HCl-mediated cascade cyclocondensation of oxygenated arylacetic acids with arylaldehydes: one-pot synthesis of 1-arylisoquinolines

Article abstract of DOI:10.1039/d0ob02431g

In this paper, a concise, open-vessel synthesis of 1-arylisoquinolines is describedviaHCl-mediated intermolecular cyclocondensation of oxygenated arylacetic acids with arylaldehydes in the presence of NH₂OH and alcoholic solvents under mild and one-pot reaction conditions. A plausible mechanism is proposed and discussed herein. In the overall reaction process, only water was generated as the byproduct. Various environmentally friendly reaction conditions are investigated for convenient transformationviathe (4C + 1C + 1N) annulation. This protocol provides a highly effective ring closureviathe formations of one carbon-carbon (C-C) bond, two carbon-nitrogen (C-N) bonds and one carbon-oxygen (C-O) bond.

Full text of DOI:10.1039/d0ob02431g

Organic &
Biomolecular Chemistry
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PAPER
HCl-mediated cascade cyclocondensation of
oxygenated arylacetic acids with arylaldehydes:
one-pot synthesis of 1-arylisoquinolines†
Cite this: Org. Biomol. Chem., 2021,
19, 1047
a,b
Nai-Chen Hsueh,a Shin-Mei Chen,a Chun-Yi Lina and Meng-Yang Chang
*
In this paper, a concise, open-vessel synthesis of 1-arylisoquinolines is described via HCl-mediated inter-
molecular cyclocondensation of oxygenated arylacetic acids with arylaldehydes in the presence of NH2OH
and alcoholic solvents under mild and one-pot reaction conditions. A plausible mechanism is proposed and
discussed herein. In the overall reaction process, only water was generated as the byproduct. Various envir-
onmentally friendly reaction conditions are investigated for convenient transformation via the (4C + 1C + 1N)
annulation. This protocol provides a highly effective ring closure via the formations of one carbon–carbon
(C–C) bond, two carbon–nitrogen (C–N) bonds and one carbon–oxygen (C–O) bond.
Received 4th December 2020,
Accepted 27th December 2020
DOI: 10.1039/d0ob02431g
rsc.li/obc
By changing the transition metal from Co(II) to Rh(III),
Wang et al. converted the three-component reaction including
Introduction
The core structure of isoquinoline is frequently found in Weinreb amide, α-diazoester and alkyne into various isoquino-
natural products, bioactive molecules, functionalized materials lines smoothly.8 Besides the difference of the catalyst, the
and synthetic intermediates.1–3 However, traditional Song7 and Wang8 teams focused on similar starting substrates,
approaches (e.g. Bischler–Napieralski reaction, Pomeranz– benzamide oxime and alkyne respectively. Furthermore,
Fritsch reaction and Pictet–Spengler reaction) often result in Balalaie and Breit reported Ag(I)-promoted one-pot tandem
poor functional group tolerance and harsh reaction annulation of o-alkynylbenzaldoxime (a conjugation of alkyne
conditions.4,5 Therefore, it is highly desirable to explore a and benzamide oxime) with propargylic alcohol.9 On the basis
facile-operational, efficient synthetic route that possesses of the recent examples of the N–O bond cleavage-mediated
simple and mild reaction conditions, less expensive reagents synthesis of the isoquinoline core, we herein present an
and uncomplicated starting substrates.
efficient synthetic route towards diverse 1-arylisoquinolines via
Among the previous studies on the synthesis of isoquino- HCl-mediated cascade cyclocondensation of oxygenated aryl-
line, most methods adopted an amine group (a N atom) as the acetic acids 1 with arylaldehydes 2 in the presence of NH2OH
source of the nitrogen atom, while only a few reports were and alcoholic solvents. In the intermolecular multicomponent
documented for the nitrogen atom that originated from a
hydroxylamine synthon (a labile N–O linkage). As shown in
Scheme 1, by using Cp*Rh(III) as the catalyst, Miura et al.
demonstrated the facile synthesis of 1-arylisoquinoline
through annulative cross-coupling of 3-aryl-1,2-benzisoxazole
bearing a N–O bond source with symmetric acetylene.6 Song
et al. investigated the preparation of isoquinoline via a Cp*-
free Co(II)-catalyzed ortho C–H promoting activation of a trace-
less aryloxime derivative followed by annulation with alkynes.7
aDepartment of Medicinal and Applied Chemistry, Kaohsiung Medical University,
Kaohsiung 807, Taiwan. E-mail: mychang@kmu.edu.tw
bDepartment of Medical Research, Kaohsiung Medical University Hospital,
Kaohsiung 807, Taiwan
†Electronic supplementary information (ESI) available: Scanned photocopies of
NMR spectral data for all compounds and X-ray analysis data of 4r, 4x and 6e.
CCDC 2000637–2000639. For ESI and crystallographic data in CIF or other elec-
Scheme 1 Labile N–O bond activation synthetic routes toward functio-
tronic format see DOI: 10.1039/d0ob02431g
nalized isoquinolines.
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(4C + 1C + 1N) annulation process, water is the only by-product 3–6). The results showed that 10 h and 15 h provided lower
obtained. This experiment is based on clean and environmen- yields of 74% and 88% respectively as compared to 20 h where
tally friendly reaction conditions that provide valuable isoqui- 92% yield was obtained. When the time was changed to 25 h
noline products. In contrast to the above-discussed benzamide (an additional 5 h), the yield was slightly decreased to 90%. As
or oxime, NH2OH-HCl is a simple synthon that can provide a indicated, a longer reaction time did not improve the yield
nitrogen atom for the formation of isoquinoline. To the best of outcome.
our knowledge, no similar report has been published regard-
Two commercially available nitrogen sources with the N–O
ing the generation of functionalized isoquinoline by combin- bonding were tested at 65 °C and 20 h (entries 7 and 8). After
ing carboxylic acid, aldehyde, alcohol and hydroxylamine.
changing the nitrogen source from NH2OH-HCl to NH2OMe-
HCl and NH2OBn-HCl, neither of them resulted in higher
yields, which were only 72% and 58% respectively of 4a.
Furthermore, a stoichiometric amount of NH2OH-HCl was
studied. When the amount of NH2OH-HCl was increased to
1.5 and 2.0 equivalents, lower yields of 78% and 68%, respect-
ively, were provided (entries 9 and 10). From these obser-
vations, we concluded that 1.1 equivalent of NH2OH-HCl pro-
vided an optimal condition for the generation of 4a (for entry
5) via the intermolecular cyclocondensation of 1a with 2a in
MeOH. Encouraged by the above-mentioned reaction con-
ditions (entries 1–10), after replacing NH2OH-HCl with 50%
aqueous NH2OH, the desired 4a was obtained in trace
amounts (10%) along with a 66% yield of benzaldehyde oxime
with a mixture of E- and Z-isomers (entry 11). However, after
the use of HCl(aq) (37%, 0.1 mL), a 72% yield of 4a was
observed (entry 12). The results suggested that HCl played a
key role during the annulation process. By maintaining the
nitrogen source as NH2OH-HCl, two solvents were screened
(entries 13 and 14). By changing the solvent to MeCN, no reac-
tion process was detected as MeCN consumed NH2OH-HCl
such that 4a could not be isolated under the reflux (82 °C) con-
dition. Additionally, it was observed that MeNO2 provided
complex and unidentified mixtures as the major products. The
reason for this could be that the in situ formed intermediate
was unstable under the refluxing MeNO2 (101 °C) condition.
