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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 Products358
as a white solid (74.8 g, 0.209 mol, 36%). The product was obtained with a purity of
95% (HPLC analysis). In the synthesis on a 2 g scale, the following compounds were
isolated via column chromatography: aurone 5 (4%), auronol 4 (11%), benzaldehyde
8 (15%), benzoic acid 6 (23%), benzoate 9 (4%), and phenols 7 (4%) and 10 (3%). 3, R
f
= 0.33, hexane/EtOAc (1:3).
1
HNMR (400 MHz, CDCl
3
): δ 7.49 (d, J = 8.4 Hz, 1H,
6′-H), 6.76 (s, 1H, OH), 6.60 (dd, J = 8.4, 2.3 Hz, 1H, 5′-H), 6.57 (d, J = 2.3 Hz, 1H,
3′-H), 6.47 (d, J = 2.2 Hz, 1H, 8-H), 6.34 (d, J = 2.2 Hz, 1H, 6-H), 3.97 (s, 3H, 5-OCH
3
),
3.86 (s, 6H, 4′-OCH
3
, 7-OCH
3
), 3.84 (s, 3H, 2′-OCH
3
).
13
CNMR (101 MHz, CDCl
3
):
δ 172.09 (C-4), 164.23 (C-7), 162.80 (C-4′), 160.77 (C-5), 159.73 (8C-C-1O), 158.99
(C-2′), 142.80 (C-2), 138.74 (C-3), 132.02 (C-6′), 112.54 (C-1′), 106.94 (4C-C-5C), 104.99
(C-5′), 99.38 (C-3′), 95.68 (C-6), 92.70 (C-8), 56.51 (5-OCH
3
), 56.03 (2′- OCH
3
), 55.87
(7-OCH
3
), 55.64 (4′-OCH
3
).
1
HNMR (400 MHz, DMSO-d
6
): δ 8.21 (s, 1H, OH), 7.36
(d, J = 8.4 Hz, 1H, 6′-H), 6.69 (d, J = 2.3 Hz, 1H, 3′-H), 6.63 (dd, J = 8.5, 2.3 Hz,
1H, 5′-H), 6.60 (d, J = 2.2 Hz, 1H, 8-H), 6.46 (d, J = 2.3 Hz, 1H, 6-H), 3.86 (s, 3H,
5-OCH
3
), 3.84 (s, 3H, 7-OCH
3
), 3.83 (s, 3H, 4′-OCH
3
), 3.78 (s, 3H, 2′-OCH
3
).
13
CNMR
(101 MHz, DMSO-d
6
): δ 171.15 (C-4), 163.47 (C-7), 162.06 (C-4′), 160.28 (C-5), 158.68
(8C-C-1O), 158.46 (C-2′), 143.11 (C-2), 138.83 (C-3), 131.88 (C-6′), 112.33 (C-1′),
106.95 (4C-C-5C), 105.05 (C-5′), 98.78 (C-3′), 95.54 (C-6), 92.68 (C-8), 56.19 (5-OCH
3
),
55.90 (7-OCH
3
), 55.79 (2′-OCH
3
), 55.44 (4′-OCH
3
). UV/vis (MeCN): λ
max
(lg ε) = 333
(3.22), 292 (3.00), 244 (3.39), 204 (3.41). MS (ESI): m/z (%) = 359 [M + H]
+
(33), 381
[M + Na]
+
(37), 739 [2 M + Na]
+
(100).
5: R
f
= 0.51, hexane/EtOAc (1:3).
1
H NMR (400 MHz, CDCl
3
): δ 8.19 (d, J = 8.7
Hz, 1H, 6′-H), 7.26 (s, 1H, 2C═CH), 6.57 (dd, J = 8.8, 2.4 Hz, 1H, 5′-H), 6.44 (d, J =
2.4 Hz, 1H, 3′-H), 6.35 (d, J = 1.8 Hz, 1H, 7-H), 6.11 (d, J = 1.8 Hz, 1H, 5-H), 3.94
(s, 3H, 4-OCH
3
), 3.89 (s, 3H, 6-OCH
3
), 3.87 (s, 3H, 2′-OCH
3
), 3.85 (s, 3H, 4′-OCH
3
).
