Large-Scale Synthesis of 2-Chlorotetrahydroquinoline and 2-Chlorotetrahydroquinolin-8-one

Article abstract of DOI:10.1055/s-0040-1707236

An efficient large-scale preparation of 2-chlorotetrahydroquinoline with cyclohexanone and benzylamine as starting materials was developed and well optimized, in which benzyl-protected enamide was successfully cyclized and benzyl group was directly removed under Vilsmeier conditions. Azeotropic distillation provided 264 g of 2-chlorotetrahydroquinoline (79%) on a 2 mol scale of reaction without intermediate isolation. The downstream product 2-chlorotetrahydroquinolin-8-one was acquired through Boekelheide rearrangement, hydrolysis of acetate via NaBH ₄reduction, and Anelli oxidation. With the developed procedure, the intermediates were not necessary to be isolated and 2-chlorotetrahydroquinolin-8-one was conveniently obtained with solvent slurry in 65% overall isolated yield in a four-step sequence.

Full text of DOI:10.1055/s-0040-1707236

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–I
paper
A
en
Z. Zong et al.
Paper
Synthesis
Large-Scale Synthesis of 2-Chlorotetrahydroquinoline and
2-Chlorotetrahydroquinolin-8-one
Zhijian Zong
Ke Wu
O
toluene
NH2
+
Ac2O/Et3N
Liqun Jin*
Nan Sun
0
0
0
0-0
0
0
2-
9
5
1
8-7
4
2
3
triphosgene/DMF
chlorobenzene
toluene, THF
Cl
N
214 g
200 g
264 g, Yield: 79%
Baoxiang Hu
Zhenlu Shen
cat. Na2WO4·2H2O
0
0
0
0-0
0
0
2-3
6
9
9-
1
1
9
8
Cl
N
H2O2
Ac2O
AcOH
NaBH4
EtOH
Xinquan Hu*
83.5 g
Anelli oxidation
The College of Chemical Engineering, Zhejiang University
of Technology, Hangzhou 310032, P. R. China
liqunjin@zjut.edu.cn
Cl
N
O
NO INTERMEDIATE ISOLATION
59.0 g, Yield: 65%
Xinquan@zjut.edu.cn
Received: 09.06.2020
Accepted after revision: 13.07.2020
Published online: 27.08.2020
plied in many transition-metal-catalyzed reactions (Figure
1b).7 In view of their inherent rigidity and electronic/steric
tunability, the thermostability of metal catalysts and reac-
tion selectivity are significantly improved. Focusing on the
derivations of tetrahydroquinoline and their homogeneous
catalysis applications, our research team have received
some achievements in the past decade.8 For example, P,N-
DOI: 10.1055/s-0040-1707236; Art ID: ss-2020-g0316-op
Abstract An efficient large-scale preparation of 2-chlorotetrahydro-
quinoline with cyclohexanone and benzylamine as starting materials
was developed and well optimized, in which benzyl-protected enamide
was successfully cyclized and benzyl group was directly removed under
Vilsmeier conditions. Azeotropic distillation provided 264 g of 2-chloro-
tetrahydroquinoline (79%) on a 2 mol scale of reaction without inter-
mediate isolation. The downstream product 2-chlorotetrahydroquino-
lin-8-one was acquired through Boekelheide rearrangement, hydrolysis
of acetate via NaBH4 reduction, and Anelli oxidation. With the devel-
oped procedure, the intermediates were not necessary to be isolated
and 2-chlorotetrahydroquinolin-8-one was conveniently obtained with
solvent slurry in 65% overall isolated yield in a four-step sequence.
(a)
N
Cl
N
N
NH
N
N
NH2
O
OH
OH
NH2
huperzine A
F
NH
ORL1 acceptor antagonist
Key words 2-chlorotetrahydroquinoline, 2-chlorotetrahydroquinolin-
8-one, large-scale synthesis, enamide, cyclization, Boekelheide rear-
rangement
AMD070
N
Ph
OOC
O
S
O
N
O
NH2
N
N
N
N
O
S
H
H
N
O
Nitrogen-containing heteroaryl compounds exist widely
in the natural products and the synthetic pharmaceutical
molecules because of their structural diversity and their
potential bioactivity. Tetrahydroquinoline framework has
received considerable attentions not only as an important
building block, but also as a structural fragment in the
pharmaceutical molecules.1 For example, an opioid recep-
tor-like 1 (ORL1) acceptor antagonist,2 containing a core
tetrahydroquinoline fragment in the molecular structure,
has been efficiently applied in the treatment of pain, de-
pression, Alzheimer’s disease, and Parkinson’s disease.
Meanwhile, tetrahydroquinoline has also been served as
the key starting material for the syntheses of Huperzine A,3
Cefquinome,4 AMD070,5 and Adenine pincer-type com-
pounds, for example, molecular tweezer (Figure 1a).6
cefquinome
molecular tweezer
(b)
R3
N
R1
R4
O
N
R1
R1
N
O
N
P
N
N
O
R1
R2
Ph
R1
R2
R2
R1
L2
L3
L1
H
R1
N
N
N
N
R1
HN
HN
N
N
R1
L6
R2
L4
Ph2P
R1
R2
L5
Recently, various bidentate and tridentate ligands de-
rived from tetrahydroquinoline have been successfully ap-
Figure 1 Applications of tetrahydroquinoline framework
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Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Z. Zong et al.
Paper
Synthesis
ligand L1, was successfully applied in the enantioselective
Cu-catalyzed diethylzinc addition to acyclic conjugate
enones with good to excellent enantiomeric excesses in
high yields.8a Geometry-constrained iminopyridyl ligands
L2 and their palladium complexes showed extremely high
efficiency in Suzuki–Miyaura cross-coupling between aryl-
boronic acids and aryl bromides (up to 4 700 000 TON),8b
and also suitable for the relative inert aryl chlorides.8c
Moreover, the iminopyridyl palladium complex could selec-
tively catalyze reductive Heck reaction between olefins and
aryl bromides for Csp2–Csp3 bond formation,8d and hydro-
arylation of alkynes to prepare trisubstituted alkenes with
alcohol as the hydrogen source.8e The unsymmetrical CNN-
palladacycles also showed catalytic capability for coupling
arylboronic acid and secondary benzylic bromides with
high selectivity.8f Very recently, we established a highly ef-
ficient Co-catalyzed Markovnikov-selective hydrosilylation,
in which up to 4950 TON was achieved and 2-methyl-sub-
stituted iminopyridyl ligand played a crucial role.8g Besides,
in cooperation with Sun’s group, quite a lot of N,N-biden-
tate and N,N,N-tridentate ligands derived from 2-chloro-
tetrahydroquinolin-8-one (L2–L4) were employed in late
transition-metal-catalyzed (Cr, Fe, Co, Ni) polymerization of
ethylene.9 Moreover, P,N,N-tridentate L5 and N,N-bidentate
L6 ligands derived from tetrahydroquinoline also showed
great efficiency in Ru-catalyzed coupling cyclization10 and
Al-catalyzed ring-opening polymerization,11 respectively.
