Synthesis of 1-benzylisoindoline and 1-benzyl-tetrahydroisoquinoline through nucleophilic addition of organozinc reagents toN,O-acetals

Article abstract of DOI:10.1039/d0ob01477j

A new approach to access 1-benzylisoindoline and 1-benzyl-tetrahydroisoquinoline has been developed through nucleophilic addition of organozinc reagents toN,O-acetals. A number of substituted organozinc reagents were amenable for this transformation, and

Full text of DOI:10.1039/d0ob01477j

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DOI: 10.1039/D0OB01477J
Journal Name
ARTICLE
Synthesis
of
1-Benzylisoindoline
and
1-Benzyl
Tetrahydroisoquinoline through Nucleophilic Addition of
Organozinc Reagents to N,O-acetals
Received 00th January 20xx,
Accepted 00th January 20xx
Rui-Jun Ma,a,b Jian-Ting Sun,a Chang-Hong Liu,a Ling Chen,a Chang-Mei Sia,* and Bang-Guo Weia,*
DOI: 10.1039/x0xx00000x
A new approach to access 1-benzylisoindoline and 1-benzyl-tetrahydroisoquinoline has been developed through
nucleophilic addition of organozinc reagents to N,O-acetals. A number of substituted organozinc reagents were amenable
to this transformation, and the desired products were obtained with excellent yields. Moreover, Sc(OTf)3 proved to be an
effective catalyst for the formation of 1-benzylisoindoline and 1-benzyl-tetrahydroisoquinoline using such nucleophilic
addition.
www.rsc.org/
anticough activities5. Noscapine (3), isolated from Papaver
somniferum L.6 is an antitussive agent7a and displays other
potential clinical utilities7 for the treatment of stroke, anxiety
and cancer. Canadine (4), a protoberberine alkaloid isolated
from Corydalis yanhusuo, can act as a calcium channel
blocker.8 (Figure 1).
Introduction
Benzylisoindoline and benzylisoquinoline scaffolds are widely
served as key intermediates in the synthesis of indole and
isoquinoline alkaloids,1 which are of great pharmaceutical
significance.2 For instance, laudanosine (1), isolated from the
roots of Polyalthia cerasoides,3 and lennoxamine (2), isolated
from barberries species,4 exhibit potent anticancer,
antineuropsychiatric, vasorelaxing, GABA receptor and
From the synthetic point of view, 1-substituted isoindoline was
readily accessible through intramolecular hydroamination of
aminoalkenes,9 Meyers' methodology (from 2, 3-dihydro-1H-
isoindole via metallation and alkylation of its tert-butyl
formamidino derivative),10 and addition-reduction elimination-
reduction of isoindoline-1,3-dione.11 Among them, only the
first method reported the synthesis of 1-benzylisoindoline.
Despite these robust processes, a straightforward and efficient
approach to 1-benzylisoindoline is still in demand. As for 1-
substituted-tetrahydroisoquinoline, recent chemistry efforts
led to a number of powerful approaches including haloamide
cyclization,12 Pictet − Spengler reaction,13 alkylation of
anodically prepared α-amino nitriles,14 de novo BIA cascades,15
Ir-catalyzed hydrogenation of 1-substituted isoquinolines,16
and metal and oxidant free C(sp3)–H functionalization.17
However, some of these methods suffer from harsh reaction
conditions or narrow adaptability, the straightforward and
efficient approach to 1-benzylisoquinoline is still quite limited.
Therefore, the preparation of 1-benzylisoindoline and 1-
benzylisoquinoline is still widely pursued, aiming for effective
approaches under mild conditions.
MeO
O
O
N
N
O
MeO
OMe
OMe
OMe
OMe
Lennoxamine 2
Laudanosine 1
O
O
N
P
O
N
O
O
O
N
O
MeO
OMe
MeO
OMe
In the past decade, slightly functionalized organozinc reagents
have been demonstrated many advantages in modern organic
synthesis.18 In addition to their applications in the synthesis of
natural products, clinical candidates and drugs,19 direct
nucleophilic addition of organozinc reagents were successfully
realized to functional groups like carbonyl,20 nitrones21 and
imine.22 Recently, synthetic chemists also focused on their
reactions with N,O-acetals.23 Our group have successfully
established the approach to 1,4 and 1,5-amino alcohols from
Noscapine 3
Canadine 4
Figure 1. Structures of several natural products.
a
Department of Natural Medicine, School of Pharmacy, Fudan University, 826
Zhangheng Road, Shanghai 201203, China
b Center for Gastrointestinal Endoscopy, Shanxi Provincial People’s Hospital, 29
ShuangTa Road, TaiYuan 030012,China
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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semicyclic N,O-acetals through TMSCl-catalyzed nucleophilic reaction of N,O-acetal with functionalized alkyl zViniecw ArretiaclgeeOnnltinse,
DOI: 10.1039/D0OB01477J
addition with functionalized organozinc reagents (Fig 2, eq could not promote this nucleophilic substitution process (Table
1).23b Subsequently, we developed a stereoselective method to 1, entry 2). It is worth mentioning that when the mixture of 5a
2,6-substituted piperidine skeleton through TiCl4-catalyzed and benzylzinc bromide was stirred at -78 oC to room
nucleophilic substitution (Fig 2, eq 2).23c Herein, we present a temperature for overnight, no desired product 8a was also
practical method to functionalized 1-benzylisoindoline and 1- observed (Table 1, entry 3). To improve the yield of this
benzylisoquinoline skeletons from N,O-acetals 5/6 through nucleophilic process, a variety of Lewis acids were then
.
Sc(OTf)3 catalyzed nucleophilic substitution process with screened. When BF3 OEt2 and TMSOTf were examined, the
functionalized organozinc reagents (Fig 2, eq 3).
yield of 8a was not dramatically increased (Table 1, entries 4-5).
However, both ZnCl2 and Cu(OTf)2 led to the desired 8a, albeit
with low yields (Table 1, entries 6-7). More metal triflates were
subsequently tested. Zn(OTf)2 and In(OTf)2 turned out to be
ineffective, and no desired product 8a was observed (Table 1,
entries 8-9). To our delight, when Sc(OTf)3 was evaluated, the
yield of 8a was significantly improved to 88% (Table 1, entry
10). Then the equivalent of Sc(OTf)3 was examined, and the
results showed reducing the equivalent of Sc(OTf)3 resulted in
significant drop for the yield of 8a (Table 1, entries 11-12).
However, elevated reaction temperature (70 °C) could bring
the yield back to 86% when 0.2 equivalent Sc(OTf)3 was used
(Table 1, entry 13).
Our previous work.23b-c
TMSCl
OH
n
+
FGCH2ZnBr
FG
n
1 N HCl
(1)
(2)
O
NHBoc
NHBoc
31 examples
n = 0, 1; FG = Substituted Aryl, alkyl
OTBS
OTBS
TiCl4
-78oC
+
FGCH2ZnX
FG
HO
N
R
N
R
Boc
Boc
FG = Substituted Aryl, Allyl
This Work
Table 1. Optimization of reaction conditions.
R1
OH
N
O
Bn
N
OH
DIBAL-H
Boc
1
Sc(OTf)3
R2
R2
N
( )n
Boc
(3)
+
R CH2ZnBr
Lewis Acid
Boc
N
Boc
N
Boc
( )n
BnZnBr (7a)
8 (n=1)
9 (n=2)
5 (n=1)
6 (n=2)
7
8a
5a
12a
Entriesa
LA (equiv.)
TMSCl (1)
TiCl4 (2)
--
BF3 OEt2 (2)
TMSOTf (2)
ZnCl2 (1)
Cu(OTf)2 (1)
Zn(OTf)2 (1)
In(OTf)2 (1)
Sc(OTf)3 (1)
Sc(OTf)3 (0.5)
Sc(OTf)3 (0.2)
Sc(OTf)3 (0.2)
Temp/oC
-78
-78
-78~r.t.
-78
Time/h
Y% b
39
NR
NR
52
44
35
65
NR
NR
88
62
19
86
Figure 2. Our strategy to access 1-benzylisoindoline and 1-benzyl-
1
2
3
4
5
6
7
8
9
10
11
12
13
12
12
12
12
12
12
12
12
12
12
12
12
1
tetrahydroisoquinoline scaffolds.
.
Results and discussion
-78
-78
The N,O-acetal substrates 5/6 were readily prepared from
lactams 10/11 through N-Boc protection (Boc2O) and
subsequent reduction (DIBAL-H) (Scheme 1).21 It is worth
mentioning that the reduced products (N,O-acetal) were not
stable and need to be used as soon as possible.
-78~r.t.
-78~r.t.
-78~r.t.
-78~r.t.
-78~r.t.
-78~r.t.
r.t.~70
O
OH
O
a
b
a
R2
R2
R2
Compound 12a (0.5 mmol) was dissolved in dry THF (3 mL) under Ar
N
( )n
Boc
N
( )n
Boc
NH
atmosphere. DIBAL-H (1 M, 1.5 equiv) was dropped slowly. After being
stirred at -78oC for 2 h, the mixture was quenched with EtOAc and
potassium sodium tartrate, and extracted with EtOAc (20 mL×3). The
combined organic layers were washed with brine, dried over MgSO4,
filtrated and concentrated, then obtained the unstable product 5a, which
was quickly uesed in next step without further purification. The above
crude 5a, 7a (2.0 mmol) and LA were dissolved in dry THF (3 mL) at
( )n
12 (n=1)
13 (n=2)
5 (n=1)
6 (n=2)
10 (n=1)
11 (n=2)
Scheme 1. The synthesis of N,O-acetals 5/6. Reagents and conditions: a.
Boc2O, DMAP, THF; b. DIBAL-H, THF, -78 oC.
b
assigned reaction temperature. Isolated yield (two steps). NR = No
Our investigation started with the reaction of reduction 12a to
obtain N,O-acetal 5a. Subsequently, the reaction of N,O-acetal
5a with benzylzinc bromide was explored. Initially, the similar
lewis acid (TMSCl)23b which was used in our previous process
was investigated in the nucleophilic substitution of N,O-acetal
5a with benzylzinc bromide, while the yield of the desired 8a
was very low (Tabele 1 entry 1). The yield of 8a was not
improved obviously after several times of exploration.
Inexplicably, TiCl423c,27, an excellent Lewis acid to catalyzed the
reaction.
With the optimized reaction conditions, we turned to
investigate the scope and limitation of the nucleophilic
addition of organozinc reagents 7 to N,O-acetal 5a. Different
substituted (methyl, fluoro, trifluoromethyl and chloro) benzyl
zinc bromides were surveyed, as summarized in Scheme 2. In
general, all these ortho-, meta- and para- substituted
benzylzinc reagents could smoothly react with 5a, affording
the desired 1-benzylisoindolines 8b-8l in moderate to excellent
2 | J. Name., 2012, 00, 1-3
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Bn
yields (68-95%). It is worth mentioning that cyano and carboxyl
substituted benzylzinc bromides could successfully provide the
products 8m, 8n and 8o in 79%, 90% and 80% yields,
respectively. When 1-naphthalene zinc bromide and 2-
naphthalene zinc bromide were used, the desired products 8p
and 8q were produced in 80% and 62% yields, respectively.
Notably, aliphatic zinc reagents, like n-decylzinc bromide and
ethylzinc bromide could also afford the desired products 8r
and 8s, albeit in low yields. Unfortunately, when ArZnBr and
reformatsky type reagents24 were examined, the reaction is
very complicated and the desired product was not observed.
