Mechanically activated ring-opening reactions of N-acyl-1,2,3,4-tetrahydroisoquinolines derived from the synthesis of praziquantel intermediate

Article abstract of DOI:10.1016/j.tet.2015.06.105

Abstract An unexpected DDQ-promoted ring-opening reaction of N-chloroacetyl-tetrahydroisoquinoline under ball milling conditions was revealed during the synthesis of Praziquantel. A variety of N-acyl-tetrahydroisoquinolines were then tested to further inv

Full text of DOI:10.1016/j.tet.2015.06.105

Tetrahedron 71 (2015) 6116e6123
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Mechanically activated ring-opening reactions of N-acyl-
1,2,3,4-tetrahydroisoquinolines derived from the synthesis
of praziquantel intermediate
,
,
Jingbo Yu a, Zhi Wang a b, Yang Zhang a, Weike Su a
*
a National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River
Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, PR China
b College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 May 2015
Received in revised form 28 June 2015
Accepted 29 June 2015
Available online 3 July 2015
An unexpected DDQ-promoted ring-opening reaction of N-chloroacetyl-tetrahydroisoquinoline under
ball milling conditions was revealed during the synthesis of Praziquantel. A variety of N-acyl-tetrahy-
droisoquinolines were then tested to further investigate the reaction, and plausible reaction mechanism
was proposed. Ball milling was demonstrated to be an efficient tool to promote this oxidative ring-
opening reaction to give products in satisfactory yields with good selectivity in short reaction times.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Tetrahydroisoquinoline
Ring-opening reaction
Praziquantel
Ball milling
1. Introduction
Praziquantel (PZQ) is an anthelmintic developed by Bayer and
Merck in 1970s, which effectively against flatworms and has been
widely used in treatment of hydatid disease, cysticercosis, and
toxocariasis. Hitherto, there have been considerable efforts at an-
alog synthesis given PZQ’s status as the preferred drug for the
treatment of the more than 200 million patients currently infected
with bilharziosis.1,2 Although there have been a couple of synthetic
routes to prepare PZQ via different intermediates (Scheme 1),3
most of them are marred by one or another drawback such as
multiple steps, harsh conditions, use of carcinogenic solvent, en-
vironmentally harmful reagents and toxic substrates. Therefore, it
is still highly desirable to develop a simpler and more efficient
synthetic protocol for the preparation of PZQ and analog under
environmentally benign conditions.
Cross-dehydrogenative-coupling (CDC) reaction has been
widely researched during the past decade, which shows as a mild
method for the direct coupling of appropriate CeH bonds.4 Our
group had reported a 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ)-promoted solvent-free CDC reaction under ball-milling
conditions.5 During the study of a novel synthesis of PZQ, we
Scheme 1. Preparation of PZQ via different intermediates.
planned to extend this solvent-free coupling method to the syn-
thesis of 1-aminomethyl tetrahydroquinoline, a key-intermediate
of praziquantel, by reduction and deprotection of the CDC prod-
uct. Unexpectedly, the reaction was also found to afford oxidative
* Corresponding author. Tel.: þ86 571 88320899; fax: þ86 571 88320752; e-mail
address: pharmlab@zjut.edu.cn (W. Su).
http://dx.doi.org/10.1016/j.tet.2015.06.105
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

J. Yu et al. / Tetrahedron 71 (2015) 6116e6123
6117
ring-opening products and acylated DDQ derivatives using differ-
ent acyl protecting groups on tetrahydroisoquinoline.
procedure was found to be relatively difficult. To ease the depro-
tection, PMP was replaced by Boc group, which afforded 3b as the
CDC product (Scheme 4). However, it could hardly undergo nitro
reduction and affording a hardly separable mixture.
Oxidative ring-opening reaction is one of the most important
processes in organic transformations. The oxidative ring opening of
heterocycles,6 metal-containing heterocycles7 and carbocycles8 are
well documented, these valuable ring-opened synthetic in-
termediates can be further manipulated to afford ring-contraction
or ring-expansion products.9 In addition, a great number of works
have applied oxidative ring opening reaction to the synthesis and
modification of bioactive natural products, such as Lavandulol,10
(þ)-Lycoricidine,11 Taxane derivatives12 and Paclitaxel analogs.13
However, most of the oxidative ring-opening reactions are con-
ducted in hazardous organic solvents, together with metal oxidants
or other explosive oxidants. In this paper, we describe an efficient
synthetic strategy of PZQ and the derivative solvent-free oxidative
ring-opening reaction of N-acyl-1,2,3,4-tetrahydroisoquinolines
under ball milling conditions.
Scheme 4. Synthesis of 1-aminomethyl tetrahydro-isoquinoline from N-Boc tetrahy-
droisoquinoline 1b.
Although the designed route in Scheme 3 gave the ideal prod-
ucts, the protection and deprotection of tetrahydroisoquinoline
resulted in relatively low atom economy, which was not in accord
with green chemistry. Therefore, we turned to use chloroacetyl as
the protecting group, by which piperazinone might form directly
after nitro reduction to eliminate the deprotection procedure
(Scheme 5).
