09 L, 39.9 mol) was added over 5 h at <10 °C. Then the reaction mixture
was allowed to slowly warm to room temperature over 2 h and stirred for another
16 h. The reaction progress was monitored with HPLC (Method 4.2.6.). Aqueous
methylamine (40%, 14.1 L, 133 mol) was added dropwise, and the reaction mixture
was stirred for another 2 h at room temperature. Then 10 N NaOH (3.0 L, 30 mol)
was added, and the reaction was stirred at room temperature for 5 h. The methyl-
amine and THF were removed by rotavap with a 35 °C bath under 600650 mmHg
vacuum. The resulting mixture was cooled to 0 ± 5 °C followed by pH adjustment to
~12 using conc. HCl (8.50 L). The resulting solid was collected by filtration, washed
with water (2 × 6.0 L), and dried in vacuum oven at 60 °C until the moisture content
of the product was below 10% by KF. Product 2 was obtained as a light-brown solid
(3.00 kg, 80% yield, 99.6% purity, moisture content 9.28 wt %).
1
HNMR (400 MHz,
DMSO-d
6
) δ 11.71 (s, 1H), 7.29 (s, 2H), 3.27 (s, 3H);
13
CNMR (100 MHz, DMSD-d
6
)
N
N
N
H
O
N
O
F
HN
F
I
S
O
O
FCN-159
MeO
2
C
CO
2
Me
F
1
1. DBU, malononitrile
2, aq. MeNH
2
3. 10 N NaOH, MeOH
80%
N
NC
H
2
N
OH
F
O
2 (3.00 kg)
N
HN
F
O
TAK-733
F
N
N
HO
HO
O
Steps
Steps
4 Mechanism Problems from Reactions Give Expected Products212
δ 154.7 (d, J = 21.9 Hz), 153.1, 151.4 (d, J = 13.2 Hz), 129.5 (d, J = 211 Hz), 115.4
(d, J = 3.7 Hz), 63.2 (d, J = 2.9 Hz), 28.7;
19
FNMR (376 MHz, DMSD-d
6
) δ − 178.9;
MS (M + H)
+
m/z calcd 184.0, found 184.0.
The Mechanism
This one-pot transformation included three telescope reactions. The first step is a
condensation between the dimethyl-ɑ-flouromalonate and malononitrile catalyzed
by DBU to form intermediate A.
The next step is an amidation of the methyl ester with methylamine to provide
intermediate B.
The final step is the intramolecular cyclization under basic condition to give
product 2.
4.6.6 Imidazole
Problem 77: Formation of 2,4-disubstituted Imidazole
Imidazole subunit exits in many pharmaceuticals and bioactive compounds.
For example, daclatasvir is an anti-HCV medication [212a]. Although the syn-
thesis of these 2,4-disubtituted imidazoles by heating ɑ-hydroxy ketone ester with
ammonium acetate was described in many medicinal chemistry articles and patents
[212, 213], the mechanism for this reaction has not been discussed in the literature.
A representative preparation is shown in the following reaction [212b]. Heating
2-oxo-2-phenylethyl pent-4-ynoate (3) in refluxing xylene with excess ammonium
acetate provided the imidazole product 4 in 98% yield.
Please provide a mechanism for this reaction.
F
1
CN
CN
H
DBU
O
MeO
NC
NC
-
F
O
DBUH
+
DBU
MeO
−
NC
CN
CO
2
Me
F
OH
NC
CN
A
A
CO
2
Me
CO
2
Me
F
OH
NC
CN
OMe
O
NH
2
Me
MeOH
F
O
NC
O
N
HN
A
B
MeNH
2
F
OH
NC
O
N
HN
F
OH
NC
O
HN
N
Isomerization
N
NC
H
2
N
OH
F
O
2
B
4.6 Formation of Monocyclic Aromatic Heterocycles 213
Experimental Procedure (from Eur. J. Med. Chem., 2014, 84, 181)
Synthesis of 2-(but-3-yn-1-yl)-4-phenyl-1H-imidazole (4).
Step a. Cs
2
CO
3
(0.5 eq, 5.10 mmol) was added to a solution of 4-pentynoic acid
(1) (1 eq, 10.20 mmol) in EtOH/H
2
O 1:1 (20 mL), and the whole stirred at room
temperature for 1 h. The solvent was evaporated and the crude residue solubilized
in dry DMF (12.5 mL); a solution of 2-bromoacetophenone (2, 1 eq, 10.20 mmol) in
dry DMF (6.5 mL) was dropwise added and the whole stirred at room temperature
for 15 min. The solvent was evaporated, the residue taken up with AcOEt and the
inorganic salt was filtered off. The filtrate was dried over Na
2
SO
4
, and the solvent
evaporated to afford a yellow oily residue.