13
C NMR (101 MHz, CDCl
3
): δ 180.69 (C-3), 168.72 (7C-C-1O), 168.54 (C-6), 162.34
(C-4′), 160.25 (C-2′), 159.40 (C-4), 146.95 (C-2), 132.94 (C-6′), 114.83 (C-1′), 105.83
(3C-C-4C), 105.65 (C-5′), 105.46 (2C═C), 98.07 (C-3′), 93.92 (C-5), 89.23 (C-7), 56.30
(4-OCH
3
), 56.15 (6-OCH
3
), 55.69 (2′-OCH
3
), 55.56 (4′-OCH
3
). UV/vis (MeCN): λ
max
(lg ε) = 398 (3.45), 251 (3.30), 204 (3.55). MS (ESI): m/z (%) = 343 [M + H]
+
(45),
365 [M + Na]
+
(55), 707 [2 M + Na]
+
(100).
8: R
f
= 0.44, hexane/EtOAc (2:1).
1
HNMR (400 MHz, CDCl
3
): δ 10.27 (s, 1H),
7.79 (d, J = 8.7 Hz, 1H), 6.53 (ddd, J = 8.7, 2.2, and 0.7 Hz, 1H), 6.43 (d, J = 2.2
Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H).
13
CNMR (101 MHz, CDCl
3
): δ 188.42, 166.30,
163.73, 130.82, 119.16, 105.88, 98.03, 55.73, 55.71. UV/vis (MeCN): λ
max
(lg ε) = 308
(3.42), 271 (3.42), 223 (3.41). MS (ESI): m/z (%) = 167 [M + H]
+
(22), 189 [M + Na]
+
(100), 355 [2 M + Na]
+
(91).
6: R
f
= 0.62, hexane/EtOAc (1:3).
1
HNMR (400 MHz, CDCl
3
): δ 12.45 (s, 1H),
10.86 (s, 1H), 6.17 (d, J = 2.3 Hz, 1H), 6.02 (d, J = 2.3 Hz, 1H), 4.00 (s, 3H), 3.81
(s, 3H).
13
CNMR (101 MHz, CDCl
3
): δ 170.87, 166.42, 165.75, 159.80, 95.20, 94.99,
91.47, 57.02, 55.81. UV/vis (MeCN): λ
max
(lg ε) = 295 (2.66), 265 (3.06), 220 (3.08).
MS (ESI): m/z (%) = 197 [M - H]
−
(100), 221 [M + Na]
+
(70), 419 [2M + Na]
+
(45).
10: R
f
= 0.51, hexane/EtOAc (2:1).
1
H NMR (400 MHz, CDCl
3
): δ 6.83 (d, J =
8.7 Hz, 1H), 6.49 (d, J = 2.8 Hz, 1H), 6.39 (dd, J = 8.7 and 2.8 Hz, 1H), 5.24 (s, 1H),
5.6 Formation of Bicyclic Aromatic Heterocycles 359
3.86 (s, 3H), 3.76 (s, 3H).
13
CNMR (101 MHz, CDCl
3
): δ 153.68, 147.19, 139.92,
114.21, 104.38, 99.57, 56.02, 55.94. MS (ESI): m/z (%) = 155 [M + H]
+
(100), 177 [M
+ Na]
+
(32).
7: R
f
= 0.42 hexane/EtOAc (2:1).
1
HNMR (400MHz, CDCl
3
): δ 6.08 (t, J = 2.2Hz,
1H), 6.03 (d, J = 2.2Hz, 2H), 5.41 (s, 1H), 3.74 (s, 6H).
13
CNMR (101MHz, CDCl
3
): δ
161.73, 157.51, 94.43, 93.33, 55.48. UV/vis (MeCN): λ
max
(lgε) = 266 (2.68), 233
(3.20). MS (ESI): m/z (%) = 155 [M + H]
+
(100).
9: Rf = 0.57, hexane/EtOAc (2:1).
1
HNMR (400MHz, CDCl3): δ 12.07 (s, 1H),
6.10 (d, J = 2.4Hz, 1H), 5.95 (d, J = 2.4Hz, 1H), 4.37 (q, J = 7.1Hz, 2H), 3.80 (s, 3H),
3.80
(s, 3H), 1.39 (t, J = 7.1 Hz, 3H).
13
CNMR (101 MHz, CDCl3): δ 171.32,
166.03, 165.34, 162.40, 97.01, 93.55, 91.74, 61.27, 56.13, 55.54, 14.34. MS (ESI): m/z
(%) = 249 [M + Na]
+
(100).
