Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
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 Products328
needles, mp 206–208 °C (EtOH);
1
H NMR (400 MHz, d
6
-DMSO, free base) δ 1.67–
1.78 (m, 1 H, piperidine H-5
eq
), 2.12–2.26 (m, 1 H, piperidine H-5
ax
), 2.34–2.48 (m,
2H, piperidine H-6
ax
and piperidine H-2
ax
), 2.90 (broad d, J = 12 Hz, 1H, piper-
idine H-6
eq
), 3.03–3.13 (m, 1H, piperidine H-4
ax
), 3.32 (obscured by H
2
O, 1H,
piperidine H-2
eq
), 5.03 (dddd, J = 49, 10, 10, and 5 Hz, 1H, piperidine H-3
ax
), 7.01
(dd, J = 8.0 and 7.5 Hz, 1H, indole H-5), 7.10 (dd, J = 8.0 and 7.5 Hz, 1H, indole
H-6), 7.38 (d, J = 8.0 Hz, 1H, indole H-7), 7.40–7.43 (m, 1H, phenyl H-4), 7.49–7.55
(m, 2H, phenyl H-3), 7.56–7.60 (m, 2H, phenyl H-2), 7.80 (d, J = 8.0 Hz, 1H,
indole H-4), 11.18 (s, 1H, indole NH); MS (ES
+
) m/z 295 (M + H)
+
. Anal. Calcd
for C
19
H
19
FN
2
.C
2
H
2
O
4
: C, 65.62; H, 5.51; N, 7.29. Found: C, 66.01; H, 5.44; N, 7.20.
The Mechanism
The mechanism was proposed in the literature [20]. The rearrangement is induced
by the indole nucleus as a neighboring group. Two possible conformations, A and
B, of the intermediate allow trans-diaxial ring opening; pathway A gives rise to
the observed fluoropiperidine 2a while pathway B (not observed) produces the
isomer 3a. A possible reason for the regioselectivity is that conformer B is desta-
bilized relative to A as a result of steric congestion caused by the group endo to
the piperidine ring.
Similar observation was also reported in the following reaction [21]. When
alcohol 7 was treated with 1 equivalent of DAST, compounds 8 and 9 were obtained
in 34% and 17%, respectively. In this case, the 4-hydroxyphenyl is the neighboring
group that participates in the formation of the spiro intermediate.
DAST
N
H
NCbz
F
Ph
Et
2
NSOF
HF
2a
N
Cbz
HO
1a (more stable)
N
Cbz
OH
NH
Ph
1b (less stable)
N
Cbz
N
Ph
H
HF
N
Cbz
N
Ph
Pathway A
diaxial ring
opening
N
H
Cbz
N
F
Ph
Non-diaxial
ring opening
HN
Ph
O
S
F
NEt
2
F
3a
A
N
Cbz
N
Ph
B
F
–
F
–
Pathway B
diaxial ring
opening
Congestion
unfavorable
H
+
5.4 Formation of Nonaromatic Heterocycles 329
5.4.4 Tetrahydropyrazine
Problem 132: Formation of an Unexpected Tetrahydropyrazine Product
Lofexidine hydrochloride (1•HCl) is an antihypertensive medication cur-
rently used to treat physical and psychological symptoms of opioid dependence.
Donnola’s group attempted to develop a process chemistry for the production of 1
by following the literature-reported method [22] for constructing the dihydro-1H-
imidazole core. Treatment of the ester 2 with ethylenediamine in the presence of
Me
3
Al in toluene, lofexidine 1 was not obtained, but the reaction quantitatively
gave an unexpected product identified as (5-(2,6-dichlorophenoxy)-6-methyl-
1,2,3,6-tetrahydropyrazine) (3) [23]. The synthetic procedure and proton-NMR were
reported in a patent application [24]. Upon further investigation, Donnola’s group
found that formation of the imidazoline ring was more efficient when performed in
a one-pot way, charging ethylenediamine, titanium isopropoxide (catalyst), toluene
(used as the solvent), and ester intermediate 2 and allowing the reaction at reflux
(110 °C). Applying this procedure, they discovered a quantitative conversion (>95%)
of 2 to lofexidine 1 in a few hours.
