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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5262_Библиотеки_им_академика_М_И_Перельмана.pdf
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products348
7.00 (t, J = 8.3 Hz, 2H), 5.50 (dd, J = 10.2 and 8.1 Hz, 1H), 5.24 (s, 2H), 4.84 (dd, J =
10.3, 8.5 Hz, 1H), 4.31 (t, J = 8.2 Hz, 1H).
13
CNMR (100 MHz, CDCl
3
) δ 161.8 (dd,
J = 254 Hz, 5 Hz), 158.2 (s), 146.3 (s), 142.3 (s), 137.3 (s), 133.0 (t, J = 10.0 Hz), 132.5
(s), 130.9 (s), 130.0 (s), 129.5 (s), 129.0 (s), 128.8 (s), 128.6 (s), 128.3 (q, J = 31.1 Hz),
127.9 (s), 127.4 (s), 126.4 (q, J = 272 Hz), 112.5 (dt, J = 20.0 and 2.0 Hz), 108.1 (t, J =
18.0 Hz), 77.0 (s), 75.4 (s), 70.6 (s). HRMS (ESI): calcd for C
24
H
19
F
5
N
2
O
2
[M + H]
+
461.1283, found 461.1280.
Formation of 2-(2,6-Difluorophenyl)-4-(p-tolyl)-oxazole (9). A small amount
of 9 could be separated from the reaction mixture. White solid. Mp: 97–98 °C.
1
HNMR (400 MHz, CDCl
3
) δ 8.01 (s, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.44–7.30 (m, 1H),
7.21 (d, J = 8.0 Hz, 2H), 7.01 (t, J = 8.4 Hz, 2H), 2.36 (s, 3H).
13
CNMR (100 MHz,
CDCl
3
) δ 160.9 (dd, J = 257.2 and 5.6 Hz), 153.2, 142.2, 138.2, 134.0, 132.0 (t, J =
10.4 Hz), 129.5, 127.9, 125.7, 112.2 (dd, J = 20.1 and 5.1 Hz), 106.7 (t, J = 16.3 Hz),
21.3. HRMS (ESI) calcd for C
16
H
11
F
2
NO [M + H]
+
272.0881, found 272.0868.
The Mechanism
The preparation of 6 from 4 and 5 is a Ritter reaction in which the cation is gener-
ated from 4-chloromethylstyrene (5) by NBS bromination. First, reaction of 5 with
NBS gives bromonium ion A, which is readily transformed to benzyl cation B. The
benzyl site of B is attacked by the nitrogen lone-pair electrons of difluorobenzoni-
trile (4) to form C, and subsequent hydrolysis gives 6.
The succinimide anion that forms from NBS attacks benzyl cation B to give 7 as
a side product.
Upon being treated with base, compound 6 will first cyclize to form an
intermediate D, then the oxime 8 attacks the benzyl chloride to produce the prod-
uct 2. However, since the proton at the benzylic position of D is relatively acidic,
under strong base conditions, such as NaH, it is easily deprotonated to give anion E.
F
F
4
N
Br
O
O
Cl
5
NBS
H
2
SO
4
Br
Cl Cl
Br
N
4
F
F
Cl
Br
HN
O
Br
Cl
F
F
6
Ritter
reaction
Ritter
reaction
A B
C
O
O
O
O
O
O
H
N
O
O
H
+
N
–
N
–
N
–
N
+
H
2
O
+
+
+
5.5 Formation of Monocyclic Aromatic Heterocycles 349
Subsequent elimination of Cl through the benzene ring leads to the formation of
F, which then rearranges to the more stable, undesired product 9 via a [1,7]-H
shift. Weaker (NaOH is weaker than NaH in basicity) base would suppress this side
reaction.
Problem 140: Formation of an Oxazoline Impurity in the Synthesis of a M1
Agonist
M1-type muscarinic acetylcholine receptors play a role in cognitive processing.
The muscarinic receptor (M1) agonist is a potential treatment for AD. The
aminoindanol-derived compound 1 is a clinical candidate for this purpose. In the
last step of the synthesis of 1, treatment of aniline 2 with thioimidate 3 in THF in
the presence of K
2
CO
3
and 4-(dimethylamino)pyridine (DMAP) provided the
desired product 1. An oxazoline impurity 4 was also identified [38].