(E)-2-((2,4-Dimethoxyphenyl)(hydroxy)methylene)-4,6-
dimethoxybenzofuran-3(2H)-one (4). Aurone 5 (100mg, 0.292mmol, 1.0 equiv)
was dissolved in ethanol (4mL) and NaOH (0.4mL, 10.87N, 15.0 equiv). The reaction
mixture was stirred at 24 °C for 0.5h. TBHP 70% aq. (0.4mL, 2.92mmol, 10.0 equiv)
was added, and the mixture was stirred for 23h at 25 °C. The reaction was quenched
with 1N HCl and adjusted to pH2. The aqueous phase was extracted with DCM (3 × 5
mL). The organic phases were combined and dried over sodium sulfate, and the
solvent was removed. Auronol 4 was obtained as a colorless solid (8.4mg, 8%) after
silica gel column chromatography. R
f
= 0.48, hexane/EtOAc (1:3).
1
HNMR
(400 MHz,
CDCl
3
): δ 9.47 (s, 1H, OH), 7.19 (d, J = 8.7 Hz, 1H, 6′-H), 6.57–6.56 (m, 2H, 5′-
H, 3′-H), 6.51 (d, J = 2.2Hz, 1H, 7-H), 6.35 (d, J = 2.2Hz, 1H, 5-H), 3.98 (s, 3H, 4-
OCH
3
), 3.85 (s, 3H, 6-OCH
3
), 3.82 (s, 3H, 4′-OCH
3
), 3.78 (s, 3H, 2′-OCH
3
).
13
CNMR (101 MHz, CDCl
3
): δ 163.00 (C-6), 162.59 (2C-C-1′C), 161.93 (C-3), 160.97
(C-4′), 158.79 (C-2′), 157.13 (C-4), 155.90 (7C-C-1O), 132.59 (C-6′), 113.11 (C-1′),
104.82 (C-5′), 100.50 (C-2), 99.25 (C-3′), 99.18 (3CC-4C), 95.47 (C-5), 94.39 (C-7),
57.00 (4-OCH
3
), 55.99 (6-OCH
3
), 55.89 (2′-OCH
3
), 55.46 (4′-OCH
3
).
1
HNMR
(400MHz, DMSO-d
6
): δ 9.80 (s, 1H, OH), 7.04 (d, J = 8.3Hz, 1H, 6′-H), 6.64 (d, J =
2.3Hz, 1H, 7-H), 6.59 (d, J = 2.3Hz, 2H, 5-H, 3′-H), 6.54 (dd, J = 8.3, 2.4Hz, 1H, 5′-
H), 3.97 (s, 3H, 4-OCH
3
), 3.87 (s, 3H, 6-OCH
3
), 3.79 (s, 3H, 4′-OCH
3
), 3.69 (s, 3H,
2′-OCH
3
).
13
CNMR (101MHz, DMSO-d
6
): δ 162.91 (C-6), 161.69 (2C-C-1′C), 161.23
(C-3), 160.21 (C-4′), 158.46 (C-2′), 157.44 (C-4), 155.12 (7C-C-1O), 132.58
(C-6′), 113.44 (C-1′), 104.59 (C-5′), 99.21 (C-2), 98.39 (C-3′), 98.31 (3C-C-4C), 95.36
(C-5),
93.93 (C-7), 56.98 (4-OCH
3
), 56.05 (6-OCH
3
), 55.37 (2′-OCH
3
), 55.19 (4′-OCH
3
).
UV/vis (MeCN): λ
max
(lgε) = 316 (3.13), 215 (3.16), 205 (3.15). MS (ESI): m/z (%) =
359 [M + H]
+
(33), 381 [M + Na]
+
(77), 739 [2 M + Na]
+
(100).
The Mechanism
The reaction begins the oxidation of the double bond in 2 with TBHP to
give the epoxide A. Then the epoxide is attacked by the neighbor phenolic hydroxyl.
The new ring could be formed by two paths.
Path A is a 6-endo-tet process [46] to
provide the 3-hydroxychroman-4-one B. After the elimination of one molecule of
water, the newly formed doublebond in C is oxidized by TBHP again to generate
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products360
Another possible ring closure of A is a 5-endo-tet process [46]. (Path B), which
gives the benzofuran F. Elimination of one molecule of water from F produces the
side product 5.
By the same manner for the formation of 3, compound 5 is further oxidized by
TBHP, via epoxide G, to generate side product 4.