Please suggest a mechanism for the formation of 3.
BocN
OH
OH
7
DAST (1.0 eq.)
CH
3
CN, 0 °C
BocN
OH
F
8 (34%)
BocN
9 (17%)
F
OH
+
DAST
HF
BocN
O
F
S
O
+ HF
a
b
a
b
BocN
O
O
S
F
F
H
F
–
F
–
NEt
2
NEt
2
F
–
Cl
Cl
O
N
H
N
HCl
.
1, Lofexidine.HCl
Cl
Cl
O
OEt
O
2
Ethylenediamine
Me
3
Al, toluene
heat
Cl
Cl
O
3, quant.
N
NH
Ethylenediamine
toluene
Cl
Cl
O
N
H
O
Ti(Oi-Pr)
4
NH
2
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products330
Experimental Procedure
Preparation of 5-(2,6-dichlorophenoxy)-6-methyl-1,2,3,6-tetrahydropyrazine
(3) (from WO2020/254580, 2020, A1)
Toluene (32 mL, 6.4 volumes) is loaded at room temperature into a 100-mL reactor
rendered inert with N
2
. The temperature is reduced to 0 °C, and 2M trimethylalumi-
num in toluene (15.50 g, 38.49 mmol) is added. While maintaining said temperature,
a solution of ethylenediamine (2.3 g, 38.40 mmol) in toluene (13.4 ml, 2.7 volumes)
is added, resulting in an exothermic reaction. At the end of the addition, the mass is
brought to room temperature, and stirred at said temperature for 1 h. The solution is
cooled again to 0 °C, and a solution of (+/−) ethyl 2-(2,6-dichlorophenoxy) propionate
(5 g, 19 mmol) in toluene (20 mL, 4 volumes) is added slowly. The reaction mixture
is stirred under reflux, 110 °C. When 95% conversion to 5-(2,6-dichlorophenoxy)-
6-methyl-l,2,3,6-tetrahydropyrazine is observed with a residue of 5% (+/−) ethyl
2-(2,6-dichlorophenoxy)propionate (after about 3 h), the yellow solution is again
cooled to 0 °C, MeOH (9 mL) is added very slowly and, when fume formation
has ended, H
2
O (20 mL, 4 volumes) is added, again at 0 °C, thus precipitating the
aluminum salts, which are removed by vacuum filtration. The solution is diluted
with ethyl acetate (40 mL, 8 volumes), the phases are separated, and the aqueous
phase is washed with further ethyl acetate (40 mL, 8 volumes). The combined organic
phases are washed with H
2
O (40 mL, 8 volumes), and finally concentrated to residue
by complete evaporation of the solvent, until a yellowish-white solid is obtained.
Yield >86%. Lofexidine (1) is not obtained, but a different product, with 95% purity, of
formula
1
HNMR (400 MHz, Chloroform-d) δ 7.42 (ddd, J = 8.3, 6.8, and 1.5 Hz, 2H
Arom), 7.26 (t, J = 8.1 Hz, 1H Arom), 4.19–3.91 (m, 4H, CH, CH
2
, CH), 3.82–3.46 (m,
2H, CH, NH), 1.21 (d, J = 6.6 Hz, 3H, CH
3
).
Synthesis of Lofexidine (1). (from Org. Process Res. Dev. 2021, 25, 1816)
Titanium isopropoxide (2.57 kg, 9.00 moles) and toluene (9.5 L, 6 volumes vs.