Thus, based on the wide application of tetrahydroquino-
line derivatives, including tetrahydroquinoline-8-amine,
tetrahydroquinoline-8-ol, and tetrahydroquinolin-8-one, it
is necessary to develop a practical synthetic method to ac-
cess a tetrahydroquinoline core.
It is clear that 2-chlorotetrahydroquinoline could pro-
vide the potential derivatives at positions 2 and 8. On the
one hand, the chlorine atom at position 2 could be conve-
niently converted into hydrogen atom via dechlorination
reduction; to aryl group via Suzuki–Miyaura cross-cou-
pling; to alkyl group via Kumada cross-coupling, etc. On the
other hand, position 8 could be further derivatized into the
corresponding alcohol, amine, or ketone via a multiple-step
transformation (Scheme 1). It was noted that the keto func-
tional group at position 8 could be diversified with nucleo-
philes to form various bidentate or tridentate ligands (Fig-
ure 1b). Thus, a practical synthesis of the tetrahydroquino-
line core was based on the availability of the compound of
2-chlorotetahydroquinoline.
N
N
N
OH
O
Cl
N
Cl
N
Cl
N
OH
O
Ar
N
R
N
O
Cl
N
O
NH2
NC
N
MeOOC
N
O
O
Scheme 1 Downstream derivatives of 2-chlorotetrahydroquinoline
quinoline to tetrahydroquinoline was a conventional organ-
ic synthetic method. However, the same method is not suit-
able for partial hydrogenation of 2-chloroquinoline.12 Alter-
natively, quinoline was first oxidized with m-CPBA to its
corresponding N-oxide, followed by reaction with MsCl,
then aqueous hydrolysis to form 2-hydroxyquinoline. The
above transformations were the standard operations in pyr-
idine chemistry. In the presence of TfOH/SbF5, ionic hydro-
genation of 2-hydroxyquinoline selectively afforded 2-hy-
droxytetrahydroquinoline under rather harsh conditions.
Finally, hydroxyl functional group at position 2 was con-
verted into chloro functional group with POCl3 to provide
the desired 2-chlorotetrahydroquinoline (Scheme 2, route
a).13 Although a rather good overall yield (66%) was
achieved, the above synthetic route was not desirable after
careful evaluation, because of the longer steps and especial-
ly the third step, in which large excess of highly toxic and
expensive TfOH/SbF5 was utilized. Route b started the syn-
thesis with cyclohexanone and acrylonitrile in the presence
of piperidine/acetic acid, and the resulting 3-(2-oxocyclo-
hexyl)propanenitrile was cyclized to form 2-hydroxytetra-
hydroquinoline with concentrated H2SO4. The last step is
the same as in the previous route (Scheme 2, route b).14 Suf-
fering from a relatively lower yield (54%) of H2SO4-mediated
cyclization, route b was not an appropriate choice for the
long-term consideration. Route c started from the easily
available cyclohexanone oxime, which was the intermedi-
ate of caprolactam and could react with acetic anhydride to
afford N-(1-cyclohexenyl)acetamide mediated by Ti(OAc)3
in the presence of pyridine. The resulting enamide was then
cyclized to form 2-chlorotetrahydroquinoline in multiple
transformations under the Vilsmeier conditions (Scheme 2,
route c).15 This synthetic route owned significant advantag-
es, such as less steps and readily available chemicals. How-
ever, serious limitations of this method were also identified
In this report, we aimed to develop a reliable, scalable,
and inexpensive synthetic route for preparing 2-chloro-
tetrahydroquinoline and its further derivation to 2-chloro-
tetrahydroquinolin-8-one.
After evaluating the reported literature, Scheme 2 sum-
marizes three potential preparation routes of 2-chloroteta-
hydroquinoline. Route a applied quinoline as the starting
material. It is well known that the partial hydrogenation of
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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Z. Zong et al.
Paper
Synthesis
as follows: the rather lower yield (46%) of enamide forma-
tion and the troublesome handling of Ti-containing effluent
during workup.
O
NH2
N
+
3
1
2
mCPBA
MsCl
H2O, rt
88%
Ac2O/Et3N
a
HO
N
DCM
N
O
N
O
N
Cl
N
5
TfOH, SbF5
83%
O
cyclohexane
4
CN
Scheme 3 A new synthetic route to 2-chlorotetrahydroquinoline (5)
POCl3
H2SO4
piperidine
b
c
PhNMe2
90%
Cl
N
HO
OH
N
AcOH
80%
H2O
54%
DMF/POCl3
62%
was removed via azeotropic distillation, followed by N-
acetylation to afford benzyl enamide 4 as a white solid
(83%). The subsequent cyclization under the Vilsmeier con-
ditions produced the desired product (overall yield 55%) as
a yellow oil. The newly designed synthetic route was rather
straightforward, all starting materials and reagents were
readily available. Repeated batches could afford the target
product in an overall yield ranging 50–60% on a 1–2 mol
scale. However, some shortcomings were found during the
repeated batches: (i) The selectivity of Schiff base 3 was
strongly dependent on the period of azeotropic water re-
moval and slightly affected by the volume of solvent
charged. Increasing the azeotropic reflux time would sig-
nificantly increase the impurity, which was confirmed as
the Knoevenagel condensation product Schiff base 6. It was
obviously found that the residual benzylamine, whose
amount was in correlation with the impurity 6, would con-
sume acetic anhydride and generated N-benzylacetamide
in the next acetylation. The impurity 6 would also produce
a dense enamide (see SI, Scheme S1). Thus, the selectivity
of Schiff base 3 would greatly influence the following steps.
(ii) The conversion of Schiff base into enamide was slow at
lower temperature and the selectivity of enamide varied
from batch to batch. Although separation of enamide could
efficiently avoid the generation of tar-like impurity in the
cyclization and improved the purity of the crude product, it
resulted in a remarkable loss of the enamide intermediate.
(iii) The batch time, especially workup procedure (see SI),
was too long. Therefore, the whole procedure needed to be
seriously optimized.
O
N
H
N
O
hydroxylamine
Ac2O, pyridine
Ti(OAc)3, DMF
46%
Scheme 2 Three potential synthetic routes to 2-chlorotetrahydroquin-
oline
Using cyclohexanone or its derivative, which is available
in bulk, as the starting material in routes b and c was highly
attractive because of the synthetic method modification or
the process optimization. However, both routes provided
the relative lower yields in the cyclization step. We reck-
oned that low efficient cyclization resulted from the poten-
tial existing of free N–H bond. If N–H bond of enamide in-
termediate in route c could be protected as a tertiary amide,
the cyclization was believed to be much more efficient. We
noticed that 2-chloro-5-methylpyridine, a similar com-
pound, which was an important starting material of phar-
maceutical and agrochemical, such as Imidacloprid16 and
Acetamiprid,17 could be efficiently synthesized in a three-
step procedure. Condensation between benzylamine and
propanal produced a Schiff base, which was converted into
benzyl-protected enamide with acetic anhydride in the
presence of triethylamine.18 Finally, cyclization of enamide
afforded the desired product under the Vilsmeier condi-
tions.19 In this synthetic sequence, benzylamine served as
both the nitrogen source and the protecting group of enam-
ide intermediate. If this synthetic strategy could be applied
to the synthesis of 2-chlorotetrahydroquinoline, the inher-
ent lower yield of enamide in route b was expected to be
improved and the troublesome Ti(OAc)3 effluent in route c
was also avoided. Moreover, the cyclization of the benzyl-
protected enamide under the Vilsmeier conditions would
provide more promising result. That is to say, the initial
condensation was carried out between benzylamine (1)
and cyclohexanone (2), to afford the desired Schiff base (3),
and accordingly converted 5 under the Vilsmeier condi-
tions. Thus, a new approach to synthesize 2-chlorotetra-
hydroquinoline with cyclohexanone and benzylamine as
the starting materials was figured out (Scheme 3).