OH
O
Ar
OMe
MeO
2
TBHP
NaOH
H
O
O
t-Bu
TBHP
t-BuOH
O
O
Ar
OMe
MeO
A
O
H
a
b
Path
A
O
OH
O
Ar
OMe
MeO
H
B
O
O
Ar
OMe
MeO
C
H
2
O
H
O
O
TBHP
t-BuOH
O
O
Ar
OMe
MeO
D
O
TBHP
H
O
OH
O
Ar
OMe
MeO
3
O
O
O
Ar
OMe
MeO
H
E
OH
O
–
Ar
OMe
MeO
O
O
t-Bu
Na
+
t-Bu
HO
–
HO
–
O
O
Ar
OMe
MeO
A
O
H
b
Path
B
OMe
MeO
O
Ar
O
F
OH
H
HO
–
H
2
O
OMe
MeO
O
O
5
Ar
OMe
MeO
O
O
5
Ar
H
O
O
t-Bu
t-BuOH
TBHP
OMe
MeO
O
O
Ar
O
OMe
MeO
O
Ar
O
OH
4
G
H
HO
–
OMe
MeO
O
Ar
O
O
H
5.6 Formation of Bicyclic Aromatic Heterocycles 361
Indeed, when isolated aurone 5 was subjected to oxidative cyclization conditions
(TBHP/NaOH, 24 h), auronol 4 (8%, 40% brsm) and flavonol tetramethylmorin
(3, 8%) were obtained together with 80% of the unreacted starting material.
The transformation from A to 5 could be reversible. Addition of H
2
O to 5 would
give the benzofuran F. The partially deprotonated hydroxyl attacks the α-carbon of
the carbonyl in the furan ring, leading to intermediate A. Compound 3 could be pro-
duced from A as we have proposed in the mechanism.
5.6.2 Benzoxazolinone
Problem 145: Formation of Undesired Benzoxazolinone from
N,2-Dihydroxybenzamide
Compound 1 was identified as a potent 5-HT
4
partial agonist with favorable safety
and pharmacokinetic profiles for treatment of AD and cognitive impairment [47].
The initial synthesis of 1 included the reaction as shown below. Due to the formation
of undesired benzoxazolinone (4), the desired product benzo[d]isoxazol-3-ol (3) was
obtained in moderate yield (43%) [48, 49].
Please suggest mechanism for the formation of 3 and 4.
Experimental Procedure (from Org. Process Res. Dev., 2016, 20, 233*)
4-[(R)-(Tetrahydrofuran-3-yl)oxy]-benzo[d]isoxazol-3-ol (3). A solution of
2,N-dihydroxy-6-[(R)-(tetrahydrofuran-3-yl)oxy]-benzamide (2, 25 g, 0.105 mol) in
250 mL of THF was heated to 50 °C. Carbonyl diimidazole was added portionwise
and the resulting mixture was stirred at 50 °C for 14 h. After cooling to room tem-
perature, 100 mL of 2N HCl was added and the aqueous layer was extracted with
ethyl acetate. The combined organic layers were then extracted three times with
10% aqueous potassium carbonate. The aqueous extracts were washed with ethyl
acetate and then acidified to pH 2–3 with 2N HCl. The acidified aqueous layer was
extracted with ethyl acetate. The ethyl acetate extracts were washed with brine,
dried (Na
2
SO
4
), and concentrated to afford 20 g of product as a yellow solid (43%
yield**).
1
HNMR (400 MHz, CDCl
3
): δ 2.20 (m, 2H), 3.89 (m, 1H), 4.01 (m, 3H), 5.05
(m, 1H), 6.48 (d, J = 7.6 Hz, 1H). 6.92 (d, J = 7.6 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H).
H
2
O
OMe
MeO
O
O
5
Ar
OMe
MeO
O
Ar
O
F
O
Ar
OMe
MeO
A
O
3
HO
–
O
–
O
–
OH
O
HN
OH
O
O
CDI
THF
50 °C
O
O
N
O
OH
O
O
NH
O
O
2
3 (43%)
4
O
O
N
O
O
1
(8 steps overall
yield 3.3%)
N
O
OH
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products362
* The mechanism for the formation of 3 and the side product 4 was discussed in the article [49].
However, the isolation and identification of 4 was not disclosed.
** I calculated the yield to be 86%.
The Mechanism
Upon the addition of CDI to compound 2, two molecules of imidazole are released,
yielding intermediate A. Subsequently, a nucleophilic attack by the hydroxyl group
on the dioxazole ring, coupled with the synergistic elimination of CO₂, leads to the
formation of the desired product 3. However, due to the electron-donating nature
of the alkoxy group, a Lossen-type rearrangement also takes place, accompanied
by the generation of CO₂, resulting in the formation of the isocyanate interme-
diate B. This intermediate readily undergoes cyclization to produce the undesired
benzoxazolinone 4.