2. Results and discussion
Our synthetic strategy of PZQ by using 1-aminomethyl tetra-
hydroisoquinoline as key intermediate was shown in Scheme 2.
CDC reaction was used to introduce the nitromethyl group to the N-
protected 1,2,3,4-tetrahydroisoquinoline. Then the target product
1-aminomethyl tetrahydroisoquinoline could be obtained after
a two-step sequence of reduction and deprotection. After the se-
quential formation of piperazinone and acylation, Praziquantel
could be finally obtained.
Scheme 5. Designed synthetic route of PZQ with 1-aminomethyl-2-chloroacteyl-tet-
rahydroisoquinoline 1c as intermediate.
The N-chloroacteyl-tetrahydroisoquinoline 1c was examined as
substrate to perform the same CDC reaction under ball milling
conditions. To our disappointment, though most of the substrate
had reacted within 50 min of ball milling, no desired product could
be isolated. After identification, we surprisingly found that oxida-
tive ring-opening product benzaldehyde derivative 3c0 was ob-
tained in 67% yield (Scheme 6). However, no matter changing the
reactant ratio or the amount of DDQ, the reaction gave only the
benzylaldehydes 3c0. The best results were obtained when 1.1 equiv
of DDQ was used, an excess of oxidant was detrimental to the yield
of the product, whereas less than 1 equiv of DDQ would result in
incomplete conversion of the starting materials. An examination of
the effect of ball milling vibration frequency on the reaction was
undertaken subsequently (Table 1). The yield declined with de-
creased frequencies, and almost no reaction occurred when the
frequency was reduced to 15 Hz even with prolonged reaction
times. Besides, without nitromethane, the reaction still proceeded
Scheme 2. Synthesis of PZQ with 1-aminomethyl tetrahydroisoquinoline as key
intermediate.
We initiated our synthesis from N-PMP tetrahydroisoquinoline,
which was subjected to a solvent-free CDC reaction under ball-
milling conditions (Scheme 3). The expected 1-nitromethyl tetra-
hydroisoquinoline 3a was obtained in 20 min with 80% yield, which
was followed by nitro reduction with Raney-Ni/H2 under atmo-
spheric pressure. After purification, PMP was removed by ammo-
nium ceric nitrate (CAN)14 to afford the target compound in 60%
yield. Recently, Todd et al. reported their research on the synthesis
of PZQ using D as key intermediate.15 According to their work, the
amino group of 4a should be pre-protected before the removal of
PMP, otherwise the deprotection yield would be very low. In our
synthetic route, moderate deprotection yield was obtained but the
Scheme 3. Synthesis of 1-aminomethyl tetrahydro-isoquinoline from N-PMP tetra-
hydroisoquinoline 1a.
Scheme 6. Oxidative ring-opening reaction of N-chloroacteyl-tetrahydroquinoline 1c.

6118
J. Yu et al. / Tetrahedron 71 (2015) 6116e6123
Table 1
group provided the product in moderate yields, but with relatively
longer reaction times.
Influence of the ball mill vibration frequency on the reactiona
Yieldb (%) of 3c0
To gain a better understanding of the reaction mechanism, the
following control experiments were carried out. First, the
reaction of 1d with DDQ was conducted under nitrogen atmo-
sphere to reveal the source of oxygen in oxidative ring-opening
products. The results showed that only 2,3-dichloro-5,6-dicyano-
4-hydroxyphenyl benzoate 6a was formed (Table 4, entry 1), which
indicated that air was the oxygen source in oxidative ring-opening
products. Various substrates were then tested under the same
conditions to give nucleophilic substituted products, except for 4h
and 4i, which still remained unreacted after a long reaction time
(Table 4, entries 5e6). The influence of the substitutes at 2-position
of tetrahydroisoquinoline was similar to that under ball milling
conditions. Mechanical force was proved to be an efficient pro-
motion for oxidative ring-opening reaction. However, when acyclic
amides such as N,N-diethyl benzamide 1m, N-acyl piperidine 1n, 1-
methyl-4-benzoyl piperazine 1o and 1-methyl-4-acetyl piperazine
1p (Table 4, entries 10e13) were used as substrates under the above
nitrogen condition, no reaction took place, indicating tetrahy-
droisoquinoline played a role as a good-leaving group for the nu-
cleophilic substitution reaction.
Additionally, it was found that when a typical radical scavenger,
tetramethylpiperidine N-oxide (TEMPO, 1 equiv), was added into
the reaction system under the standard conditions, the reaction
was not appreciably suppressed, which excluded significant in-
volvement of any radical intermediate. On the basis of these ex-
perimental results and previous reports,21,22 a plausible reaction
mechanism was suggested, as shown in Scheme 7. N-formyl tetra-
hydroisoquinoline was initially converted to imine-type in-
termediate I in the presence of DDQ, meanwhile DDQ was
transformed into the corresponding anion oxygen intermediate III.