Bn
Bn
N
View Article Online
DOI: 10.1039/D0OB01477J
Br
N
Boc
N
Boc
Boc
Cl
Br
8da, 91%
8ca, 89%
8ba, 89%
Bn
N
Bn
N
H3CO
Boc
Boc
OCH3
8fa, 84%
8ea, 76%
a
Scheme 3. The reactions of N,O-acetals 5b-5f with benzylzinc bromide.
R1
O
OH
Compound 12b-12f (0.5 mmol) was dissolved in dry THF (3 mL) under Ar
atmosphere. DIBAL-H (1 M, 1.5 equiv) was dropped slowly. After being
stirred at -78oC for 2 h, the mixture was quenched with EtOAc and
potassium sodium tartrate, and extracted with EtOAc (20 mL×3). The
combined organic layers were washed with brine, dried over MgSO4,
filtrated and concentrated, then obtained the unstable product 5b-5f,
which was quickly uesed in next step without further purification. The
above crude 5b-5f, 7a (2.0 mmol) and Sc(OTf)3 (0.1 mmol) were dissolved in
dry THF (3 mL) at r.t.~70 oC for 1 h. b Isolated yield (two steps).
DIBAL-H
Sc(OTf)3
N
Boc
N
Boc
N
Boc
R1CH2ZnBr
7
8a-8s
5a
12a
R1
CN
N
Boc
DIBAL-H
Sc(OTf)3
N
N
N
R1CH ZnBr
N
Boc
N
Boc
Boc
Boc
Boc
2
8a R1=C6H5, 86%
7
O
8b R1=2-MeC6H4, 90%
8c R1=3-MeC6H4, 89%
8d R1=4-MeC6H4, 83%
8e R1=2-FC6H4, 95%
8f R1=3-FC6H4, 84%
8g R1=4-FC6H4, 84%
8h R1=2-CF3C6H4, 77%
8i R1=3-CF3C6H4, 68%
8j R1=4-CF3C6H4, 81%
8k R1=3-ClC6H4, 81%
OH
R1
8l, 84%
8m, 79%
9a-9m
13
6
N
CN
COOEt
N
N
Boc
Boc
Boc
N
Boc
N
Boc
8n, 90%
9a, R=H, 85%
9b, R=Me, 87%
F
9c, 81%
8o, 80%
9d, 74%
R
CF3
Boc
R1
N
N
N
Boc
Boc
N
Boc
N
Boc
N
Boc
8r, R1=C9H19, 30%
8s, R1=CH3,16%
CN
8q, 62%
8p, 80%
Br
9f, 69%
9e, 90%
9g, 71%
a
Scheme 2. Syntheses of 1-substituted isoindolines. Compound 12a (0.5
mmol) was dissolved in dry THF (3 mL) under Ar atmosphere. DIBAL-H (1 M,
1.5 equiv) was dropped slowly. After being stirred at -78oC for 2 h, the
mixture was quenched with EtOAc and potassium sodium tartrate, and
extracted with EtOAc (20 mL×3). The combined organic layers were washed
with brine, dried over MgSO4, filtrated and concentrated, then obtained
the unstable product 5a, which was quickly uesed in next step without
further purification. The above crude 5a, 7 (2.0 mmol) and Sc(OTf)3 (0.1
mmol) were dissolved in dry THF (3 mL) at r.t.~70 oC for 1 h. b Isolated yield
(two steps).
N
N
N
Boc
Boc
Boc
OCF3
F
CF3
9j, 66%
9h, 74%
9i, 72%
Then, the scope and limitation of N,O-acetals was also
explored for this nucleophilic addition with benzylzinc bromide
and the results are summarized in Scheme 3. The N,O-acetals
5b-5f (obtained from reduction of 12b-12f) with different
substituents in benzene ring, including halogen and methoxy,
could smoothly react with benzylzinc bromide to give the
desired products 8ba-8fa in excellent yields.
N
N
N
Boc
Boc
Boc
F
F
O
S
F
O
F
9l, 64%
9m, 75%
9k, 78%
a
Scheme 4. Syntheses of 1-benzyl-tetrahydroisoquinolines. Compound 13
(0.5 mmol) was dissolved in dry THF (3 mL) under Ar atmosphere. DIBAL-H
(1 M, 1.5 equiv) was dropped slowly. After being stirred at -78oC for 2 h, the
mixture was quenched with EtOAc and potassium sodium tartrate, and
extracted with EtOAc (20 mL×3). The combined organic layers were washed
with brine, dried over MgSO4, filtrated and concentrated, then obtained
the unstable product 6, which was quickly uesed in next step without
further purification. The above crude 6, 7 (2.0 mmol) and Sc(OTf)3 (0.1
O
OH
Bn
N
DIBAL-H
Boc
Sc(OTf)3
R2
R2
N
N
Boc
R2
Boc
BnZnBr
7a
12b-12f
5b-5f
8ba-8fa
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mmol) were dissolved in dry THF (3 mL) at r.t.~70 oC for 1 h. b Isolated yield
(two steps).
A possible mechanism for this nucleophilic addition was
illustrated in Figure 3. First, the hydroxyl group in N,O-acetal
View Article Online
DOI: 10.1039/D0OB01477J
5/6 was removed by Sc(OTf)3 catalyst to give iminium
intermediate 15.26 Then, the nucleophilic benzylzinc attacked
the C=N bond in 15 to afford the addition product 8/9 and
release Sc(OTf)3, which went back to participate in the reaction
cycle.
Next, we extended this method to construct 1-benzyl-
tetrahydroisoquinolines. With Sc(OTf)3 as the catalyst, various
benzyl zinc bromides were examined and the results are
summarized in Scheme 4. In general, most substituted benzyl
zinc bromides could react smoothly to afford 1-benzyl-
tetrahydroisoquinolines in moderate to excellent yields (9a-9j).
Difluorobenzylzinc could also react well, and the yield of 2,6-
difluoro-substituted benzyl zinc was slightly higher than that of
3,5-difluoro-substituted (78% for 9k, 64% for 9l), probably due
to different electron cloud distribution. In addition, the
sulfoxide substituted benzyl zinc bromide could also afford the
corresponding product 9m in 75% yield. The chemical
structures of compounds 9a-9m were unambiguously assigned
based on the X-ray crystallographical analysis of compound
9i.25
Conclusions
In summary, we have established a new and practical
approach for the synthesis of 1-benzylisoindolines 8a-8s, 8ba-
8bf and 1-benzyl-tetrahydroisoquinolines 9a-9m through
nucleophilic addition of N,O-acetals 5a-5f, 6 with organozinc
reagents 7. Sc(OTf)3 was found to be an effective catalyst for
this tranformation, and a variety of substituted benzyl groups
were
successfully
introduced
to
isoindoline
and
Finally, we turn our attention to synthesize the laudanosine (1)
through this process (Scheme 5). However, when the 13b was
treated with DIBAL-H to obtain N,O-acetal 6b, which was
quickly uesed to react with freshly prepared (3,4-
dimethoxybenzyl)zinc(II) bromide, the mixture became very
complicated and no product 9n was produced. The N,O-acetal
6 was also examined and the result is still fruitless. We suspect
that the (3,4-dimethoxybenzyl)zinc(II) bromide reagent was
not well formed. Although the (3,4-dimethoxybenzyl)zinc(II)
bromide reagent has been emerged in one literature28, the
result is still negative. Combined with our previous results of
tetrahydroisoquinoline skeletons in moderate to excellent
yields. To the best of our knowledge, the present process is
not only the first direct method using organozinc reagents for
the preparation of 1-benzylisoindolines and 1-benzyl-
tetrahydroisoquinolines, but also the first example
demonstrating that Sc(OTf)3 could catalyze the addition or
substitution reaction of N,O-acetals with organozinc reagents.
Experimental
General
organic zinc reagents23b-d
, we think that the methoxy
General: THF was distilled from sodium/benzophenone, DCM
was distilled from phosphorus pentoxide. Zinc dust was
activated by being stirred for 15 min with HCl (2 N), followed
by washing successively with water, ethyl alcohol, acetone,
and ether. Reactions were monitored by TLC-FID. Flash
chromatography was performed on silica gel (300-400 mesh)
with petroleum/EtOAc as the eluent. HRMS was conducted on
Thermo Scientific LTQ Orbitrap XL apparatus. IR spectra were
measured using a film on a Fourier transform infrared
spectrometer. NMR spectra were recorded at 400 MHz, and
chemical shifts are reported in δ (ppm) referenced to an
substituted benzyl zinc reagents are very special and difficult
for preparation.
MeO
MeO
1. DIBAL-H
2. Sc(OTf)3
N
N
MeO
Boc
MeO
Boc
OMe
OMe
O
MeO
ZnX
9n
13b
MeO
Scheme 5. Syntheses of laudanosine (1).
OH
1
internal TMS standard for H NMR and CDCl3 (77.16 ppm) for
R2
13C{1H} NMR. The heat source was oil bath.The Benzyl zinc
bromide reagents were synthesized according to the known
method.23b
N Boc
( )n
Sc(OTf)3
5/6
General Procedure for the Synthesis of 8 or 9. Compound 12
or 13 (0.5 mmol) was dissolved in dry THF (3 mL) under Ar
atmosphere. DIBAL-H (1 M, 1.5 equiv) was dropped slowly.
After being stirred at -78oC for 2 h, the mixture was quenched
with EtOAc and potassium sodium tartrate, and extracted with
EtOAc (20 mL×3). The combined organic layers were washed
with brine, dried over MgSO4, filtrated and concentrated, then
obtained the unstable product 5 or 6, which was quickly uesed
in next step without further purification. The above crude 5 or
6 and Sc(OTf)3 (0.1 mmol, 49 mg) were dissolved in dry THF (3
mL) under Ar atmosphere. The freshly prepared substituted
benzylzinc bromide reagent (2.0 mL, 1 M in THF) was added
dropwise at room temperature, then stirred at 70oC for 1h.
Sc(OTf)3
HO
Sc(OTf)3
R2
R1
R2
N Boc
( )n
14
N Boc
( )n
8/9
R1CH2ZnBr
R2
N Boc
( )n
Sc(OH)(OTf)3
15
Figure 3. Proposed mechanism of the nucleophilic addition.
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The mixture was quenched with a saturated aqueous solution tert-Butyl 1-(4-methylbenzyl)isoindoline-2-carbVoiexwyAlartticele On8lidne.
DOI: 10.1039/D0OB01477J
of NaHCO3 and extracted with EtOAc (20 mL × 3). The Colourless oil (134 mg, 83%); IR (film): v 2975, 2923, 1698,
max
combined organic layers were washed with brine, dried over 1515, 1394, 1172, 1108, 900, 811, 750 cm-1; 1H NMR (400 MHz,
MgSO4, filtrated and concentrated. The residue was purified by CDCl3, mixture of rotamers) δ 7.23-7.16 (m, 2H), 7.15-7.10 (m,
flash chromatography on silica gel (PE/EA=20:1~5:1) to give 0.55H), 7.06-7.02 (m, 0.45H), 6.99-6.95 (m, 1.45H), 6.95-6.90
the desired product 8 or 9.