To inhibit the Lossen rearrangement, a fluoro substituent—an electron-withdrawing
group—was introduced at the C-6 position. This group could also serve as a leaving
group for the subsequent introduction of the chiral tetrahydrofuran moiety. In prac-
tice, treatment of the fluoro compound 5 with CDI in refluxing THF provided the
desired product 6 in 92% yield without any detectable Lossen rearrangement side
product [49].
OH
O
HN
O
O
O
2
R=
N
N
N
O
N
CDI
H
CDI
HN
N
OH
O
N
O
OR
O
N
N
H
HN
N
O
OR
O
O
N
O
A
H
CO
2
Desired
phenolic
addition
OR
N
O
OH
3
Lossen
rearrangement
O
N
OR
H
C
O
B
OR
4
NH
O
O
OH
O
HN
OH
F
CDI, THF
50 °C
F
N
O
OH
5
6
O
O
N
O
O
N
O
OH
92%
1
(7 steps overall
yield 41%)
5.6 Formation of Bicyclic Aromatic Heterocycles 363
5.6.3 Quinoline
Problem 146: Formation of Quinoline-4-carboxylic Acids by Pfitzinger
Reaction Conditions
Quinoline-4-carboxylic acid was a core structure in several interesting pharma-
ceutical compounds, such as antinorovirus compound 1, [50] antimycobacterial
compound 2, [51] and PPARβ/δ inhibitor 3 [52]. Ivachtchenko et al. carried out a
reaction in which N,N-diethyl-2,3-dioxoindoline-5-sulfonamide (4) was reacted
with diethyl malonate under standard Pfitzinger reaction conditions. Instead of
obtaining the expected product, 6-(N,N-diethylsulfamoyl)-2-hydroxyquinoline-4-
carboxylic acid (5), they identified 6-(N,N-diethylsulfamoyl) quinoline-4-carboxylic
acid (6) as the major product [53].
Please suggest a mechanism for the formation of 6.
Experimental Procedure (from Tetrahedron Lett., 2004, 45, 5473)
General Procedure for the Synthesis of 6-sulfamoylquinoline-4-carboxylic
Acids. Method A: Using Conventional Heating. 5-Sulfamoylisatin 4 (5.0 mmol)
was added to a solution of 5.64 g (100.7 mmol) of KOH in 32 mL of ethanol–water
(1:1). The reaction mixture was heated at reflux for 8 h, then cooled to room tem-
perature and acidified with 1N HCl until pH 1. The resulting mixture was extracted
with ethyl acetate (3 × 50 mL), the organic extracts were combined and dried over
anhydrous MgSO
4
. The solvent was removed in vacuo, and the residue was purified
by silica gel chromatography (eluent CHCl
3
–CH
3
OH, 19:1 v/v) or by recrystalliza-
tion from ethyl acetate. Yield: 40% (6). Spectroscopic data of 6: IR (KBr) 1705 cm
−1
(νC═O);
1
HNMR (DMSO-d
6
, 300 MHz (Varian), ppm) δ 1.05 (t, 6H, NCH
2
CH
3
),
3.22 (q, 4H, NCH
2
CH
3
), 8.11 (d, 1H, Ar), 8.13 (dd, 1H, Ar), 8.30 (d, 1H, Ar), 9.21
(d, 1H, Ar), 9.30 (d, 1H, Ar), 14.2 (br s, 1H, OH);
13
CNMR (DMSO-d
6
75 MHz
(Varian), ppm) δ 14.48, 42.26, 124.7, 126.02, 126.65, 131.73, 136.87, 139.21, 149.62,
163.63, 167.12; m/z 309.0901 [M + H]. Anal. Calcd. For C
14
H
16
N
2
O
4
S: C, 54.53; H,
5.23; N, 9.08; S, 10.40. Found: C, 54.67; H, 5.46; N, 9.21; S, 10.51.
N
H
O
O
S
Et
2
N
O O
CH
2
(CO
2
Et)
2
KOH, EtOH-H
2
O (1:1)
reflux, 8 h
S
O O
N
S
O O
N
OH
5 (not obtained)
6 (40%)
4
O
O
H
N
N
O
O
H
1
N
O
O
2
N
H
N
O
S
N
O
O
3
Et
2
N
Et
2
N
CO
2
H
CO
2
H
CF
3
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products364
The Mechanism
If the reaction underwent an aldol condensation pathway, the mechanism should
be as below and 5 should be the product. However, under the strong basic (KOH)
condition, diethyl malonate would hydrolyze to malonic acid dianion. That
makes the methylene not active enough to attack the carbonyl of the hydrolyzed
intermediate A. Malonic acid dianion is not an electrophile to be attacked by the
aniline in A. Therefore, neither aldol reaction nor amidation between A and malo-
nic acid dianion would happen at this strong base conditions. Typical preparation of
2-hydroxyquinoline-4-carboxylic acids from isatins and malonic acid by Pfitzinger
reaction is carried out at weak acidic conditions [54, 55].