In particular, NH2NH2-2HCl could also provide 4a in an 80%
yield (entry 15). From the experimental data, it is obvious that
NH2OH-HCl provided better results than NH2NH2-2HCl. On
the basis of the above-mentioned results, we can conclude that
entry 5 provided the optimal conditions for the formation of
4a (92%) via an intermolecular benzannulation of 1a with 2a
in MeOH.
On the basis of the results, the plausible reaction mecha-
nism of 4a is illustrated in Scheme 2. Initially, coupling of 2a
with NH2OH-HCl yielded oxime A and water via a conden-
sation reaction. With the use of 1a, a lone pair of nitrogen
atoms on A promoted the acylation to lead to B with an
ammonium ion. Following the Pictet–Spengler-type intra-
molecular ring closure, the C3-methoxy group on the benzene
ring triggered the p-carbon to attack oximium, thereby generat-
ing C. After chloride-mediated dehydrogenative aromatization,
D could be formed spontaneously. By the use of in situ gener-
ated HCl, both dehydration of D and protonation of E could
give F having a conjugated cyclohexdienyl system. Sequentially,
the addition reaction of F with MeOH resulted in G. Finally,
proton exchange from G to H occurred and aromatizative de-
hydration of H took place; 4a could be obtained along with the
Results and discussion
According to the previous studies on the synthetic applications
of oxygenated arylacetic acids and the ongoing efforts to
emphasize the synthesis of benzofused molecules,10 the initial
research began by including an NH2OH-HCl (a nitrogen
source)-promoted reaction of model homoveratric acid (1a, Ar
= 3,4-(MeO)2C6H3, 1.0 mmol) and benzaldehyde (2a, Ar′ = Ph,
1.0 equiv.) in different solvents (10 mL). First, by the addition
of NH2OH-HCl (1.1 equiv.) and MeOH (3a), 4a was obtained in
a 21% yield at 25 °C after 5 h via intermolecular cascade annu-
lation (Table 1, entry 1). On the basis of the results, we exam-
ined the optimal annulation conditions in the next step. By
using 1.1 equivalent of NH2OH-HCl as a nitrogen synthon and
10 mL of methanol as the reaction solvent, we surveyed the
parameters associated with the reaction temperature and time
which could affect the benzannulation process. However, a
slightly higher yield (58%) of 4a was observed at reflux temp-
erature (65 °C, entry 2). To increase the isolated yield, four
elongated times (10, 15, 20 and 25 h) were checked (entries
Table 1 Reaction conditionsa
Nitrogen
source
Temperature
(°C)
Time
(h)
4a b
(%)
Entry
Solvent
1
2
3
4
5
6
7
8
NH2OH-HCl
NH2OH-HCl
NH2OH-HCl
NH2OH-HCl
NH2OH-HCl
NH2OH-HCl
NH2OMe-HCl
NH2OBn-HCl
NH2OH-HClc
NH2OH-HCld
NH2OH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeCN
MeNO2
MeOH
25
65
65
65
65
65
65
65
65
65
65
65
82
101
65
5
5
21
58
74
88
92
90
72
58
78
68
<10e
72
10
15
20
25
20
20
20
20
20
20
20
20
20
9
10
11
12
13
14
15
NH2OHf
g
NH2OH-HCl
NH2OH-HCl
NH2NH2-2HCl
—
h
—
80
a Reaction conditions: 1a (196 mg, 1.0 mmol), 2a (106 mg, 1.0 equiv.),
solvent (10 mL), and NH2OH-HCl (75 mg, 1.1 equiv.). b Isolated yields.
c 1.5 equiv. d 2.0 equiv. e Benzaldehyde oxime (66%) was isolated.
f HCl(aq) (37%, 0.1 mL) was added. g No reaction. h A complex and un-
identified mixture was detected.
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Table 2 Synthesis of 4a–4am a
Entry
1a, Ar =
2, Ar′ =
4
b (%)
1
2
3
4
5
6
7
8
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1a, 3,4-(MeO)2C6H3
1b, 3,4-CH2O2C6H3
1b, 3,4-CH2O2C6H3
1b, 3,4-CH2O2C6H3
1b, 3,4-CH2O2C6H3
1b, 3,4-CH2O2C6H3
1b, 3,4-CH2O2C6H3
1c, 3,4-(nPrO)2C6H3
1d, 3,4,5-(MeO)3C6H2
1e, 3-MeOC6H4
2a, Ph
2b, 2-BrC6H4
2c, 2-NO2C6H4
2d, 2-FC6H4
2e, 3-MeOC6H4
2f, 3-NO2C6H4
2g, 3-CF3C6H4
2h, 4-FC6H4
2i, 4-ClC6H4
2j, 4-MeSC6H4
2k, 4-MeC6H4
2l, 4-MeOC6H4
2m, 4-NO2C6H4
2n, 4-CF3C6H4
2o, 4-NCC6H4
2p, 4-PhC6H4
2q, 2-naphthyl
2r, 9-anthryl
4a, 92
4b, 90
4c, 86
4d, 88
4e, 90
4f, 90
4g, 93
4h, 89
4i, 87
4j, 90
4k, 85
4l, 88
4m, 86
4n, 90
4o, 93
4p, 90
4q, 83
4r, 80
Scheme 2 Plausible mechanism.
9
formation of water and HCl was recovered. In the overall cyclo-
condensation process, four equivalents of water were
generated.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
To explore the substrate scope and limitations of this facile
HCl-mediated synthetic route, homoveratric acid (1a) and the
related derivatives of 1b–1e were reacted with diverse arylben-
zaldehydes 2a–2ad to afford functionalized 1-arylisoquinolines
4a–4am in the presence of NH2OH and MeOH 3a, as shown in
Table 2. On the basis of the established optimal conditions
(Table 1, entry 5) and a plausible mechanism (Scheme 2), we
found that this route allowed a direct (4C + 1N + 1C) annula-
tion process under easily-operational and environmentally
friendly conditions with moderate to good yields (75%–93%).