Subsequently, I was transformed to II via oxidation by air, which
then underwent CeN bond breaking and proton transferring to
afford 5. Meanwhile, 6 was obtained from the nucleophilic attack of
III to the carbonyl of I, with dihydroisoquinolinium as the leaving
molecule.
Entry
Frequency (Hz)
Time (min)
1
2
3
4
30
25
20
15
50
50
60
90
67
55
26
trace
a
1c (1.0 mmol), DDQ (1.1 equiv, 0.25 g) and silica gel (0.5 g) were added to the
stainless steel vial, milling at different Hz.
b
Isolated yields based on 1c.
to afford the oxidative ring-opening product. Comparative experi-
ments16 were performed under stirring conditions by using nitro-
methane or dichloromethane (DCM) as solvent, the corresponding
reaction times were much longer (>10 h) and the product yields
(60% and 45%, respectively) were lower than those obtained under
milling conditions.
Oxidative ring-opening reaction of 2-aryl tetrahydroisoquino-
line had been reported by Stanforth by using N-bromosuccinimide
(NBS) as oxidant under refluxing condition in DCM.17 However, the
reaction was limited to electron-withdrawing N-aryl tetrahy-
droisoquinoline, especially for substrates that are prone to form
intramolecular hydrogen bond. In our reaction, benzaldehydes 5,
which might play the role as the intermediates of taspine,18 calcium
receptor-active compounds19 and EP2 receptor antagonist,20 were
obtained probably due to the influence of ketone carbonyl on N-2-
position resulting in the facile breaking and oxidation of the CeN
bond under ball milling conditions.
The reaction scope was then investigated with various N-aroyl
tetrahydroisoquinolines and the results were summarized in Table
2. In most of the reactions, DDQ acylation products 6, which
resulted from the nucleophilic substitution of DDQ and N-acyl
substrates were surprisingly detected (Table 2, entries 1e4 and
7e9). For the substrates with meta-substituted aroyl in N-2-
position, corresponding oxidative ring-opening products were
readily obtained (Table 2, entries 3e4). Single oxidative ring-
opening products were obtained when the substrates with ortho-
substituted (methoxy) or poly-substituted (2,3,4,5-fluoro) aroyl at
2-nitrogen (Table 2, entries 5e6). In this case, steric hindrance of
the ortho substituents prohibited the nucleophile substitution of
aroyl. However, when N-alkanoyl tetrahydroisoquinoline 1j was
used as the substrate, the reaction afforded only a small amount
(15%) of DDQ acylation product with lots of oxypolymerized by-
products, indicating that aroyl group can facilitate the substrate
to undergo oxidative ring-opening reaction.
The substituents on tetrahydroisoquinoline could also play an
important role in the reaction selectivity. The result turned out that
6,7-dimethoxyl tetrahydroisoquinolines took part in the reaction
smoothly under the milling conditions, but providing large amount
of acyl substituted DDQ. If the reaction was taken by intermittent
milling with portion-wise addition of DDQ, a small amount of ox-
idative ring-opening product 5g was obtained (Table 2, entry 8).
However, in contrast with 1g, only trace of ring-opening product 5h
was detected when 1l was used as substrate (Table 2 entry 4 and 9).
Aliphatic amides were also studied under continuous milling con-
ditions, but after a long reaction time (>60 min), the substrates still
remained unreacted (Table 2, entries 10e11). Comparative experi-
ments16 performed in solution were also studied, the results
showed that longer reaction times were required to afford acyl
substituted DDQ as the main product, but with poorer selectivity
(Table 2, entries 1e3 and 5 in parentheses).
3. Conclusions
In summary, a new type of DDQ-promoted ring-opening re-
action of N-acyl-tetrahydroisoquinoline was revealed to afford or-
tho-substituted benzaldehyde derivatives, the intermediates of
several biological compounds, during the research of a novel syn-
thesis of Praziquentel. Compared to traditional stirring conditions,
ball milling was demonstrated to be an efficient tool to promote
this oxidative ring-opening reaction combining the advantages of
good selectivity, short reaction times, and free of reaction solvents.
The reaction mechanism in both solution and under solvent-free
conditions was preliminary explored. The detailed mechanism
and its application in the preparation of bioactive products are
under further study.
4. Experimental section
4.1. General information and materials
The reactions were conducted in a high-energy vibrational
micromill (volume of stainless steel vial: 10 mL; diameter of
stainless steel balls: 8.0 mm). Melting points (mp) were obtained
To extend the applicability of the ring-opening reaction, acyl-
substituted benzazepine derivatives were tested as substrates un-
der the above milling conditions. As shown in Table 3, the electronic
nature of the aroyl substituents had no significant effect on the
reaction. Both electron-withdrawing group and electron-donating
on a digital melting point apparatus and uncorrected. 1H NMR, 13
C
NMR were recorded at 400 MHz and 100 MHz, respectively, and
TMS as internal standard. Mass spectra were measured with an
HRMS-APCI instrument or a low-resolution MS instrument using
ESI or APCI ionization.

