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5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products338
5.5 Formation of Monocyclic Aromatic Heterocycles
5.5.1 Pyrrole
Problem 136: Formation of an Amino Pyrrole Impurity
Heating the furan precursor 1 with ammonium acetate in N-methylpyrrolidone
at 100–105 °C yielded the pyrrole product 2. However, chemists at Pfizer discov-
ered that an impurity was also generated during the reaction at a level of 0.7%.
Even after recrystallization and Darco treatment, the impurity persisted at 0.5%.
Through comparison with a synthetic standard, the impurity was identified as
2-aminopyrrole 3 [31]. The electron-deficient pyrrole 2 was further derivatized via
diazotization using p-nitrobenzene diazonium chloride. Subsequent reduction of
the diazo intermediates 4 and 5 produced 2- and 1-aminopyrroles (3 and 6, respec-
tively). Understanding the formation mechanism of this impurity is essential for
developing strategies to suppress its generation.
Please suggest a mechanism for the formation of impurity 3.
Experimental Procedure (from Org. Process Res. Dev., 2002, 6, 64)
4-Oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylic acid (2-fluoro-
4-methoxy-phenyl)amide (2). Under nitrogen atmosphere, a mixture of 1 (735 g,
2.32 mol) and ammonium acetate (1249 g, 16.22 mol) in N-methylpyrrolidinone
NO
2
–
OTs
Pt-C
N
A
O
B
1
2
H
Pathway
A
N
H
Pathway
B
H
N
H H
D
E
3
N
O
1
A
[2+2]
Pathway
C
N
O
F
O
2
N
N
+
O
N
G
H
4
Retro
[2+2]
N
H
H
C
N
+
H
2
–
OTs
N
+
H
2
–
OTs
N
+
NH
2
NH
2
–
OTs
N
+
N
+
N
+
N
+
N
+
–
OTs
–
OTs
H
2
–
OTs
N
+
–
OTs
N
+
–
OTs
N
+
–
OTs
–
OTs
–
OTs
N
+
NO
2
H
2
H
2
–
OTs
H
2
H
2
NO
2
5.5 Formation of Monocyclic Aromatic Heterocycles 339
(1.47 L) was heated to 100–105 °C for 24 h. The reaction was cooled to 25 °C, and
water (13.2 L) was added. The resulting mixture was stirred for 17 h at 25 °C, and fil-
tered. The filter cake was rinsed with water and dried under vacuum at 40–45 °C to
give 729 g of crude product as dark brown solids (purity 94.8% by HPLC). The crude
product was stirred in methanol (33.7 L), and filtered through celite. To the filtrate
was added 116 L of water, and the resulting slurry was stirred for 24 h. The mixture
was filtered, and the solids were dried under vacuum at 40–45 °C to give 567 g of dark
colored solids (purity 98.5% by HPLC). This crude product was stirred in acetone
(17.0 L), and Darco G-60 (567 g) was added. After stirring for 30 min at 20–25 °C,
the mixture was filtered. The filtrate was concentrated under vacuum to ~0.85 L
and crystallization occurred. The mixture was granulated for 30 min and then fil-
tered. The filter cake was rinsed with acetone (120 mL) and dried under vacuum
at 50–60 °C to yield 320 g (1.01 mol, 43%) of 2 as off-white solids (purity 99.3% by
HPLC).
1
HNMR * δ 12.40 (s, 1H), 12.04 (s, 1H), 8.18 (t, J = 8.8 Hz), 6.91 (s, 1H), 6.89
(dd, 1H, J = 2.4 and 12.8 Hz), 6.72 (dd, 1H, J = 2.4 and 8.8 Hz);
13
CNMR δ 200.12,
161.12, 155.88, 155.78, 154.78, 152.34, 146.57, 126.16, 123.62, 120.21, 117.84, 109.55,
101.76, 101.54, 55.56, 40.93, 25.34, 23.11, 20.69. MS m/z 317 (M + 1), 177, 149.