For entries 1–16, efficient formations of 4a–4p showed that the
Ar group with mono-substituent halogens, electron-donating
methoxy groups, electron-withdrawing nitro, cyano and tri-
fluoromethyl groups, and methylthio group did not exert any
influence on the isolated yields. In entries 17 and 18, bicyclic
2-naphthyl and tricyclic 9-anthryl aromatic groups provided 4q
and 4r in yields of 83% and 80%, respectively. The molecular
structure of 4r with the anthryl-conjugated isoquinoline was
determined by single-crystal X-ray analysis.11 For the Ar group
with di-substituent halogen and oxygen-rich groups, entries
19–23 showed that the yields of 4s–4w were in the range of
80%–90%. Adjusting the Ar group to combine one nitro group
2s, 3,4-Cl2C6H3
2t, 3,4-F2C6H3
4s, 83
4t, 90
2u, 2-F-6-ClC6H3
2v, 3,4-(MeO)2C6H3
2w, 3,4-CH2O2C6H3
2x, 3-NO2-6-MeOC6H3
2y, 3-NO2-4-MeOC6H3
2z, 3-NO2-6-C5H9OC6H3
2aa, 3-NO2-4-MeC6H3
2ab, 2,3,4-(MeO)3C6H2
2ac, 3,4,5-(MeO)3C6H2
2ad, 5-NO2-2-thienyl
2f, 3-NO2C6H4
2m, 4-NO2C6H4
2v, 3,4-(MeO)2C6H3
2w, 3,4-CH2O2C6H3
2ab, 2,3,4-(MeO)3C6H2
2ac, 3,4,5-(MeO)3C6H2
2v, 3,4-(MeO)2C6H3
2v, 3,4-(MeO)2C6H3
2v, 3,4-(MeO)2C6H3
4u, 89
4v, 82
4w, 80
4x, 88
4y, 86
4z, 84
4aa, 90
4ab, 79
4ac, 82
4ad, 83c
4ae, 90
4af, 90
4ag, 80
4ah, 80
4ai, 75
4aj, 87
4ak, 80
4al, 78
4am, 78
a Reaction conditions: Oxygenated arylacetic acids 1 (1.0 mmol), aryl-
aldehydes 2 (1.0 equiv.), NH2OH-HCl (75 mg, 1.1 equiv.), and MeOH 3a
and one oxygenated or methyl group, a similar yield distri- (10 mL) for 20 h at 65 °C. b Isolated yields. c 4ad-1 (∼5%) was isolated.
bution (84%–90%) was observed in the formation of 4x–4aa
(entries 24–27). The structure of 4x was determined by single-
crystal X-ray analysis.11
The tri-substituted oxygenated Ar group produced 4ab and Regarding the association of 1e with the 3-methoxyphenyl
4ac in slightly lower yields (79% and 82%, entries 28 and 29, group, 4am was afforded in
a 78% yield (entry 39).
respectively). In particular, entry 30 showed that 4ad with a Furthermore, NH2OH-HCl-promoted cyclocondensation of 1a
heterocyclic nitrothienyl group was afforded in an 83% yield, with hexanal (an aliphatic aldehyde) in the presence of MeOH
along with ∼5% yield of 4ad-1. One possible reason for this is 3a was examined. However, only hexyl oxime was detected. We
that trace amounts of H2O in MeOH produced the side observed that oxime–enamine tautomerization was easily trig-
product 4ad-1. By changing homoveratric acid (1a) to 2,3- gered such that a desirable amount of 1-pentylisoquinoline
methylenedioxyphenylacetic acid (1b), 4ae–4aj were obtained was not generated. Although the substrate was limited to alka-
in similar yields (75%–90%, entries 31–36). After elongating nals, the expeditious synthetic route sets up the 1-arylisoqui-
the carbon chain from dimethoxy to di-n-propoxy on the Ar noline skeleton, including the formation of one carbon–
group (for 1c), however, the yield of 4ak was maintained at carbon (C–C) single bond, one carbon–nitrogen (C–N) single
80% (entry 37). Additionally, 3,4,5-trimethoxyphenylacetic acid bond and one carbon–nitrogen (CvN) double bond via a
(1d) provided 4al in a slightly lower yield (78%, entry 38). tandem (4C + 1C + 1N) benzannulation process.
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(formed from the reaction of arylaldehydes with HCl(g)) gener-
ating II via a Friedel–Crafts process. Finally, excess HCl(g)
-
mediated etherification of II with MeOH 3a provided 6a–6g.
This was an efficient transformation for preparing the skeleton
of benzhydryl ether. Benzhydryl derivatives are widely used as
intermediates in pharmaceuticals (including antihistamines)
and other organic compounds.12,13 They are also used as pre-
cursors to prepare modafinil,14 benztropine15 and diphenhy-
dramine.16 Furthermore, conversion from benzhydryl deriva-
tives to 1-arylisoquinolines was examined. Under the refluxing
MeOH condition, treatment of 6a with NH2OH-HCl could
provide 4a in a good yield (88%).
Based on the above results, 7 with one deuterium and one
deuterium methyl-labelling was isolated in an 88% yield after
changing MeOH 3a to CD3OD 3f (Scheme 4, eqn (1)). For the
one-pot formation of 1-arylisoquinoline, this important result
confirmed the proposed reaction mechanism. After the reac-
tion equilibrium was achieved, we envisioned that the reaction
equation “NH2OH-HCl + CD3OD ⇄ NH2OH-DCl + CD3OH”
occurred easily under reflux temperature conditions.17,18
Similar to intermediate E of Scheme 2, I could be generated by
the in situ formation of the NH2OH-DCl-promoted stepwise
pathway. Following that, I could be converted into J by proton
exchange from two α-hydrogen to α-deuterium atoms.
Furthermore, by the use of CD3OD and DCl, the releasing
chloride-mediated dehydrogenative aromatization could afford
7. Changing the condition from NH2OH-HCl to DCl, the reac-
tion of 1a with 2f produced 8 in a 70% yield (eqn (2)).
Specifically, 8 exhibited eight deuterium atoms, including one
deuterium methoxy and one deuterium methyl ester group
and two α-deuterium atoms. The possible reaction mechanism
was similar as shown in Table 3. These steps included (1) ester-
ification of 1a with CD3OD in the presence of DCl, (2) the
Friedel–Crafts reaction of the resulting ester with 2a, (3) the
Scheme 3 Synthesis of 5a–5c.
By using the starting homoveratric acid (1a) and 3-nitroben-
zaldehyde (2f) as the sources of arylacetic acid and arylalde-
hyde, different alcohols 3b–3e (3b, EtOH; 3c, iPrOH; 3d,
nBuOH) were screened next (Scheme 3). By the use of four
alcoholic solvents, 5a–5c were produced in 80%, 80% and 82%
yields, respectively. From the above-mentioned observations,
we concluded that the synthesis of the 1-arylisoquinoline skel-
eton with different 3-alkoxy (3-RO) substituents could be
accomplished by using different alcoholic solvents.