While the EtO
–
is active enough to attack the carbonyl of the starting material 4
to provide species A. Then intramolecular disproportionation occurs to release acet-
aldehyde and 3-hydroxyindolone 7. Meanwhile, hydrolysis of 4 at the strong basic
conditions will give aniline C. The acetaldehyde is active enough to readily react
with the amine, after elimination of water, to provide vinylaniline E. Finally, vinyl-
aniline E undergoes cyclization and dehydration to give product 6. Diethyl malo-
nate does not play any role in this reaction. 3-Hydroxyindolone 7 is the by-product
of this reaction.
N
H
O
O
S
Et
2
N
O O
R
O
R
R
N
OH
4
5
R
R
N
H
O
O
R
N
H
O
A
CO
2
–
HO
–
CH
2
(CO
2
–
)
2
H
2
O
–
O
2
C
CO
2
–
H
2
O
H
2
O
NH
2
CO
2
–
CO
2
–
CO
2
–
CO
2
–
CO
2
–
H
2
O
CO
2
CO
2
CO
2
H
CH
2
(CO
2
Et)
2
KOH, H
2
O
CH
2
(CO
2
–
)
2
NH
2
N
H
O
O
S
Et
2
N
O O
R
N
O
CH
3
CHO
R
N
H
O
OH
R
N
R
N
HO
H
HOH
C
R
7
N
H
OH
O
O
H
E
6
R
R
O
H
H
R
N
4
N
H
O
R
O
H H
R
N
H
OH
A
B
D
F
EtO
–
EtO
–
O
–
O
–
HO
−
CO
2
−
NH
2
CO
2
−
H
3
+
O
H
2
O
CO
2
−
H
3
+
O
CO
2
H
CO
2
H
CO
2
−
5.6 Formation of Bicyclic Aromatic Heterocycles 365
Upon the reaction of 4 with
13
C-ethanol under the described conditions,
13
C-
labeled product 8 was obtained.
Based on this mechanism, acetaldehyde is necessary for the formation of quin-
oline ring. Since for generation of one molecule of acetaldehyde, one molecule of
the starting material 4 will be consumed, theoretically the maximum yield would
be 50%. We can predict that if extra acetaldehyde, e.g., >1 equivalent, were added
at the beginning of the reaction, the yield of product 6 would be improved and the
formation of 7 would be suppressed. Other α-hydrogen-containing aldehydes would
also react with isatins to give quinoline-4-carboxylic acids.
Problem 147: Formation of a Tricyclic Impurity During Alkylation of
8-hydroxyquinoline
The 3,4,8-trisubstituted quinoline derivatives 1a and 1b are reversible (H
+
/K
+
)
ATPase inhibitors for the treatment of peptic ulcers, gastroesophageal reflux dis-
ease, and related disorders. In a process chemistry study [56], treatment of the
8-hydroxyquinoline 1c with ethylene carbonate in i-PrOH in the presence of
1,4-diazabicyclo[2.2.2]octane (DABCO) gave the desired product 1b (yield 66%)
together with small quantities of the tricyclic compound 2, the symmetrical car-
bonate 3, and isopropyl carbonate 4.
Please propose mechanisms for the formation of impurities 2, 3, and 4.
Experimental Procedure (from Org. Process Res. Dev., 1997, 1, 185)
3-Butyryl-8-(2-hydroxyethoxy)-4-[(2-methylphenyl)-amino]quinoline (1b).
Method A. Molten ethylene carbonate (2.6 kg, 29.5 mol) was heated to 90 °C and
treated with the 8-hydroxyquinoline 1c (260 g, 0.81 mol), added portionwise over
~5 min. The mixture was reheated to 90 °C and the resulting suspension treated
with anhydrous K
2
CO
3
(11.2 g, 81 mmol). The reaction mixture was heated at 90 °C
for 3.5 h and subsequently allowed to cool to ~60 °C before water (2 dm
3
) was added
with stirring. The resulting slurry was poured into more water (2 dm
3
) and stirring
continued for 45 min. The solid was collected via suction filtration, washed with
water, and dried at 50 °C to give a crude product (277 g), which was recrystallized
from EtOAc (5 dm
3
) to give 1b (233 g, 71%) as yellow crystals: mp 115–118 °C (lit.
mp 117–120 °C). The mother liquors from the above were concentrated in vacuo,
and the residue was triturated with toluene (60 cm
3
). The resulting solid was fil-
tered off, washed with toluene, and dried at 50 °C to give yellow crystals (12.7 g).