2-Amino-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carbox-
ylic acid (2-fluoro-4-methoxy-phenyl)amide (3). To 4-nitroaniline (1.57 g,
11.4 mmol) in 6 N HCl (8.55 mL) at 0 °C was added dropwise with 30% NaNO
2
solution in water (wt/wt). After 10 min at 0 °C, 2 (1.20 g, 3.8 mmol) with NaOAc
(2.50 g) in AcOH (50 mL) was added. The resulting reaction mixture was stirred
at room temperature for 3 h and worked up by extraction with ethyl acetate. The
2-azo (47 mg) and N-azo (3.0 mg) intermediates were obtained by silica gel column
chromatography: 0.87 g of 2 was recovered. The 2-azo intermediate (5, 45 mg) was
heated with SnCl
2
(100 mg) in AcOH (2 mL) at 80 °C for 1 h to give the desired prod-
uct 3 (17.5 mg) after preparative TLC purification:
1
HNMR * δ 12.29 (s, 1H), 8.14 (t,
J = 9.2 Hz, 1H), 6.88 (dd, J = 12.8 and 2.8 Hz, 1H), 6.72 (dd, J = 9.2 and 2.8 Hz), 6.48
(s, 2H), 2.83–2.85 (s, 2H), 2.62–2.65 (s, 2H), 1.69–1.76 (s, 2H);
13
CNMR δ 198.28,
164.45, 155.07, 154.99, 154.33, 152.39, 148.24, 141.83, 123.38, 120.72, 116.39, 109.33,
101.57, 101.38, 55.52, 40.84, 25.22, 22.98, 20.70; MS m/z 331** (M + 1), 191, 163, 135.
O
O
N
H
O
F
O
1
NH
4
OAc
NMP
105 °C
N
H
O
N
H
O
F
O
2 (43%)
N
H
O
N
H
O
F
O
3 (0.7%)
N
H
O
N
H
O
F
O
4
N
N
N
O
N
H
O
F
O
+
5
SnCl
2
HOAc
N
N
SnCl
2
HOAc
N
O
N
H
O
F
O
6
O
2
N
N
2
+
CI
–
NH
2
NO
2
NO
2
NH
2
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products340
*The
1
H NMR spectra of 2 and 3 were not fully presented here. “6.72 (dd, J = 9.2 and 2.8 Hz)” did not
indicate the number of protons. Several proton signals, such as OMe, were missing.
**The molecule weight of 3 is 331 and the mass spectrum should show m/z 332 (M + H
+
). There
might be a typo here.
The Mechanism
Since the initial procedure for that reaction was not deoxygenated, the furan unit
could be oxidized by oxygen from air to form 1,2-dioxetane A or B via radical
reaction.
The dioxetane A is attacked by NH
3
(from ammonium acetate) to give the hydro-
peroxyl alcohol C. After the elimination of hydrogen peroxide and ring opening,
diketone imine D is formed, which in turn cyclizes to hydroxyl pyrrole E. A second
NH
3
is added to the hydroxyl pyrrole followed by elimination of water to produce
the impurity 3.
Starting from possible intermediate B, the impurity 3 could be formed analo-
gously by following mechanism.
O
O
N
O
F
O
1
O
O
1
2
3
4
5
H
O O
O
O
NHAr
O
4
5
O
O
A
O
O
NHAr
O
B
O
O
O
O
NHAr
O
5
4
O
O
A
NH
3
O
O
NHAr
O
O
C
O
H
N H
H
O
O
NHAr
O
D
HN
HO
O
NHAr
O
E
N
HO
O
NHAr
O
F
N
H
H
N
H
O
N
H
O
F
O
3
NH
3
H
2
O
2
NH
2
H
2
O
NH
3
NH
3
NH
2
O
O
NHAr
O
B
O
O
NH
3
O
O
NHAr
O
G
O
NH
H
OH
O
NHAr
O
H
NH
O
O
NHAr
O
I
N
OH
H
O
NHAr
O
J
N
H
OH
O
NHAr
O
K
N
H
OH
H
3
NH
3
H
2
O
2
NH
2
NH
3
5.5 Formation of Monocyclic Aromatic Heterocycles 341
Once hydrogen peroxide is generated, it could oxidize the furan to the C2─C3
epoxide or the C4─C5 epoxide and those would also lead to the impurity 3. That
mechanism was proposed in the literature [31].
Reaction conditions free of oxidants helped prevent the formation of the
2-aminopyrrole impurity 3; nitrogen sparging of the reaction mixture prior to
heating eliminated the impurity formation.