O
Ac2O (1.2 equiv)
Et3N (1.1 equiv)
Bn
O
toluene
N
BnNH2
+
Bn
rt ,overnight
N
toluene, THF
5–65 °C
azeotropic reflux
1
2
3
4
(2 mol) (1.02 equiv)
yield: 83%
DMF (1.25 equiv)
POCl3 (2.4 equiv)
N
Cl
N
toluene
5–25 °C (2 h) → 45 °C (3 h)
80 °C (12 h) → reflux (10 h)
5 (185 g)
overall isolated yield: 55%
by-product 6
Preparation of 2-chlorotetrahydroquinoline (5) follow-
ing the procedure shown in Scheme 4 was then carried out.
Benzylamine reacted with cyclohexanone, in which water
Scheme 4 Preliminary experiments to prepare 2-chlorotetrahydro-
quinoline (5)
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Z. Zong et al.
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Synthesis
Based on the in-process analysis, it was found that the
impurity 6 was high at the late stage of the azeotropic dis-
tillation. Presumably, it was formed via a Knoevenagel con-
densation between Schiff base 3 and cyclohexanone, which
was equilibrated from the decomposition of Schiff base 3,
and its amount was gradually increased on prolonging the
azeotropic distillation, together with the liberation of ben-
zylamine. To avoid the competitive side reaction, we con-
sidered taking two methods. One was using dehydrating re-
agents to drive the completion of Schiff base formation un-
der mild conditions rather than longer azeotropic reflux.
The other was strictly controlling the reaction selectivity by
clarifying the relationship between impurity content and
the azeotropic reflux time. Referring to the reported litera-
ture,20 when triethyl phosphite was employed as the dehy-
drating reagent, the full conversion could be conveniently
obtained and the selectivity was as perfect as expected. Un-
fortunately, the crude Schiff base cannot work well in the
next acetylation, which was ascribed to the less efficiency
of removal of phosphate during the workup procedure.
Considerable efforts made no significant improvement,
thus, the method with dehydrating reagent was given up.
Alternatively, it was found that the timely in-process con-
trol in the azeotropic water removal could ensure a reason-
able selectivity (see SI, Table S1). The competitive Knoeve-
nagel condensation by-product 6 was strongly related to the
azeotropic reflux time. If the endpoint of the condensation
was decided only by observing the aqueous drainage in
Dean–Stark trapper, it would mislead the over azeotropic
reflux and result in the more by-product because of the po-
tential equilibrium as previous mentioned. Thus, after a
reasonable azeotropic reflux time of less than 2 hours, the
toluene solution was slightly cooled and then used in the
next step.
tions, the formed cyclization product 5 could be observed
in both phases, the hydrochloric salt of 5 in aqueous phase
and the free 5 in toluene phase, which resulted in a compli-
cated and tedious workup procedure. It was obvious that all
drawbacks in the Vilsmeier cyclization can be ascribed to
the use of POCl3. Therefore, an alternative Vilsmeier reagent
was sought to replace the POCl3. Triphosgene, which is
available in bulk and widely used in melamine resin indus-
try,21 was considered to replace POCl3 in this cyclization. Af-
ter evaluating the possibility of using triphosgene in the cy-
clization, we found that it worked well, while the single
temperature was not suitable for the complicated cycliza-
tion when scaling up. After careful optimization (see SI), a
programmed temperature manipulation was confirmed as
shown in Scheme 5. After completion of the reaction, the
workup process only involved neutralization, filtration,
concentration, and final azeotropic distillation.
O
Ac2O (1.07 equiv)
Et3N (1.09 equiv)
toluene
BnNH2
+
Bn
N
toluene, THF
65 °C, 3.5 h
reflux, 1 h
1 (2 mol) 2 (1.02 equiv)
3 selectivity: 92%
triphosgene (1.4 equiv)
DMF (1.05 equiv)
Bn
N
Cl
N
chlorobenzene
<45 °C (4 h) → 50 °C (0.5 h)
85 °C (1 h) → reflux (4 h)
5 (264 g)
overall isolated yield: 79%
O
4 selectivity: 95%
Scheme 5 Synthesis of 2-chlorotetrahydroquinoline on a 2 mol scale
At this point, we have developed the process for the
preparation of 2-chlorotetrahydroquinoline (5). As shown
in Scheme 5, a 2 mol scale of reaction starting from 1 and 2
could deliver 264 g of the target product 5, and 79% overall
isolated yield was obtained without isolation of intermedi-
ate 3 and 4.
With enough amount of 2-chlorotetrahydroquinoline
(5) in hand, we then focused on preparing 2-chlorotetrahy-
droquinolin-8-one (10). The general synthetic sequence is
summarized in Scheme 6. 2-Chlorotetrahydroquinolin-8-yl
acetate (8) was initially synthesized according to Boekel-
heide rearrangement.22 Acetate 9 was hydrolyzed to the in-
termediate 2-chlorotetrahydroquinolin-8-ol (9), followed
Concerning the stability of Schiff base and the very slow
acetylation under lower temperature even with a high con-
centration of acetic anhydride, we decided to perform a
slow addition of the dried toluene solution of Schiff base to
the preheated mixture (65 °C) of acetic anhydride, triethyl-
amine, and THF, which avoided the potential instability of
Schiff base and simplified the operation. The reaction com-
pleted almost on finishing the addition, and the typical
enamide content ranged 90–94% (GC area normalization).
After quenching with water, washing with water and aque-
ous NaHCO3, and stripping part of solvent, together with
most water, the solution could be directly used in the next
step.