J. Yu et al. / Tetrahedron 71 (2015) 6116e6123
6119
Table 2
Reaction of 1 with DDQ under ball mill conditiona
Entry
Substrate
Product
Time (min)
50 (480d)
Yield (%)b of 5 and 6
5
6
1
70 (35e)
10 (50e)
2
50 (540d)
52 (20e)
16 (60e)
3
4
30 (360d)
74 (40e)
5 (45e)
30
75
2
5
6
d
d
60 (960d)
70 (58e)
d
d
100
63
7
d
30
60
60
d
15
38
86
8c
49
9c
trace
10
d
d
60
d
d
(continued on next page)

6120
J. Yu et al. / Tetrahedron 71 (2015) 6116e6123
Table 2 (continued )
Entry
Substrate
Product
Time (min)
Yield (%)b of 5 and 6
5
6
11
d
d
60
d
d
a
N-acyl tetrahydroisoquinoline (1.0 mmol), DDQ (1.1 equiv, 0.25 g) and silica gel (0.5 g) were added to the stainless steel vial, milling at 30 Hz.
Isolated yields based on 1.
Milling at 30 Hz for 10 min by a 5 min pause; DDQ was added in five portions.
Reaction time of comparative experiment in solvent (CH3NO2, 10 mL).
Isolated yields of the comparative experiment.
b
c
d
e
Table 3
Ring-opening reaction of N-acyl benzazepinesa
Entry
R
Product
Time (h)
Yield (%)b of 8 and 6
8
6
1
2
3
Ph
3-MeC6H4
3-ClC6H4
7a
7b
7c
8a
8b
8c
d
6c
6d
3.5
3
3
60
68
63
d
3
2
a
N-acyl benzazepine (1.0 mmol), DDQ (1.1 equiv, 0.25 g) and silica gel (0.5 g)
were added to the stainless steel vial, milling at 30 Hz.
b
Isolated yields based on 7.
Scheme 7. Plausible reaction mechanism.
All reagents were purchased from commercial sources and used
without treatment, unless otherwise indicated. 1-nitro-2-(4-
methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline 3a and tert-butyl
Table 4
Reaction of 1 with DDQ in solution under N2 atmospherea
1-(nitromethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
3b
were prepared according to published procedures.5
4.1.1. tert-Butyl 1-(nitromethyl)-3,4-dihydroisoquinoline-2(1H)-car-
boxylate (3b). Colorless oil. 1H NMR (CDCl3, 400 MHz, ppm)
d
7.28e7.09 (m, 4H), 5.95e5.88 (m, 0.26H [minor]) 5.84 (dd, J¼9.2,
3.6 Hz, 0.56H [major]), 4.72e4.62 (m, 1H), 4.60e4.53 (m, 1H),
4.33e4.24 (m, 0.59H [major]), 3.99e3.89 (m, 0.28H [minor]),
3.26e3.16 (m, 1H), 3.03e2.87 (m, 1H), 2.82e2.72 (m, 1H), 1.45 (s,
Entry
1
Product
Time (h)
Yield (%)b
9H); 13C NMR (CDCl3,100 MHz, ppm)
d 154.5 (minor),153.6 (major),
R1¼R2
H
H
H
H
H
H
H
R
135.1 (major), 134.8 (minor), 131.7 (minor), 131.5 (major), 129.4,
127.9 (2C), 126.6, 81.3 (major), 80.8 (minor), 79.1 (major), 78.6
(minor), 53.9 (major), 53.1 (minor), 39.3 (minor), 36.9 (major), 28.5
(minor), 28.4 (minor), 28.2 (major), 28.1 (major); MS (EI) m/z (%):
176 (4), 132 (24), 131 (89), 130 (100), 77 (25); HRMS (ESI)
1
2
3
4
5
6
7
8
9
Ph
d
e
f
g
h
i
j
k
l
6a
6b
6c
d
d
d
6e
6a
6d
3
3
4
90
90
88
90
d
4-BrC6H4
3-MeC6H4
3-ClC6H4
2-MeOC6H4
2,3,4,5-tetraFC6H
H
4
10
10
10
3
d
C
15H21N2NaO4 ([MþNa]þ): calcd: 315.1315, Found: 315.1315.
30
85
92
OMe
OMe
Ph
3-ClC6H4
4
4.2. Procedure for the preparation of 1-aminomethyl-2-(4-
methoxy phenyl)-1,2,3,4-tetrahydroisoquinoline (4a)
10
11
12
m
n
d
d
10
10
d
d
Raney-Ni (150 mesh, 10 mL) was added to a solution of 1-nitro-
2-PMP-1,2,3,4-tetrahydroisoquinoline (0.596 g, 2 mmol) in ethanol
(30 mL), and stirred for 6 h under H2 balloon (1 atm) at room
temperature. After the completion of the reaction (monitored by
TLC), the resulting mixture was filtered. Ethanol was distilled off
under reduced pressure, then extracted with EA (4ꢀ10 mL). The
combined organic layers were washed with brine (2ꢀ10 mL), dried
over Na2SO4 and concentrated in vacuum. Purification by silica gel
column chromatography using CH2Cl2/CH3OH (v/v¼30:1) as an
eluent afforded 4a.
o
p
d
d
10
10
d
d
13
a
DDQ (1.1 mmol, 0.250 g) in 10 mL CH2Cl2 or MeNO2 was added to N-acyl tet-
rahydroisoquinoline (1 mmol) under N2 atmosphere.
b
Isolated yields based on 1.