5.5.2 Pyridine
Problem 137: Pyridyl Walks to Hydroxyl from Sulfone During an Alkylation
SB-462795 is a potent cathepsin K inhibitor under development for the treatment of
osteoporosis and osteoarthritis. One of the key building blocks for the synthesis of
SB-462795 is diene 3, which is prepared from sulfonamide 1 and epoxide 2. In the
reaction, except the desired product 3, an impurity 4 was also isolated and identi-
fied, in which the pyridyl group moved to hydroxyl and eliminated SO
2
[32]. The
amount of 4 increased to 3–5% over prolonged reaction times. Treatment of 3 with
Cs
2
CO
3
in acetonitrile at 80 °C provided 4 in 70% yield.
Please suggest a mechanism for the formation of 4.
Experimental Procedure (from Org. Process Res. Dev., 2008, 12, 226)
1,3,4,5-Tetradeoxy-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[[(1R)-1-methyl-
2-propen-1-yl](2-pyridinylsulfonyl)amino]-L-threo-pent-4-enitol (3). In a glass-
lined reactor, a slurry of (2R,3S)-3-(1,3-dioxoisoindolin-2-yl)-2-hydroxypent-4-en-1-yl
4-methylbenzenesulfonate (8.5 kg, 21.2 mol) and toluene (34 L) was heated to 56 °C
under nitrogen, and DBU (3.3 kg, 21.7 mol) was added via pressure vessel to main-
tain the temperature between 55 and 65 °C. The starting material dissolved during the
O
O
N
H
O
F
O
1
H
O
O
H
H
2
O
2
H
2
O
H
2
O
H
2
O
NH
2
NH
3
NH
3
NH
3
O
NHAr
O
O
O
O
H
H
Cat.
O
NHAr
O
O
O
3
O
NHAr
O
O
OH
O
NHAr
O
N
HO
NH
3
N
SO
2
N
3
OH
N
OO
RCM
N
N
HO
N
O
O
N
N
HO
H
N
N
H
O
O
O
SB-462795
Steps
SO
2
SO
2
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products342
addition and the mixture was aged at this temperature for 60 min. Upon completion of
the reaction, the mixture was cooled to 25 °C and 10% w/w aq. citric acid (0.42 L water
with 45 g citric acid monohydrate) was added. After stirring for 10 min, water (25.5 L)
was added, the mixture stirred and the layers allowed to separate. The organic layer was
then washed twice with water (2 × 8.5 L). The solution of crude 2 was then transferred
to a second reactor via an inline filter to remove a small layer of film, and the transfer
line then rinsed with toluene (8.5 L). To this second reactor was charged 1 (4.5 kg,
21.2 mol) and the solvent partially removed by vacuum distillation to reach 15 L total
volume (36.0 L toluene removed). 2-Propanol (25.5 L) was charged and the system
vacuum distilled to achieve 15 L total volume (25.5 L removed). The total solvent
volume was adjusted to 3.4 volumes using 2-propanol (15.0 L added), (tert-Butylimino)
tris(pyrrolidino)phosphorane (BTPP) (0.7 kg, 2.12 mol) was added and the mixture
heated to 80 °C over ~30 min. After aging for 3.5 h, the reaction was complete, and
heptane was added (17.0 L) while maintaining the temperature 60 °C. The tempera-
ture was then adjusted to 53 °C and seeds of 3 (4.5 g in 2:1 heptane:2-propanol) were
charged to the reactor. The slurry was held at 52 °C for 60 min, then cooled to ~10 °C at
0.5 °C/min. After holding for 30 min, the slurry was isolated by centrifugal filtration,
washed with cold heptane/2-propanol (2:1 v/v, 2 × 8.5 L). The product was dried under
vacuum at 45 °C to afford 3: 7.25 kg (16.4 mol, 78%), >99.9% pure by HPLC.
1
HNMR
(CDCl
3
, 400 MHz) δ 8.62 (dm, 1H, J = 4.0 Hz), 8.02 (d, 1H, J = 7.9 Hz), 7.93 (td, 1H, J =
7.7, 1.6 Hz), 7.83 (m, 2H), 7.70 (m, 2H), 7.50 (dm, 1H, J = 0.9 Hz), 6.29 (m, 1H), 5.81
(m, 1H), 5.39 (d, 1H, J = 17.1 Hz), 5.30 (dd, 1H, J = 10.2, 0.5 Hz), 5.13 (m, 2H), 4.89
(bs, 1H), 4.68 (t, 1H, J = 9.0 Hz), 4.60 (dt, 1H, J = 9.2, 2.6 Hz), 4.39 (m, 1H), 3.56 (dd,
1H, J = 15.1, 2.6 Hz), 3.45 (dd, 1H, J = 15.3, 9.2 Hz), 1.30 (d, 3H, J = 6.9 Hz).