Cl
N
Cl
N
O
7
Cl
N
OAc
5
8
As previous described, the final cyclization of the puri-
fied enamide and with POCl3/DMF as Vilsmeier reagent
could smoothly provide the desired 2-chlorotetrahydro-
quinoline (5) in a comparable yield (60–65%). However,
during the aqueous workup, the reaction mixture released
large amount of phosphoric acid and also gaseous HCl be-
cause of the excess POCl3. Under the strong acidic condi-
Cl
N
Cl
N
OH
O
9
10
Scheme 6 Synthetic route to prepare 2-chlorotetrahydroquinolin-8-
one (10)
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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Synthesis
by oxidation to afford the desired 2-chlorotetrahydroquino-
lin-8-one (10).8a A 0.5 mole scale reaction sequence was
then carefully investigated.
also tested. For example, using acetyl chloride with DMF as
additive, the acetylation could be carried out at ambient
temperature, but the isolated yield of the desired acetate 8
was low as quite a lot of unreacted 5 was observed. Accord-
ing to the literature, using trifluoroacetic anhydride (TFAA)
as acetylating reagent, the N-oxide can be directly convert-
ed into the next alcohol 9 during workup.22b,24 However, up
to 20% of 5 was still observed in the crude product (see SI,
Table S2, entry 9). After completion of the reaction and sim-
ple workup, crude acetate 8 contained still some starting
material 5, which did not affect the following steps and
could be rejected during the final purification of the target
ketone 10. Then, solvent was switched to ethanol, and the
mixture was directly used for the next hydrolysis. Hydroly-
sis of acetate to alcohol was one of the most common trans-
formations in organic synthesis. From acetate 8 to alcohol 9,
we found that conventional saponification with NaOH/H2O
at 50 °C would lead to a high content of eliminated by-prod-
uct 2-chlorodihydroquinoline, which was presumably
formed under hot strong basic conditions. Although non-
aqueous KOH/MeOH conditions under room temperature
could significantly improve the selectivity, the resulting
dark grey crude product could not be addressed by recrys-
tallization, and silica gel column chromatography was nec-
essary for the purification. Other than the competitive
elimination, the formation of deep-colored impurities was
possibly because the strong basic conditions activated the
C–Cl bond at position 2. In fact, reduction of ester to pre-
pare alcohol by NaBH4 was also widely reported,25 although
the alcohols were usually from the acyl components in
most cases. If the acetate 8 could be reduced by NaBH4, the
desired alcohol 9 would be released. After careful optimiza-
tions, we found that the reduction with NaBH4 could be
successfully performed in EtOH at 75 °C. It was interesting
that 0.27 equivalent of NaBH4 could furnish the complete
Boekelheide rearrangement is a classic reaction in pyri-
dine chemistry, in which the preparation of the N-oxide
and its rearrangement with acetic anhydride were com-
bined as a single operation.22a For the oxidation of 5 to 7,
with AcOH as the solvent, our initial experiment showed
that only aqueous H2O2 cannot drive the reaction to com-
pletion (Table 1, entries 1 and 2); additives were expected
to provide some assistance. As most transition metals can
catalyze the decomposition of H2O2, they were not consid-
ered in this reaction. According to the literature, H2O2 could
–
react with WO4 anion to form cyclo-W-peroxide, which
could enhance the oxidation and/or the epoxidation.23
When 10 mol% of Na2WO4·2H2O was added to the reaction
mixture, we were pleased to find that the conversion was
significantly improved (entry 3). Reducing the amount of
Na2WO4·2H2O to 1 mol% could also provide the similar re-
sult, however, the conversion seemed to exist in an ultimate
value even with prolonging the reaction time (entry 4). Pre-
sumably, the less effectiveness at a late stage resulted from
a lower concentration of H2O2 and/or the decomposition of
H2O2 in the hot reaction mixture. Therefore, additional H2O2
provided almost quantitative conversion (entry 5).
Table 1 Effects on the Conversion of 5 into N-Oxide 7a
Cl
N
O
Cl
N
7
5
Entry Oxidant Catalyst (mol%)
Solvent
Temp
(°C)
Time Conv.
(h)
(%)b
1
2
3
4
H2O2
H2O2
H2O2
H2O2
–
AcOH
AcOH
AcOH
AcOH
80
80
80
80
6
84
88
90
–
reduction. In other words, all four hydrides of BH4 were
–
8
2
utilized in the reduction, this could be due to the less hin-
dered acetyl group. After completion of the reaction and
usual workup, the crude alcohol product 9 was obtained as
a yellowish solid, in which 2-chlorotetrahydroquinoline (5)
still contained as a major impurity because no isolations
were done in the previous two steps. Since 5 showed no in-
fluence on the next oxidation, the crude product 9 was di-
rectly used for the next step (see SI, Table S3).
As expected, the Anelli oxidation could smoothly oxi-
dize the crude product 9 into the desired ketone 10 quanti-
tatively. After the usual workup, the resulting crude prod-
uct was slurried with a mixture of petroleum ether and eth-
yl acetate (v/v = 50:1) twice to afford the desired 10 in 98%
purity by GC area normalization. Under the optimal condi-
tions, a 0.5 mole scale reaction starting from 2-chlorotetra-
hydroquinoline (5) was carried out and up to 65% overall
yield of 2-chlorotetrahydroquinolin-8-one (10) could be
obtained in a four-step synthetic consequence. Separation
Na2WO4·2H2O (10)
Na2WO4·2H2O (1)
3
6
10
92
94
95
5c
H2O2
Na2WO4·2H2O (1)
AcOH
80
6
8
10
96
97
98
a Reaction conditions: 2-Chlorotetrahydroquinoline (5; 0.1 mol), solvent
(20 mL), 30% H2O2 (1.5 equiv).
b The conversion was determined by HPLC area normalization.
c Extra 0.3 equiv of 30% H2O2 was added after 1 h.
After removal of acetic acid and water under reduced
pressure, the resulting solvent-free N-oxide 7 was diluted
with acetic acid, and then added to hot acetic anhydride in
order to avoid strong exotherm when mixing crude N-oxide
with acetic anhydride/acetic acid directly. The optimal re-
action was carried out with 3 equivalents of acetic anhy-
dride for 2 hours at 80 °C. Other acetylation reagents were
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Z. Zong et al.
Paper
Synthesis
of intermediates and column chromatography were not
necessary, the desired ketone 10 was conveniently purified
by a simple slurry process (Scheme 7).
mometer, were added toluene (400 mL) and cyclohexanone (2; 200 g,
2.04 mol, 1.02 equiv). After mixing well, benzylamine (1; 214 g, 2.0
mol, 1 equiv) was slowly added, and rinsed with another portion of
toluene (200 mL). The mixture was heated to reflux and H2O was
azeotropically removed for 1 h and then the mixture was cooled to rt.
GC analysis of a sample showed that the conversion of benzylamine
(2) was 96% with 90% of selectivity based on area normalization.
Na2WO4·2H2O (1 mol%)
Ac2O (3 equiv)
H2O2 (1.8 equiv)
Cl
N
Cl
N
O
AcOH, 85 °C
80 °C
5 (83.5 g, 0.5 mol)
7
Enamide 4 (Step 2)
NaBH4 (0.27 equiv)
EtOH, 75 °C
To a 2000 mL four-necked jacketed flask, fitted with a mechanical
stirrer, an addition funnel, a condenser, and a thermometer were add-
ed THF (200 mL), Ac2O (220 g, 2.14 mol, 1.07 equiv), and Et3N (220 g,
2.18 mol, 1.09 equiv). The resulting mixture was heated to 65 °C via a
jacket with hot H2O, and then a toluene solution of Schiff base 3 from
step 1 was dropwise added over a period of 3 h. After completion of
addition, the mixture was stirred for another 0.5 h, then a sample
(quenched with sat. aq NaHCO3) was analyzed by GC, which showed
that Schiff base 3 was totally converted; the selectivity of enamide 4
was 92% based on area normalization.