Please propose a mechanism for the formation of 4.
N
–
O
O
Cl
Br
Br
Cl
N
O
O
7
B
+
HN
O
Br
Cl
F
F
6
F
F
N
O
Cl
6a
H
F
F
N
O
Cl
H
Br
H
NaH
NaBr
F
F
N
O
Cl
NaH
H
2
Na
+
E
NaCl
F
F
N
O
H
[1,7]-H shift
9
D
F
H
–
H
2
OH
HN
Ph
O
H
2
N
2
F
S
+
3
K
2
CO
3
(0.5 eq.)
DMAP (0.1 eq.)
THF, rt, 16 h
OH
HN
Ph
O
N
1 (yield, 84%)
N
F
N
4
N
F
O
N
Ph
N
+
I
−
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products350
Experimental Procedure (from Org. Process Res. Dev., 2009, 13, 198*)
N-[(1R,2R)-6-[[1-[[(4-Fluorophenyl)methyl]methylamino]-ethyli-
dene]amino]-2,3-dihydro-2-hydroxy-1H-inden-1-yl]-[1,1′-biphenyl]-
4-carboxamide, Hemihydrate (1). Kilolab procedure. To a slurry of aniline 2
(0.969 kg, 2.8 mol) in THF (9.7 L) at room temperature was added thioimidate 3
(0.954 kg, 2.8 mol) and DMAP (34.5 g, 0.28 mol). When HPLC indicated that thio-
imidate 3 was <2 area % (20–24 h), the mixture was transferred to a rotary evaporator,
and the solvent was removed in vacuo. The resulting foam was dissolved in CH
2
Cl
2
(12.5 L), and the organic phase was washed with 1.0 N HCl (aq) (1 × 4 and 1 × 3 L),
1.0 M NaOH (aq) (1 × 2.44 L), and sat. NaCl (aq) (1 × 4 L). The organic phase was sep-
arated, dried (Na
2
SO
4
, 2.5 kg), and filtered, and the solvent was removed in vacuo to
yield crude amidine 1 as a solid (1.8 kg, 93.5 area% by HPLC). The solid was dissolved
in acetonitrile (9 L) while heating to 35–40 °C. After 0.5 h, seed crystals were added,
and a thick, white slurry formed. The mixture was cooled to −10 to −15 °C in an ice/
acetone bath and stirred for 1–2 h. The slurry was filtered, and the resulting solid was
rinsed with cold acetonitrile (2 × 0.5 L) and dried in vacuo to provide amidine 1 as
a partial CH
3
CN solvate (1.10 kg, 77%, 98.6 area% by HPLC). Three CH
3
CN solvate
lots (2.86 kg) were combined and dissolved in 21.8 L of methanol. The solution was
passed through a 0.45 μm carbon impregnated filter, and the tank and filter were
rinsed with 24 L of methanol. To the solution was added 5.7 kg of H
2
O over 35 min
followed by 15 g of seed crystals. After 20 min, 1.15 kg of H
2
O was added followed
by 15 g of seed crystals. After 1 h, 1.15 kg of H
2
O was added over 30 min followed by
15 g of seed crystals. After 10 min, 3.4 kg of H
2
O was added over 1 h, and the slurry
was stirred at room temperature for 1 h and at 0 °C for 45 min. The solid was collected
by filtration, rinsed with a cold solution of 11.4 L of methanol and 2.9 L of H
2
O, and
dried under vacuum at 50 °C for 24 h. The solid was equilibrated in air for 4 h to
afford amidine 1 as a white solid (hemihydrate), 2.19 kg, 76% recovery (typical labo-
ratory recovery is 87%, but the wash of the carbon-impregnated filter was inadequate
on scale), 99.3 area% by HPLC, 99.5 wt/wt% assay. [α]
D
+ 105.2 (MeOH, c = 1.0). IR
(CHCl
3
, cm
−1
): 3489, 1643, 1606, 1600, 1509, 1482.