13
CNMR
(CDCl
3
, 100 MHz) δ 168.6, 158.6, 150.1, 138.9, 137.9, 134.3, 132.7, 132.4, 127.2, 123.7,
123.4, 121.3, 117.7, 69.2, 58.1, 56.2, 49.4, 18.1.
1,3,4,5-Tetradeoxy-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-
{[(1R)-1-methyl-2-propen-1-yl]amino}-2-O-2-pyridinyl-Lthreo-pent-4-enitol
(4). Diene 3 (1.0 g, 2.27 mmol) and Cs
2
CO
3
(0.775 g, 2.38 mmol) were heated in ace-
tonitrile (5 mL) to 80 °C and stirred overnight. Upon cooling, the slurry was filtered
through celite to remove solid residues, and the solvent removed under vacuum. The
product was purified by flash column chromatography: 0.60 g, 70% yield. ES-MS:
m/z: 378 (M + H
+
).
1
HNMR (CDCl
3
, 300 MHz) δ 7.88 (ddd, 1H, J = 5.0, 2.1, 0.8 Hz),
7.70 (m, 2H), 7.63 (m, 2H), 7.33 (ddd, 1H, J = 9.1, 7.1, 2.0 Hz), 6.61 (ddd, 1H, J = 7.2,
5.0, 0.9 Hz), 6.54 (dm, 2H, J = 9.2 Hz), 6.45 (m, 1H), 6.05 (m, 1H), 5.67 (m, 1H), 5.48
N
NH
1
+
O
N
OO
2
BTPP (0.1 eq.)
2-propanol
80 °C
N
N
3 (78%)
OH
N
OO
H
N
4 (3–5%)
O
N
OO
N
N
P
N
N
N
BTPP
+
70%
SO
2
SO
2
Cs
2
CO
3
, CH
3
CN
80 °C
5.5 Formation of Monocyclic Aromatic Heterocycles 343
(dm, 1H, J = 17 Hz), 5.32 (dd, 1H, J = 9.8, 1.4 Hz), 5.16 (t, 1H, J = 9.4 Hz), 5.01 (m,
2H), 3.13 (m, 2H), 2.81 (dd, 1H, J = 13, 6.2 Hz), 1.13 (d, 3H, J = 6.5 Hz).
13
CNMR
(CDCl
3
, 100 MHz) δ 167.83, 163.11, 146.53, 142.64, 138.44, 133.53, 131.83, 131.69,
122.83, 120.73, 116.71, 114.10, 111.01, 72.99, 56.47, 56.41, 47.87, 21.32.
The Mechanism
As the reaction proceeded, it is likely that the concentration of sulfonamide 1 grad-
ually decreased. Concurrently, the deprotonation of the hydroxyl group in product
3 by BTPP emerged as a competing side reaction. The resulting alkoxide could then
attack the pyridine ring, triggering an irreversible loss of SO₂ and migration of the
pyridyl group to the hydroxyl, ultimately forming impurity 4. This proposed mech-
anism is corroborated by experimental evidence, where treating 3 with Cs₂CO₃ in
acetonitrile resulted in the efficient conversion of 3 to 4 in high yield.
Design of experiments (DoE) model indicated that increased concentration of
reactants would permit lower BTPP loading and minimize formation of 4, which
was verified by scale-up of these conditions to multigram scales.
5.5.3 Pyrazole
Problem 138: Ring Expansion by [3 + 2] Cycloaddition During the Synthesis
of Pyrazoles
The pyrazole motif is found in many marketed drugs, such as pazopanib 1 and crizo-
tinib 2. In 2004, Jiang and Li reported a synthesis of pyrazoles by [3 + 2] cycloaddition
of α-diazocarbonyl compounds with alkynes catalyzed by indium trichloride. [33].
Later on, Legros’ group discovered that this reaction can be carried out by just
heating the mixture of α-diazocarbonyl compounds and alkynes in neat [34]. Both
articles reported that in the cases of diazo-indanone 3a and diazo-tetralone 3b as
substrates, ring expansion products 5a and 5b were obtained in excellent yield [33].