J. Yu et al. / Tetrahedron 71 (2015) 6116e6123
6121
Brownish oil. 1H NMR (CDCl3, 400 MHz, ppm)
d
7.21e7.03 (m,
HRMS (ESI) C16H14BrNNaO2 ([MþNa]þ): calcd: 354.0106, Found:
4H), 6.92 (d, J¼8.8 Hz, 2H), 6.77 (d, J¼8.8 Hz, 2H), 4.48 (dd, J¼8.4,
4.8 Hz, 1H), 3.73 (s, 3H), 3.57e3.47 (m, 2H), 3.10e3.01 (m, 1H),
3.00e2.85 (m, 2H), 2.63 (ddd, J¼16.0, 4.0, 3.6 Hz, 1H), 2.34 (br s,
354.0104.
4.4.4. N-(2-Formylphenethyl)-3-methylbenzamide
oil. 1H NMR (CDCl3, 400 MHz, ppm)
(5c). Colorless
10.12 (s, 1H), 7.78 (d, J¼7.2 Hz,
2H); 13C NMR (CDCl3, 100 MHz, ppm)
d
153.2, 144.6, 136.1, 135.3,
d
128.7, 127.0, 126.4, 125.9, 118.8 (2C), 114.5 (2C), 62.4, 55.6, 46.8, 43.7,
1H), 7.57e7.40 (m, 3H), 7.38e7.25 (m, 4H), 6.66 (br s, 1H), 3.71 (q,
26.1; MS (ESI): 269 ([MþH]þ).
J¼6.8 Hz, 2H), 3.35 (t, J¼6.8 Hz, 2H), 2.37 (s, 3H); 13C NMR (CDCl3,
100 MHz, ppm)
d 193.6, 167.5, 141.2, 138.1, 134.2, 134.1, 133.8, 131.9,
4.3. Procedure for the preparation of 1-aminomethyl-1,2,3,4-
tetrahydroisoquinoline (D)
131.8, 128.2, 127.8, 127.6, 127.1, 123.6, 41.7, 32.5, 21.5; MS (ESI): 290
([MþNa]þ); HRMS (ESI) C17H17NNaO2 ([MþNa]þ): calcd: 290.1157,
Found: 290.1175.
1-aminomethyl-2-(4-methoxyphenyl)-1,2,3,4 tetrahydro-isoqui
noline 4a (0.268 g, 1 mmol) in acetonitrile were added dropwise
to a solution of ceric ammonium nitrate in 10 mL water at ꢁ10 ꢂC
under nitrogen atmosphere. The mixture was then stirred for 1 h at
the same temperature. After a portion of solvent was distilled off
under reduced pressure, hydrochloric acid was added, and refluxed
for 1 h. The resulting mixture was cooled to room temperature by
adding 10 mL water, the mixture was extracted with EtOAc
(3ꢀ10 mL). The aqueous layer was basified to pH¼9 with 2 M NaOH,
then extracted with DCM (3ꢀ10 mL). The combined organic layers
were washed with brine (2ꢀ10 mL), dried over Na2SO4 and con-
centrated in vacuum. Purification by silica gel column chromatog-
raphy using CH2Cl2/CH3OH/NH3$H2O (v/v/V¼30:1:0.1)as an eluent
afforded D.
4.4.5. N-(2-Formylphenethyl)-3-chlorobenzamide (5d). White crys-
tals. Mp: 87.2e88.3 ꢂC; 1H NMR (CDCl3, 400 MHz, ppm)
d 10.12 (s,
1H), 7.77 (dd, J¼7.6, 1.2 Hz, 1H), 7.70e7.67 (m, 1H), 7.57e7.50 (m,
2H), 7.46e7.38 (m, 2H), 7.35e7.27 (m, 2H), 6.89 (br s, 1H), 3.70 (q,
J¼6.8 Hz, 2H), 3.33 (t, J¼6.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz,
ppm)
d 193.8, 166.0, 141.0, 136.1, 134.5, 134.4, 134.2, 133.9, 131.8,
131.2, 129.6, 127.2, 124.8, 41.9, 32.4; MS (ESI): 310, 312 ([MþNa]þ);
HRMS (ESI) C16H14ClNNaO2 ([MþNa]þ): calcd: 310.0611, Found:
310.0619.