1
HNMR (CDCl
3
): δ 7.90 (d, 2, J =
8.6), 7.69 (d, 2, J = 8.6), 7.63 (d, 2, J = 8.2), 7.48 (t, 2, J = 8.2, 7,6), 7.41 (d, 1, J = 7.3),
7.24 (dd, 2, J = 8.5 and 5.2), 7.14 (d, 1, J = 7.9), 7.04, (t, 2, J = 8.7), 6.72–6.63 (m, 3), 5.31
(t, 1, J = 5.6), 4.84 (br s, 1), 4.64 (dd, 2, J = 21.4, 15.6), 4.54 (dd, 1, J = 14.0, 7.9), 3.32
(dd, 1, J = 15.6, 7.9), 3.01 (s, 3), 2.95 (dd, 1, J = 15.7, 8.0), 1.97 (s, 3).
13
CNMR (CDCl
3
):
δ 15.3, 36.2, 38.3, 52.6, 65.2, 82.7, 115.7, 115.8, 116.7, 123.2, 125.9, 127.5, 127.6, 127.9,
128.4, 128.9, 129.2, 132.2, 133.8, 134.2, 139.7, 140.0, 145.1, 151.8, 157.6, 163.2, 169.7.
MS (m/z): 508.2 (M + 1). EA calcd for C
32
H
30
N
3
O
2
· ½ H
2
O: C, 74.40; H, 6.05; N, 8.13.
Found: C, 74.50; H, 5.93; N, 8.17.
**The mechanisms for the formation of the impurity 4 and other impurities were discussed in the
article. However, the isolation and identification of 4 were not disclosed.
The Mechanism
Excess thioimidate 3 could be attacked by the alcohol of the desired product 1
to form the onium salt A, in which the masked hydroxyl is activated as a leaving
group for ring closure, intramolecular S
N
2, to oxazoline 4 with the stereochemistry
inversion.
5.5 Formation of Monocyclic Aromatic Heterocycles 351
This side product was suppressed by fixing the 2:3 stoichiometry at 1:1.
5.5.5 Triazole
Problem 141: Formation of Dimethylcarbamoyl-OBt in a HBTU-promoted
Amide Preparation
In a synthesis of cyclic Peptide Q at Ferring Pharmaceuticals, the last manufacturing
upstream processing step was an amide formation by employing HBTU in DMF.
A non-peptide-related impurity with an abundance of 0.09% was detected in the final
API of Peptide Q [39]. For quality control and analytical purpose, determining its
structure and understanding its formation mechanism are crucial. The structure of
the impurity was identified as 1-[((dimethylamino)carbonyl]oxy)-1H-benzotriazole
(1) or its isomer 1-(dimethylcarbamoyl)-1H-1,2,3-benzotriazol-3-ium-3-olate (2),
both were abbreviated as dimethylcarbamoyl-OBt.
Please propose a mechanism for the formation of 1 or 2.
Experimental Procedure (from Org. Process Res. Dev., 2021, 25, 1923, Supporting
Information*)
The Fate of HBTU Under Peptide Q Cyclization-like Conditions. 0.41 g
(1.09 mmol) HBTU was dissolved in 3 mL DMF, and the derived HBTU/DMF solu-
tion was loaded in Syringe A. 5 mL DMF was loaded in Syringe B. In Syringe C,
0.88 mL DIPEA was loaded. The contents in Syringe A, B, and C were simultaneously
N
4
N
O
N
OH
HN
Ph
O
NN
F
Ar
1
1
F
SMe
3
Ar
1
HN
N
N
O
O
N
SMe
HI
K
2
CO
3
KI
KHCO
3
N
NN
O
O
H
MeS
–
MeSH
KSMe
+
N
O
A
Ar
2
Ar
1
Ar
2
Ar
1
Ar
1
Ar
2
Ar
1
Ar
2
Ar
1
Ar
1
K
2
CO
3
KHCO
3
N
+
N
+
I
–
NH
2
HO
O
HBTU, DMF
NMM
N
H
O
N
N
N
O
N
O
1
N
N
N
O
2
Linear peptide Q
Peptide
Q
Dimethylcarbamoyl-OBt
N
+
O
–
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products352
slowly added at ambient temperature through a syringe pump to a reactor contain-
ing 7 mL DMF within 120 min. The solution in the reactor was stirred at ambient
temperature, and its pH value was maintained above 8 by the addition of DIPEA,
if necessary. After the addition, the solution in the reactor was stirred further at
ambient temperature for 10 min before being poured to 135 mL 1% AcOH aqueous
solution at 5 °C. The derived solution was stored overnight at 2–8 °C and filtered
through a 2.4 μm filter. The content of the solution was analyzed by LC/MS.