Encouraged by the above experimental results, gaseous
HCl-mediated reactions of homoveratric acid 1a with arylalde-
hydes 2a, 2b, 2e, 2i, 2o, 2p and 2t were studied next in the
presence of MeOH 3a (Table 3). By removing the nitrogen
source of NH2OH, 6a–6g were obtained in a yield range of
70%–80%. In entries 1–7, efficient formation of 6a–6g showed
that the Ar substituent with mono- or di-halogen groups, elec-
tron-donating 3-methoxy group, electron-withdrawing 4-cyano
group and biphenyl group were well tolerated. The structure of
6e was determined by single-crystal X-ray analysis.11 Gaseous
HCl was freshly prepared from the reaction between PCl5 and
water (general equation, PCl5 + 4H2O → H3PO4 + 5HCl). For
the proposed mechanism, in situ generated HCl triggered the
initial esterification of 1a and provided I. Then, the C3-
methoxy group on the benzene ring promoted the p-carbon to
attack the oxocarbenium ion of 2a, 2b, 2e, 2i, 2o, 2p and 2t
Table 3 Synthesis of 6a–6g a
Entry
2, Ar =
6
b (%)
1
2
3
4
5
6
7
2a, Ph
6a, 73
6b, 78
6c, 74
6d, 76
6e, 70
6f, 80
6g, 73
2b, 2-BrC6H4
2e, 3-MeOC6H4
2i 4-ClC6H4
2o, 4-NCC6H4
2p, 4-PhC6H4
2t, 3,4-F2C6H4
a Reaction conditions: 1a (196 mg, 1.0 mmol), 2 (1.0 equiv.), MeOH 3a
(10 mL), and excess freshly prepared gaseous HCl. b Isolated yields.
Scheme 4 Synthesis of 7, 8 and 9.
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proton–deuterium exchange, and (4) etherification with of 1-arylisoquinolines via HCl-mediated intermolecular cyclo-
CD3OD. On the other hand, by the use of NaBH4, the removal condensation of oxygenated arylacetic acids with arylaldehydes
of the secondary alkoxy group on the benzhydryl skeleton was in the presence of NH2OH and alcoholic solvents. The syn-
investigated. By using the above HCl(g)-mediated reaction con- thesis of benzhydryl derivatives was also discussed. The struc-
dition (eqn (3)), the reaction of 1a with 2f in the presence of tures of the key products were confirmed by X-ray crystallogra-
EtOH 3b generated the initial structure of ester 6. Sequentially, phy. The uses of various reaction conditions and related plaus-
NaBH4-mediated reduction afforded
Compared with the ester, the reduction condition was pre- transformation. Further investigations regarding the synthetic
ferred to transform benzhydryl ether into diarylmethane. application of oxygenated arylacetic acids will be conducted
9 in a 46% yield. ible mechanisms were investigated and proposed for efficient
To understand the electronic influences of the aromatic and published in due course.
ring (for Ar) on 1, the electron-rich 2-thienyl (for 1f) and 3,4-
dichlorophenyl (for 1g) groups were examined for the (4C + 1C
+ 1N) annulation (Scheme 5) under the above reaction con-
Experimental
ditions. In the presence of NH2OH-HCl, the reaction of 1f with
General
2a provided only benzaldehyde oxime in a 69% yield and the
All reagents and solvents were obtained from commercial
desired product 4an could not be isolated (eqn (4)). Next, by
changing 1f to 1g, however, the expected 4ao could not be
obtained and only benzaldehyde oxime was yielded (73%, eqn
(5)). Under the standard reaction conditions, the two results
were similar. From this phenomenon, we understood that an
oxygenated group could enrich the electron density of the Ar
ring easily than 2-thienyl and 3,4-dichlorophenyl groups.
Although substrate 1 was limited to the oxygenated aryl group,
it still provided a novel and efficient synthesis of the 1-aryliso-
quinoline skeleton.
Because of the potential application of this protocol in the
synthesis of various 1-arylisoquinolines, attempts to scale up
the transformation would improve the significance of the
results. Thus, the development of a gram-scale route was in
high demand. As shown in Scheme 6, cyclocondensation of 1a
(980 mg, 5.0 mmol) and 2a (530 mg, 5.0 mmol) could produce
4a in an 82% (1.21 g) yield in the presence of NH2OH-HCl
under the refluxing MeOH 3a condition. Compared with the
1 mmol scale (92%), 5 mmol provided a slightly lower yield
sources and used without further purification. Reactions were
routinely carried out under an atmosphere of dry air with mag-
netic stirring. Products in organic solvents were dried with
anhydrous magnesium sulfate before concentration in vacuo.
Melting points were determined with an SMP3 melting appar-
atus. 1H and 13C NMR spectra were recorded on a Varian
INOVA-400 spectrometer operating at 400 and 100 MHz,
respectively. Chemical shifts (δ) are reported in parts per
million (ppm) and the coupling constants (J) are given in
hertz. High resolution mass spectra (HRMS) were measured
with a mass spectrometer Finnigan/Thermo Quest MAT 95XL.
X-ray crystal structures were obtained with an Enraf-Nonius
FR-590 diffractometer (CAD4, Kappa CCD).
The starting substrates oxygenated arylacetic acids 1a–1g
and arylaldehydes 2a–2ad were purchased commercially and
were used without further purification.
General synthetic procedure of 4a–4am
(82%). Although the obtained yield was lower, the gram-scale NH2OH-HCl (75 mg, 1.1 mmol) was added to a solution of sub-
synthetic route of 1-arylisoquinolines was well established. stituted arylaldehydes 2a–2ad (1.0 mmol) in methanol 3a
In summary, we have developed a facile and environmen- (5 mL) at 25 °C. The reaction mixture was stirred at 25 °C for
tally friendly (4C + 1C + 1N) annulation route for the synthesis 15 min. A solution of oxygenated arylacetic acids 1a–1e
(1.0 mmol) in methanol 3a (5 mL) was added to the reaction
mixture at 25 °C. The reaction mixture was stirred at reflux for
20 h. The reaction mixture was cooled to 25 °C and the solvent
was concentrated. The residue was diluted with water (10 mL)
and the mixture was extracted with CH2Cl2 (3 × 20 mL). The
combined organic layers were washed with brine, dried, fil-
tered and evaporated to afford the crude product under
reduced pressure. Purification on silica gel (hexanes/EtOAc =
8/1–4/1) afforded 4a–4am.
3,6,7-Trimethoxy-1-phenylisoquinoline (4a). 4a was prepared
according to the general synthetic procedure from 1a (196 mg,
Scheme 5 Reactions of 1f and 1g with 2a.
1.0 mmol), 2a (106 mg, 1.0 mmol) and MeOH 3a (10 mL);
yield = 92% (272 mg); white solid; mp = 80–82 °C (recrystal-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+
calcd for C18H18NO3 296.1287, found 296.1292; 1H NMR
(400 MHz, CDCl3): δ 7.76–7.73 (m, 2H), 7.54–7.44 (m, 3H), 6.73
(s, 1H), 6.97 (s, 1H), 6.88 (s, 1H), 4.02 (s, 3H), 4.00 (s, 3H), 3.83
Scheme 6 Gram-scale synthesis of 4a.
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 159.7, 156.1, 153.1,
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148.2, 139.6, 137.7, 129.8 (2x), 128.4, 128.2 (2x), 118.4, 105.2, 0.8, 2.4, 8.0 Hz, 1H), 8.12 (dt, J = 2.4, 8.0 Hz, 1H), 7.72 (t, J =
103.8, 99.7, 55.9, 55.7, 54.0.