intermediate 2) were charged at 25 °C into a 50-L Kilolab Hastelloy reactor blanketed
by a N
2
flow. A solution of ethylenediamine (0.55 kg, 9.00 moles) in toluene (4 L, 2.5
volumes vs. intermediate 2) was then added. The reaction mixture was stirred at 25 °C
for 1 h, and a toluene solution of ethyl 2-(2,6-dichlorophenoxy)propionate (2) (7.08 kg,
6.000 moles) was added. The reaction mixture was heated to reflux (110 °C) and stirred
for 18 h. The reaction was checked by ultra performance liquid chromatography
(conversion: 98%). The mixture was then cooled to 25 °C, and the yellow-orange solu-
tion was added to a 30% tartaric acid solution (23.8 L, 15 volumes vs. intermediate 2)
previously prepared in a 50-L Kilolab glass-lined reactor (titanium isopropoxide
reacted with tartaric acid in an aqueous environment, forming a soluble Ti species;
in this case, no TiO
2
was formed, and Ti salts were completely soluble). The organic
layer was discarded, and toluene was added to the aqueous acidic layer containing
titanium salts and the product as the tartrate salt (8.9 L, 5.6 volumes vs. intermediate 2).
The mixture was basified by adding 30% sodium hydroxide until it reached a pH of 12.
The layers were separated, and the aqueous layer was washed with toluene (14.3 L,
9 volumes vs. intermediate 2). The mixed organic phases were washed with water
(8.9 L, 5.6 volumes vs. intermediate 2) and concentrated to a low volume. The obtained
suspension was filtered at 25 °C, and the needles were dried at 40 °C to yield the crude
lofexidine-free base as a yellowish solid. Yield >90% was calculated from the starting
5.4 Formation of Nonaromatic Heterocycles 331
material (2,6-dichlorophenol) of the previous step. Purity >95% (Area %). The result-
ing product could be used for the precipitation of hydrochloride salt 1 or could be
further purified by crystallization with heptane or hexane or by pulping at room tem-
perature in methylisobutylketone or methylethylketone.
1
HNMR characterization of
lofexidine-free base (400MHz, chloroform-d) δ 7.31 (d, J = 8.1 Hz, 2H Arom), 7.01 (t, J =
8.1 Hz, 1H Arom), 5.16 (q + s (broad), J = 6.6 Hz, 2H, CH, NH), 3.65 (dd, J = 25.5 and
8.6 Hz, 4H, CH
2
─CH
2
), 1.59 (d, J = 6.6 Hz, 3H, CH
3
).
13
CNMR of lofexidine-free base
(400 MHz, chloroform-d) δ 167.9, 149.5, 129.6, 129.2, 125.3, 77.0, 51.7, 18.9.
The Mechanism
The literature discussed the mechanism for the formation of 3 [ 23 ]. The first reac-
tion should be an amidation of the ester 2 by ethylenediamine to give intermediate
A. Then a dyotropic rearrangement [ 25 ] occurs to provide ester B. Finally, the ester
B undergoes cyclization leading to the unexpected product 3 .
However, the above mechanism seems implausible. We can be almost certain that
the amino amide A is the first intermediate. Due to the tautomerization, amide
C─N single bond is a partially double bond, thus, much stronger than a simple
C─N single bond and much stronger than an ester C─O single bond. Therefore,
conversion of amide A to ester B via a dyotropic rearrangement is not thermo-
dynamically favored. Secondly, even if the amino ester B were formed, intramo-
lecular attack of the terminal amino group on the ester carbonyl could lead to its
decomposition into 2,6-dichlorophenol ( C) and 3-methylpiperazin-2-one ( D), as the
2,6-dichlorophenoxy group is a good leaving group.
Cl
Cl
O
OEt
O
2
H
2
N
EtOH
Cl
Cl
O
N
H
O
A
Cl
Cl
N
H
Cl
Cl
O
O
NH
B
Cl
Cl
O
3
N
NH
Cl
Cl
O
N
H
N
1
Cl
Cl
O
N
NH
OH
H
NH
2
NH
2
NH
2
O
–
O
+
H
2
O
H
2
N
N
O
Tautomerization
N
+
Cl
Cl
O
O
NH
B
H
2
N
Cl
Cl
OH
HN
NH
O
+
C
D
R
3
R
1
R
2
R
1
R
3
R
2
O
–
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products332
The
1
H NMR spectrum alone is insufficient to determine the structure of
compound 3 (as described in patent [24]). Based on the structure of 3 assigned
in both the article [23] and the patent, [24] the provided
1
H NMR data are incor-
rect for the signal at δ 7.42 (ddd, J = 8.3, 6.8, and 1.5 Hz, 2H Arom). This signal
should instead appear as a doublet corresponding to the 4-H and 6-H protons
on the phenyl ring. Without this correction, the
1
H NMR data do not align with
the proposed structure of 3. To conclusively confirm the structure of the unex-
pected product 3, additional analytical techniques such as
13
C NMR, mass spec-
trometry, elemental analysis, or HRMS are required. A plausible mechanism for
the formation of compound 3 can only be proposed once its structure has been
definitively established.