LC/MS Analysis of the Dimethylcarbamoyl-OBt Impurity. The comparison
of HBTU degradant and reference material 1-[((dimethylamino)carbonyl)oxy]-
1Hbenzotriazole (dimethylcarbamoyl-OBt) by LCMS analysis is displayed in Figure
S1. The results indicate a strikingly high similarity between the subject degradant
from HBTU/DIPEA/DMF simulation reaction and the dimethylcarbamoyl-OBt ref-
erence. Both the retention time and the MS fragmentation strongly corroborate that
HBTU was partially degraded into dimethylcarbamoyl-OBt adduct in DIEPA/DMF
solution.
The subject non-peptide-related impurity in Peptide Q was isolated and subjected
to NMR analysis by 1D
1
H - and
13
CNMR, COSY, NOESY,
13
C-HSQC,
13
C-HMBC,
and
15
N-HMBC. The 1D
1
HNMR spectrum of the impurity identified four aro-
matic signals and two methyl signals as part of the impurity.
1
HNMR (600 MHz,
DMSO-d
6
) δ 8.10 (dd, J = 8.4 and 1.0 Hz, 1H), 7.79 (dd, J = 8.3 and 1.0 Hz, 1H), 7.63
(ddd, J = 8.2, 7.0, and 0.9 Hz, 1H), 7.48 (ddd, J = 8.1, 6.9, and 1.0 Hz, 1H), 3.21 (s,
3H), 3.00 (s, 3H).
13
CNMR (150.8 MHz, DMSO-d
6
) δ 152.13, 143.09, 129.36, 128.89,
125.55, 120.20, 109.76, 38.08, 36.53.
The Mechanism
The formation of dimethylcarbamoyl-OBt (1 or 2) is presumably initiated by DMF
as a nucleophile-attacking HBTU. One of the dimethylamino group in the formed
species A migrates to the formimidate carbon to give the cation species B, which
is possibly resonance with tautomers C and D. Water is added to those species to
provide adduct E; simultaneously HPF
6
is released and trapped by NMM. Finally,
elimination of DMF and dimethylamine from E leads to the impurity 2.
N
N
HBTU
F
6
P
–
N
O
DMF
N
N
N
O
N
N
O
+
N
N
A B
C
N
N
O
D
OH
2
NMM
O
H
N
N
E
O
O
H
N
N
N
O
2
O
N
+
F
6
P
–
N
+
NMe
2
N
+
O
–
N
+
O
–
NMe
2
Me
2
N
Me
2
N
F
6
P
–
NMe
2
Me
2
N
Me
2
N
F
6
P
–
O
+
N
+
N
+
O
–
NMe
2
Me
2
N
Me
2
+
N
F
6
P
–
F
6
P
–
N
+
HPF
6
N
+
Me
2
N
Me
2
N
NMe
2
H
2
O
O
–
O
–
NMe
2
Me
2
NH
O
–
N
+
N
+
NMe
2
O
–
5.5 Formation of Monocyclic Aromatic Heterocycles 353
Similar to the above mechanism, compound 1 could be generated by the following
mechanism.
Compound 1 and compound 2 should be interconvertible via intermolecular car-
bamoyl transformation between N and O atoms.
5.5.6 Tetrazole
Problem 142: Formation of a Tetrazole Impurity Caused by Acetone
Olmesartan medoxomil (OLM, 2) is an antihypertensive prodrug used in the
treatment and management of hypertension either alone or in combination with
other drugs. In the process of deprotection of 1 by implementing the acetone-HCl
system, an impurity 3 of 0.23 area% was identified [40]. It was proved challenging
to purge out this impurity during the final recrystallization. The generation of 3
was suppressed (<0.1%) using statistical methods (DoE) via a definitive screening
design.
Please propose a mechanism for the formation 3.