4.4.6. N-(2-Formylphenethyl)-2-methoxybenzamide (5e). Colorless
oil. 1H NMR (CDCl3, 400 MHz, ppm)
d
10.23 (s, 1H), 8.18 (dd, J¼7.6,
1.8 Hz, 1H), 7.94 (br s, 1H), 7.83 (dd, J¼7.6, 1.2 Hz, 1H), 7.58e7.50 (m,
1H), 7.45e7.34 (m, 3H), 7.07e7.02 (m, 1H), 6.92 (d, J¼8.0, Hz, 1H),
3.84 (s, 3H), 3.74 (q, J¼6.8 Hz, 2H), 3.37 (t, J¼6.8 Hz, 2H); 13C NMR
Colorless oil.23 1H NMR (CDCl3, 400 MHz, ppm)
d 7.23e7.15 (m,
2H), 7.10e7.00 (m, 2H), 4.29 (t, J¼12.0 Hz, 1H), 3.90e3.73 (m, 2H),
3.55e3.42 (m, 1H), 3.00e2.85 (m, 2H), 2.79e2.71 (m, 1H), 2.17 (br s,
3H); MS (EI) m/z (%): 132 (100).
(CDCl3, 100 MHz, ppm) d 192.3, 165.1, 157.2, 141.7, 134.1, 133.6, 132.8,
132.5, 132.1, 131.6, 126.9, 121.1, 111.1, 55.8, 41.2, 32.5; MS (ESI): 306
([MþNa]þ); HRMS (ESI) C17H17NNaO3 ([MþNa]þ): calcd: 306.1106,
Found: 306.1111.
4.4. General procedure for the ring-opening reactions of N-
acyl-1,2,3,4-tetrahydroisoquinolines by ball milling
4.4.7. N-(2-Formylphenethyl)-2,3,4,5-tetrafluorobenzamide
(5f). Colorless crystals. Mp: 79.5e80.7 ꢂC; 1H NMR (CDCl3,
The following components were added to the screw-capped
stainless
steel
vial:
N-acyl-1,2,3,4-tetrahydroisoquinolines
400 MHz, ppm)
d
10.14 (s, 1H), 7.80 (d, J¼7.2 Hz, 1H), 7.73e7.63 (m,
(1 mmol), DDQ (1.1 mmol), and silica gel (0.5 g), along with two
stainless steel balls (d¼8.0 mm), then the vial was placed in a vi-
brational micromill (MM 400), and the contents were ball milled at
30 Hz under room temperature. At the end of the experiment, all of
the reaction mixture was scratched off the vessel and then directly
separated and purified by column chromatography. Elution of the
column with PE/EtOAc (v/v¼15:1) afforded the title product.
1H), 7.58e7.42 (m, 2H), 7.33 (d, J¼7.6 Hz, 1H), 6.84 (br s, 1H), 3.74 (q,
J¼6.8 Hz, 2H), 3.36 (t, J¼6.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz,
ppm) d 193.2, 160.3, 140.6, 134.5, 134.3, 133.8, 131.7, 127.3, 112.7 (m),
41.9, 32.5; 19F NMR (CDCl3, 376 MHz, ppm)
d
ꢁ137.0 (m, 1F), ꢁ139.6
(m, 1F), ꢁ149.4 (m, 1F), ꢁ153.9 (m, 1F); MS (ESI): 348 ([MþNa]þ);
HRMS (ESI) C16H11F4NNaO2 ([MþNa]þ): calcd: 348.0624, Found:
348.0633.
4.4.1. 2-Chloro-N-(2-formylphenethyl)acetamide (3c0). Pale yellow
4.5. Procedure for the preparation of N-(2-formyl-4,5-
dimethoxyphenethyl)benzamide (5g)
oil. 1H NMR (CDCl3, 400 MHz, ppm)
d
10.13 (s, 1H), 7.80 (d, J¼7.6 Hz,
1H), 7.57e7.51 (m, 1H), 7.46 (dd, J¼7.6, 7.4 Hz, 1H), 7.31 (d, J¼7.6 Hz,
1H), 6.84 (br s, 1H), 3.99 (s, 2H), 3.58 (q, J¼6.8 Hz, 2H), 3.29 (t,
The following components were added to the screw-capped
stainless steel vial: N-(2-methoxybenzoyl) tetrahydroisoquinoline
(0.267 g, 1.0 mmol), DDQ (0.05 g, 0.22 mmol), and silica gel (0.5 g),
along with two stainless steel balls (d¼8.0 mm). The vial was placed
in a vibrational micromill (MM 400) and the contents were ball
milled at 30 Hz, with a milling cycle of 10 min followed by a 5 min
pause with addition of 0.05 g DDQ (0.22 mmol). This cycle can be
repeated for five times by adding a total amount of 0.25 g DDQ
(1.1 mmol) until the reaction was complete. All of the reaction
mixture was finally scratched off the vessel and then directly sep-
arated and purified by column chromatography. Elution of the
column with PE/EtOAc (v/v¼10:1) afforded the product 5g.
J¼6.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz, ppm)
d 193.2, 165.9, 140.4,
134.5, 134.0, 133.8, 131.7, 127.3, 42.6, 41.1, 32.4; MS (ESI): 226, 228
([MþH]þ); HRMS (ESI) C11H13ClNNaO2 ([MþNa]þ): calcd: 248.0449,
Found: 248.0450.