8.0 Hz, 1H), 7.17 (s, 1H), 7.02 (s, 1H), 6.97 (s, 1H), 4.04 (s, 6H),
1-(2-Bromophenyl)-3,6,7-trimethoxyisoquinoline (4b). 4b 3.85 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 159.6, 153.6,
was prepared according to the general synthetic procedure 152.7, 149.1, 148.3, 140.8, 138.2, 135.9, 129.4, 124.9, 123.4,
from 1a (196 mg, 1.0 mmol), 2b (184 mg, 1.0 mmol) and 118.3, 104.1, 103.9, 101.1, 56.1, 55.9, 54.3.
MeOH 3a (10 mL); yield = 90% (336 mg); colorless liquid;
3,6,7-Trimethoxy-1-(3-trifluoromethylphenyl)isoquinoline (4g).
HRMS (ESI-TOF) m/z: [M
+
H]+ calcd for C18H17BrNO3 4g was prepared according to the general synthetic procedure
1
374.0392, found 374.0387; H NMR (400 MHz, CDCl3): δ 7.73 from 1a (196 mg, 1.0 mmol), 2g (174 mg, 1.0 mmol) and
(d, J = 8.0 Hz, 1H), 7.47–7.45 (m, 2H), 7.36–7.32 (m, 1H), 6.99 MeOH 3a (10 mL); yield = 93% (338 mg); white solid; mp =
(s, 1H), 6.65 (d, J = 0.8 Hz, 1H), 6.72 (s, 1H), 4.02 (s, 3H), 4.00 109–111 °C (recrystallized from hexanes and EtOAc); HRMS
(s, 3H), 3.77 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 159.6, (ESI-TOF) m/z: [M + H]+ calcd for C19H17F3NO3 364.1161,
155.3, 153.3, 148.4, 140.1, 137.1, 132.9, 131.5, 129.8, 127.3, found 364.1153; 1H NMR (400 MHz, CDCl3): δ 8.04 (s, 1H),
123.0, 119.0, 104.9, 103.7, 100.4, 56.0, 55.8, 54.3.
7.95 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 7.6
3,6,7-Trimethoxy-1-(2-nitrophenyl)isoquinoline (4c). 4c was Hz, 1H), 7.20 (s, 1H), 6.99 (s, 1H), 6.91 (s, 1H), 4.03 (s, 3H),
prepared according to the general synthetic procedure from 1a 4.02 (s, 3H), 3.83 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
(196 mg, 1.0 mmol), 2c (151 mg, 1.0 mmol) and MeOH 3a 159.8, 154.2, 153.2, 148.6, 140.4, 137.8, 133.1, 130.7 (q, J = 32.6
(10 mL); yield = 86% (292 mg); colorless liquid; HRMS Hz), 128.8, 126.8 (q, J = 3.8 Hz), 125.1 (q, J = 3.8 Hz), 124.1 (q,
(ESI-TOF) m/z: [M + H]+ calcd for C18H17N2O5 341.1138, found J = 270.6 Hz), 118.4, 104.4, 103.9, 100.5, 56.0, 55.7, 54.0.
341.1132; 1H NMR (400 MHz, CDCl3): δ 8.09 (dd, J = 1.2, 8.4
1-(4-Fluorophenyl)-3,6,7-trimethoxyisoquinoline (4h). 4h was
Hz, 1H), 7.74 (dt, J = 1.2, 7.6 Hz, 1H), 7.67–7.61 (m, 2H), 6.99 prepared according to the general synthetic procedure from 1a
(s, 1H), 6.93 (s, 1H), 6.83 (s, 1H), 3.93 (s, 6H), 3.78 (s, 3H); 13C (196 mg, 1.0 mmol), 2h (124 mg, 1.0 mmol) and MeOH 3a
{1H} NMR (100 MHz, CDCl3): δ 159.5, 153.5, 151.7, 148.9, (10 mL); yield = 89% (279 mg); white solid; mp = 139–141 °C
137.5, 132.6, 132.1, 129.4, 124.6, 118.7, 116.9, 114.5, 104.0, (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
1
103.4, 101.0, 56.0, 55.8, 54.2.
[M + H]+ calcd for C18H17FNO3 314.1193, found 314.1186; H
1-(2-Fluorophenyl)-3,6,7-trimethoxyisoquinoline (4d). 4d was NMR (400 MHz, CDCl3): δ 7.74–7.70 (m, 2H), 7.24–7.19 (m,
prepared according to the general synthetic procedure from 1a 2H), 7.23 (s, 1H), 6.99 (s, 1H), 6.89 (s, 1H), 4.022 (s, 3H), 4.019
(196 mg, 1.0 mmol), 2d (124 mg, 1.0 mmol) and MeOH 3a (s, 3H), 3.84 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 163.0
(10 mL); yield = 88% (276 mg); white solid; mp = 113–115 °C (d, J = 246.3 Hz), 159.6, 155.0, 153.3, 148.4, 137.8, 135.4, 131.6
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: (d, J = 8.4 Hz, 2x), 118.4, 115.3 (d, J = 21.2 Hz, 2x), 105.0, 103.9,
1
[M + H]+ calcd for C18H17FNO3 314.1193, found 314.1187; H 99.8, 56.0, 55.8, 54.1.
NMR (400 MHz, CDCl3): δ 7.60 (dt, J = 2.0, 7.6 Hz, 1H),
1-(4-Chlorophenyl)-3,6,7-trimethoxyisoquinoline (4i). 4i was
7.50–7.44 (m, 1H), 7.31 (dt, J = 1.2, 7.6 Hz, 1H), 7.23 (dt, J = prepared according to the general synthetic procedure from 1a
1.2, 7.6 Hz, 1H), 6.99 (s, 1H), 6.94 (s, 1H), 6.91 (d, J = 3.2 Hz, (196 mg, 1.0 mmol), 2i (140 mg, 1.0 mmol) and MeOH 3a
1H), 4.02 (s, 3H), 4.01 (s, 3H), 3.82 (s, 3H); 13C{1H} NMR (10 mL); yield = 87% (286 mg); white solid; mp = 147–149 °C
(100 MHz, CDCl3): δ 159.9 (d, J = 247.2 Hz), 159.8, 153.4, 151.1, (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
1
148.5, 137.2, 132.2 (d, J = 3.8 Hz), 130.4 (d, J = 8.3 Hz), 127.1 [M + H]+ calcd for C18H17ClNO3 330.0897, found 330.0893; H
(d, J = 16.0 Hz), 124.3 (d, J = 3.8 Hz), 119.5, 115.8 (d, J = 21.2 NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.4, 2H), 7.49 (d, J = 8.8
Hz), 104.9 (d, J = 3.0 Hz), 103.7, 100.5, 56.0, 55.7, 54.2.