Experimental Procedure (from Org. Process Res. Dev. 2021, 25, 1112, the spectra
data were reported in the Supporting Information)
N
N
HBTU
N
O
DMF
N
N
N
O
–
HOBT
O
N
N
N
N
O
G
O
N
N
N
O
H
O
N
N
N
O
J
N
N
N
O
O
I
N
N
N
O
O
K
O
H
HPF
6
NMM
O
H
N
N
N
O
1
O
O
NMe
2
F
6
P
–
O
−
N
+
N
+
F
6
P
–
N
+
N
+
F
6
P
–
Me
2
N
NMe
2
N
+
F
6
P
–
Me
2
N
NMe
2
NMe
2
NMe
2
Me
2
N
Me
2
N
F
6
P
–
NMe
2
Me
2
N
Me
2
+
N
F
6
P
–
F
6
P
–
N
+
H
2
O
OH
2
NMe
2
NMe
2
Me
2
NH
Me
2
N
Me
2
N
Me
2
N
O
+
N
N
N
2
N
N
O
N
2
O
N
N
N
O
N
O
1
N
N
N
O
N
O
1
N
+
N
+
O
–
O
–
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products354
(5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-
propyl-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-imidazole-5-car-
boxylate (2). A three-neck flask was charged with trityl-protected ester 1 (8.00 g,
9.92 mmol, 1.0 equiv), suspended in acetone (16 mL). Then while stirring, 1.56 M
hydrochloric acid (16 mL) was added to the suspension. After being stirred at
ambient temperature for 3 h, the complete conversion was indicated by TLC anal-
ysis (50% AcOEt/petroleum ether). The reaction mixture was diluted with H
2
O
(32 mL), cooled to 0 °C in an ice bath for another 0.5 h. Triphenylmethanol was
filtered and washed with H
2
O (2 × 5 mL). The combined filtrate was diluted with
CH
2
Cl
2
(20 mL), followed by careful neutralization with aqueous Na
2
CO
3
solu-
tion (0.2 g/mL) to adjust the pH to 5.5. The organic layer was separated, and the
aqueous layer was extracted with CH
2
Cl
2
(3 × 10 mL). The combined organic layer
was washed with H
2
O (30 mL), dried over Na
2
SO
4
, and condensed in vacuo to afford
an off-white solid. Recrystallization from acetone afforded olmesartan medoxomil
as a pure white crystalline powder (4.38 g, 80.1% yield).
(5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-(2-hydroxypropan-2-yl)-1-((2′-(2-
(2-methyl-4-oxopentan-2-yl)-2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-
2-propyl-1H-imidazole-5-carboxylate (3). To a three-neck flask, olmesartan
medoxomil (2, 1.13 g, 2.02 mmol, 1.0 equiv) and mesityl oxide (2.98 g, 30.31 mmol,
15 equiv) were added. BF
3
·Et
2
O (0.32 g, 2.23 mmol, 1.1 equiv) was added dropwise
to the reaction mixture. After being stirred at 50 °C for 5 h, the complete conversion
was indicated by TLC analysis (50% AcOEt/petroleum ether). While stirring, H
2
O
(10 mL) was added dropwise to the reaction mixture, followed by extraction with
ethyl acetate (3 × 10 mL). The organic layer was combined, washed with brine
(10 mL), dried over Na
2
SO
4
, and condensed in vacuo to afford a yellow oil. The crude
product was purified using short column chromatography (50% AcOEt/petroleum
ether) to eliminate the mesityl oxide. The product was obtained as a light yellow oil
(1.10 g, 82.9% yield).
1
HNMR (400 MHz, DMSO-d
6
) δ 7.76 (dd, J = 7.6 and 1.5 Hz,
1H), 7.61 (td, J = 7.6 and 1.5 Hz, 1H), 7.53 (td, J = 7.5 and 1.4 Hz, 1H), 7.47 (dd, J =
7.6 and 1.4 Hz, 1H), 7.02 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 5.45–5.40 (s,
2H), 5.22 (s, 1H), 5.08 (s, 2H), 3.18 (s, 2H), 2.60 (t, J = 7.6 Hz, 2H), 2.08 (s, 3H), 1.95
(s, 3H), 1.63 (h, J = 7.4 Hz, 1H), 1.53 (s, 6H), 1.47 (s, 6H), 0.90 (t, J = 7.3 Hz, 3H).