5.4.5 Tetrahydropyrimidine
Problem 133: Formation of Impurities During a CDI-promoted Cyclization
LY2886721 (1) is a potent and selective inhibitor of beta-amyloid-cleaving enzyme
that was advanced to phase 2 clinical trials as a potential treatment for Alzheimer’s
disease (AD). In a process synthesis of 1, key intermediate 2 was converted to
compound 3 in 75% yield by the following reactions. Two impurities 4 and 5 were
also identified from the reaction [26]. The process was optimized by fine tuning the
operation, controlling the equivalents of triethanolamine, BzNCS, and carbonyldi-
imidazole (CDI) [27].
Please provide mechanism for the formation of 3, 4, and 5.
Experimental Procedure (from Org. Process Res. Dev., 2015, 19, 1214*)
N-((4aS,7aS)-7a-(5-acetamido-2-fluorophenyl)-4a,5,7,7a-tetrahydro-
4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide 4-methylbenzenesulfonate
(3·TsOH). To amino alcohol 2 (40 kg, 131 mol) was added THF (333 kg), Et
3
N
(14.6 kg, 144 mol, 1.1 equiv), and a THF (25 kg) rinse of the charge vessel. The
mixture was heated at 50 °C as a solution of BzNCS (21.4 kg, 131 mol, 1.0 equiv)
F
NHAc
O
H
OH
.
HCl
2
F
N
H
O
H
LY2886721 (1)
N
S
NH
2
N
F
O
F
NHAc
O
H
OH
2
1. TEA, BzNCS
2. CDI
3. EtOAc, p-TsOH
F
NHAc
O
H
N
S
NHCOPh
3 (75%)
F
NHAc
O
H
N
H
O
NBz
4
F
NHAc
O
H
N
NBz
N
5
N
NH
2
NH
2
.
HCl
.TsOH
5.4 Formation of Nonaromatic Heterocycles 333
in THF (66 kg) was added over 1.5 h, followed by a THF (5 kg) rinse of the charge
vessel. After 1 h, the in-process control (IPC) showed <2.0% remaining 2, or an
additional charge of BzNCS (0.66 kg, 4.0 mol, 0.03 equiv) was added (required on
only one batch). To this solution at 50 °C was added CDI (21.3 kg, 131 mol, 1.0
equiv) as a solid through the reactor inlet connected to a glove bag. After 60 min,
the IPC showed <2.0% remaining alcohol intermediate 3a or an additional charge
of CDI (charge adjusted based on the area % remaining 3a, i.e., if 3% 3a, then
add 3% of the original CDI charge) was added. For 3 of 8 batches, an additional
charge of CDI was required. After the IPC was met, the mixture was heated at
reflux for 8 h. The mixture was transferred to another reactor with a THF (40 kg)
rinse, and the solvent was exchanged under vacuum using EtOAc (890 kg) added
in two portions, until GC showed <2% THF remaining. 10% aqueous citric acid
(200 kg) was added, and the layers were agitated and separated at 20 °C. An addi-
tional wash with 10% aqueous citric acid (200 kg) was completed. The organic
layer was heated at 60 °C as an 8% solution of p-TsOH·H
2
O (130 kg, 54.7 mol
p-TsOH·H
2
O, 0.42 equiv) in EtOAc was added. The solution was seeded with
0.2 kg of 3·TsOH in 0.5 L of EtOAc. After 30–45 min, a slurry resulted, and an
8% solution of p-TsOH·H
2
O (182 kg, 76.6 mol p-TsOH·H
2
O, 0.58 equiv) in EtOAc
was added over 3 h. After an additional 1 h at 60 °C, the mixture was cooled to
20 °C over 3 h and stirred for 1 h. The solids were collected by filtration on a
1-m
2
(1000 L) agitated filter and washed with EtOAc (2 × 72 kg) to afford the
wet cake product. A total of 8 wet cake batches were collected and combined for
drying in 5 batches to afford 478 kg (75% average yield for four 40 kg batches
and four 42.5 kg batches) of aminothiazine 3·TsOH. Purity = 99.8–99.9 HPLC
area%. Assay = 98.7–99.6%. mp 144 °C. HPLC Method A t
R
= 6.15 min.