Hz, 2H), 7.21 (s, 1H), 6.97 (s, 1H), 6.88 (s, 1H), 4.009 (s, 3H),
3,6,7-Trimethoxy-1-(3-methoxyphenyl)isoquinoline (4e). 4e 4.006 (s, 3H), 3.84 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
was prepared according to the general synthetic procedure 159.6, 154.7, 153.2, 148.4, 138.0, 137.8, 134.5, 131.1 (2x), 128.5
from 1a (196 mg, 1.0 mmol), 2e (136 mg, 1.0 mmol) and (2x), 118.4, 104.7, 103.9, 100.1, 56.0, 55.8, 54.0.
MeOH 3a (10 mL); yield = 90% (293 mg); colorless liquid;
3,6,7-Trimethoxy-1-(4-methylsulfanylphenyl)isoquinoline (4j).
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H20NO4 326.1392, 4j was prepared according to the general synthetic procedure
1
found 326.1385; H NMR (400 MHz, CDCl3): δ 7.42 (t, J = 8.0 from 1a (196 mg, 1.0 mmol), 2j (152 mg, 1.0 mmol) and
Hz, 1H), 7.33 (s, 1H), 7.32–7.29 (m, 2H), 7.02 (ddd, J = 0.8, 2.4, MeOH 3a (10 mL); yield = 90% (307 mg); white solid; mp =
8.0 Hz, 1H), 6.98 (s, 1H), 6.88 (s, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 180–182 °C (recrystallized from hexanes and EtOAc); HRMS
3.87 (s, 3H), 3.84 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ (ESI-TOF) m/z: [M + H]+ calcd for C19H20NO3S 342.1164, found
159.63, 159.57, 155.9, 153.1, 148.2, 140.9, 137.7, 129.2, 122.2, 342.1169; 1H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 8.4 Hz, 2H),
118.5, 115.1, 114.4, 105.2, 103.8, 99.8, 55.9, 55.8, 55.3, 54.0.
7.81 (d, J = 8.4 Hz, 2H), 7.20 (s, 1H), 7.00 (s, 1H), 6.93 (s, 1H),
3,6,7-Trimethoxy-1-(3-nitrophenyl)isoquinoline (4f). 4f was 4.027 (s, 3H), 4.025 (s, 3H), 3.84 (s, 3H), 2.82 (s, 3H); 13C{1H}
prepared according to the general synthetic procedure from 1a NMR (100 MHz, CDCl3): δ 159.5, 154.2, 153.6, 148.8, 146.0,
(196 mg, 1.0 mmol), 2f (151 mg, 1.0 mmol) and MeOH 3a 138.1, 130.9 (2x), 125.9, 123.7 (2x), 118.4, 104.5, 104.0, 100.5,
(10 mL); yield = 90% (306 mg); white solid; mp = 188–190 °C 56.1, 55.9, 54.3, 43.9.
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
3,6,7-Trimethoxy-1-p-tolylisoquinoline (4k). 4k was prepared
[M + H]+ calcd for C18H17N2O5 341.1138, found 341.1132; 1H according to the general synthetic procedure from 1a (196 mg,
NMR (400 MHz, CDCl3): δ 8.64 (t, J = 1.6 Hz, 1H), 8.34 (ddd, J = 1.0 mmol), 2k (120 mg, 1.0 mmol) and MeOH 3a (10 mL);
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yield = 85% (263 mg); white solid; mp = 100–102 °C (recrystal-
1-Biphenyl-4-yl-3,6,7-trimethoxyisoquinoline (4p). 4p was
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ prepared according to the general synthetic procedure from 1a
calcd for C19H20NO3 310.1443, found 310.1436; 1H NMR (196 mg, 1.0 mmol), 2p (182 mg, 1.0 mmol) and MeOH 3a
(400 MHz, CDCl3): δ 7.65 (d, J = 8.0 Hz, 2H), 7.333 (s, 1H), (10 mL); yield = 90% (334 mg); white solid; mp = 173–175 °C
7.332 (d, J = 7.6 Hz, 2H), 6.98 (s, 1H), 6.87 (s, 1H), 4.024 (s, (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
3H), 4.018 (s, 3H), 3.84 (s, 3H), 2.46 (s, 3H); 13C{1H} NMR [M + H]+ calcd for C24H22NO3 372.1600, found 372.1593; 1H
(100 MHz, CDCl3): δ 159.5, 156.1, 153.2, 148.2, 138.5, 137.8, NMR (400 MHz, CDCl3): δ 7.86–7.76 (m, 4H), 7.71–7.69 (m,
136.4, 129.8 (2x), 129.0 (2x), 118.5, 105.5, 103.9, 99.5, 56.0, 2H), 7.51–7.47 (m, 2H), 7.41–7.37 (m, 2H), 7.02 (s, 1H), 6.92 (s,
55.8, 54.1, 21.3.
1H), 4.06 (s, 3H), 4.04 (s, 3H), 3.87 (s, 3H); 13C{1H} NMR
3,6,7-Trimethoxy-1-(4-methoxyphenyl)isoquinoline (4l). 4l was (100 MHz, CDCl3): δ 159.4, 155.5, 153.6, 148.6, 141.6, 140.6,
prepared according to the general synthetic procedure from 1a 138.1, 134.5, 130.4 (2x), 128.9 (2x), 127.6, 127.2 (2x), 127.1 (2x),
(196 mg, 1.0 mmol), 2l (136 mg, 1.0 mmol) and MeOH 3a 118.5, 105.4, 104.0, 99.9, 56.1, 56.0, 55.9.
(10 mL); yield = 88% (286 mg); white solid; mp = 97–99 °C
3,6,7-Trimethoxy-1-naphthalen-2-ylisoquinoline (4q). 4q was
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: prepared according to the general synthetic procedure from 1a
[M + H]+ calcd for C19H20NO4 326.1392, found 326.1397; 1H (196 mg, 1.0 mmol), 2q (156 mg, 1.0 mmol) and MeOH 3a
NMR (400 MHz, CDCl3): δ 7.70 (d, J = 9.2 Hz, 2H), 7.33 (s, 1H), (10 mL); yield = 83% (286 mg); white solid; mp = 140–142 °C
7.05 (d, J = 8.8 Hz, 2H), 6.97 (s, 1H), 6.84 (s, 1H), 4.02 (s, 3H), (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
4.01 (s, 3H), 3.89 (s, 3H), 3.85 (s, 3H); 13C{1H} NMR (100 MHz, [M + H]+ calcd for C22H20NO3 346.1443, found 346.1438; 1H
CDCl3): δ 159.9, 159.5, 155.8, 153.1, 148.2, 137.8, 131.8, NMR (400 MHz, CDCl3): δ 8.23 (d, J = 1.2 Hz, 1H), 8.00 (d, J =
131.1 (2x), 118.4, 113.7 (2x), 105.4, 103.9, 99.2, 55.9, 55.8, 55.3, 8.4 Hz, 1H), 7.95–7.88 (m, 3H), 7.57–7.51 (m, 2H), 7.37 (s, 1H),
54.1.