13
CNMR (101 MHz, DMSO-d
6
) δ 204.61, 163.55, 160.72, 157.66, 151.68, 150.95,
N
N
OH
O
O
O
O
O
N
NN
N
Ph
3
C
HCl
(1.56 M in H
2
O)
Acetone, rt, 3 h
N
N
OH
O
O
O
O
O
N
NHN
N
N
N
OH
O
O
O
O
O
N
NN
N
O
1
2 (80%)
3
5.5 Formation of Monocyclic Aromatic Heterocycles 355
140.90, 140.44, 139.11, 136.01, 132.87, 130.52, 130.03, 129.14, 127.75, 126.06, 125.10,
116.14, 69.65, 63.65, 54.92, 54.17, 51.25, 48.02, 30.77, 29.67, 28.30, 26.97, 20.52, 13.69,
8.74.
15
NNMR (60.8 MHz, CDCl
3
) δ 1.12, −44.72, −72.53, −74.67, −114.56, −207.50.
MS m/z 657 (M + H
+
).
The Mechanism
At the acidic condition, acetone dimerizes to form mesityl oxide by aldol condensa-
tion and dehydration [41]. Deprotection of the trityl in the starting material 1 yields
the desired product 2, which further reacts with the mesityl oxide via Michael-type
addition to generate the impurity 3. Indeed, treatment of 2 with mesityl oxide at the
acetone-H
2
O-HCl system provided 3 in 87% yield [40].
Mesityl oxide is genotoxic and could be generated from acetone in acidic envi-
ronments, including acid salts. It could be further attacked by nucleophile via
Michael-type addition. Notably, plenty of small-molecule drugs and intermediates
have nitrogen-containing moieties or nucleophilic functional groups; therefore,
more attention should be paid to impurities formed between mesityl oxide and reac-
tive substrates.
5.5.7 Diazepine
Problem 143: Accidental Discovery of Librium
Chlordiazepoxide (3), trade name Librium, is a tranquilizer and approved for med-
ical use in 1960. It was discovered accidently by Sternbach and Reeder in 1957. When
they wanted to do an amination of 6-chloro-2-(chloromethyl)-4-phenylquinazoline
3-oxide (1) with methylamine, the expected product 2 was not obtained. Instead, the
rearranged product 3 was obtained in high yield (82%) [42].
Could you please suggest a mechanism for its formation?
Experimental Procedure (from J. Org. Chem. 1961, 26, 1111)
7-Chloro-9-methylamino-5-phenyl-3H-l,4-benzodiazepine 4-oxide (3). Into
600 cc. of a cold 25% solution of methylamine in methanol was introduced with
stirring 98 g of the hydrochloride of 6-chloro-2-chloromethyl-4-phenylquinazoline
3-oxide (1). The mixture was initially cooled to about 30° and then stirred at room
temperature for 15 h. The precipitated chemically pure reaction product (50 g) was
N
N
OH
O
O
O
O
O
N
NN
N
O
3
O
H
Cat.
HCl
O
H
O
O
O
H
H
O
Mesityl oxide
N
N
OH
O
O
O
O
O
N
NHN
N
2
O
Mesityl
oxide
Cat.
HCl
H
+
H
+
H
+
H
2
O
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products356
then filtered off. The mother liquor was concentrated in vacuo and the residue dis-
solved in methylene chloride. The methylene chloride solution was washed with
water, dried with sodium sulfate, and concentrated in vacuo. The crystalline residue
was triturated with a small amount of hot acetone to dissolve the more soluble
impurities. The mixture was then cooled to 5° for 10 h and filtered, yielding 20.3 g of
almost chemically pure material. The total yield was 70.3 g (82%). The product was
recrystallized from a 15-fold volume of boiling ethanol, forming light yellow plates
with a melting point of 236–236.5°. Anal. Calcd for C
16
H
14
N
3
OCl: C, 64.11; H, 4.71.
Found: C, 64.38; H, 4.66.
The NMR data were reported by Haran and Tuchagues [43].