1
H NMR
(CDCl
3
) 12.52 (br s, 1H), 11.91 (br s, 1H), 9.33 (s, 1H), 8.19–8.08 (m, 1H), 8.05
(d, J = 8.3 Hz, 2H), 7.67 (d, J = 7.8 Hz, 2H), 7.65–7.63 (m, 1H), 7.57 (t, J = 7.3 Hz,
1H), 7.34 (t, J = 7.8 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 7.09 (dd, J = 9.3, 12.2 Hz,
1H), 4.29 (s, 1H), 4.27–4.24 (m, 2H), 4.16 (dd, J = 6.6 and 9.0 Hz, 1H), 3.83–3.76
(m, 1H), 3.34 (dd, J = 2.9 and 13.7 Hz, 1H), 3.00 (dd, J = 4.4 and 14.2 Hz, 1H), 2.36
(s, 3H), 2.09 (s, 3H).
13
C NMR (CDCl
3
) 171.38, 169.56, 166.71, 155.85, 153.95, 140.89,
136.30, 134.41, 129.72, 128.96, 128.91, 125.81, 123.34, 123.27, 122.12, 122.02, 120.39,
117.55, 117.36, 76.50, 76.47, 70.12, 68.07, 68.03, 39.34, 39.30, 25.18, 24.09, 21.32.
HRMS (ESI): calcd for C
21
H
21
FN
3
O
3
S [M + H
+
]: 414.1282; found 414.1267.
*The mechanisms for the formation of the side products 4 and 5 were discussed in the article [26, 27].
However, the isolation and identification of 4 and 5 were not disclosed.
The Mechanism
The mechanisms for the formation of 3, 4, and 5 were discussed in the literature
[26, 27] and can be summarized below. The impurity 4 is generated by excess of
BzNCS, and the impurity 5 is generated by excess of CDI. Therefore, the equiva-
lents of BzNCS and CDI, along with the addition rate, reaction temperature, solvent
selection, concentration, and stirring speed are crucial parameters.
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products334
5.4.6 Oxazepane
Problem 134: An Unusual Stevens Rearrangement Catalyzed by Acid
During a total synthetic study of nucleoside antibiotic liposidomycin, Knapp’s
group wanted to run a thioglycosylation reactions of compound 1 with (methylthio)
trimethylsilane catalyzed by trimethylsilyl trifluoromethanesulfonate (TMSOTf) in
refluxing CCl
4
. Only a trace amount of the expected thioglycoside 2 was observed,
with the major product being the rearranged diacetate 3 [28].
Please provide a mechanism for the formation of 3.