Step b. The oily residue was solubilized in xylene (50 mL). NH
4
OAc (15 eq,
153.00 mmol) was added and the resulting solution refluxed for 12 h using a
Dean-Stark trap. The solution was cooled to room temperature, washed with H
2
O
and the organic phase evaporated to give a residue which was taken up with AcOEt.
The organic phase was washed with saturated aqueous NaHCO
3
solution, brine,
dried with Na
2
SO
4
and evaporated to give 2-(but-3-yn-1-yl)-4-phenyl-1H-imidaz-
ole (4) as crude residue purified by FC (petroleum ether/AcOEt 6:4). Orange solid
(1.960 g, 98%); R
f
0.10 (petroleum ether/AcOEt 6:4); mp 53–55 °C;
1
HNMR (CDCl
3
)
7.67 (d, J = 7.4 Hz, 2H), 7.40–7.23 (m, 4H), 3.02 (t, J = 6.8 Hz, 2H), 2.63 (dt, J = 2.4,
6.8 Hz, 2H), 2.12 (t, J = 2.4 Hz, 1H).
The Mechanism
Ammonium acetate plays dual roles in this reaction, a catalyst and a nucleophile
(NH
3
). Ketone is activated by NH
4
OAc, then NH
3
condenses with the carbonyl to
form imine A, which is isomerized to enamine B. Then the NH
2
intramolecularly
attacks the ester carbonyl to give the amide/enol C, which is isomerized to alde-
hyde D. The second condensation between NH
3
and the aldehyde group provides
enamine E. Final cyclization and dehydration leads to product 4 (next page).
Problem 78: Synthesis of Substituted 2-Aryl-N-benzylbenzimidazoles
Benzimidazole and benzoxazole derivatives are pharmaceutical interesting com-
pounds [214], such as veliparib [215], a PARP inhibitor, and prinaberel (ERB-041)
[216], an estrogen receptor. Punniyamurthy’s group reported a synthesis of substi-
tuted 2-aryl-N-benzylbenzimidazoles (2) from N-benzyl bisarylhydrazones (1) in the
N
H
N
N
N
H
NN
O
O
HNNH
O
O
O
O
Daclatasvir
2 HCl
NH
4
OAc, xylene
reflux, 12 h
98%
OH
O
O
O
PhO
Br
Ph
O
HN
N
Ph
1
2
3
4
4 Mechanism Problems from Reactions Give Expected Products214
presence of Cu(OTf)
2
[217]. Similarly, 2-arylbenzoxazoles (4) were prepared from
bisaryloxime ethers (3).
Please propose a mechanism for these reactions.
Experimental Procedure (from J. Org. Chem., 2011, 76, 5295)
General Procedure for the Cyclization of N-Benzyl Bisarylhydrazones 1a-y.
Substrates 1a-y (0.5 mmol) and Cu(OTf)
2
(0.5 mmol) were stirred at 110 °C in tol-
uene (2 mL) under a nitrogen balloon (Table 2). Progress of the reaction was mon-
itored by TLC using ethyl acetate and hexane as eluent. The reaction mixture was
then cooled to room temperature and poured into 30% aqueous NH
4
OH (5 mL).
The solution was extracted with EtOAc (3 × 15 mL). Drying (Na
2
SO
4
) and evapo-
ration of the solvent gave a residue that was purified on silica gel column chroma-
tography using ethyl acetate and hexane as eluent to afford the desired N-benzyl
2-arylbenzimidazoles 2a-x in analytically pure form.
Ph
O
O
O
NH
4
OAc
Ar
NH
O
O
Ar
O
O
Ar
HN
OH
O
Ar
HN
O
O
HOAc, H
2
O
Ar
HN
O
HN
N
Ar
3
4
NH
3
H
AcO
A
B
C
D
E
NH
4
OAc
HOAc, H
2
O
NH
2
H
2
O
NH
2
N
H
N
H
2
N O
Veliparib
N
H
N
O
Prinaberel
HO
F
OH
N
N
Ph
Cu(OTf)
2
(1 eq.)
toluene, N
2
110 °C, 6 h
N
N
Ph
1
2
31%–78%
O
N
Cu(OTf)
2
(0.2 eq.)
toluene, O
2
80 °C, 1–4 h
O
N
R
1
3
4
38%–88%
R
2
R
2
R
1
R
2
R
1
R
2
R
1
4.6 Formation of Monocyclic Aromatic Heterocycles 215
1-Benzyl-2-phenyl-1H-benzo[d]imidazole 2a (R
1
= R
2
= H). Analytical TLC
on silica gel, 1:9 ethyl acetate/hexane R
f
= 0.20; colorless solid; yield 64%; mp 123–
124 °C (lit.