1
HNMR (90 MHz,
DMSO-d
6
) δ 8.11 (q, J = 4.4 Hz, 1H), 6.79–7.55 (m, 8H), 4.42 (brs, 2H), 2.85 (d, J = 4.7
Hz, 3H).
13
CNMR (62.86 MHz, DMSO-d
6
) δ 152.80, 147.92, 140.54, 133.52, 130.55,
129.08, 128.81, 128.33, 127.86, 125.89, 124.45, 64.53, 27.96.
The Mechanism
Due to the electron-withdrawing property of the N-oxide, the C-2 is more electro-
philic than the chloromethyl. Thus, methylamine would preferentially attack C-2 to
give adduct A. Then ring opening releases imidamide oxime B. Recyclization of B
along with lose HCl leads to Librium.
Secondary amines, such as dimethylamine and piperazine, provided only the
normal products [42].
5.6 Formation of Bicyclic Aromatic Heterocycles
5.6.1 Benzofuran
Problem 144: Formation of Two Benzofuran Side Products During the
Synthesis of Morin
Morin (1) is a natural product found in various plants of the Moraceae family. It is
an antioxidant and is being considered as a promising chemo preventive anticancer
Cl
N
Cl
NH
2
Me
Cl
N
HN
Cl
H
Cl
N
N
O
HN
Cl
H
Cl
N
H
N
Librium
2
A
B
N
+
N
+
O
–
O
–
– HCI
N
+
O
–
Cl
N
+
N
Cl
O
–
O
–
MeNH
2
MeOH, rt
82%
Cl
N
H
N
3, Librium
1
Cl
N
N
H
O
–
2
1
2
4
6
N
+
N
+
5.6 Formation of Bicyclic Aromatic Heterocycles 357
agent that does not exhibit toxicity [44]. In a synthesis of morin, the oxidative cycli-
zation of 2 by tert-butyl hydroperoxide (TBHP) provided desired product 3 in 39%
yield. Meanwhile, two side products 4 and 5 were also obtained [45].
Please suggest mechanisms for the formation of 3, 4, and 5.
Experimental Procedure (from Org. Process Res. Dev., 2023, 27, 890)
2-(2,4-Dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromen-4-one
(3). In a 50 L reactor, a mixture of 3-(2,4-dimethoxyphenyl)-1-(2-hydroxy-4,
6-dimethoxyphenyl)prop-2-en-1-one (2, 200 g, 0.581 mol, 1.00 equiv), ethanol (8 L),
and NaOH (800 mL, 10.87 M, 15.0 equiv) was stirred at 24 °C for 0.5 h. Then, TBHP
(70% aq., 800 mL, 5.81 mol, 10.0 equiv) was added, and the mixture was stirred at
24 °C for 23 h. The reaction was quenched with 1 M HCl and adjusted to pH 2–4.
The aqueous phase was extracted with DCM (3 × 5 L). The organic phases were
combined, and the solvent was removed. The remaining brown oily crude product
was recrystallized from n-butanol and dried under vacuum at 50 °C. The dried yellow
solid was added to aqueous NaOH (2 M, 1.1 L) and stirred at 24 °C overnight. The
resulting suspension was filtered, and the filter cake was acidified by addition of 1 M
HCl (13 L) to pH 4 and stirred for 1 h at 100 °C. The color of the suspension changed
from yellow to white. The suspension was cooled to 25 °C and stirred for 12 h. After
filtration of the suspension, the filter cake was dried under vacuum at 50 °C to give 3
O
OH
O
HO OH
OH
HO
1 (morin)
O
OH
O
MeO OMe
OMe
MeO
3 (39%)
OH
O
MeO OMe
OMe
MeO
2
TBHP, NaOH
EtOH, H
2
O
25 °C
OMe
MeO
O
O
OMe
OMe
OH
4 (11%)
OMe
MeO
O
OMe
OMe
O
5 (4%)
HBr
3
(39%)
OH
O
MeO OMe
OMe
MeO
2
TBHP, NaOH
EtOH, H
2
O
25 °C
4
(11%)
5
(4%)
CO
2
H
CO
2
Et
OMeHO
OMe
6 (23%)
OMeHO
OMe
7 (3%)
CHO
OMe
OMe
8 (15%)
OMeHO
OMe
9 (4%)
OH
OMe
OMe
10 (4%)