7.00 (s, 1H), 6.92 (s, 1H), 4.06 (s, 3H), 4.01 (s, 3H), 3.79 (s, 3H);
3,6,7-Trimethoxy-1-(4-nitrophenyl)isoquinoline (4m). 4m was 13C{1H} NMR (100 MHz, CDCl3): δ 159.7, 155.9, 153.0, 148.2,
prepared according to the general synthetic procedure from 1a 137.7, 137.0, 133.12, 133.07, 129.1, 128.3, 127.8, 127.6, 127.5,
(196 mg, 1.0 mmol), 2m (151 mg, 1.0 mmol) and MeOH 3a 126.4, 126.2, 118.6, 105.1, 103.8, 99.7, 55.8, 55.6, 54.0.
(10 mL); yield = 86% (292 mg); white solid; mp = 242–244 °C
1-Anthracen-9-yl-3,6,7-trimethoxyisoquinoline (4r). 4r was
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: prepared according to the general synthetic procedure from 1a
[M + H]+ calcd for C18H17N2O5 341.1138, found 341.1132; 1H (196 mg, 1.0 mmol), 2r (206 mg, 1.0 mmol) and MeOH 3a
NMR (400 MHz, CDCl3): δ 8.38 (d, J = 8.8 Hz, 2H), 7.92 (d, J = (10 mL); yield = 80% (316 mg); white solid; mp = 249–251 °C
8.4 Hz, 2H), 7.15 (s, 1H), 7.01 (s, 1H), 6.96 (s, 1H), 4.03 (s, 3H), (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
4.02 (s, 3H), 3.85 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ [M + H]+ calcd for C26H22NO3 396.1600, found 396.1595; 1H
159.7, 153.4, 153.1, 149.0, 147.7, 146.0, 138.0, 130.8 (2x), 123.6 NMR (400 MHz, CDCl3): δ 8.59 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H),
(2x), 118.4, 104.0, 103.9, 101.2, 56.1, 55.9, 54.2.
7.50 (dt, J = 1.2, 7.6 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H), 7.29 (dt, J
3,6,7-Trimethoxy-1-(4-trifluoromethylphenyl)isoquinoline (4n). = 1.2, 7.6 Hz, 2H), 7.11 (s, 1H), 7.10 (s, 1H), 6.31 (s, 1H), 4.03
4n was prepared according to the general synthetic procedure (s, 3H), 3.99 (s, 3H), 3.32 (s, 3H); 13C{1H} NMR (100 MHz,
from 1a (196 mg, 1.0 mmol), 2n (174 mg, 1.0 mmol) and CDCl3): δ 160.0, 154.6, 153.7, 148.6, 137.3, 131.4 (3x), 130.4
MeOH 3a (10 mL); yield = 90% (327 mg); white solid; mp = (2x), 128.4 (2x), 127.8, 126.3 (2x), 125.9 (2x), 125.2 (2x), 121.4,
153–155 °C (recrystallized from hexanes and EtOAc); HRMS 105.1, 103.7, 100.5, 56.0, 55.6, 54.4. Single-crystal X-ray
(ESI-TOF) m/z: [M + H]+ calcd for C19H17F3NO3 364.1161, diagram: the crystal of compound 4r was grown by slow
1
found 364.1156; H NMR (400 MHz, CDCl3): δ 7.85 (d, J = 8.0 diffusion of EtOAc into a solution of compound 4r in CHCl3 to
Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.19 (s, 1H), 6.97 (s, 1H), 6.91 yield colorless prisms. The compound crystallizes in the tri-
(s, 1H), 4.01 (s, 6H), 3.83 (s, 3H); 13C{1H} NMR (100 MHz, clinic crystal system, space group P1, a = 9.82420(10) Å, b =
ˉ
CDCl3): δ 159.7, 154.2, 153.2, 148.6, 143.3, 137.8, 130.3 (q, J = 13.6944(2) Å, c = 17.0549(3) Å, V = 2226.41(6) Å3, Z = 2, dcalcd
=
32.6 Hz), 130.1 (2x), 124.2 (q, J = 269.6 Hz), 125.2 (q, J = 3.8 Hz, 1.358 g cm−3, F(000) = 948, 2θ range 4.08–52°, R indices (all
2x), 118.4, 104.4, 103.9, 100.6, 55.9, 55.8, 53.9.
data) R1 = 0.0770, wR2 = 0.1861.
4-(3,6,7-Trimethoxyisoquinolin-1-yl)benzonitrile (4o). 4o was
1-(3,4-Dichlorophenyl)-3,6,7-trimethoxyisoquinoline (4s).
prepared according to the general synthetic procedure from 4s was prepared according to the general synthetic procedure
1a (196 mg, 1.0 mmol), 2o (131 mg, 1.0 mmol) and MeOH 3a from 1a (196 mg, 1.0 mmol), 2s (174 mg, 1.0 mmol) and
(10 mL); yield = 93% (298 mg); white solid; mp = 205–207 °C MeOH 3a (10 mL); yield = 83% (301 mg); white solid; mp =
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/ 184–186 °C (recrystallized from hexanes and EtOAc); HRMS
z: [M + H]+ calcd for C19H17N2O3 321.1239, found 321.1244; (ESI-TOF) m/z: [M + H]+ calcd for C18H16Cl2NO3 364.0507,
1
1H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 8.0 Hz, 2H), 7.82 (d, found 364.0502; H NMR (400 MHz, CDCl3): δ 7.85 (d, J = 1.2
J = 8.0 Hz, 2H), 7.14 (s, 1H), 7.00 (s, 1H), 6.94 (s, 1H), 4.03 (s, Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.18
3H), 4.02 (s, 3H), 3.84 (s, 3H); 13C{1H} NMR (100 MHz, (s, 1H), 6.98 (s, 1H), 6.91 (s, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 3.86
CDCl3): δ 159.7, 153.5, 153.4, 148.9, 144.0, 138.0, 132.2 (2x), (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 159.6, 153.4, 153.2,
130.5 (2x), 118.7, 118.3, 112.2, 104.03, 104.01, 101.0, 56.1, 148.7, 139.4, 137.9, 132.72, 132.66, 131.8, 130.3, 129.0, 118.3,
55.8, 54.2.
104.3, 103.9, 100.6, 56.0, 55.8, 54.1.