N
N
O
N
OO
H
N
4
O
N
OO
N
H
BTPP
BTPP
N
O
–
N
–
N
–
N
OO
N
BTPPH
+
N
O
N
OO
O
N
OO
N
BTPP
BTPPH
+
BTPPH
+
3
SO
2
O
2
S
O
2
S
SO
2
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products344
Please provide a mechanism for the ring expansion reaction.
Experimental Procedure (from Green Chem., 2009, 11, 156, Supplementary
Information)
General Procedure for the 1,3-dipolar Cycloaddition of Diazo Compounds
3a-f to Alkynes: A 5 mL round bottom flask equipped with a reflux condenser was
charged with the diazo compound and the alkyne (1 mmol of the heaviest reagent/
1.1 mmol of the most volatile one) and was heated at 80 °C. After completion of
the reaction (see Table 2 in the article), the excess of reagent was evaporated under
vacuum to afford the corresponding pyrazole as pure solid.
Ethyl 4,9-dihydro-9-oxopyrazolo[1,5-b]isoquinoline-2-carboxylate (5a, R=Et):
90% yield, yellow crystals; mp 171 °C.
1
HNMR (CDCl
3
, 300 MHz), δ: 1.41 (t, J = 7.1,
3H); 4.43 (q, J = 7.1, 2H); 4.47 (s, 2H); 6.88 (s, 1H); 7.46 (d, J = 7.9, 1H); 7.52 (t, J = 7.9,
1H); 7.68 (t, J = 7.9, 1H); 8.43 (d, J = 7.9, 1H).
13
CNMR (CDCl
3
, 75 MHz), δ: 14.2; 27.1;
61.6; 107.9; 125.4; 127.9; 128.4; 130.0; 134.3; 136.6; 142.7; 148.3; 157.6; 161.9. APCI m/z
(rel.int.): 257 [M + H]
+
(100%). IR (ν, cm
−1
): 1719.
Ethyl 10-oxo-5,10-dihydro-4H-pyrazolo[1,5-b][2]benzazepine-2-carboxylate
(5b, R=Et): 88% yield, red solid; mp: 115–116 °C.
1
HNMR (CDCl3, 300 MHz), δ: 1.41
(t, J = 7.2, 3H); 3.15 (t, J = 5.2, 2H); 3.19 (t, J = 5.2, 2H); 4.42 (q, J = 7.2, 2H); 6.71 (s,
1H); 7.28 (d, J = 7.5, 1H); 7.43 (t, J = 7.5, 1H); 7.54 (t, J = 7.5, 1H); 8.25 (d, J = 7.5,
1H).
13
CNMR (CDCl
3
, 75 MHz), δ: 14.0; 26.8; 32.6; 61.3; 109.6; 127.3; 129.1; 130.1;
133.8; 133.9; 140.7; 146.6; 147.0; 161.5; 163.5. APCI m/z (rel.int.): 271 [M + H]
+
(100%).
IR (ν, cm
−1
): 1705.
The Mechanism
Legros’ group proposed a putative mechanism for the formation of the ring expanded
product [34]. The 1,3-dipolar cycloaddition of 3a with alkyne 4 affords the spiro
O
n
+
N
O
N
n
5a, n = 1, R = Et, 90%
5b, n = 2, R = Et, 88%
80 °C
4
3a, n = 1
3b, n = 2
H
N
N
N
N
N
N
S
H
2
N
O O
.HCl
1, pazopanib
O
N
N
N
NH
Cl
Cl
F
2, crizotinib
N
2
CO
2
R
CO
2
R
NH
2
5.5 Formation of Monocyclic Aromatic Heterocycles 345
pyrazole adduct A. Upon heating, the nitrogen in pyrazole attacks the carbonyl to
form the tetracyclic species B, which rearranges to ring expanded product 5a.