Cl
N
Cl
N
OH
OAc
8
9
selectivity: 82%
selectivity: 82%
TEMPO (0.1 mol%)
KBr (10 mol%)
NaHCO3 (4 equiv)
Cl
N
NaClO (1.1 equiv)
H2O, DCM, 0–5 °C
O
10 (59.0 g)
overall isolated yield: 65%
GC-MS (EI): m/z (%) = 187.1 (M+, 35), 91.0 (100).
Scheme 7 Synthesis of 2-chlorotetrahydroquinolin-8-one on a 0.5 mol
scale
Then H2O (100 mL) was added to the mixture and stirred for 30 min
to quench the excess Ac2O. The mixture was slightly cooled and trans-
ferred to a 3 L separating funnel, and the aqueous phase was separat-
ed. The organic phase was successively washed with 300 mL each of
H2O, sat. aq NaHCO3, and H2O. The residual organic phase was concen-
trated via rotovapor under reduced pressure. After no volatile was ob-
served, chlorobenzene (100 mL) was added and stripped under re-
duced pressure, Repeating this operation twice afforded 440 g of
crude enamide 4, which was directly used in the next step. A sample
for NMR was purified by recrystallization with hexanes; white solid;
mp 51–52 °C.
In summary, an efficient and scalable synthetic route to
prepare 2-chlorotetahydroquinoline (5) and 2-chlorotetra-
hydroquinolin-8-one (10) has been successfully developed
via careful exploration and optimization of every synthetic
step. We finally prepared 264 g of 2-chlorotetrahydroquin-
oline (5; 79% yield, three steps) on a 2 mol reaction scale
and 59 g of 2-chlorotetrahydroquinolin-8-one (10; 65%
yield, four steps) on a 0.5 mol reaction scale. No isolation of
intermediates was essential. 2-Chlorotetahydroquinoline
was isolated via azeotropic distillation and its downstream
product 2-chlorotetrahydroquinolin-8-one was isolated
and simply purified with solvent slurry. All chemicals and
reagents in the newly developed process were available in
bulk and less expensive. Overall, the newly developed pro-
cess was suitable for scale-up.
FT-IR (KBr): 3028.3, 2935.5, 1644.9, 1495.8, 1437.9, 1395.3, 704.8 cm–1
.
1H NMR (500 MHz, DMSO-d6):  = 7.34–7.26 (m, 2 H), 7.26–7.18 (m, 3
H), 5.42 (s, 1 H), 4.54 (s, 2 H), 1.98 (s, 3 H), 2.00–1.92 (m, 4 H), 1.64–
1.54 (m, 2 H), 1.50–1.40 (m, 2 H).
13C NMR (125 MHz, CDCl3):  = 169.9, 138.9, 138.1, 128.7, 128.2,
128.1, 127.1, 49.4, 28.1, 24.7, 22.7, 21.6, 21.5.
HRMS-EI: m/z calcd for C15H19NO [M]+: 229.1467; found: 229.1471.
2-Chlorotetrahydroquinoline (5) (Step 3)
To a 2000 mL four-necked jacketed flask, fitted with a mechanical
stirrer, an addition funnel, a thermometer, and a condenser whose
outlet was connected to a 3 N aq NaOH scrubber, were transferred all
of the above crude enamide (440 g, 2 mol, 1 equiv), DMF (153 g, 2.1
mol, 1.05 equiv), and chlorobenzene (100 mL). To the mixture, which
was cooled to 15 °C with a cooling liquid via a jacket, was slowly add-
ed a solution of triphosgene (207 g, 0.7 mol) in chlorobenzene (500
mL) over a period of 4 h by keeping the inner temperature not higher
than 45 °C. TLC monitoring showed that the enamide 4 was complete-
ly converted after 2 h. Then additional amounts of solid triphosgene
(207 g) were added in portions to the reaction mixture over 20 min.
Obvious exotherm and gas releasing could be observed, the inner
temperature was gradually increased as the addition of solid triphos-
gene progressed and it was about 50 °C after the complete addition.
The mixture was kept stirring till all solid dissolved to form a homo-
geneous solution. The mixture was heated to 85 °C and held for 1 h.
Then the mixture was carefully transferred to a 2 L four-necked
round-bottomed flask, and heated to reflux for 4 h. The mixture was
gradually cooled to rt and further cooled on a water bath to 10–15 °C,
and treated with aq 3 N of NaOH till pH to 9 (200 mL in total). After
All 1H and 13C NMR spectra were recorded on Bruker Avance 400 MHz
and 500 MHz spectrometers in deuterium solvents with TMS as inter-
nal standard. Standard abbreviations were used to denote NMR mul-
tiplicities. Chemical shifts are given in ppm and are referenced to TMS
(1H, 13C). Melting points were determined on a Büchi M-565 appara-
tus. GC analysis were performed on an Agilent 6890N instrument
with flame ionization detector (FID). DB-5 capillary column (30 m,
0.32 mm i.d., 0.25 m film thicknesses) was used and N2 as the carrier
gas. IR spectra were recorded on a Thermo Fisher Nicolet 6700 FT-IR
spectrophotometer. High-resolution mass spectra were recorded in
the EI mode on Waters GCT Premier TOF MS. All chemicals were com-
mercially available and used as received.
Synthesis of 2-Chlorotetrahydroquinoline (5) on a 2 Mol Scale
Schiff Base 3 (Step 1)
To a 2000 mL four-necked round-bottomed flask, which was fitted
with a mechanical stirrer, Dean–Stark trap, a condenser, and a ther-
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

G
Z. Zong et al.
Paper
Synthesis
achieving a constant pH of 9, the mixture was filtered to remove the
inorganic salt formed. The filtrate was concentrated in vacuo. To the
residue was added H2O (300 mL) and the H2O was removed by azeo-
tropic distillation using a Dean–Stark trapper. The earlier cut was
mainly the mixture of chlorobenzene and benzyl chloride. The de-
sired component 2-chlorotetrahydroquinoline (5) was collected as a
pale yellow liquid in 97% purity based on the GC area normalization;
yield 263 g (79% over 3 steps).
HRMS-EI: m/z calcd for C11H12ClNO2 [M]+: 225.0557; found: 225.0575.