(m, 1H), 6.88-6.84 (m, 0.55H), 6.82-6.76 (m, 2H), 5.32-5.17 (m,
1H), 4.63 (d, J = 14.8 Hz, 0.55H), 4.49 (d, J = 14.4 Hz, 0.45H),
4.12 (d, J = 14.8 Hz, 0.55H), 3.97 (d, J = 14.4 Hz, 0.45H), 3.29-
3.15 (m, 1.45H), 3.06-2.99 (m, 0.55H), 2.29-2.24 (m, 3H), 1.59
(s, 4.95H), 1.54 (s, 4.05H) ppm; 13C{1H} NMR (100 MHz, CDCl3,
mixture of rotamers) δ 154.3, 154.2, 140.6, 140.3, 137.4,
137.0, 135.8, 135.6, 134.0, 134.0, 129.9, 129.8, 128.8, 128.5,
127.4, 127.4, 126.9, 126.9, 123.2, 123.0, 122.5, 122.2, 79.9,
79.5, 64.2, 63.9, 52.2, 51.7, 41.0, 39.5, 28.7, 28.7, 21.1 ppm;
tert-Butyl 1-benzylisoindoline-2-carboxylate 8a. Yellow oil
(133 mg, 86%); IR (film): vmax 2974, 2925, 1698, 1454, 1397,
1366, 1172, 1110, 759, 700 cm-1; H NMR (400 MHz, CDCl3,
mixture of rotamers) δ 7.21-7.15 (m, 3H), 7.14-7.09 (m, 2H),
7.07-6.97 (m, 1H), 6.96-6.81 (m, 3H), 5.36-5.31 (m, 0.45H),
5.28-5.20 (m, 0.55H), 4.63 (d, J = 14.8 Hz, 0.55H), 4.49 (d, J =
14.4 Hz, 0.45H), 4.12 (d, J = 14.8 Hz, 0.55H), 3.93 (d, J = 14.8
Hz, 0.45H), 3.36-3.28 (m, 0.45H), 3.26-3.19 (m, 1H), 3.12-3.04
(m, 0.55H), 1.59 (s, 4.95H), 1.54 (s, 4.05H) ppm; 13C{1H} NMR
(100 MHz, CDCl3, mixture of rotamers) δ 154.3, 140.5, 140.2,
1
+
HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C21H26NO2 :
324.1958, found: 324.1958.
137.4, 137.2, 137.1, 137.0, 130.1, 130.0, 128.1, 127.8, 127.5, tert-Butyl 1-(2-fluorobenzyl)isoindoline-2-carboxylate 8e.
127.0, 126.9, 126.4, 126.2, 123.2, 123.0, 122.6, 122.3, 80.0, Colourless oil (156 mg, 95%); IR (film): vmax 2975, 1698, 1492,
1
79.6, 64.1, 63.9, 52.2, 51.7, 41.5, 39.9, 28.8, 28.7 ppm; HRMS 1395, 1366, 1231, 1171, 1111, 955, 754 cm-1; H NMR (400
+
(ESI-Orbitrap) m/z: [M + H]+ Calcd for C20H24NO2 : 310.1802, MHz,CDCl3,mixture of rotamers) δ 7.24-7.09 (m,4H), 6.97-6.84
found: 310.1803.
(m, 4H), 5.41-5.36 (m, 0.38H), 5.33-5.27 (m, 0.62H), 4.69 (d, J
= 14.8 Hz, 0.62H), 4.55 (d, J = 14.8 Hz, 0.38H), 4.25 (d, J = 14.8
Hz, 0.62H), 4.13 (d, J = 14.8 Hz, 0.38H), 3.39-3.32 (m, 0.38H),
3.29-3.20 (m, 1H), 3.16-3.10 (m, 0.62H), 1.54 (s, 9H) ppm;
13C{1H} NMR (100 MHz, CDCl3, mixture of rotamers) δ 161.6 (d,
J = 244.3 Hz), 161.5 (d, J = 244.3 Hz), 162.7, 160.4, 160.3,
154.4, 154.3, 140.3, 139.8, 137.2, 137.0, 132.3, 132.3, 128.3 (d,
J = 7.9 Hz), 128.1 (d, J = 7.9 Hz), 127.6, 127.5, 127.0, 126.9,
124.4 (d, J = 16.0 Hz), 124.3 (d, J = 16.0 Hz), 123.5, 123.5,
123.3, 123.1, 122.5, 122.2, 115.2 (d, J = 22.1 Hz), 115.0 (d, J =
22.2 Hz), 80.0, 79.7, 63.2, 63.1, 52.2, 51.6, 34.8, 33.0, 28.7,
28.6 ppm; 19F NMR (376 MHz, CDCl3, mixture of rotamers) δ -
117.0, -117.1 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd
tert-Butyl 1-(2-methylbenzyl)isoindoline-2-carboxylate 8b.
Yellow oil (146 mg, 90%); IR (film): vmax 2974, 1698, 1463,
1395, 1366, 1171, 1106, 890, 750, 721 cm-1; 1H NMR (400 MHz,
CDCl3, mixture of rotamers) δ 7.27-7.16 (m, 2H), 7.14-7.04 (m,
4H), 6.96-6.91 (m, 1H), 6.57-6.53 (m, 0.4H), 6.50-6.44 (m,
0.6H), 5.35-5.29 (m, 0.4H), 5.26-5.20 (m, 0.6H), 4.78 (d, J = 14.8
Hz, 0.6H), 4.63 (d, J = 14.8 Hz, 0.4H), 4.47 (d, J = 14.8 Hz, 0.6H),
4.34 (d, J = 14.8 Hz, 0.4H), 3.53-3.48 (m, 0.4H), 3.38-3.30 (m,
0.6H), 2.95-2.87 (m, 0.4H), 2.86-2.79 (m, 0.6H), 2.21-2.18 (m,
3H), 1.54 (s, 3.61H), 1.51 (s, 5.42H) ppm; 13C{1H} NMR (100
MHz, CDCl3, mixture of rotamers) δ 154.4, 154.3, 140.6, 140.3,
137.3, 137.2, 136.9, 135.9, 135.8, 131.3, 131.1, 130.3, 130.2,
127.5, 127.4, 126.7, 126.5, 125.8, 125.4, 123.7, 123.4, 122.6,
+
for C20H23FNO2 : 328.1707, found: 328.1705
122.3, 80.1, 79.6, 63.2, 51.8, 51.4, 39.4, 37.9, 28.7, 19.8,19.7 tert-Butyl 1-(3-fluorobenzyl)isoindoline-2-carboxylate 8f.
+
ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C21H26NO2 : Light-Yellow oil (138 mg, 84%); IR (film): vmax 2975, 1698, 1588,
1
324.1958, found: 324.1958.
1488, 1396, 1254, 1172, 1111, 774, 750 cm-1; H NMR (400
MHz, CDCl3, mixture of rotamers) δ 7.25-7.17 (m,2H), 7.17-
7.10 (m, 1H), 7.07-7.02 (m, 1.52H), 6.91-6.90 (m, 0.52H), 6.87-
6.77 (m, 1.52H), 6.74-6.69 (m, 0.48H), 6.64-6.57 (m, 1.52H),
5.37-5.30 (m, 0.52H), 5.27-5.21 (m, 0.48H), 4.65 (d, J = 14.8 Hz,
0.48H), 4.49 (d, J = 14.4 Hz, 0.52H), 4.14 (d, J = 15.2 Hz, 0.48H),
3.95 (d, J = 14.4 Hz, 0.52H), 3.42-3.36 (m, 0.48H), 3.23-3.15 (m,
1H), 3.12-3.06 (m, 0.52H), 1.58 (s, 4.41H), 1.54 (s, 4.59H) ppm;
13C{1H} NMR (100 MHz, CDCl3, mixture of rotamers) δ 162.6 (d,
J = 243.9 Hz), 162.5 (d, J = 243.2 Hz), 154.2, 154.2, 140.1,
139.8, 139.7, 137.3, 136.9, 129.5 (d, J = 8.1 Hz), 129.1 (d, J =
8.1 Hz), 127.7, 127.2, 127.1, 125.7, 125.6, 123.0, 122.9, 122.7,
122.4, 116.9 (d, J = 20.7 Hz), 116.7 (d, J = 20.6 Hz), 113.3 (d, J =
21.5 Hz), 113.1 (d, J = 21.3 Hz), 80.1, 79.7, 63.9, 63.6, 52.2,
51.8, 41.2, 39.6, 28.7, 28.6 ppm; 19F NMR (376 MHz, CDCl3,
mixture of rotamers) δ -114.1 (dd, J = 8.3, 15.4 Hz), -114.7 (dd,
J = 8.3, 15.4 Hz) ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd
tert-Butyl 1-(3-methylbenzyl)isoindoline-2-carboxylate 8c.
Colourless oil (144 mg, 89%); IR (film): vmax 2975, 2923, 1693,
1478, 1394, 1254, 1172, 1110, 772, 750 cm-1; H NMR (400
1
MHz, CDCl3, mixture of rotamers) δ 7.23-7.14 (m, 2H), 7.13-
7.12 (m, 0.52H), 7.09-7.03 (m, 1H), 7.02-6.93 (m, 2H), 6.86-
6.81 (m, 0.48H), 6.78-6.75 (m, 1H), 6.75-6.71 (m, 0.52H), 6.67-
6.62 (m, 0.48H), 5.35-5.27 (m, 0.48H), 5.25-5.20 (m, 0.52H),
4.65 (d, J = 14.8 Hz, 0.52H), 4.49 (d, J = 14.8 Hz, 0.48H), 4.16 (d,
J = 14.8 Hz, 0.52H), 3.97 (d, J = 14.8 Hz, 0.48H), 3.24-3.20 (m,
1H), 3.20-3.18 (m, 0.48H), 3.02-2.95 (m, 0.52H), 2.24-2.19 (m,
3H), 1.58 (s, 4.68H), 1.55 (s, 4.32H) ppm; 13C{1H} NMR (100
MHz, CDCl3, mixture of rotamers) δ 154.2, 154.2, 140.6, 137.5,
137.4, 137.2, 137.1, 137.1, 136.9, 130.9, 130.8, 128.0, 127.6,
127.5, 127.4, 127.1, 126.9, 123.2, 123.1, 122.5, 122.2, 79.9,
79.5, 64.1, 63.9, 52.1, 51.7, 41.5, 39.9, 28.7, 21.4, 21.3 ppm;
HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C21H26NO2 :
324.1958, found: 324.1957.
+
+
for C20H23FNO2 : 348.1707, found: 328.1704.
tert-Butyl 1-(4-fluorobenzyl)isoindoline-2-carboxylate 8g.