Alternatively, species B seems much tensioned, instable, and not easy to be
formed. Jiang and Li discovered that reaction of methyl α-diazoarylacetates 7
and methyl propiolate 4 (R = Me) gave two pyrazole products 8 and 9 in excel-
lent combined yields [33]. The possible mechanism for the formation of the minor
product 9 proceeds by an initial 1,3-dipolar cycloaddition followed by a subsequent
1,3(5)-carboxylate shift of the initially formed 3,5-dicarboxylate-3-aryl-3H-pyrazole
(C). The formation of the major product 8 could proceed by three steps: an initial
1,3-dipolar cycloaddition, a subsequent 1,5-aryl shift, and a 1,3-hydrogen shift of the
4H-pyrazole intermediate (D).
Based on above mechanism, a simple 1,2-carbonyl shift of the initially formed
spiro pyrazole (A) seems a more reasonable mechanism for the formation of 5a.
Judging by the
1
H and
13
CNMR data, can we exclude the possibility that the
structure of the product is 5a′ as shown below?
O
N
N
O
N
N
O
1,3-dipolar
cycloaddition
N
N
O
–
N
N
+
CO
2
Et
O
N
–
3a
4
5a
A
B
CO
2
Et
CO
2
Et
CO
2
Et
N
+
+
InCl
3
(0.2 eq.)
H
2
O, 20 °C
4
CO
2
Me
X
7
HN
N
X
8 (77–90%)
N
N
9 (4–12%)
+
X
N
N
Ar
1,5-carboxylate
shift
N
N
Ar
9
N
N
Ar
9
or
1,3-carboxylate
shift
or
Position of NCO
2
Me in 9 was not confirmed.
N
N
Ar
C
C
1,5-aryl
shift
N
N
Ar
H
1,3-H
shift
HN
N
8
Ar
D
N
2
CO
2
Me
MeO
2
C
CO
2
Me
CO
2
Me
CO
2
Me
CO
2
Me
CO
2
Me
CO
2
Me
MeO
2
C
CO
2
Me
MeO
2
C
MeO
2
C
CO
2
Me
CO
2
Me
MeO
2
C
CO
2
Me
MeO
2
C
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products346
A
13
CDEPT NMR would address this uncertainty, since there are different num-
bers of CHs and quaternary carbons in 5a and 5a′.
5.5.4 Oxazole
Problem 139: Formation of 2-(2,6-difluorophenyl)-4-(p-tolyl)oxazole as an
impurity
Etoxazole (1) is a narrow spectrum systemic acaricide used to combat spider mites.
o-Trifluoromethyl benzaldehyde oxime (FET-II-L, 2) and mercaptobenzimidazole
NK-12 (3) are more active than etoxazole (1) against mites in both greenhouse and
field tests [35, 36].
In a process study for the synthesis of 2 and 3, the key intermediate 6 was pre-
pared from 2,6-difluorobenzonitrile (4) and 1-(chloromethyl)-4-vinylbenzene (5) as
shown below. Except the desired product 6 was obtained in 86% yield, a side prod-
uct 7 (6–8%) was also generated. To complete the synthesis of the target molecule
2, 6 was treated with oxime 8 in the presence of sodium hydride, resulting in low
yields of 2. The main side product under these strongly alkaline conditions was 9. By
employing sodium hydroxide in methanol, 2 was obtained in 82% yield [37].
Please provide mechanisms for the formation of 6, 7, and 9.
Experimental Procedure (from Org. Process Res. Dev., 2020, 24, 216)
Preparation of N-(2-Bromo-1-(4-(chloromethyl)-phenyl)ethyl)-2,6-difluoro-
benzamide (6) via Ritter Reaction. To a solution of 2,6-difluorobenzonitrile
(4, 15.3 g, 110 mmol), 1-(chloromethyl)-4-vinylbenzene (5, 15.2 g, 100 mmol), and
NBS (19.6 g, 110 mmol) in 125 mL of CH
2
Cl
2
was added H
2
SO
4
(6.5 mL, 120 mmol)
dropwise at 0 °C, and then the reaction mixture was stirred at 0 °C for 8 h until
the reaction was complete, indicated by TLC (PE/EA = 4/1). The reaction was
O
N
N
A
N
N
5a
O
CO
2
Et
1,2-carbonyl
shift
CO
2
Et
N
H
N
O
O
N
N
A
N
N
O
H
5aʹ
1,2-carbonyl
shift
1,3-H
shift
CO
2
Et
CO
2
Et
CO
2
Et
F
F
N
O
O
1 (Etoxazole)
F
F
N
O
O
2 (FET-II-L)
N
CF
3
F
F
N
O
S
3 (NK-12)
N
S
5.5 Formation of Monocyclic Aromatic Heterocycles 347
quenched by adding ice water (100 mL), and the aqueous phase was extracted with
dichloromethane (50 mL × 3). The combined organic phase was washed with sat-
urated Na
2
CO
3
(100 mL) and brine (100 mL), dried over anhydrous sodium sulfate
(about 3 g), and filtered. After removal of the organic solvent, the residue was puri-
fied by column chromatography on silica gel with PE/EA (5/1) as eluent to give 6
(33.4 g, 86 mmol, yield 86%) as a yellow solid. Mp 128–129 °C.