2-Chlorotetrahydroquinolin-8-ol (9) (Step 6)
To a 1000 mL four-necked jacketed flask, fitted with a mechanical
stirrer, an addition funnel, a thermometer, and a condenser, were
added the above crude 2-chlorotetrahydroquinolin-8-ol acetate (8;
92.0 g, 0.4 mol) and absolute EtOH (500 mL). The resulting mixture
was heated to 75 °C, and solid NaBH4 (4.20 g, 0.27 equiv) was carefully
added in portions to the solution and the mixture was stirred at that
temperature for 6 h. GC analysis showed that all acetate 8 was con-
verted. The mixture was cooled down to rt, sat. aq NH4Cl (100 mL)
was added to quench the reaction mixture and stirred for 1 h. The
mixture was concentrated under reduced pressure. Then MTBE (200
mL) and brine (300 mL) were added to the mixture. The aqueous
phase was separated and extracted with MTBE (2 × 200 mL). The
combined organic layers were concentrated under vacuum to afford
the crude 9 (76.0 g) as a brown solid (82% of GC area). An analytical
sample of alcohol 9 was obtained by purification by column chroma-
tography as a white solid; mp 51–52 °C.
FT-IR (neat): 2938.2, 2860.3, 1579.0, 1566.2, 1442.0, 1133.2, 1101.2,
986.4, 856.0, 808.1 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.30 (d, J = 8.2 Hz, 1 H), 7.04 (d, J = 8.2
Hz, 1 H), 2.88 (t, J = 6.2 Hz, 2 H), 2.72 (t, J = 6.2 Hz, 2 H), 1.90–1.84 (m,
2 H), 1.83–1.75 (m, 2 H).
13C NMR (125 MHz, CDCl3):  = 158.4, 147.9, 139.7, 131.2, 121.3, 32.4,
28.2, 22.8, 22.6.
HRMS-EI: m/z calcd for C9H10ClN [M]+: 167.0502; found: 167.0508.
Synthesis of 2-Chlorotetrahydroquinolin-8-one (10) on a 0.5 Mol
Scale
FT-IR (KBr): 3262.3, 3050.1, 2937.5, 1566.4, 1443.1, 1427.9, 1196.2,
1103.1, 967.6, 842.3, 638.2 cm–1
.
2-Chlorotetrahydroquinoline N-Oxide (7) (Step 4)
1H NMR (500 MHz, CDCl3):  = 7.38 (d, J = 8.1 Hz, 1 H), 7.14 (d, J = 8.1
Hz, 1 H), 4.72–4.64 (m, 1 H), 3.56 (br, 1 H), 2.84–2.70 (m, 2 H), 2.28–
2.18 (m, 1 H), 2.05–1.95 (m, 1 H), 1.86–1.72 (m, 2 H).
To a 1000 mL four-necked jacketed flask fitted with a mechanical stir-
rer, an addition funnel, a thermometer, and a condenser were added
2-chlorotetrahydroquinoline (5; 83.5 g, 0.5 mol,
1
equiv),
13C NMR (125 MHz, CDCl3):  = 158.8, 148.6, 140.0, 130.7, 123.1, 68.7,
Na2WO4·2H2O (1.65 g, 1 mol%), and AcOH (200 mL). The resulting
mixture was heated to 80 °C. H2O2 (30 wt%, 85.0 g) was slowly added
over a period of 3 h, and an additional portion of 30% H2O2 (17.0 g)
was added after 1 h. HPLC analysis of the crude mixture showed that
the conversion of 2-chlorotetrahydroquinoline (5) was almost com-
plete. The cooled reaction mixture was directly concentrated under
reduced pressure, then AcOH (100 mL) was added and again concen-
trated. The operation was repeated twice to afford the crude N-oxide
7 (108 g) as a brown oil and directly used in the next step.
30.4, 27.9, 19.3.
HRMS-EI: m/z calcd for C9H10ClNO [M]+: 183.0451; found: 183.0453.
2-Chlorotetrahydroquinolin-8-one (10) (Anelli Oxidation, Step 7)
To a 2000 mL four-necked jacketed flask, fitted with a mechanical
stirrer, an addition funnel, a thermometer, and a condenser, were
added the above crude 2-chlorotetrahydroquinolin-8-ol (9; 92.0 g, 0.4
mol), DCM (300 mL), solid NaHCO3 (134 g 1.6 mol, 4 equiv), KBr (4.76
g, 40 mmol, 10 mol%), TEMPO (62.4 mg, 0.4 mmol, 0.1 mol%), and dis-
tilled H2O (300 mL). The resulting mixture was cooled to below 5 °C,
and to this mixture was added a 5 wt% NaClO solution (312 g, 0.44
mol, 1.1 equiv) dropwise over a period of 2 h, and the reaction tem-
perature was kept below 5 °C. After complete addition, the mixture
was stirred at that temperature for another 4 h. GC analysis showed
that the alcohol 9 was converted into the desired ketone 10. The mix-
ture was filtered to remove the inorganic solid, and the two phases in
the filtrate were separated. The aqueous phase was extracted with
DCM (2 × 300 mL), and the combined organic layers were concentrat-
ed under reduced pressure to afford the crude ketone (85.1 g) as a
brown solid with 73% of GC area. The crude product was transferred
to a 1000 mL four-necked flask, and petroleum ether (500 mL) and
EtOAc (10 mL) were added, and the mixture was heated to reflux for
2 h. The mixture was cooled to rt while kept stirring. The solid prod-
uct was collected by suction filtration to afford 10 (65.9 g 94% of GC
area) as a yellow solid. Concentration of the mother liquid gave 19.3 g
of a yellow oil, which only contained trace amount of the desired
ketone 10 according to GC analysis. Repeating the slurry operation
afforded 58.7 g of ketone 10 (65% overall yield over 4 steps) as a
yellow solid (98% of GC area); mp 127–128 °C.
2-Chlorotetrahydroquinolin-8-yl Acetate (8) (Step 5)
To a 1000 mL four-necked jacketed flask fitted with a mechanical stir-
rer, an addition funnel, a thermometer, and a condenser was added
Ac2O (155 g, 1.5 mol, 3 equiv), and heated to 65 °C. The crude 2-chlo-
rotetrahydroquinoline N-oxide (7; 108 g, 0.5 mol, 1 equiv) from the
above step was diluted with AcOH (100 mL) and slowly added to the
hot Ac2O over 1 h, and the temperature was held at 65 °C for another
8 h. TLC analysis showed a complete conversion and GC analysis
showed the selectivity of acetate 8 was 82% of GC area. To the reaction
mixture was added H2O (200 mL) to quench the excess Ac2O, and the
mixture was kept stirring at 80 °C for 1 h. The cooled mixture was
concentrated to afford 130 g of a brown oil. Then MTBE (500 mL) and
brine (150 mL) were added. The aqueous phase was separated, and
the organic phase was washed with brine (5 × 150 mL). The resulting
organic phase was concentrated in vacuo to afford 92.0 g (82% of GC
area) of crude acetate 8 as a brown oil and was directly used in the
next step. An analytical sample of acetate 8 was obtained by purifica-
tion by column chromatography as a white solid; mp 74–75 °C.
FT-IR (KBr): 3446.4, 3074.7, 2967.1, 2950.2, 1732.2, 1567.9, 1449.0,
1235.1, 970.1, 851.4 cm–1
.