Colourless oil (138 mg, 84%); IR (film): vmax 2975, 1698, 1509,
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1
1395, 1366, 1221, 1173, 1110, 825, 750 cm-1; H NMR (400 (m,2H), 7.27-7.22 (m, 2H), 7.15-6.94 (m, 4H), 5.40-5.35 (m,
View Article Online
MHz, CDCl3, mixture of rotamers) δ 7.25-7.18(m,2H), 7.15-7.07 0.53H), 5.31-5.26 (m, 0.47H), 4.64 (d, J =D1O4I:.810H.10z,390/.D407OHB)0,144.7479J
(m, 0.51H), 7.07-7.02 (m, 1H), 6.96-6.90 (m, 0.49H), 6.85-6.77 (d, J = 14.8 Hz, 0.53H), 4.05 (d, J = 14.8 Hz, 0.47H), 3.91 (d, J =
(m, 4H), 5.35-5.29 (m, 0.49H), 5.25-5.20 (m, 0.51H), 4.62 (d, J = 14.8 Hz, 0.53H), 3.50-3.42 (m, 0.53H), 3.25-3.19 (m, 1.47H),
14.8 Hz, 0.51H), 4.48 (d, J = 14.8 Hz, 0.5H), 4.05 (d, J = 14.8 Hz, 1.58 (s, 4.22H), 1.54 (s, 4.78H) ppm; 13C{1H} NMR (100 MHz,
0.49H), 3.90 (d, J = 14.8 Hz, 0.52H), 3.41-3.34 (m, 0.49H), 3.15- CDCl3, mixture of rotamers) δδ 154.3, 154.2, 141.5, 141.4,
3.11 (m, 1.51H), 1.59 (s, 4.51H), 1.54 (s, 4.59H) ppm; 13C{1H} 139.9, 139.7, 137.3, 137.0, 130.4, 130.2, 128.6 (q, J = 32.3 Hz),
NMR (100 MHz, CDCl3, mixture of rotamers) δ 161.7 (d, J = 128.6 (q, J = 32.4 Hz), 127.8, 127.3, 127.2, 125.8, 125.7, 125.0
242.9 Hz), 154.2, 137.4, 131.4,131.3,131.3, 127.6, 127.1, (d, J = 3.2 Hz), 124.7 (d, J = 3.3 Hz), 123.1, 123.0, 122.8, 122.5,
127.0, 122.9 (d, J = 14.9 Hz), 122.5 (d, J = 27.9 Hz), 114.9 (d, J = 80.3, 79.9, 77.5, 77.2, 76.8, 63.9, 63.7, 52.3, 51.8, 41.3, 39.7,
20.7 Hz), 114.6 (d, J = 20.8 Hz), 80.1, 79.7, 64.0, 63.8, 52.3, 28.8, 28.7 ppm; 19F NMR (376 MHz, CDCl3, mixture of
51.8, 40.4, 39.0, 28.8, 28.7 ppm; 19F NMR (376 MHz, CDCl3, rotamers) δ -57.5, -57.6 ppm; HRMS (ESI-Orbitrap) m/z: [M +
+
mixture of rotamers) δ -117.0, -117.4 ppm; HRMS (ESI- H]+ Calcd for C21H23F3NO2 : 378.1675, found: 378.1674.
+
Orbitrap) m/z: [M + H]+ Calcd for C20H23FNO2 : 328.1707,
found: 328.1707.
tert-Butyl 1-(3-chlorobenzyl)isoindoline-2-carboxylate 8k.
Colourless oil (139 mg, 81%); IR (film): vmax 2975, 2928, 1698,
1
tert-Butyl
1-(2-(trifluoromethyl)benzyl)isoindoline-2- 1598, 1477, 1395, 1172, 1078, 961, 807 cm-1; H NMR (400
carboxylate 8h. Colourless oil (145 mg, 77%); IR (film): vmax MHz, CDCl3, mixture of rotamers) δ 7.29-7.18 (m, 2.46H), 7.17-
2978, 1698, 1392, 1314, 1164, 1111, 1060, 1039, 767, 754 cm- 7.09 (m, 2H), 7.07-7.04 (m, 1H), 7.03-6.99 (m, 0.54H), 6.93-
1
1; H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.68-7.67 6.89 (m, 1H), 6.84-6.80 (m, 0.46H), 6.70-6.66 (m, 0.54H), 5.36-
(m, 0.7H), 7.63-7.59 (m, 0.3H), 7.47-7.42 (m, 1.3H), 7.39-7.35 5.29 (m, 0.54H), 5.26-5.21 (m, 0.46H), 4.66 (d, J = 14.8 Hz,
(m, 0.7H), 7.31-7.26 (m, 1H), 7.26-7.21 (m, 1H), 7.20-7.17 (m, 0.46H), 4.49 (d, J = 14.4 Hz, 0.54H), 4.14 (d, J = 14.4 Hz, 0.46H),
1H), 7.15-7.10 (m, 0.7H), 7.07-7.03 (m, 0.3H), 6.73-6.68 (m, 3.92 (d, J = 14.8 Hz, 0.54H), 3.42-3.35 (m, 0.54H), 3.18-3.11 (m,
0.7H), 6.49-6.45 (m, 0.3H), 5.47-5.40 (m, 0.3H), 5.37-5.32 (m, 1H), 3.10-3.04 (m, 0.46H), 1.58 (s, 4.14H), 1.55 (s, 4.86H) ppm;
0.7H), 4.90 (d, J = 15.2 Hz, 0.7H), 4.71 (d, J = 15.2 Hz, 0.3H), 13C{1H} NMR (100 MHz, CDCl3, mixture of rotamers) δ 154.2,
4.63-4.57 (m, 1H), 3.68-3.50 (m, 0.3H), 3.24-3.15 (m, 0.7H), 140.1, 139.8, 139.3, 139.3, 137.4, 137.0, 133.9, 133.6, 130.2,
3.14-3.05 (m, 1H), 1.49 (s, 2.7H), 1.29 (s, 7.3H) ppm; 13C{1H} 130.0, 129.4, 129.0, 128.2, 128.1, 127.8, 127.3, 127.2, 126.7,
NMR (100 MHz, CDCl3, mixture of rotamers) δ154.7, 154.4, 126.5, 123.0, 122.9, 122.7, 122.4, 80.2, 79.8, 63.9, 63.6, 52.3,
141.0, 140.2, 137.0, 133.2, 132.3, 132.3, 131.7, 131.5, 129.4 (q, 51.8, 41.3, 39.5, 28.8, 28.7 ppm; HRMS (ESI-Orbitrap) m/z: [M
+
J = 29.1 Hz), 129.3 (q, J = 29.6 Hz), 127.7 (d, J = 8.4Hz), 126.9 + H]+ Calcd for C20H23ClNO2 : 344.1412, found: 344.1415.
(d, J = 8.6 Hz ), 126.7, 126.5, 126.2, 126.1, 123.3, 123.2, 123.1,
tert-Butyl 1-(4-(tert-butyl)benzyl)isoindoline-2-carboxylate 8l.
122.7, 122.4, 80.0, 79.8, 63.9, 63.8, 51.8, 51.3, 40.1, 38.0, 28.6,
Colourless oil (154 mg, 84%); IR (film): vmax 2964, 2866, 1699,
28.3 ppm; 19F NMR (376 MHz, CDCl3, mixture of rotamers) δ -
1
1464, 1395, 1365, 1173, 1108, 830, 772 cm-1; H NMR (400
58.5, -58.9 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for
MHz, CDCl3, mixture of rotamers) δ 7.24-7.14 (m, 4.6H), 7.09-
7.04 (m, 0.4H), 6.92-6.83 (m, 3H), 5.32-5.28 (m, 0.4H), 5.24-
+
C20H23F3NO2 : 378.1675, found: 378.1677.
tert-Butyl
1-(3-(trifluoromethyl)benzyl)isoindoline-2- 5.19 (m, 0.6H), 4.66 (d, J = 14.8 Hz, 0.6H), 4.52 (d, J = 14.8 Hz,
carboxylate 8i. Colourless oil (128 mg, 68%); IR (film): vmax 0.4H), 4.16 (d, J = 14.8 Hz, 0.6H), 4.02 (d, J = 14.8 Hz, 0.4H),
2977, 1698, 1396, 1367, 1326, 1167, 1124, 1075, 750, 705 cm- 3.27-3.14 (m, 1.4H), 3.04-2.97 (m, 0.6H), 1.56 (s, 5.4H), 1.54 (s,
1
1; H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.44-7.36 3.6H), 1.29-1.26 (m, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3,
(m, 1H), 7.32-7.25 (m, 1H), 7.23-7.15 (m, 2H), 7.13-7.08 (m, mixture of rotamers) δ 154.3, 154.2, 149.2, 149.0, 140.8,
2H), 7.03-6.99 (m, 0.58H), 6.97-6.92 (m, 1H), 5.41-5.35 (m, 140.5, 137.4, 137.0, 134.2, 129.7, 129.6, 127.5, 127.4, 126.9,
0.58H), 5.30-5.25 (m, 0.42H), 4.62 (d, J = 14.8 Hz, 0.42H), 4.45 125.1, 124.7, 123.3, 123.0, 122.5, 122.2, 79.9, 79.5, 64.2, 64.0,
(d, J = 14.8 Hz, 0.58H), 4.01 (d, J = 14.4 Hz, 0.42H), 3.79 (d, J = 52.1, 51.7, 41.2, 39.7, 34.4, 31.5, 28.7 ppm; HRMS (ESI-
+
14.8 Hz, 0.58H), 3.58-3.52 (m, 0.58H), 3.23-3.13 (m, 1.42H), Orbitrap) m/z: [M + H]+ Calcd for C24H32NO2 : 366.2428, found:
1.59 (s, 3.78H), 1.54 (s, 5.22H) ppm; 13C{1H} NMR (100 MHz, 366.2430.
CDCl3, mixture of rotamers) δ154.3, 154.2, 139.5, 138.1, 137.4,
137.0, 133.4, 133.3, 129.4 (q, J = 29.5 Hz), 129.3 (q, J = 29.6
Hz), 128.6, 128.1, 127.9, 127.8, 127.3, 127.2, 126.9 (d, J = 3.2
tert-Butyl 1-(4-cyanobenzyl)isoindoline-2-carboxylate 8m.
Colourless oil (132 mg, 79%); IR (film): vmax 2975, 2929, 2227,
1
1697, 1608, 1394, 1171, 1109, 823, 750 cm-1; H NMR (400
Hz), 126.7 (d, J = 3.4 Hz), 125.6, 125.5, 123.3, 123.1, 123.1,
MHz, CDCl3, mixture of rotamers) δ 7.44-7.36 (m, 2H), 7.27-
122.9, 122.8, 122.7, 122.4, 80.3, 79.9, 63.9, 63.6, 52.3, 51.8,
7.21 (m, 2H), 7.15-7.01 (m, 2H), 6.98-6.93 (m, 2H), 5.40-5.27
(m, 1H), 4.61 (d, J = 15.2 Hz, 0.42H), 4.48 (d, J = 14.4 Hz,
0.58H), 3.98 (d, J = 14.8 Hz, 0.42H), 3.86 (d, J = 14.4 Hz, 0.58H),
3.58-3.47 (m, 0.58H), 3.34-3.25 (m, 0.42H), 3.21-3.13 (m, 1H),
41.3, 39.5, 28.7, 28.6 ppm; 19F NMR (376 MHz, CDCl3, mixture
of rotamers) δ -57.9, -58.0 ppm; HRMS (ESI-Orbitrap) m/z: [M
+
+ H]+ Calcd for C21H23F3NO2 : 378.1675, found: 378.1672.
tert-Butyl
1-(4-(trifluoromethyl)benzyl)isoindoline-2- 1.59 (s, 3.76H), 1.54 (s, 5.22H) ppm; 13C{1H} NMR (100 MHz,
carboxylate 8j. Colourless oil (153 mg, 81%); IR (film): vmax CDCl3, mixture of rotamers) δ 154.1, 153.9, 143.0, 137.1,
2977, 1698, 1617, 1394, 1325, 1288, 1166, 1108, 836, 751 cm- 131.6, 131.4, 130.6, 130.6, 127.8, 127.3, 127.2, 122.7, 122.6,
1
1; H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.43-7.34 122.6, 122.4, 110.2, 110.1, 80.2, 79.8, 63.6, 63.4, 52.2, 51.8,
6 | J. Name., 2012, 00, 1-3
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41.3, 39.8, 28.6, 28.5 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ 1696, 1508, 1395, 1366, 1255, 1169, 1110, 816, V7ie4w7Arcticmle-O1;nlinHe
+
DOI: 10.1039/D0OB01477J
NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.86-7.74 (m,
Calcd for C21H23N2O2 : 335.1754, found: 335.1756.