30c
mp 132–133 °C);
1
HNMR (400 MHz,CDCl
3
) δ 7.91 (d, J = 8.0 Hz, 1H),
7.70 (d, J = 7.6 Hz, 2H), 7.47 (d, J = 7.2 Hz, 3H), 7.36–7.30 (m, 4H), 7.26–7.21 (m,
2H), 7.12 (d, J = 6.8 Hz, 2H), 5.47 (s, 2H);
13
CNMR (100 MHz, CDCl
3
) δ 154.3,
143.0, 136.5, 136.1, 132.7, 130.2, 129.5, 129.2, 128.9, 128.0, 126.1, 123.3, 123.0, 120.1,
110.7, 48.5; FTIR (KBr) 3060, 3029, 2962, 2928, 1706, 1600, 1508, 1492, 1469, 1449,
1441, 1392, 1361, 1330, 1314, 1261, 1177, 1163, 1097, 1028, 1002 cm
1
; (ESI-MS) m/z
285.14 [M + H]
+
. Anal. Calcd for C
20
H
16
N
2
: C, 84.48; H, 5.67; N, 9.85. Found: C,
84.60; H, 5.65; N, 9.75.
General Procedure for the Cyclization of Bisaryloxime Ethers 3a-z.
Substrates 3a-z (0.5 mmol) and Cu(OTf)
2
(20 mol %) were stirred at 80 °C in tol-
uene (2 mL) under an oxygen balloon (Table 3). Progress of the reaction was mon-
itored by TLC using ethyl acetate and hexane as eluent. The reaction mixture was
then cooled to room temperature and passed through a short pad of silica gel using
hexane followed by a mixture of ethyl acetate and hexane as eluent to afford the
titled compounds 4a-z in analytically pure form.
2-(2-Bromophenyl)benzo[d]oxazole 4b (R
1
= 2-Br, R
2
= H). Analytical TLC
on silica gel, 1:19 ethyl acetate/hexane R
f
= 0.35; colorless solid; yield 60%; mp
54–55 °C;
1
HNMR (400 MHz, CDCl
3
) δ 8.07 (d, J = 7.6 Hz, 1H), 7.85–7.83 (m, 1H),
7.77 (d, J = 8.0 Hz, 1H), 7.62–7.60 (m, 1H), 7.47–7.33 (m, 4H);
13
CNMR (100 MHz,
CDCl
3
) δ 161.6, 150.7, 141.7, 134.8, 132.3, 132.1, 127.7, 127.6, 125.7, 124.8, 122.0,
120.6, 110.9; FTIR (KBr) 2925, 1606, 1565, 1530, 1469, 1450, 1427, 1307, 1262, 1251,
1235, 1081, 1016 cm
1
; (ESI-MS)m/z 273.99, 275.99 [M + H]
+
. Anal. Calcd for
C
13
H
8
BrNO: C, 56.96; H, 2.94; N, 5.11. Found: C, 56.91; H, 2.96; N, 5.14.
The Mechanism
The imine/oxime nitrogen in the substrate 1/3 chelates with the Lewis acid cat-
alyst Cu(OTf)
2
and then the aniline/cyclohexa-2,4-dien-1-one attacks the catalyst
(Cu(OTf)
2
) to form the organocopper coordination complex A. Cyclization of A pro-
vides the six-membered organocopper compound B. After reductive elimination of
copper metal, the product 2/4 is generated. The copper(0) species may undergo reac-
tion with trifluoromethanesulfonic acid to regenerate the catalyst. In the case of the
reaction 3 to 4, the oxygen may accelerate the oxidation of the Cu(0) to Cu(OTf)
2
.