4.4.2. N-(2-Formylphenethyl)benzamide (5a).24 Colorless oil. 1H
NMR (CDCl3, 400 MHz, ppm)
d
10.16 (s, 1H), 7.79 (dd, J¼7.6, 1.2 Hz,
1H), 7.72e7.69 (m, 2H), 7.56e7.51 (m, 1H), 7.47e7.35 (m, 5H), 6.70
(br s, 1H), 3.73 (q, J¼6.8 Hz, 2H), 3.36 (t, J¼6.8 Hz, 2H); 13C NMR
(CDCl3, 100 MHz, ppm) d 194.1, 167.6, 141.5, 134.7, 134.2, 132.2, 131.5,
130.3, 128.7 (2C), 127.5, 127.4, 127.0 (2C), 42.1, 32.8; MS (ESI): 276
([MþNa]þ).
Colorless crystals. Mp: 142.9e143.3 ꢂC; 1H NMR (CDCl3,
400 MHz, ppm)
d
10.08 (s, 1H), 7.71 (d, J¼7.2 Hz, 1H), 7.50e7.39 (m,
4.4.3. N-(2-Formylphenethyl)-4-bromo-benzamide (5b). Colorless
3H), 7.28 (s, 1H), 6.78 (s,1H), 6.61 (br s, 1H), 3.93 (s, 3H), 3.90 (s, 3H),
oil. 1H NMR (CDCl3, 400 MHz, ppm)
d
10.12 (s, 1H), 7.59e7.49 (m,
3.72 (q, J¼6.8 Hz, 2H), 3.33 (t, J¼6.8 Hz, 2H); 13C NMR (CDCl3,
5H), 7.44 (t, J¼8.0 Hz, 1H), 7.37e7.28 (m, 2H), 6.80 (br s, 1H), 3.71 (q,
100 MHz, ppm) d 190.9, 167.3, 156.5, 151.8, 136.4, 134.3, 134.1, 131.3,
J¼6.8 Hz, 2H), 3.33 (t, J¼6.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz,
128.4 (2C), 126.7 (2C), 114.3, 113.9, 56.3, 56.2, 42.1, 31.7; MS (ESI):
312 ([MꢁH]ꢁ); HRMS (ESI) C18H19NNaO4 ([MþNa]þ): calcd:
336.1212, Found: 336.1206.
ppm) d 194.0, 166.3, 141.1, 134.6, 133.9, 133.1, 131.9, 131.6 (2C), 129.0,
128.4 (2C), 127.2, 125.9, 42.0, 32.4; MS (ESI): 354, 356 ([MþNa]þ);

6122
J. Yu et al. / Tetrahedron 71 (2015) 6116e6123
4.6. General procedure for the reaction of 1 with DDQ in
solution
2H); 13C NMR (CDCl3, 100 MHz, ppm)
d 193.6, 167.3, 144.0, 135.1,
134.4, 133.8, 133.4, 131.2, 131.1, 128.3 (2C), 126.8 (2C), 126.6, 39.6,
31.2, 30.6. MS (ESI): 290.2 ([MþNa]þ); HRMS (ESI) C17H17NNaO2
([MþNa]þ): calcd: 290.1151, Found: 290.1153.
Under the protection of N2, a solution of DDQ (0.250 g, 1.1 mmol)
in DCM (10 mL) was added dropwise into N-benzoyl-1,2,3,4-
tetrahydroisoquinoline, the mixture was stirred at room tempera-
ture for 3 h. After the reaction was complete, the mixture was fil-
tered, and the residue recrystallized in DCM to afford 2,3-dichloro-
5,6-dicyano-4-hydroxyphenyl formyl ester (6).
4.7.2. N-(3-(2-Formylphenyl)propyl)-3-methylbenzamide
(8b). Colorless oil. 1H NMR (CDCl3, 400 MHz, ppm)
d 10.13 (s, 1H),
7.79 (d, J¼7.6 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J¼7.2 Hz, 1H), 7.55e7.28
(m, 1H), 7.41 (t, J¼7.2 Hz, 1H), 7.35e7.26 (m, 3H), 6.90 (br s, 1H),
3.55e3.46 (m, 2H), 3.13 (t, J¼8.0 Hz, 2H), 2.40 (s, 3H), 1.96e1.85 (m,
4.6.1. 2,3-Dichloro-5,6-dicyano-4-hydroxyphenyl
benzoate
2H). 13C NMR (CDCl3, 100 MHz, ppm)
d 193.4, 167.6, 159.2, 144.0,
(6a). Colorless crystals. Mp: 248.0e248.9 ꢂC; 1H NMR (CDCl3,
138.1, 134.8, 134.4, 133.8, 131.8, 131.2, 128.2, 127.7, 126.7, 123.7, 39.6,
31.3, 30.7. MS (ESI): 304.3 ([MþNa]þ); HRMS (ESI) C18H19NNaO2
([MþNa]þ): calcd: 304.1308, Found: 304.1321.