1
HNMR (400 MHz,
DMSO-d
6
) δ 9.43 (d, J = 8.4 Hz, 1H), 7.57–7.50 (m, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.31
(d, J = 8.0 Hz, 2H), 7.18 (t, J = 8.0 Hz, 2H), 5.29 (dd, J = 8.8, 4.4 Hz, 1H), 3.80 (dd, J
= 10.4, 4.8 Hz, 1H), 3.63 (t, J = 10.0 Hz, 1H).
13
CNMR (100 MHz, DMSO-d
6
) δ 159.9,
159.3 (dd, J = 248.9, 8.0 Hz), 140.4, 138.1, 132.2 (t, J = 9.9 Hz), 129.9, 127.7, 115.6 (t,
J = 23.0 Hz), 112.4 (dd, J = 19.3 and 5.2 Hz), 55.0, 36.1, 34.5. HRMS (ESI): calcd for
C
16
H
14
BrClF
2
N
2
O [M + H]
+
389.9889, found 389.9889.
Formation of 1-(2-Bromo-1-(4-(chloromethyl)-phenyl)ethyl)pyrrolidine-
2,5-dione (7). A small amount of 7 could also be separated from the above reaction
mixture.
1
HNMR (400 MHz, DMSOd
6
) δ 7.51–7.36 (m, 4H), 5.35 (dd, J = 10.4 and
5.6 Hz, 1H), 4.75 (s, 2H), 4.42 (t, J = 10.4 Hz, 1H), 4.19 (dd, J = 10.0, 5.6 Hz, 1H),
2.73 (s, 4H).
13
CNMR (100 MHz, DMSO-d
6
) δ 178.1, 138.2, 137.2, 129.6, 128.4, 56.0,
44.9, 31.9, 28.3. HRMS (ESI): calcd for C
13
H
14
BrClNO
2
[M + H]
+
329.9891, found
329.9892.
Preparation of Target Compound 2 (FET-II-L) via Stepwise Procedure.
A solution of compound 6 (19.4 g, 0.05 mol, 1.0 equiv) and NaOH (2.4 g, 0.06 mol,
1.2 equiv) in methanol (100 mL) was stirred at room temperature for 12 h until full
consumption of 6 indicated by TLC (PE/EA = 4/1). Compound 8 (9.6 g, 0.051 mol,
1.02 equiv) and another 1.2 equiv of NaOH (2.4 g, 0.06 mol) were added, and
the mixture was stirred for another 48 h. After evaporation of the solvent, water
(50 mL) and ethyl acetate (50 mL) were added, and the water layer was extracted
with ethyl acetate (50 mL × 3). The combined organic layer was washed with 10%
NaHCO
3
(50 mL), water (50 mL), and brine (50 mL), then dried over anhydrous
sodium sulfate (about 3 g), filtrated, and concentrated to give the title compound
2 (21.8 g, 94% crude yield, 87% HPLC purity) as a yellow oil. After recrystallization
with petroleum ether and ethyl acetate (100 mL/10 mL), 19.2 g of product (83%
yield) were obtained with 96% HPLC purity (quantitative method). White solid. Mp
52–53 °C.
1
HNMR (400 MHz, CDCl
3
) δ 8.50 (s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.66 (d,
J = 7.7 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.49–7.41 (m, 4H), 7.37 (d, J = 8.1 Hz, 2H),
HN
O
Br
CN
Cl
F
F
4
5
+
1. NBS, H
2
SO
4
DCM, 0 °C
Cl
F
F
6 (86%)
Br
Cl
N
O
O
7 (6–8%)
F
F
N
O
Cl
base
HO
N
CF
3
8
2 +
F
F
N
O
9
6a
2. H
2
O