FT-IR (KBr): 3375.3, 3081.4, 2961.8, 2937.4, 2885.1, 1697.7, 1439.4,
1H NMR (500 MHz, CDCl3):  = 7.40 (d, J = 8.1 Hz, 1 H), 7.17 (d, J = 8.1
Hz, 1 H), 5.83 (t, J = 4.5 Hz, 1 H), 2.85–2.65 (m, 2 H), 2.18–2.12 (m, 1
H), 2.09 (s, 3 H), 2.02–1.94 (m, 1 H), 1.93–1.79 (m, 2 H).
13C NMR (125 MHz, CDCl3):  = 170.3, 153.8, 148.9, 140.1, 132.6,
124.0, 70.5, 28.7, 27.8, 21.5, 18.2.
1220.0, 1108.2, 817.1 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.62 (d, J = 8.2 Hz, 1 H), 7.39 (d, J = 8.2
Hz, 1 H), 2.99 (t, J = 6.1 Hz, 2 H), 2.76 (t, J = 6.6 Hz, 2 H), 2.22-2.14 (m,
2 H).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

H
Z. Zong et al.
Paper
Synthesis
13C NMR (125 MHz, CDCl3):  = 195.1, 151.0, 148.2, 140.7, 139.7,
128.3, 39.4, 28.6, 22.6.
HRMS-EI: m/z calcd for C9H8ClNO [M]+: 181.0294; found: 181.0299.
(c) Lai, Y.; Zong, Z.; Tang, Y.; Mo, W.; Sun, N.; Hu, B.; Shen, Z.;
Jin, L.; Sun, W.-h.; Hu, X. Beilstein J. Org. Chem. 2017, 13, 213.
(d) Jin, L.; Qian, J.; Sun, N.; Hu, B.; Shen, Z.; Hu, X. Chem.
Commun. 2018, 54, 5752. (e) Wu, K.; Sun, N.; Hu, B.; Shen, Z.;
Jin, L.; Hu, X. Adv. Synth. Catal. 2018, 360, 3038. (f) Jin, L.; Wei,
W.; Sun, N.; Hu, B.; Shen, Z.; Hu, X. Org. Chem. Front. 2018, 5,
2484. (g) Zong, Z.; Yu, Q.; Sun, N.; Hu, B.; Shen, Z.; Hu, X.; Jin, L.
Org. Lett. 2019, 21, 5767.
Funding Information
This work was supported by the National Natural Science Founda-
tions of China (21972125, 21773210, and 21776260) and the Funda-
mental Research Funds for the Provincial Universities of Zhejiang (RF-
(9) (a) Yu, J.; Hu, X.; Zeng, Y.; Zhang, L.; Ni, C.; Hao, X.; Sun, W.-H.
New J. Chem. 2011, 35, 178. (b) Chai, W.; Yu, J.; Wang, L.; Hu, X.;
Redshaw, C.; Sun, W.-H. Inorg. Chim. Acta 2012, 385, 21. (c) Sun,
W.-H.; Kong, S.; Chai, W.; Shiono, T.; Redshaw, C.; Hu, X.; Guo,
C.; Hao, X. Appl. Catal., A. 2012, 447-448, 67. (d) Zhang, W.; Chai,
W.; Sun, W.-H.; Hu, X.; Redshaw, C.; Hao, X. Organometallics
2012, 31, 5039. (e) Ye, B.; Wang, L.; Hu, X.; Redshaw, C.; Sun, W.-
H. Inorg. Chim. Acta 2013, 407, 281. (f) Huang, F.; Xing, Q.; Liang,
T.; Flisak, Z.; Ye, B.; Hu, X.; Yang, W.; Sun, W.-H. Dalton Trans.
2014, 43, 16818. (g) Ba, J.; Du, S.; Yue, E.; Hu, X.; Flisak, Z.; Sun,
W.-H. RSC Adv. 2015, 5, 32720. (h) Huang, F.; Sun, Z.; Du, S.; Yue,
E.; Ba, J.; Hu, X.; Liang, T.; Galland, G. B.; Sun, W.-H. Dalton
Trans. 2015, 44, 14281. (i) Huang, C.; Zhang, Y.; Liang, T.; Zhao,
Z.; Hu, X.; Sun, W.-H. New J. Chem. 2016, 40, 9329. (j) Huang, F.;
Zhang, W.; Sun, Y.; Hu, X.; Solan, G. A.; Sun, W.-H. New J. Chem.
2016, 40, 8012. (k) Huang, F.; Zhang, W.; Yue, E.; Liang, T.; Hu,
X.; Sun, W.-H. Dalton Trans. 2016, 45, 657. (l) Zhang, Y.; Huang,
C.; Hao, X.; Hu, X.; Sun, W.-H. RSC Adv. 2016, 6, 91401.
(m) Nurdin, L.; Spasyuk, D. M.; Piers, W. E.; Maron, L. Inorg.
Chem. 2017, 56, 4157. (n) Suo, H.; Zhang, Y.; Ma, Z.; Yang, W.;
Flisak, Z.; Hao, X.; Hu, X.; Sun, W.-H. Catal. Commun. 2017, 102,
26. (o) Wang, Z.; Zhang, Y.; Ma, Y.; Hu, X.; Solan, G. A.; Sun, Y.;
Sun, W.-H. J. Polym. Sci., Part A: Polym. Chem. 2017, 55, 3494.
(p) Zhang, Y.; Suo, H.; Huang, F.; Liang, T.; Hu, X.; Sun, W.-H.
J. Polym. Sci., Part A: Polym. Chem. 2017, 55, 830. (q) Huang, C.;
Huang, Y.; Ma, Y.; Solan, G. A.; Sun, Y.; Hu, X.; Sun, W.-H. Dalton
Trans. 2018, 47, 13487. (r) Huang, Y.; Zhang, R.; Liang, T.; Hu, X.;
Solan, G. A.; Sun, W.-H. Organometallics 2019, 38, 1143.
(s) Zhang, R.; Huang, Y.; Solan, G. A.; Zhang, W.; Hu, X.; Hao, X.;
Sun, W.-H. Dalton Trans. 2019, 48, 8175.
(10) Pan, B.; Liu, B.; Yue, E.; Liu, Q.; Yang, X.; Wang, Z.; Sun, W.-H. ACS
Catal. 2016, 6, 1247.
(11) Liu, S.; Zhang, J.; Zuo, W.; Zhang, W.; Sun, W.-H.; Ye, H.; Li, Z.
Polymers 2017, 9, 83.
(12) Skupinska, K. A.; McEachern, E. J.; Skerlj, R. T.; Bridger, G. J.
J. Org. Chem. 2002, 67, 7890.
(13) (a) Koltunov, K. Yu.; Surya Prakash, G. K.; Rasul, G.; Olah, G. A.
Heterocycles 2004, 62, 757. (b) Xie, L.-Y.; Duan, Y.; Lu, L.-H.; Li,
Y.-J.; Peng, S.; Wu, C.; Liu, K.-J.; Wang, Z.; He, W.-M. ACS Sustain.
Chem. Eng. 2017, 5, 10407.
(14) Meyers, A. I.; Garcia-Munoz, G. J. Org. Chem. 1964, 29, 1435.