A sample (1.22 g) of the latter was subjected to chromatography on silica gel, elut-
ing with EtOAc to give 6-butyryl-7-[(2-methylphenyl)imino]-2,3-dihydro-
7H-pyrido[1,2,3-de]-1,4-benzoxazine (2) (0.6 g) as bright yellow crystals: mp
178–180 °C (Found: C, 76.2; H, 6.5; N, 7.9. C
22
H
22
N
2
O
2
requires C, 76.3; H, 6.4; N, 8.1);
N
H
O
O
S
Et
2
N
O O
CH
3
13
CH
2
OH
KOH-H
2
O
S
O O
N
CO
2
H
8
4
35%
Et
2
N
13
C
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products366
ν
max
(KBr)/cm
−1
1686 (C═O), 1670 (C═N), 1620 (C═C), 1605 (Ar), and 1560 (Ar); δ
H
(270 MHz;
[
2
H
6
]
DMSO) 0.70 (3H, t, J 7.3, CH
3
CH
2
CH
2
CO), 1.20 (2H, sextet, J 7.3,
CH
3
CH
2
CH
2
CO), 2.13 (3H, s, ArCH
3
), 2.33 (2H, t, J 7.3, CH
3
CH
2
CH
2
CO), 4.15–4.19
(2H, m, -NCH
2
CH
2
O-), 4.37–4.41 (2H, m, -NCH
2
CH
2
O-), 6.44–6.47 (1H, m, Ar), 6.75–
6.81 (1H, m, Ar), 6.91–7.13 (4H, m, Ar), 7.65–7.67 (1H, m, Ar), and 7.71 (1H, s, 5-H);
δ
C
(62.5 MHz;
[
2
H
6
]
DMSO) 13.0 (CH
3
CH
2
CH
2
CO), 16.7 (CH
3
CH
2
CH
2
CO), 17.4
(ArCH
3
), 42.0 (CH
3
CH
2
CH
2
CO), 47.5 (-NCH
2
CH
2
O-), 63.2 (-NCH
2
CH
2
O-), 115.9–
150.9 (13C, ArC and 7-C), 141.1 (5-C), and 199.1 (CO); m / z (EI) 346 (M
+
, 30), 317
(M
+
− C
2
H
5
, 100), 303 (M
+
− C
3
H
7
, 13), and 275 (M
+
− C
3
H
7
CO, 53).
Crude 1b prepared as above (70 g) was chromatographed on silica gel (200 g)
eluting with acetone followed by 5% MeOH in acetone to give the crude car-
bonate 3 (0.5 g) as the earlier eluting fraction, the bulk (0.3 g) of which was
rechromatographed on silica gel (50 g) eluting with CH
2
Cl
2
to give bis[[[3-butyryl-
4-[(2-methylphenyl)amino]quinol-8-yl]oxy]ethyl] carbonate (3) (0.28 g) as a
yellow foam: δ
H
(400 MHz) 1.02 (3H, t, J 7.4, CH
3
CH
2
CH
2
CO), 1.80 (2H, sextet,
J 7.4, CH
3
CH
2
CH
2
CO), 2.34 (3H, s, ArCH
3
), 3.07 (2H, t, J 7.4, CH
3
CH
2
CH
2
CO),
4.42–4.49 (2H, m, ArOCH
2
-CH
2
OCO), 4.70–4.75 (2H, m, ArOCH
2
CH
2
OCO), 6.85–
7.30 (7H, m, Ar), 9.25 (1H, s, 2-H), and 11.80 (1H, s, NH); δ
C
(100 MHz) 13.9
(CH
3
CH
2
CH
2
CO), 18.2 (CH
3
CH
2
CH
2
-CO), 18.5 (ArCH
3
), 41.7 (CH
3
CH
2
CH
2
CO),
65.9 (ArOCH
2
-CH
2
OCO), 66.5 (ArOCH
2
CH
2
OCO), 111.7–155.0 (16C, Ar C, OCO.O),
and 203.1 (ArCO); m / z (FAB) 755 (MH
+
, 8) and 347 [M( 32)H
+
, 100].