2H), 7.69-7.65 (m, 1H), 7.61-7.57 (m, 0.50H), 7.45-7.37 (m, 4H),
7.23-7.18 (m, 1H), 7.17-7.14 (m, 0.50H), 7.13-7.09 (m, 1H),
7.04-6.97 (m, 1.50H), 6.87-6.82 (m, 0.50H), 5.47-5.40 (m,
0.50H), 5.36-5.31 (m, 0.50H), 4.65 (d, J = 14.8 Hz, 0.50H), 4.48
(d, J = 14.8 Hz, 0.50H), 4.13 (d, J = 15.2 Hz, 0.50H), 3.91 (d, J =
15.2 Hz, 0.50H), 3.47-3.38 (m, 1H), 3.25-3.16 (m, 1H), 1.61 (s,
4.50H), 1.56 (s, 4.50H) ppm; 13C{1H} NMR (100 MHz, CDCl3,
mixture of rotamers) δ 154.4, 135.0, 134.9, 133.4, 132.2,
128.7, 128.6, 128.2, 128.0, 127.7, 127.6, 127.5, 127.2, 127.1,
127.0, 126.6, 126.0, 125.9, 125.7,125.5, 125.3, 123.2, 123.1,
122.7, 122.4, 80.1, 79.7, 64.2, 64.0, 52.3, 51.8, 41.8, 40.1, 38.2,
28.8, 28.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for
tert-Butyl 1-(2-cyanobenzyl)isoindoline-2-carboxylate 8n.
White solid (150 mg, 90%); m.p. 87-89oC; IR (film): vmax 2975,
1
2224, 1697, 1449, 1392, 1367, 1169, 1110, 957, 762 cm-1; H
NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.63-7.51 (m,
1H), 7.47-7.42 (m, 1H), 7.35-7.27 (m, 2H), 7.24-7.20 (m,2H),
7.18-7.14 (m, 1H), 7.08-7.02 (m, 1H), 5.45-5.39 (m, 1H), 4.76
(d, J = 15.2 Hz, 0.55H), 4.62 (d, J = 14.8 Hz, 0.45H), 4.33-4.25
(m, 1H), 3.50-3.42 (m, 1H), 3.42-3.38 (m, 0.45H), 3.32-3.27 (m,
0.55H), 1.52 (s, 4.05H), 1.46 (s, 4.95H) ppm; 13C{1H} NMR (100
MHz, CDCl3, mixture of rotamers) δ 154.2, 141.5, 141.4, 139.5,
136.8, 133.0, 132.8, 132.6, 132.4, 132.3, 132.2, 130.8, 129.8,
127.8, 127.2, 127.0, 127.0, 126.8, 123.2, 123.0, 122.5, 122.3,
118.0, 113.6, 80.2, 79.8, 63.5, 63.4, 52.0, 51.6, 40.2, 39.0, 35.6,
+
C24H26NO2 : 360.1958, found: 360.1955.
28.5, 28.4 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for tert-Butyl 1-decylisoindoline-2-carboxylate 8r. Light-yellow oil
+
C21H23N2O2 : 335.1754, found: 335.1755.
(54 mg, 30%); IR (film): vmax 2925, 1701, 1464, 1392, 1366,
1
1288, 1255, 1173, 1107, 748 cm-1; H NMR (400 MHz, CDCl3,
tert-Butyl
1-(4-(ethoxycarbonyl)benzyl)isoindoline-2-
mixture of rotamers) δ 7.28-7.15 (m, 4H), 5.15-5.00 (m, 1H),
4.80-4.65 (m, 1H), 4.60-4.50 (m, 1H), 2.17-1.98 (m, 1H), 1.84-
1.69 (m, 1H), 1.52 (s, 9H), 1.30-1.15 (m, 16H), 0.93-0.81 (m,
3H) ppm; 13C{1H} NMR (100 MHz, CDCl3, mixture of rotamers) δ
154.7, 154.4, 141.5, 141.4, 137.2, 136.9, 127.3, 122.7, 122.6,
122.5, 122.4, 79.7, 79.5, 63.1, 52.7, 52.4, 35.4, 34.4, 32.0, 29.9,
29.7, 29.4, 28.7, 23.8, 23.6, 22.8, 14.2 ppm; HRMS (ESI-
Orbitrap) m/z: [M + Na]+ Calcd for C23H37NO2Na+: 382.2717,
found: 382.2713.
carboxylate 8o. Colourless oil (153 mg, 80%); IR (film): vmax
2977, 1718, 1698, 1394, 1275, 1176, 1104, 1022, 761, 709 cm-
1
1; H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.87-7.82
(m, 1H), 7.81-7.77 (m, 1H), 7.25-7.16 (m, 2H), 7.15-7.08 (m,
0.46H), 7.07-7.02 (m, 1H), 7.00-6.95 (m, 1H), 6.95-6.92 (m, 1H),
6.92-6.87 (m, 0.54H), 5.40-5.34 (m, 0.54H), 5.31-5.25 (m,
0.46H), 4.62 (d, J = 14.8 Hz, 0.46H), 4.48 (d, J = 14.4 Hz, 0.54H),
4.37-4.30 (m, 2H), 4.05 (d, J = 14.4 Hz, 0.46H), 3.89 (d, J = 14.8
Hz, 0.54H), 3.50-3.44 (m, 0.54H), 3.26-3.21 (m, 1H), 3.21-3.18
(m, 0.46H), 1.60 (s, 4.14H), 1.55 (s, 4.86H), 1.41-1.34 (m, 3H) tert-Butyl 1-ethylisoindoline-2-carboxylate 8s. Colourless oil
ppm; 13C{1H} NMR (100 MHz, CDCl3, mixture of rotamers) δ (20 mg, 16%); IR (film): vmax 2969, 2875, 1698, 1455, 1393,
166.9, 166.8, 154.3, 154.2, 142.8, 142.6, 140.0, 139.7, 137.3, 1289, 1179, 1113, 876, 746 cm-1;1H NMR (400 MHz, CDCl3,
137.0, 130.1, 130.0, 129.4, 129.1, 128.7, 128.5, 127.8, 127.2, mixture of rotamers) δ 7.21-7.09 (m,4H), 5.10-5.04 (m, 0.42H),
127.1, 123.0, 122.9, 122.7, 122.5, 80.2, 79.8, 63.9, 63.7, 61.0, 5.02-4.95 (m, 0.58H), 4.71 (d, J = 14.8 Hz, 0.58H), 4.63 (d, J =
52.3, 51.8, 41.4, 39.9, 28.8, 28.7, 14.5 ppm; HRMS (ESI- 15.2 Hz, 0.42H), 4.52-4.45 (m, 1H), 2.18-2.01 (m, 1H), 1.84-1.62
+
Orbitrap) m/z: [M + H]+ Calcd for C23H28NO4 : 382.2013, found: (m, 1H), 1.45 (s, 9H),0.66-0.57 (m, 3H) ppm; 13C{1H} NMR (100
382.2013.
MHz, CDCl3, mixture of rotamers) δ 154.7, 154.4, 141.0, 140.9,
137.3, 137.1, 127.4, 127.4, 122.7, 122.6, 122.5, 122.4, 79.7,
79.5, 63.8, 52.9, 52.6, 28.7, 28.1, 27.0, 7.8, 7.7, 1.2 ppm; HRMS
tert-Butyl
1-(naphthalen-1-ylmethyl)isoindoline-2-
carboxylate 8p. Whitefoam (144 mg, 80%); IR (film): vmax 2975,
1695, 1453, 1394, 1366, 1169, 1108, 791, 774, 753 cm-1; H
NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.52-8.48 (m,
+
(ESI-Orbitrap) m/z: [M + H]+ Calcd for C15H22NO2 : 248.1645,
1
found: 248.1641.
0.40H), 8.38-8.31 (m, 0.60H), 7.92-7.82 (m, 1H), 7.80-1.72 (m, tert-Butyl 1-benzyl-4-bromoisoindoline-2-carboxylate 8ba.
1H), 7.57-7.53 (m, 0.40H), 7.52-7.50 (m, 1H), 7.49-7.45 (m, Colourless oil (173 mg, 89%); IR (film): vmax 2975, 1699, 1576,
1
0.60H), 7.39-7.26 (m, 1H), 7.24-7.10 (m, 2H), 7.02-6.94 (m, 2H), 1474, 1394, 1366, 1170, 1111, 776, 701 cm-1; H NMR (400
6.36-6.29 (m, 0.40H), 6.20-6.15 (m, 0.60H), 5.55-5.48 (m, MHz, CDCl3, mixture of rotamers) δ 7.36-7.31 (m, 1H), 7.22-
0.40H), 5.47-5.41 (m, 0.60H), 4.82 (d, J = 14.8 Hz, 0.6H), 4.62 7.13 (m, 3H), 7.09-7.01 (m, 1H), 6.97-6.88 (m, 2H), 6.87-6.83
(d, J = 14.4 Hz, 0.4H), 4.55 (d, J = 14.4 Hz, 0.6H), 4.32 (d, J = (m, 0.50H), 6.72-6.67 (m, 0.50H), 5.42-5.37 (m, 0.5H), 5.32-
14.8 Hz, 0.4H), 4.13-4.07 (m, 0.4H), 3.97-3.91 (m, 0.6H), 3.23- 5.28 (m, 0.5H), 4.66 (d, J = 15.6 Hz, 0.5H), 4.47 (d, J = 15.2 Hz,
2.93 (m, 1H), 1.56 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3, 0.5H), 4.12 (d, J = 15.2 Hz, 0.5H), 3.92 (d, J = 15.2 Hz, 0.5H),
mixture of rotamers) δ 154.4, 136.8, 133.9, 133.8, 133.7, 3.25-3.20 (m, 1.5H), 3.05-2.96 (m, 0.5H), 1.58 (s, 4.49H),
129.1, 128.9, 128.4, 127.5, 127.4, 127.3, 126.5, 126.4, 126.3, 1.55(s, 4.51H) ppm; 13C{1H} NMR (100 MHz, CDCl3, mixture of
125.8, 125.7, 125.6, 125.4, 125.0, 124.4, 124.2, 124.0, 122.5, rotamers) δ 154.0, 142.3, 142.1, 138.1, 137.8, 136.7, 130.5,
122.3, 80.5, 79.7, 63.1, 62.8, 51.9, 51.5, 40.2, 38.4, 28.8 ppm; 130.5, 130.0, 129.8, 128.9, 128.8, 128.3, 128.0, 126.7, 126.5,
+
HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C24H26NO2 : 122.0, 121.9, 117.4, 117.1, 80.2, 80.0, 65.2, 65.0, 53.4, 53.1,
360.1958, found: 360.1959.
41.6, 40.1, 28.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd
for C20H23BrNO2 : 388.0907, 390.0886, found: 388.0907,
390.0886.