F
NHAc
NH
2
O
H
OH
2
TEA
BzNCS
F
NHAc
N
H
O
H
OH
3a
NHBz
S
CDI
F
NHAc
N
O
H
O
3b
N
H
S
N
O
N
Bz
TsOH
HN
N
3
HN
N
+ CO
2
CS
2
Im
Im
O
S
C
N
Bz
H
F
NHAc
N
H
O
H
OH
3a
NHBz
S
Excess
BzNCS
F
NHAc
N
H
O
H
O
4a
N
S
NHBz
S
Bz
H
F
NHAc
N
H
O
H
OH
4b
N
S
NHBz
S
Bz
4
Ph
O
+
H
2
N
F
N
O
H
O
3b
N
S
Bz
H
N
O
N
Excess
CDI
F
NHAc
N
O
H
O
5a
N
H
S
N
O
N
Bz
O
N
N
H
Im Im
O
HN
N
COS
F
NHAc
N
O
H
O
5b
N
N
O
N
N
NHBz
5
HN
N
HN
N
+ CO
2
N
N
O
O
OAc
AcO
O
TPS
H
H
N
N
O
OAc
O
OAc
AcO
O
CO
2
Et
H
TMS-SMe
TMSOTf, CCl
4
reflux, 3 h
1
3 (60%)
N
N
O
SMe
O
OAc
AcO
O
TPS
H
2 (trace)
+
TPS
CO
2
Et
CO
2
Et
5.4 Formation of Nonaromatic Heterocycles 335
Experimental Procedure (from Tetrahedron Lett. 2002, 43, 5797)
Combination of the triacetate 1, (methylthio)trimethylsilane (10 equiv), and
TMSOTf (2.5 equiv) in dry carbon tetrachloride solution was heated at reflux for 3 h,
whereupon 1 was consumed. Although a trace of the expected thioglycoside 2 was
present, preparative thin-layer chromatography (TLC) of the reaction mixture gave
a rearranged diacetate 3 (LC-FAB-MS m/z 665, MH
+
for M = C38H50N2O9Si) as
the major product in 60% yield.
1
H and
13
CNMR assignments, nuclear Overhauser
effect spectroscopy (NOESY), and heteronuclear multiple bond correlation (HMBC)
for 3 can be found in the literature [28].
The Mechanism
This is a Stevens rearrangement catalyzed by Lewis acid. Usually, Stevens rear-
rangement is catalyzed by strong base. Loss of acetate from 1 promoted by TMSOTf
and accompanied by least-motion N-participation on the furanose β-face would lead
to the anomeric ammonium salt A. Elimination of trifluoromethanesulfonic acid
assisted by O-silylation of the amide would give the iminium intermediate B, and
then Mannich-like ring closure provides the product 3.
Based on the above mechanism, the nucleophilic ability of the tertiary amine
could be decreased by protonation of the nitrogen as HCl salt. Since the TPS pro-
tecting group is not compatible with acidic HCl salt, switching the TPS to acetate
would address this issue. The problem was finally solved by employing the hydro-
chloride salt of the tetraacetate donor 4. Even with the initial protonation of the
tertiary amine, the reaction of 4 with bis(trimethylsilyl)uracil 5 gave the required
uracil nucleoside 6 in 18% isolated yield, which was sufficient for the constitutional
synthesis [29].
N
N
O
OAc
O
OAc
AcO
O
TPS
CO
2
Et
H
N
O
O
OAc
AcO
O
TPS
H
–
OTf
–
OTf
TfO
Si
N
O
O
OAc
AcO
O
TPS
TMS
N
N
O
O
OAc
AcO
O
TPS
H
H
TfO
TMSOTf
SiMe
3
AcO
1
3
TMSOTf
A
B
TMSOTf
TfOH
TMSOAc
TMSOTf
HOAc
SiMe
3
CO
2
Et
CO
2
Et
CO
2
Et
N
+
N
+
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products336
5.4.7 Tetrahydroquinoline
Problem 135: Formation of Unexpected Tetrahydrobenzoquinoline Side
Product in a Hydrogenation
(S)-Enantiomer of 2-[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide (MSA100, 5) is
an active 5-HT (5-hydroxytryptamine or serotonin) receptor antagonist. In a process
study, [30] methylpyridinium p-toluenesulfonate 1 was chosen as a key intermediate.
Catalytic hydrogenation of 1 generated the desired product 2 in 59% yield along with
side products 3 and 4.
Please suggest mechanism for the formation of 3 and 4.