400 MHz, ppm)
d
8.23 (d, J¼7.2 Hz, 2H), 7.73 (dd, J¼7.6, 7.2 Hz, 1H),
7.57 (dd, J¼8.0, 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz, ppm)
d 162.1,
148.9, 135.4, 135.0, 130.7 (2C), 128.9 (2C), 126.3, 110.8, 110.5; MS
(ESI): 332 ([MꢁH]ꢁ); HRMS (ESI) C15H5Cl2N2O3 ([MꢁH]ꢁ): calcd:
330.9677, Found: 330.9697.
4.7.3. N-(3-(2-Formylphenyl)propyl)-3-chlorobenzamide
(8c). Colorless oil. 1H NMR (CDCl3, 400 MHz, ppm)
d 10.11 (s, 1H),
7.93e7.90 (m, 1H), 7.80 (d, J¼7.2 Hz, 1H), 7.56e7.50 (m, 1H),
7.48e7.35 (m, 3H), 7.32 (d, J¼7.6 Hz, 1H), 7.05 (br s, 1H), 3.55e3.46
(m, 2H), 3.13 (t, J¼7.8 Hz, 2H). 1.96e1.85 (m, 2H). 13C NMR (CDCl3,
4.6.2. 2,3-Dichloro-5,6-dicyano-4-hydroxyphenyl 4-bromobenzoate
(6b). Colorless crystals. Mp: 248.5e249.2 ꢂC; 1H NMR (CDCl3,
400 MHz, ppm)
d
8.08 (d, J¼8.4 Hz, 2H), 7.72 (d, J¼8.4 Hz, 2H); 13
C
100 MHz, ppm) d 193.9, 166.0, 143.9, 136.3, 135.6, 134.6, 133.9, 131.3,
NMR (CDCl3, 100 MHz, ppm)
d
161.6, 148.8, 135.6, 132.5 (2C), 132.1
131.2, 129.7, 127.4, 126.8, 124.9, 39.7, 31.1, 30.8. MS (ESI): 302.3
([MþH]þ); HRMS (ESI) C17H16ClNNaO4 ([MþNa]þ): calcd: 324.0762,
Found: 324.0754.
(2C), 130.8, 125.2, 110.9, 110.4; MS (ESI): 411 ([MꢁH]ꢁ); HRMS (ESI)
C
15H4BrCl2N2O3 ([MꢁH]ꢁ): calcd: 408.8782, Found: 410.8765.
4.6.3. 2,3-Dichloro-5,6-dicyano-4-hydroxyphenyl 3-methylbenzoate
Acknowledgements
(6c). Colorless crystals. Mp: 182.3e183.5 ꢂC; 1H NMR (CDCl3,
400 MHz, ppm)
d
8.05e8.01 (m, 2H), 7.53 (d, J¼8.0 Hz, 2H), 7.46
We gratefully acknowledge the National Natural Science Foun-
dation of China (No. 21406201) and the Special Program for Key
Basic Research of the Ministry of Science and Technology, China
(No. 2014CB460608) for financial support. We also thank Dr. Tucai
Zheng in Quzhou University for his assistance in the preparation of
this manuscript.
(d,¼8.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz, ppm)
d 162.4, 149.0,
138.9, 135.9, 131.2, 128.8, 128.0, 126.3, 110.9, 110.6, 21.4; MS (ESI):
346 ([MꢁH]ꢁ); HRMS (ESI) C16H7Cl2N2O3 ([MꢁH]ꢁ): calcd:
344.9834, Found: 344.9872.
4.6.4. 2,3-Dichloro-5,6-dicyano-4-hydroxyphenyl 3-chlorobenzoate
(6d). Colorless crystals. Mp: 205.7e207.5 ꢂC; 1H NMR (CDCl3,
Supplementary data
400 MHz, ppm)
d
8.29 (t, J¼2.0 Hz, 1H), 8.14e8.09 (m, 1H), 7.747.67
(m,1H), 7.53 (dd, J¼8.0, 7.6 Hz,1H); 13C NMR (CDCl3,100 MHz, ppm)
Supplementary data (NMR spectra of the products can be
founded in the Supplementary data) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/
j.tet.2015.06.105.
d
161.3, 149.0, 135.7, 135.6, 135.4, 130.9, 130.5, 129.0, 128.4, 110.2,
110.6; MS (ESI): 366 ([MꢁH]ꢁ); HRMS (ESI) C15H4Cl3N2O3
([MꢁH]ꢁ): calcd: 364.9288, Found: 364.9277.
4.6.5. 2,3-Dichloro-5,6-dicyano-4-hydroxyphenyl
acetate
(6e). Colorless crystals. Mp: 180.1e181.1 ꢂC; 1H NMR (CDCl3,
References and notes
400 MHz, ppm)
d
d
2.49 (s, 3H); 13C NMR (CDCl3, 100 MHz, ppm)
166.0, 148.5, 135.1, 110.5 (2C), 20.3; MS (ESI): 270 ([MꢁH]ꢁ);
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