+
tert-Butyl
1-(naphthalen-2-ylmethyl)isoindoline-2-
carboxylate 8q. Whitefoam (111 mg, 62%); IR (film): vmax 2974,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Organic & Biomolecular Chemistry
Page 8 of 11
ARTICLE
Journal Name
tert-Butyl 1-benzyl-6-bromoisoindoline-2-carboxylate 8ca. 5.13H), 1.54 (s, 3.87H) ppm; 13C{1H} NMR (100VMiewHAzrt,iclCe DOnCliln3e,
Colourless oil (173 mg, 89%); IR (film): vmax 2975, 1698, 1476, mixture of rotamers) δ 159.0, 158.9, D1O5I4: 1.02.,101394/1D.09O, B1041417.76J,
1
1454, 1396, 1366, 1168, 1112, 812, 701 cm-1; H NMR (400 137.3, 137.2, 130.1, 130.0, 128.2, 127.9, 126.5, 126.3, 123.2,
MHz, CDCl3, mixture of rotamers) δ 7.34-7.29 (m, 1H), 7.18- 123.0, 114.2, 114.0, 108.1, 108.0, 79.9, 79.5, 64.3, 64.0, 55.4,
7.17 (m, 1H), 7.16-7.11 (m, 2H), 7.02-6.97 (m, 1H), 6.97-6.84 51.6, 51.2, 41.5, 40.0, 28.7, 28.7 ppm; HRMS (ESI-Orbitrap)
+
(m, 3H), 5.31-5.27 (m, 0.43H), 5.23-5.17 (m, 0.57H), 4.55 (d, J = m/z: [M + H]+ Calcd for C21H26NO3 : 340.1907, found:
15.2 Hz, 0.57H), 4.41 (d, J = 14.8 Hz, 0.43H), 4.00 (d, J = 14.8 340.1905.
Hz, 0.57H), 3.83 (d, J = 14.8 Hz, 0.43H), 3.36-3.30 (m, 0.44H),
tert-Butyl
1-benzyl-3,4-dihydroisoquinoline-2(1H)-
3.18-3.14 (m, 1H), 3.11-3.04 (m, 0.57H), 1.58 (s, 5.13H), 1.54
(s,3.87H) ppm; 13C{1H} NMR (100 MHz, CDCl3, mixture of
rotamers) δ 154.0, 142.8, 142.5, 136.6, 136.5, 136.4, 136.1,
130.6, 130.0, 129.9, 128.2, 127.9, 126.6, 126.4, 126.3, 126.2,
124.1, 123.8, 120.7, 120.6, 80.2, 79.8, 63.8, 63.6, 51.8, 51.4,
41.3, 39.8, 28.7, 28.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+
carboxylate 9a. Whitefoam (137 mg, 85%); IR (film): vmax2973,
1
2927, 1690, 1417, 1390, 1364, 1164, 1118, 753cm-1; H NMR
o
(400 MHz, DMSO-d6, 80 C) δ 7.50-6.90 (m, 9H), 5.36-5.14 (m,
1H), 3.94 (brs, 1H), 3.36-3.26 (m, 1H), 3.07-3.02 (m, 2H), 2.84-
2.66 (m, 2H), 1.26 (s, 9H) ppm; 1H NMR (400 MHz, CDCl3,
mixture of rotamers) δ 7.31-7.26 (m, 1H), 7.25-7.23 (m, 0.7H),
7.23-7.19 (m, 1H), 7.19-7.11 (m, 4H), 7.11-7.03 (m, 2H), 6.91-
6.86 (m, 0.3H), 5.37 (dd, J = 7.2, 6.4 Hz, 0.3H), 5.22 (dd, J = 8.4,
+
Calcd for C20H23BrNO2 : 388.0907, 390.0886, found: 388.0901,
390.0880.
tert-Butyl 1-benzyl-5-chloroisoindoline-2-carboxylate 8da. 5.6 Hz, 0.7H), 4.25-4.17 (m, 0.7H), 3.83-3.75 (m, 0.3H), 3.37-
Colourless oil (156 mg, 91%); IR (film): vmax2976, 1697, 1478, 3.33 (m, 0.3H), 3.32-3.24 (m, 0.7H), 3.09-2.97 (m, 2H), 2.97-
1394, 1258, 1169, 1076, 865, 738, 701 cm-1; 1H NMR (400 MHz, 2.87 (m, 0.7H), 2.84-2.76 (m, 0.3H), 2.74-2.67 (m, 0.7H), 2.65-
CDCl3, mixture of rotamers) δ 7.19-7.12 (m, 4H), 7.11-6.98 (m, 2.57 (m, 0.3H), 1.40 (s, 2.7H), 1.21 (s, 6.3H) ppm; 13C{1H} NMR
1H), 6.93-6.72 (m, 3H), 5.31-5.23 (m, 0.47H), 5.22-5.15 (m, (100 MHz, CDCl3, mixture of rotamers) δ 154.7, 154.6, 138.7,
0.53H), 4.60 (d, J = 14.8 Hz, 0.53H), 4.45 (d, J = 14.8 Hz, 0.47H), 138.4, 137.2, 137.1, 134.9, 134.7, 129.8, 129.2, 128.5, 128.4,
4.09 (d, J = 14.8 Hz, 0.53H), 3.91 (d, J = 14.8 Hz, 0.47H), 3.31- 128.2, 127.7, 127.3, 126.8, 126.7, 126.5, 126.3, 126.0, 79.7,
3.24 (m, 0.43H), 3.24-3.16 (m, 1H), 3.08-3.00 (m, 0.57H), 1.59 79.6, 56.9, 55.8, 43.1, 42.9, 39.4, 37.0, 28.8, 28.7, 28.5, 28.2
(s, 4.77H), 1.54 (s, 4.23H) ppm; 13C{1H} NMR (100 MHz, CDCl3, ppm; HRMS (ESI-Orbitrap) m/z: [M
mixture of rotamers) δ 154.0, 139.3, 139.0, 138.9, 138.7, C21H25NO2Na+: 346.1778, found: 346.1776.
136.8, 136.7, 133.4, 133.3, 130.0, 129.9, 128.2, 128.0, 127.3,
+
Na]+ Calcd for
tert-Butyl 1-(3-methylbenzyl)-3,4-dihydroisoquinoline-2(1H)-
carboxylate 9b. Whitefoam (147 mg, 87%); IR (film): vmax2974,
127.2, 126.6, 126.4, 124.3, 124.2, 122.8, 122.5, 80.2, 79.8,
63.7, 63.5, 51.8, 51.4, 41.3, 39.8, 28.7, 28.6 ppm; HRMS (ESI-
2927, 1692, 1418, 1365, 1165, 1119, 770, 699 cm-1; H NMR
(400 MHz, CDCl3, mixture of rotamers) δ 7.19-6.98 (m, 6H),
6.95-6.83 (m, 2H), 5.35 (dd, J = 7.2, 6.4 Hz, 0.28H), 5.21 (dd, J =
1
+
Orbitrap) m/z: [M + H]+ Calcd for C20H23ClNO2 : 344.1412,
found: 344.1412.
tert-Butyl 1-benzyl-4-methoxyisoindoline-2-carboxylate 8ea. 8.8, 5.2 Hz, 0.72H), 4.26-4.17 (m, 0.72H), 3.85-3.75 (m, 0.28H),
Colourless oil (129 mg, 76%); IR (film): vmax 2973, 1697, 1615, 3.38-3.35 (m, 0.28H), 3.33-3.25 (m, 0.72H), 3.07-2.96 (m, 2H),
1
1489, 1441, 1396, 1297, 1111, 775, 701 cm-1; H NMR (400 2.95-2.87 (m, 0.72H), 2.84-2.77 (m, 0.28H), 2.75-2.68 (m,
MHz, CDCl3, mixture of rotamers) δ 7.21-7.10 (m, 4H), 6.99- 0.72H), 2.66-2.58 (m, 0.28H), 2.32 (s, 2H), 2.28 (s, 1H), 1.41 (s,
6.90 (m, 2H), 6.72-6.65 (m, 1H), 6.60-6.53 (m, 0.55H), 6.46- 2.52H), 1.20 (s, 6.48H) ppm ; 13C{1H} NMR (100 MHz, CDCl3,
6.40 (m,0.45H), 5.35-5.27 (m, 0.55H), 5.25-5.19 (m,0.55H), mixture of rotamers) δ 154.8, 154.6, 138.7, 138.3, 137.8,
4.62 (d, J = 14.8 Hz, 0.45H), 4.47 (d, J = 14.8 Hz, 0.55H), 4.08 (d, 137.6, 137.4, 137.2, 134.8, 134.7, 130.6, 130.5, 129.2, 128.5,
J = 14.8 Hz, 0.45H), 3.92 (d, J = 14.8 Hz, 0.55H), 3.77 (s, 3H), 128.4, 128.0, 127.8, 127.4, 127.2, 127.1, 126.9, 126.8, 126.7,
3.27-3.20 (m, 1.55H), 3.07-3.00 (m, 0.45H), 1.58 (s, 4.05H), 126.6, 126.0, 125.9, 79.6, 57.0, 55.9, 43.1, 42.8, 39.5, 37.0,
1.54 (s, 4.95H) ppm; 13C{1H} NMR (100 MHz, CDCl3, mixture of 28.8, 28.7, 28.6, 28.2, 21.5 ppm; HRMS (ESI-Orbitrap) m/z: [M
+
rotamers) δ 154.7, 154.4, 154.3, 142.3, 142.1, 137.3, 130.1, + Na]+ Calcd for C22H27NO2Na : 360.1934, found: 360.1936.
130.0, 128.7, 128.6, 128.2, 127.9, 126.4, 126.3, 125.5, 125.2,
115.5, 115.2, 108.9, 108.7, 79.9, 79.6, 64.7, 64.4, 55.4, 55.3,
tert-Butyl 1-(2-fluorobenzyl)-3,4-dihydroisoquinoline-2(1H)-
carboxylate 9c. Whitefoam (138 mg, 81%); IR (film): vmax 2975,
50.2, 49.8, 41.5, 40.0, 28.8, 28.7 ppm; HRMS (ESI-Orbitrap)
1
2929, 1692, 1492, 1419, 1365, 1230, 1164, 1120, 754 cm-1; H
+
m/z: [M + H]+ Calcd for C21H26NO3 : 340.1907, found:
NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.24-7.21 (m,
1H), 7.20-7.18 (m, 2H), 7.17-7.12 (m, 2H), 7.09-6.99 (m, 3H),
340.1908.