(15) Meth-Cohn, O.; Westwood, K. T. J. Chem. Soc., Perkin Trans. 1
1984, 1173.
(16) (a) Yamamoto, I. In Nicotinoid Insecticides and the Nicotinic Ace-
tylcholine Receptor; Yamamoto, I.; Casida, J. E., Ed.; Springer:
Tokyo, 1999, 3. (b) Flores-Céspedes, F.; Figueredo-Flores, C. I.;
Daza-Fernández, I.; Vidal-Peña, F.; Villafranca-Sánchez, M.;
Fernández-Pérez, M. J. Agric. Food Chem. 2012, 60, 1042.
(c) Belov, V.; Käfferlein, H. U. J. Labelled Compd. Radiopharm.
2019, 62, 126.
(17) Brunet, J.-L.; Badiou, A.; Belzunces, L. P. Pest Manag. Sci. 2005,
61, 742.
(18) Gangadasu, B.; Narender, P.; Bharath Kumar, S.; Ravinder, M.;
Ananda Rao, B.; Ramesh, C.; China Raju, B.; Jayathirtha Rao, V.
Tetrahedron 2006, 62, 8398.
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Acknowledgment
X.H. would like to thank all former students for their contributions to
the synthesis, especially Mr. Yinjun Xie for his initiation of the later
four-step synthesis; Mr. Fang Huang for the initial optimization of the
overall process; Mr. Pan Li for the observation of extremely exother-
mic of direct mixing N-oxide and acetic acid; Mr. Youfu Zhang and Mr.
Yongfeng Huang for the contribution on the NaBH4 reduction.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707236.
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References
(1) (a) Glase, S. A.; Corbin, A. E.; Pugsley, T. A.; Heffner, T. G.; Wise,
L. D. J. Med. Chem. 1995, 38, 3132. (b) Enhsen, A.; Karabelas, K.;
Heerding, J. M.; Moore, H. W. J. Org. Chem. 1990, 55, 1177.
(c) Bosch, J.; Roca, T.; Pérez, C. G.; Montanari, S. Bioorg. Med.
Chem. Lett. 2000, 10, 563. (d) Sucheck, S. J.; Greenberg, W. A.;
Tolbert, T. J.; Wong, C.-H. Angew. Chem. Int. Ed. 2000, 39, 1080.
(e) Zimmerman, S. C.; Zeng, Z. J. Org. Chem. 1990, 55, 4789.
(f) Zimmerman, S. C.; Zeng, Z.; Wu, W.; Reichert, D. E. J. Am.
Chem. Soc. 1991, 113, 183.
(2) Yoshizumi, T.; Takahashi, H.; Miyazoe, H.; Sugimoto, Y.; Tsujita,
T.; Kato, T.; Ito, H.; Kawamoto, H.; Hirayama, M.; Ichikawa, D.;
Azuma-Kanoh, T.; Ozaki, S.; Shibata, Y.; Tani, T.; Chiba, M.; Ishii,
Y.; Okuda, S.; Tadano, K.; Fukuroda, T.; Okamoto, O.; Ohta, H.
J. Med. Chem. 2008, 51, 4021.
(3) Högenauer, K.; Baumann, K.; Enz, A.; Mulzer, J. Bioorg. Med.
Chem. Lett. 2001, 11, 2627.
(4) (a) Rudolf, L.; Manfred, W.; Walter, D.; Jirgen, B.; Karl, S. PCT Int.
Appl. US 5071979, 1982. (b) Brown, R. F.; Kinnick, M. D.; Morin,
J. M.; Vasileff, R. T.; Counter, F. T.; Davidson, E. O.; Ensminger, P.
W.; Eudaly, J. A.; Kasher, J. S. J. Med. Chem. 1990, 33, 2114.
(5) Crawford, J. B.; Chen, G.; Gauthier, D.; Wilson, T.; Carpenter, B.;
Baird, I. R.; McEachern, E.; Kaller, A.; Harwig, C.; Atsma, B.;
Skerlj, R. T.; Bridger, G. J. Org. Process Res. Dev. 2008, 12, 823.
(6) Zimmerman, S. C.; Wu, W. J. Am. Chem. Soc. 1989, 111, 8054.
(7) (a) Suo, H.; Solan, G. A.; Ma, Y.; Sun, W.-H. Coord. Chem. Rev.
2018, 372, 101. (b) Bariashir, C.; Huang, C.; Solan, G. A.; Sun, W.-
H. Coord. Chem. Rev. 2019, 385, 208. (c) Woodmansee, D. H.;
Müller, M.-A.; Neuburger, M.; Pfaltz, A. Chem. Sci. 2010, 1, 72.
(8) (a) Xie, Y.; Huang, H.; Mo, W.; Fan, X.; Shen, Z.; Shen, Z.; Sun, N.;
Hu, B.; Hu, X. Tetrahedron: Asymmetry 2009, 20, 1425. (b) Tang,
Y.; Zeng, Y.; Hu, Q.; Huang, F.; Jin, L.; Mo, W.; Sun, N.; Hu, B.;
Shen, Z.; Hu, X.; Sun, W.-H. Adv. Synth. Catal. 2016, 358, 2642.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

I
Z. Zong et al.
Paper
Synthesis
(19) Kürti, L.; Czakó, B. In Strategic Applications of Named Reactions
in Organic Synthesis: Background and Detailed Mechanisms;
Elsevier Academic Press: Amsterdam, 2005, 468.
(20) Chen, C. Y. In The Art of Process Chemistry; Yasuda, N., Ed.;
Wiley: New York, 2010, 117.
(21) Cotarca, L.; Geller, T.; Répási, J. Org. Process Res. Dev. 2017, 21,
1439.
(22) (a) Boekelheide, V.; Linn, W. J. J. Am. Chem. Soc. 1954, 76, 1286.
(b) Oae, S.; Tamagaki, S.; Negoro, T.; Kozuka, S. Tetrahedron
1970, 26, 4051.
(23) (a) Hu, X.-Q.; Wang, J.-W.; Zhou, N.; Zhao, C.-X. Fenzi Cuihua
2001, 15, 481. (b) Wang, J.; Zhou, N.; Zhao, C.; Cao, G.; Hu, X.
Cuihua Xuebao 2001, 22, 87.
(24) (a) McKillop, A.; Bhagrath, A. M. Heterocycles 1985, 23, 1697.
(b) Konno, K.; Hashimoto, K.; Shirahama, H.; Matsumoto, M.
Heterocycles 1986, 24, 2169. (c) Fontenas, C.; Bejan, E.; Haddou,
H. A.; Balavoine, G. G. A. Synth. Commun. 1995, 25, 629.
(25) (a) Akita, H.; Takano, Y.; Nedu, K.; Kato, K. Tetrahedron: Asym-
metry 2006, 17, 1705. (b) Santaniello, E.; Ferraboschi, P.;
Sozzani, P. J. Org. Chem. 1981, 46, 4584. (c) Kim, J.; De Castro, K.
A.; Lim, M.; Rhee, H. Tetrahedron 2010, 66, 3995.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I