Experimental Procedure (from Org. Process Res. Dev. 2015, 19, 290*)
2-[2-(1-Methyl-2-piperidinyl)ethyl]-benzenamine 4-methylbenzenesulfonate
(1:1) (2). To an inert hydrogenation vessel was charged 1 (43.9 g, 0.106 mol), 10%
NO
2
–
OTs
–
OTs
1
2 (59%)
H
H2, Pt-C
MeOH
2
, 25 °C
+
N
H
H
H
TsO
–
3
NH
–
OTs
4
H
+
NH
N
5 (MSA100)
O
NH
2
N
+
N
+
N
+
N
+
H
2
N
N
O
OAc
AcO
OAc
AcO
O
CO
2
Et
4
H
Cl
–
N N
O
O
TMS TMS
5
+
OAc
O
AcO
OAc
6
N
N
O
N NH
O
O
18%
N
+
EtO
2
C
5.4 Formation of Nonaromatic Heterocycles 337
Pt/C (1.87 g, 62.4% wet), and methanol (396 g) under N
2
atmosphere. The headspace
was purged with N
2
, and the vessel was charged with H
2
by pressurizing with H
2
to 65 psi, followed by depressurizing to 14.5 psi. The H
2
pressurization/depressur-
ization cycle was repeated four times. After the final depressurization, the reactor’s
temperature, hydrogen pressure, and agitation speed were set at 30 °C, 75 psi, and
450 rpm, respectively. Hydrogenation was maintained under these conditions for an
additional 6 h. The batch was cooled to 25 °C. The vessel was depressurized, purged
with N
2
by pressurizing to 65 psi, and depressurized. The pressurizing–depressur-
izing cycle was repeated five times. The mixture was filtered over a pad of celite
(8 g) and rinsed with methanol (2 × 45 g). The combined filtrate was concentrated
at 35–45 °C under reduced pressure (80–160 mbar) until a final volume of ~150 mL
was reached. 2-Propanol (353 g) was added and the mixture was concentrated at
35–45 °C under reduced pressure (80–160 mbar) until a final volume of ~150 mL
was reached. The residue was heated to 60 °C and isopropyl acetate (44 g) was added
while maintaining the temperature at 55–65 °C. The mixture was cooled to 40 °C over
a period of 20 min and seeded with 2 (160 mg). The mixture was cooled to 20 °C over
a period of 1 h and stirred for 4 h. The precipitate was filtered, rinsed with a solu-
tion of 2-propanol/isopropyl acetate (1:2 v/v) (2 × 42 g), and dried under reduced
pressure (15–40 mbar) at 60 °C for 16 h to afford 2 (26.3 g, 64% yield) as a solid:
mp 133–135 °C; HPLC for 2 (t
R
= 5.20 min) 98.8% purity: Waters YMC ODS-AQ S-3
120 A, 150 × 3.0 mm, flow rate = 0.8 mL/min, 25 °C, gradient elution from 90:10
A–B to 40:60 A–B over 22 min; A = 10 mM NH4OAc in water; B = acetonitrile; UV
λ = 240 nm.
* The mechanisms for the formation of the side products 3 and 4 were discussed in the article [30].
However, the isolation and identification of 3 and 4 were not disclosed.
The Mechanism
Complete hydrogenation of nitro, double bond, and the pyridinium ring will lead
to the desired product 2 (pathway A). Alternatively, since the hydrogenation of the
double bond and the pyridinium ring to piperidine are much slower than that of
the nitro/nitroso group to aniline B, through pathway B, a cyclization of aniline
B gives a spiro intermediate C. After subsequent three transformations from B,
hydrogenation to D, rearrangement to E, and hydrogenation of E, side product 3
is provided. Under another scenario, a thermal [2 + 2] cycloaddition reaction bet-
ween nitroso intermediate A and starting material 1 via pathway C is conceivable.
The four-membered ring intermediate F thus formed undergoes a retro [2 + 2]
cycloaddition to afford an imine intermediate H with concomitant generation of
aldehyde G. Further hydrogenation of H generates side product 4.
Employing the improved conditions (30 °C, 75 psi, and 450 rpm), 2 was generated
in 71% yield containing no detectable amount of 4 and 14% of 3. Side product 3 was
easily removed from 2 by crystallization.