tert-Butyl 1-benzyl-6-methoxyisoindoline-2-carboxylate 8fa. 5.45 (dd, J = 8.8, 5.6 Hz, 0.24H), 5.34 (dd, J = 10.4, 4.0 Hz,
Colourless oil (143 mg, 84%); IR (film): vmax2974, 1697, 1498, 0.76H), 4.33-4.25 (m, 0.76H), 3.95-3.87 (m, 0.24H), 3.46-3.40
1398, 1271, 1207, 1170, 1109, 881, 772 cm-1;1H NMR (400 (m, 0.24H), 3.35-3.26 (m, 0.76H), 3.20-3.13 (m, 1H), 3.09-3.03
MHz, CDCl3, mixture of rotamers) δ 7.20-7.13 (m, 3H), 7.03- (m, 0.24H), 3.02-2.97 (m, 0.76H), 2.96-2.91 (m, 0.76H), 2.86-
6.93 (m, 3H), 6.77-6.73 (m, 1H), 6.45-6.40 (m, 0.47H), 6.33- 2.80 (m, 0.24H), 2.77-2.67 (m, 1H), 1.33 (s, 2.16H), 1.15 (s,
6.28 (m, 0.53H), 5.31-5.24 (m, 0.47H), 5.21-5.16 (m, 0.53H), 6.84H) ppm; 13C{1H} NMR (100 MHz, CDCl3, mixture of
4.57 (d, J = 14.4 Hz, 0.53H), 4.43 (d, J = 14.0 Hz, 0.47H), 4.09 (d, rotamers) δ 161.9 (d, J = 243.4 Hz), 161.8 (d, J = 241.5 Hz),
J = 14.0 Hz, 0.53H), 3.92 (d, J = 14.0 Hz, 0.47H), 3.72-3.68 (m, 154.6, 154.5, 137.3, 134.8, 132.1, 132.1, 129.3, 128.4, 128.3,
3H), 3.26-3.21 (m, 1.47H), 3.05-2.96 (m, 0.53H), 1.59 (s, 127.5, 127.4, 126.9, 126.8, 126.2, 126.1, 124.1, 123.8, 115.4,
8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
115.1, 79.6, 79.5, 55.3, 54.7, 38.9, 36.6, 36.4, 35.6, 28.9, 28.7, 79.5, 79.3, 55.5, 55.3, 40.1, 40.0, 39.6, 36.5, 28.7, 28.5, 27.6
View Article Online
28.5, 28.1 ppm; 19F NMR (376 MHz, CDCl3, mixture of ppm; HRMS (ESI-Orbitrap) m/z: [MDOI: 10.1039/D0OB01477J
+
Na]+ Calcd for
+
rotamers) δ -118.5, -118.6 ppm; HRMS (ESI-Orbitrap) m/z: [M C25H27NO2Na : 396.1934, found: 396.1932.
+
+ Na]+ Calcd for C21H24FNO2Na : 364.1683, found: 364.1684.
tert-Butyl 1-(3-bromobenzyl)-3,4-dihydroisoquinoline-2(1H)-
tert-Butyl
1-(3-(trifluoromethyl)benzyl)-3,4- carboxylate 9g. Whitefoam (143 mg, 71%); IR (film): vmax2973,
1
dihydroisoquinoline-2(1H)-carboxylate 9d. Whitefoam (145 2928, 1690, 1418, 1365, 1243, 1162, 1118, 762cm-1; H NMR
mg, 74%); IR (film): vmax 2976, 2931, 1692, 1452, 1418, 1366, (400 MHz, CDCl3, mixture of rotamers) δ 7.38-7.35 (m, 0.68H),
1330, 1164, 1123, 1074, 960, 749, 702cm-1; 1H NMR (400 MHz, 7.35-7.29 (m, 1H), 7.21-7.14 (m, 3H), 7.14-7.05 (m, 2H), 7.05-
CDCl3, mixture of rotamers) δ 7.53-7.25 (m, 4H), 7.21-7.08 (m, 7.01 (m, 1H), 6.92-6.86 (m, 0.32H), 5.34 (dd, J = 7.2, 6.4 Hz,
3H), 7.07-7.00 (m, 0.64H), 6.93-6.86 (m, 0.36H), 5.37 (dd, J = 0.32H), 5.21 (dd, J = 8.4, 6.0 Hz, 0.68H), 4.29-4.17 (m, 0.68H),
7.2, 6.4 Hz, 0.36H), 5.21 (dd, J = 8.4, 5.6 Hz, 0.64H), 4.28-4.12 3.85-3.75 (m, 0.32H), 3.39-3.32 (m, 0.32H), 3.31-3.22 (m,
(m, 0.64H), 3.85-3.72 (m, 0.36H), 3.38-3.27 (m, 1H), 3.15-3.03 0.68H), 3.05-2.97 (m, 2H), 2.96-2.87 (m, 0.68H), 2.86-2.77 (m,
(m, 2H), 3.02-2.77 (m, 1H), 2.76-2.69 (m, 0.64H), 2.64-2.55 (m, 0.32H), 2.76-2.68 (m, 0.68H), 2.67-2.59 (m, 0.32H), 1.41 (s,
0.36H), 1.39 (s, 3.24H), 1.20 (s, 5.76H) ppm; 13C{1H} NMR (100 2.88H), 1.23(s, 6.12H) ppm; 13C{1H} NMR (100 MHz, CDCl3,
MHz, CDCl3, mixture of rotamers) δ 154.8, 154.4, 139.7, 139.3, mixture of rotamers) δ 154.8, 154.4, 141.2, 140.8, 136.9,
136.7, 134.9, 134.7, 133.2, 130.8 (q, J = 31.6 Hz), 129.3, 128.9, 136.8, 134.8, 134.7, 132.8, 132.7, 130.0, 129.7, 129.6, 129.5,
128.7, 128.6, 127.5, 127.3, 127.1, 127.0, 126.5, 126.4, 126.2, 129.3, 128.7, 128.5, 127.6, 127.3, 127.0, 126.9, 126.1, 122.5,
125.7, 123.4 (d, J = 3.3 Hz), 123.2 (d, J = 3.0 Hz), 79.9, 56.8, 122.2, 79.9, 79.8, 56.7, 55.6, 42.8, 42.5, 39.5, 37.0, 28.8, 28.6,
55.6, 43.0, 42.6, 39.5, 37.2, 28.7, 28.6, 28.4, 28.1 ppm; 19F 28.5, 28.2 ppm; HRMS (ESI-Orbitrap) m/z: [M + Na]+ Calcd for
+
NMR (376 MHz, CDCl3) δ -62.5 ppm; HRMS (ESI-Orbitrap) m/z: C21H24BrNO2Na : 424.0883, 426.0862, found: 424.0881,
+
[M
+
Na]+ Calcd for C22H24F3NO2Na : 414.1651, found: 426.0861.
414.1650.
tert-Butyl 1-(4-fluorobenzyl)-3,4-dihydroisoquinoline-2(1H)-
tert-Butyl 1-(4-cyanobenzyl)-3,4-dihydroisoquinoline-2(1H)- carboxylate 9h. Whitefoam (126 mg, 74%); IR (film): vmax2974,
carboxylate 9e. Whitefoam (157 mg, 90%); IR (film): vmax2974, 2929, 1690, 1509, 1417, 1365, 1222, 1163, 1119, 958, 749cm-1;
2929, 1688, 1418, 1365, 1245, 1163, 1120, 750cm-1;1H NMR 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.21-7.13 (m,
(400 MHz, CDCl3, mixture of rotamers) δ 8.02-7.98 (m, 0.58H), 2H), 7.13-7.08 (m, 1H), 7.08-6.98 (m, 3H), 6.97-6.87 (m, 2H),
7.87-7.83 (m, 0.42H), 7.58-7.57 (m, 0.58H), 7.53-7.52 (m, 5.32 (dd, J = 7.2, 6.4 Hz, 0.35H), 5.17(dd, J = 8.0, 6.0 Hz, 0.65H),
0.42H), 7.25-7.18 (m, 3H), 7.16-7.12 (m, 1H), 7.08-7.01 (m, 4.25-4.11 (m, 0.65H), 3.84-3.73 (m, 0.35H), 3.39-3.31 (m,
0.58H), 6.93-6.87 (m, 0.42H), 5.37 (dd, J = 7.2, 6.4 Hz, 0.42H), 0.35H), 3.29-3.20 (m, 0.65H), 3.07-2.97 (m, 2H), 2.96-2.87 (m,
5.21 (dd, J = 8.4, 5.6 Hz, 0.58H), 4.25-4.11 (m, 0.58H), 3.85- 0.65H), 2.84-2.76 (m, 0.35H), 2.72-2.65 (m, 0.65H), 2.64-2.57
3.74 (m, 0.42H), 3.41-3.33 (m, 0.42H), 3.31-3.22 (m, 0.58H), (m, 0.35H), 1.41 (s, 3.15H), 1.25 (s, 5.85H) ppm; 13C{1H} NMR
3.16-3.06 (m, 2H), 2.97-2.88 (m, 0.58H), 2.86-2.78 (m, 0.42H), (100 MHz, CDCl3, mixture of rotamers) δ 161.9 (d, J = 242.8 Hz),
2.74-2.62 (m, 1H), 1.39 (s, 3.78H), 1.23 (s, 5.22H) ppm; 13C{1H} 161.8 (d, J = 242.3 Hz), 154.8, 154.6, 136.9, 134.9, 134.7, 134.4
NMR (100 MHz, CDCl3, mixture of rotamers) δ 190.7, 154.8, (d, J = 5.8 Hz), 134.1 (d, J = 3.0 Hz), 131.2, 131.1, 129.2, 128.6,
154.3, 144.4, 144.1, 138.9, 136.7, 136.3, 134.9, 134.6, 133.0, 127.6, 127.3, 126.9, 126.8, 126.1, 115.2 (d, J = 21.0 Hz), 114.9
132.2, 131.9, 130.6, 130.0, 129.4, 128.8, 127.4, 127.2, 126.2, (d, J = 21.1 Hz), 79.8, 79.7, 56.9, 55.9, 42.2, 42.0, 39.5, 37.2,
119.2, 119.0, 117.8, 117.7, 110.4, 110.3, 80.1, 80.0, 56.5, 55.6, 28.8, 28.6, 28.5, 28.3 ppm; 19F NMR (376 MHz, CDCl3, mixture
43.2, 43.1, 39.5, 37.3, 28.7, 28.5, 28.5, 28.3 ppm; HRMS (ESI- of rotamers) δ -116.9, -117.1 ppm; HRMS (ESI-Orbitrap) m/z:
+
+
Orbitrap) m/z: [M + Na]+ Calcd for C22H24N2O2Na : 371.1730, [M + Na]+ Calcd for C21H24FNO2Na : 364.1683, found: 364.1681.
found: 371.1726.