Method B. The 8-hydroxyquinoline 1c (10 g, 31.2 mmol) was stirred with i-PrOH
(60 cm
3
) to give a thick slurry. Ethylene carbonate (13.21 g, 0.15 mol) was added and
the mixture heated to give a clear solution. Following addition of DABCO (0.5 g,
NH
N
OR
O
1a, R
=
Me
1b, R
=
CH
2
CH
2
OH
1c, R
=
H
N
N
1,4-diazabicyclo[2.2.2]octane
(DABCO)
NH
N
OH
O
1c
+
O
O
O
DABCO
i-PrOH
reflux, 10 h
N
N
O
O
NH
N
O
O
OH
1b (66%)
2
NH
N
O
O
NH
N
O
O
O)
2
3
4
O
O O
O
5.6 Formation of Bicyclic Aromatic Heterocycles 367
4.5 mmol), the mixture was heated at reflux for 10 h. HPLC analysis of the reac-
tion solution revealed mainly desired product 1b together with small quantities of
the tricyclic compound 2, the symmetrical carbonate 3 (both identified by HPLC
comparison with samples isolated above), and [[3-butyryl-4-[(2-methylphenyl)
amino]quinol-8-yl]oxy]ethyl 2-methylethyl carbonate (4), assigned on the
basis of LC-ionspray-MS, m/z 451 (MH
+
, 100), 409 (MH
+
− C
3
H
6
, 26), 365 (MH
+
−
C
3
H
6
− CO
2
, 44), and 321 (MH
+
− C
3
H
6
− CO
2
− C
2
H
4
O, 36). Water (40 cm
3
)
was added to the reaction mixture, and the product crystallized on cooling. The
suspension was stirred for 18 h at ambient temperature and the product collected
via suction filtration, washed with 40% aqueous i-PrOH (20 cm
3
), and air-dried to
give the 8-(2-hydroxyethoxy) quinoline 1b (7.7 g, 66%) as a yellow solid, mp 116–
118 °C, identical to the product previously reported and containing very low levels
of impurities.
Method C. Ethylene carbonate (66.1 g, 0.75 mol) was taken up in t-BuOH
(200 cm
3
) at 40–50 °C, and the resulting solution was treated with the
8-hydroxyquinoline 1c (50 g, 0.156 mol) and DABCO (2.5 g, 22.3 mmol). The solu-
tion was heated under reflux for 2 h. More t-BuOH (100 cm
3
) and water (200 cm
3
)
were added with the temperature of the flask being maintained at >70 °C. The
reaction mixture was subsequently cooled with rapid stirring to ~10 °C. The result-
ing precipitated product was collected via suction filtration, washed with a chilled
i-PrOH (120 cm
3
)/water (80 cm
3
) mixture, and dried under reduced pressure to give
1b (51.2 g, 90%) as a yellow crystalline solid: mp 118–120 °C; δ
H
(400 MHz) 1.02
(3H, t, J 7.4, CH
3
CH
2
CH
2
CO), 1.79 (2H, sextet, J 7.4, CH
3
CH
2
CH
2
CO), 2.34 (3H, s,
ArCH
3
), 3.05 (2H, t, J 7.4, CH
3
CH
2
CH
2
CO), 3.70 (1H, br s, OH), 4.04–4.07 (2H, m,
ArOCH
2
CH
2
OH), 4.23–4.27 (2H, m, ArOCH
2
CH
2
OH), 6.90–7.30 (7H, m, Ar), 9.10
(1H, s, 2-H), and 11.97 (1H, s, NH).
The Mechanism
8-Hydroxyquinoline 1c is activated by DABCO to form salt A, which in turn attacks
ethylene carbonate to give carbonate B. At this stage, the major pathway is decar-
boxylation to provide the desired product 1b.
Meanwhile, the salt carbonate B may also exist in equilibrium with the hydrogen
carbonate C, accompanied by the release of free base DABCO. Once C is generated,
it could be attacked by alcohol 1b to produce symmetric carbonate 3. Hydrogen car-
bonate C can also be attacked by the solvent isopropanol, leading to the formation
of carbonate 4. Cyclization of 4 leads to tricyclic compound 2 and releases CO
2
and
isopropanol. Tricyclic compound 2 could be also generated from carbonate 3 and
from C.
NH
N
O
n-Pr
O
1c
H
DBACO
DABCO
NH
N
O
–
n-Pr
O
A
DBACOH
+
NH
N
O
n-Pr
O
B
DBACOH
+
O
O
O
O
O
Major
pathway
DABCO
CO
2
NH
N
O
n-Pr
O
OH
1b
O
–