X
N
X
N
Cu
H
TfOH
X
Cu
H
N
R
1
TfOH
X
Cu
N
Cu
0
1, X
=
NBn
3, X
=
O
2, X
=
NBn
4, X
=
O
Chelation
catalyst
Cyclization
Reductive
elimination
2 TfOH
H
2
Catalyst recycle
A
B
OTf
OTf
OTf
R
1
R
1
R
2
R
1
R
2
R
2
R
2
4 Mechanism Problems from Reactions Give Expected Products216
Problem 79: Preparation of 1-Isopropenyl-1,3-dihydro-2H-benzo[d]imidazol-
2-one
The reaction between benzene-1,2-diamine (1) and ethyl acetoacetate (2) was ini-
tially documented by Sexton in 1942 [218]. However, due to the limitations of ana-
lytical techniques available at the time, the structure of the resulting product was
mistakenly identified as 1-(1H-benzo[d]imidazol-2-yl)propan-2-one (4). It was
not until 1960 that Davoll correctly determined the structure of the product to be
1-(prop-1-en-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (3). This conclusion
was reached by comparing the hydrogenation product (5) with an authentic sample
synthesized from N-isopropylbenzene-1,2-diamine (6) and phosgene [219]. In 1968,
Israel, Jones, and Modest further explored the mechanistic details of this reaction
[220]. Over time, this “classic” reaction has found renewed relevance in medicinal
chemistry [221, 222], particularly in the synthesis of flibanserin [223, 224], a drug
used to treat hypoactive sexual desire disorder in premenopausal women. The
one-pot synthesis of compound 3 is illustrated as follows [224].
Please provide your own mechanism for the formation of 3 from 1 and 2.
Experimental Procedure (from Org. Proc. Res. Dev., 2016, 20, 1576)
1-(Prop-1-en-2-yl)-1H-benzo[d]imidazol-2(3H)-one (3). KOH solution in eth-
anol (1.8 g, 9.2 mL) and subsequently ethyl acetoacetate (2, 132.3 g, 1.017 mol) in
xylene (50 mL) was added dropwise within 2.5 h to a refluxing solution of 1 (100 g,
0.924 mol) in xylene (400 mL) under nitrogen, while the water produced during the
reflux was removed using a Dean-Stark trap. It was refluxed for another 5 h and then
cooled to 40 °C. An aqueous solution of KOH (71.8 g, 250 mL) was added, and the
mixture was stirred at 40 °C for 0.5h. The organic layer was separated, and acetic acid
(111 mL) was added slowly. The resulting slurry was filtered, washed with n-heptane,
and dried under vacuum to give compound 3 (89.7 g) as a pale brown solid with yield
of 56%.
1
HNMR (400 MHz, CDCl
3
) δ 10.57 (s, 1H), 7.187.12 (m, 1H), 7.127.04
(m, 3H), 5.42 (d, J = 1.5 Hz, 1H), 5.26 (s, 1H), 2.25 (s, 3H). ESI-MS (m/z): 175.4 [M +
H]
+
, 173.3 [M H]
; HPLC: retention time of 12.5 min, 99.5% purity.
N
H
N
O
NH
2
+
CO
2
Et
O
1
2
3
NaOH, xylene
130 °C, 7 h
94%
Steps
N
H
N
O
Flibanserin
N
H
N
O
4
N
H
N
O
5
H
2
, PdO
EtOH
85%
NH
6
Phosgene
N
N
CF
3
NH
2
NH
2
4.6 Formation of Monocyclic Aromatic Heterocycles 217
The Mechanism
The first stage of the reaction is the normal condensation between the amino and
the carbonyl followed by intramolecular amidation to give 4-methyl-1,3-dihydro-
2H-benzo[b][1,4]diazepin-2-one (3a). This was converted to the product 3 via a
[1,3]-sigma tropic rearrangement at high temperature.
4.6.7 Isoxazole
Problem 80: Formation of 5-Chloro-3-phenylbenzo[c]isoxazole
In 1960, Davis and Pizzini reported the preparation of 3-phenylbenzo[c]isoxa-
zoles from nitrobenzenes and phenylacetonitriles in the presence of KOH [225].
The product 3 was a key intermediate for synthesizing the drug Diazepam [226].
Benzo[c]isoxazole is the pharmacophore of a series of IP6K inhibitors for the
treatment of obesity and obesity-induced metabolic dysfunctions [227]. Some SF
5
or
CF
3
group containing analogs were also prepared by this reaction [228].
Please propose a mechanism for this reaction.
Experimental Procedure (from Beil. J. Org. Chem., 2013, 9, 411, Supporting
Information)
NH
2
1
OEt
O
O
2
N
OH
O
EtO
H
H
2
O
N
O
EtO
EtOH
N
H
N
O
3a
[1,3]-sigmatropic
N
H
N
O
3
NH
2
NH
2
NH
2
Cl
N
N
O
NO
2
KOH, MeOH
0–5 °C
O
N
46%
Cl
CN
+
Cl
3
1
2
Diazepam
NO
2
NaOH, EtOH
rt, 1 h
O
N
66%
F
5
S
CN
+
5
4
2
F
5
S