tert-Butyl
1-(4-(trifluoromethyl)benzyl)-3,4-
tert-Butyl
1-(naphthalen-1-ylmethyl)-3,4- dihydroisoquinoline-2(1H)-carboxylate 9i. White solid (141
o
dihydroisoquinoline-2(1H)-carboxylate 9f. Whitefoam (129 mg, 72%); m.p. 109-111 C. IR (film): vmax 2976, 2931, 1692,
mg, 69%); IR (film): vmax 2975, 2931, 1688, 1453, 1420, 1240, 1418, 1366, 1325, 1245, 1165, 1123, 1067, 752cm-1; H NMR
1
1166, 1120, 778, 757 cm-1; H NMR (400 MHz, CDCl3, mixture (400 MHz, CDCl3, mixture of rotamers) δ 7.57-7.42 (m, 2H),
1
of rotamers) δ 9.29-8.23 (m, 1H), 7.89-7.86 (m, 0.8H), 7.82- 7.27-7.24 (m, 1H), 7.23-7.11 (m, 4H), 7.10-7.07 (m, 0.63H),
7.80 (m, 0.2H), 7.76-7.74 (m, 0.8H), 7.71-7.67 (m, 0.2H), 7.61- 6.97-6.88 (m, 0.37H), 5.39 (dd, J = 10.8, 6.4 Hz, 0.37H), 5.22
7.52 (m, 1H), 7.52-7.47 (m, 1H), 7.40-7.32 (m, 1H), 7.25-7.16 (dd, J = 8.4, 5.6 Hz, 0.63H), 4.30-4.17 (m, 0.63H), 3.87-3.74 (m,
(m, 3.8H), 7.14-7.12 (m, 0.8H), 6.95-6.90 (m, 0.2H), 6.60 (d, J 0.37H), 3.39-3.23 (m, 1H), 3.16-3.04 (m, 2H), 2.98-2.89 (m,
=7.6Hz, 0.2H), 5.56-5.51 (m, 0.2H), 5.51-5.47 (m, 0.8H), 3.72- 0.63H), 2.86-2.79 (m, 0.37H), 2.76-2.68 (m, 0.63H), 2.67-2.60
3.66 (m, 0.2H), 3.64-3.57 (m, 1H), 3.48-3.42 (m, 1H), 3.40-3.30 (m, 0.37H), 1.37 (s, 3.33H), 1.18 (s, 5.67H) ppm; 13C{1H} NMR
(m, 1H), 3.02-2.93 (m, 0.8H), 2.83-2.76 (m, 1H), 2.67-2.59 (m, (100 MHz, CDCl3, mixture of rotamers) δ 154.7, 154.4, 142.9,
0.2H), 1.41 (s, 1.8H), 0.76 (s, 7.2H) ppm; 13C{1H} NMR (100 142.5, 136.7, 134.9, 134.6, 130.1, 129.5, 129.4, 129.0 (q, J =
MHz, CDCl3, mixture of rotamers) δ 154.9, 154.4, 137.5, 136.9, 32.7 Hz), 128.8, 128.8, 128.5,127.5, 127.2, 127.0, 126.9, 126.2,
134.7, 134.6, 134.0, 133.8, 132.8, 132.5, 129.4, 129.1, 128.6, 125.4 (d, J = 3.4 Hz), 125.5 (d, J = 3.3 Hz) , 80.0, 79.8, 56.7,
128.2, 128.2, 128.1, 127.9, 127.4, 127.2, 127.1, 126.8, 126.7, 55.5, 42.9, 42.7, 39.4, 37.1, 28.8, 28.6, 28.5, 28.2 ppm; 19F
126.2, 126.1, 125.8, 125.7, 125.6, 125.5, 125.2, 124.3, 123.6, NMR (376 MHz, CDCl3, mixture of rotamers) δ -62.3, -62.4
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
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Organic & Biomolecular Chemistry
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Journal Name
ppm; HRMS (ESI-Orbitrap) m/z: [M
C22H24F3NO2Na : 414.1651, found: 414.1651.
+
Na]+ Calcd for tert-Butyl
1-(4-(methylsulfonyl)benzyl)-3,4-
View Article Online
DOI: 10.1039/D0OB01477J
+
dihydroisoquinoline-2(1H)-carboxylate 9m. Whitefoam (151
mg, 75%); IR (film): vmax 2974, 2928, 1687, 1418, 1303, 1150,
1091, 957, 759cm-1; 1H NMR (400 MHz, CDCl3, mixture of
rotamers) δ 7.89-7.85 (m, 1H), 7.84-7.77 (m, 1H), 7.36-7.33 (m,
1H), 7.33-7.27 (m, 1H), 7.21-7.11 (m, 3H), 7.07-6.92 (m, 1H),
5.40 (dd, J = 7.2, 6.4Hz, 0.44H), 5.25 (dd, J = 6.4, 5.6 Hz, 0.56H),
4.25-4.16 (m, 0.56H), 3.87-3.78 (m, 0.44H), 3.40-3.25 (m, 1H),
3.18-3.11 (m, 2H), 3.04-3.01 (m, 3H), 2.96-2.79 (m, 1H), 2.76-
2.63 (m, 1H), 1.38 (s, 3.96H), 1.22 (s, 5.04H) ppm; 13C{1H} NMR
(100 MHz, CDCl3, mixture of rotamers) δ 154.7, 154.3, 145.3,
145.1, 138.9, 138.5, 136.3, 134.8, 134.6, 130.7, 129.3, 128.8,
127.5, 127.3, 127.2, 127.1, 127.0, 126.2, 79.9, 79.8, 56.5, 55.5,
tert-Butyl
1-(4-(trifluoromethoxy)benzyl)-3,4-
dihydroisoquinoline-2(1H)-carboxylate 9j. Whitefoam (134
mg, 66%); IR (film): vmax2975, 2930, 1692, 1418, 1366, 1260,
1163, 1120, 754cm-1; 1H NMR (400 MHz, CDCl3, mixture of
rotamers) δ 7.21-7.16 (m, 2H), 7.16-7.13 (m, 3H), 7.13-7.09 (m,
2H), 7.09-7.06 (m, 0.66H), 6.95-6.91 (m, 0.34H), 5.37 (dd, J =
7.6, 6.8 Hz, 0.34H), 5.20 (dd, J = 8.4, 5.6 Hz, 0.66H), 4.27-4.19
(m, 0.66H), 3.86-3.78 (m, 0.34H), 3.38-3.34 (m, 0.36H), 3.31-
3.23 (m, 0.64H), 3.09-3.01 (m, 2H), 2.98-2.91 (m, 0.64H), 2.85-
2.78 (m, 0.36H), 2.75-2.67 (m, 0.64H), 2.64-2.59 (m, 0.36H),
1.37 (s, 3.06H), 1.20 (s, 5.94H) ppm; 13C{1H} NMR (100 MHz,
CDCl3, mixture of rotamers) δ 154.7, 154.5, 148.1, 148.0,
137.6, 137.2, 136.9, 134.9, 134.6, 131.0, 129.3, 128.7, 127.5,
127.3, 127.0, 126.9, 126.2, 121.1, 120.7, 120.6 (q, J = 255.1
Hz), 119.4, 79.9, 79.8, 56.8, 55.6, 42.4, 42.2, 39.3, 37.0, 28.8,
28.6, 28.4, 28.2 ppm; 19F NMR (376 MHz, CDCl3, mixture of
rotamers) δ -110.6, -111.0 ppm; HRMS (ESI-Orbitrap) m/z:[M +
44.6, 43.0, 42.8, 39.4, 37.2, 28.7, 28.5, 28.4, 28.2 ppm; HRMS
(ESI-Orbitrap) m/z:[M
424.1553, found: 424.1551.
+
+
Na]+ Calcd for C22H27NO4SNa :
Acknowledgements
+
Na]+ Calcd for C22H24F3NO3Na : 430.1601, found: 430.1600.
We thank the National Natural Science Foundation of China
(21702032 to C.-M. Si and 21772027 to B.-G. Wei) and the
Open Research Fund Program of Beijing Key Lab of Plant
Resource Research and Development, BTBU (No. PRRD-2019-
YB2) for financial support. The authors also thank Dr. Han-Qing
Dong (Arvinas, Inc.) for helpful suggestions.
tert-Butyl
1-(2,6-difluorobenzyl)-3,4-dihydroisoquinoline-
2(1H)-carboxylate 9k. Whitefoam (140 mg, 78%); IR (film): vmax
2976, 2931, 1694, 1469, 1419, 1366, 1166, 1119, 1029, 781,
747cm-1; 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ
7.24-7.17 (m, 4H), 7.17-7.09 (m, 1H), 6.90-6.79 (m, 2H), 5.52
(dd, J= 5.6, 4.8 Hz, 0.24H), 5.38 (dd, J= 10.8, 4 Hz, 0.76H), 4.32-
4.23 (m, 0.76H), 4.15-3.95 (m, 0.24H), 3.50-3.43 (m, 0.24H),
3.42-3.31 (m, 0.76H), 3.25-3.13 (m, 1H), 3.11-3.01 (m, 1H),
3.00-2.91 (m, 0.76H), 2.90-2.82 (m, 0.24H), 2.79-2.71 (m, 1H),
1.28 (s, 2.16H), 1.15 (s, 6.84H) ppm; 13C{1H} NMR (100 MHz,
CDCl3, mixture of rotamers) δ 162.4 (d, J = 245.6 Hz), 162.3 (d,
J = 245.6 Hz), 161.2, 161.1, 154.5, 154.3, 137.2, 137.1, 134.9,
134.6, 129.4, 128.9, 128.2，128.1, 128.0, 128.0, 127.5, 127.3,
127.0, 126.9, 126.8, 126.3, 126.2, 114.8 (t, J = 20.2 Hz), 114,6
(t, J = 20.2 Hz), 111.2, 111.1, 111.0, 110.9, 110.8, 110.7, 79.6,
79.4, 54.5, 53.5, 38.3, 36.4, 29.4, 29.3, 28.9, 28.6, 28.3, 28.0
ppm; 19F NMR (376 MHz, CDCl3, mixture of rotamers) δ -115.5,
-115.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + Na]+ Calcd for
Notes and references
1
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2
+
C21H23F2NO2Na : 382.1589, found: 382.1594.
tert-Butyl
1-(3,5-difluorobenzyl)-3,4-dihydroisoquinoline-
2(1H)-carboxylate 9l. Whitefoam (115 mg, 64%); IR (film):
vmax2975, 2931, 1691, 1624, 1595, 1417, 1366, 1330, 1163,
1
1117, 985, 850, 747cm-1; H NMR (400 MHz, CDCl3, mixture of
3
4
5
S. Kanokmedhakul, K. Kanokmedhakul and R. Lekphrom, J.
Nat. Prod. 2007, 70, 1536-1538.
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rotamers) δ 7.21-7.11 (m, 3H), 7.07-6.98 (m, 0.63H), 6.96-6.90
(m, 0.37H), 6.73-6.58 (m, 3H), 5.34 (dd, J = 7.2, 6.4 Hz, 0.37H),
5.22 (dd, J = 8.4, 5.6 Hz, 0.63H), 4.24-4.15 (m, 0.63H), 3.89-
3.77 (m, 0.37H), 3.37-3.32 (m, 0.37H), 3.29-3.18 (m, 0.63H),
3.06-2.67 (m, 4H), 1.41 (s, 3.33H), 1.28 (s, 5.67H) ppm; 13C{1H}
NMR (100 MHz, CDCl3, mixture of rotamers) δ 163.1 (d, J =
246.3 Hz), 163.0 (d, J = 245.0 Hz), 154.8, 154.4, 142.6, 142.3,
136.5, 134.8, 134.6, 129.4, 128.8, 127.4, 127.2, 127.1, 126.2,
112.7, 112.6, 112.5, 112.4, 102.0 (t, J = 25.5 Hz), 101.9 (t, J =
25.1 Hz), 80.0, 56.4, 55.5, 42.9, 42.6, 39.4, 37.2, 28.8, 28.5,
28.5, 28.3 ppm; 19F NMR (376 MHz, CDCl3, mixture of
rotamers) δ -110.6, -111.0 ppm; HRMS (ESI-Orbitrap) m/z:[M +
(a) W. Cui, K. Iwasa, H. Tokuda, A. Kashihara, Y. Mitani, T.
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Pharmacology of Plant Alkaloids and Their Use in Medicine
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6
P.-J. Robiquet, Ann. Chim. Phys. 1817, 5, 275-278.
+
Na]+ Calcd for C21H23F2NO2Na : 382.1589, found: 382.1584.
10 | J. Name., 2012, 00, 1-3
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25 CCDC-2011532 (compound 9i) contain the supplementary
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