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1-(3,4-Difluorophenyl)-3,6,7-trimethoxyisoquinoline (4t). 4t 371.1237; 1H NMR (400 MHz, CDCl3): δ 8.36 (dd, J = 2.8, 8.8
was prepared according to the general synthetic procedure Hz, 1H), 8.35 (s, 1H), 7.11 (dd, J = 1.6, 8.0 Hz, 1H), 6.99 (s, 1H),
from 1a (196 mg, 1.0 mmol), 2t (142 mg, 1.0 mmol) and 6.94 (s, 1H), 6.68 (s, 1H), 4.01 (s, 3H), 3.98 (s, 3H), 3.83 (s, 3H),
MeOH 3a (10 mL); yield = 90% (298 mg); white solid; mp = 3.76 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 161.9, 159.8,
183–185 °C (recrystallized from hexanes and EtOAc); HRMS 153.4, 151.3, 148.4, 141.5, 137.1, 129.4, 127.5, 126.0, 119.4,
(ESI-TOF) m/z: [M + H]+ calcd for C18H16F2NO3 332.1098, 110.8, 104.5, 103.7, 100.7, 56.2, 56.0, 55.7, 54.2. Single-crystal
found 332.1104; 1H NMR (400 MHz, CDCl3): δ 7.61–7.55 (m, X-ray diagram: the crystal of compound 4x was grown by slow
1H), 7.49–7.45 (m, 1H), 7.33–7.26 (m, 1H), 7.20 (s, 1H), 6.97 (s, diffusion of EtOAc into a solution of compound 4x in CH2Cl2
1H), 6.89 (s, 1H), 4.011 (s, 3H), 4.005 (s, 3H), 3.85 (s, 3H); 13C to yield colorless prisms. The compound crystallizes in the
{1H} NMR (100 MHz, CDCl3): δ 159.6, 153.5, 153.3, 150.5 (dd, J monoclinic crystal system, space group P21/c, a = 10.5325(2) Å,
= 9.1, 244.8 Hz), 150.3 (dd, J = 9.1, 253.2 Hz), 148.6, 137.9, b = 8.1523(2) Å, c = 19.8965(4) Å, V = 1702.70(6) Å3, Z = 4, dcalcd
136.6 (t, J = 5.3 Hz), 125.9 (dd, J = 3.0, 6.1 Hz), 119.0 (d, J = 17.4 = 1.445 g cm−3, F(000) = 776, 2θ range 3.88–54.028°, R indices
Hz), 118.2, 117.1 (d, J = 17.4 Hz), 104.4, 103.9, 100.4, 56.0, (all data) R1 = 0.0440, wR2 = 0.0939.
55.8, 54.0.
3,6,7-Trimethoxy-1-(4-methoxy-3-nitrophenyl)isoquinoline (4y).
1-(2-Chloro-6-fluorophenyl)-3,6,7-trimethoxyisoquinoline (4u). 4y was prepared according to the general synthetic procedure
4u was prepared according to the general synthetic procedure from 1a (196 mg, 1.0 mmol), 2y (181 mg, 1.0 mmol) and
from 1a (196 mg, 1.0 mmol), 2u (158 mg, 1.0 mmol) and MeOH 3a (10 mL); yield = 86% (318 mg); white solid; mp =
MeOH 3a (10 mL); yield = 89% (309 mg); white solid; colorless 228–230 °C (recrystallized from hexanes and EtOAc); HRMS
liquid; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H16ClFNO3 (ESI-TOF) m/z: [M + H]+ calcd for C19H19N2O6 371.1243, found
348.0803, found 348.0810; 1H NMR (400 MHz, CDCl3): δ 371.1236; 1H NMR (400 MHz, CDCl3): δ 8.29 (d, J = 2.0 Hz, 1H),
7.45–7.36 (m, 2H), 7.17 (dt, J = 1.2, 8.4 Hz, 1H), 7.01 (s, 1H), 7.99 (dd, J = 2.0, 8.8 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.23 (s,
6.99 (s, 1H), 6.64 (s, 1H), 4.02 (s, 3H), 4.00 (s, 3H), 3.78 (s, 3H); 1H), 6.99 (s, 1H), 6.90 (s, 1H), 4.06 (s, 3H), 4.03 (s, 3H), 4.02 (s,
13C{1H} NMR (100 MHz, CDCl3): δ 160.8 (d, J = 248.7 Hz), 3H), 3.88 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 159.7,
159.7, 153.7, 148.9 (2x), 148.3, 137.2, 135.1, 130.4 (d, J = 9.1 153.4, 153.0, 152.7, 148.8, 139.4, 138.0, 135.5, 132.0, 127.1,
Hz), 125.5 (d, J = 3.8 Hz), 119.9, 114.4 (d, J = 22.0 Hz), 103.84, 118.2, 113.5, 104.2, 104.1, 100.5, 56.7, 56.0, 55.9, 54.1.
103.78, 101.2, 56.1, 55.8, 54.4.
1-(2-Cyclopentyloxy-5-nitrophenyl)-3,6,7-trimethoxyisoquino-
1-(3,4-Dimethoxyphenyl)-3,6,7-trimethoxyisoquinoline (4v). line (4z). 4z was prepared according to the general synthetic
4v was prepared according to the general synthetic procedure procedure from 1a (196 mg, 1.0 mmol), 2z (235 mg, 1.0 mmol)
from 1a (196 mg, 1.0 mmol), 2v (166 mg, 1.0 mmol) and and MeOH 3a (10 mL); yield = 84% (356 mg); white solid; mp
MeOH 3a (10 mL); yield = 82% (291 mg); white solid; mp = = 158–160 °C (recrystallized from hexanes and EtOAc); HRMS
112–114 °C (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H25N2O6 425.1713, found
(ESI-TOF) m/z: [M + H]+ calcd for C20H22NO5 356.1498, found 425.1707; 1H NMR (400 MHz, CDCl3): δ 8.35 (d, J = 2.4 Hz, 1H),
1
356.1491; H NMR (400 MHz, CDCl3): δ 7.37 (s, 1H), 7.32–7.30 8.32 (dd, J = 2.8, 9.2 Hz, 1H), 7.6 (d, J = 9.2 Hz, 1H), 6.97 (s,
(m, 2H), 7.01 (d, J = 8.8 Hz, 1H), 6.97 (s, 1H), 6.85 (s, 1H), 4.02 1H), 6.92 (s, 1H), 6.69 (s, 1H), 4.84–4.80 (m, 1H), 4.01 (s, 3H),
(s, 3H), 4.01 (s, 3H), 3.96 (s, 3H), 3.04 (s, 3H), 3.85 (s, 3H); 13C 3.98 (s, 3H), 3.76 (s, 3H), 1.89–1.82 (m, 1H), 1.77–1.70 (m, 1H),
{1H} NMR (100 MHz, CDCl3): δ 159.6, 155.9, 153.1, 149.4, 1.48–1.47 (m, 2H), 1.45–1.30 (m, 4H); 13C{1H} NMR (100 MHz,
148.8, 148.1, 137.8, 132.3, 122.4, 118.4, 113.1, 110.8, 105.4, CDCl3): δ 160.7, 159.8, 153.1, 151.8, 148.1, 141.0, 136.9, 130.0,
103.9, 99.2, 56.0, 55.9 (2x), 55.8, 54.0.
127.7, 125.8, 119.4, 112.5, 104.8, 103.7, 100.5, 80.9, 55.9, 55.6,
1-Benzo[1,3]dioxol-5-yl-3,6,7-trimethoxyisoquinoline
(4w). 54.2, 32.8, 32.7, 23.9, 23.8.
4w was prepared according to the general synthetic procedure
3,6,7-Trimethoxy-1-(4-methyl-3-nitrophenyl)isoquinoline (4aa).
from 1a (196 mg, 1.0 mmol), 2w (150 mg, 1.0 mmol) and 4aa was prepared according to the general synthetic procedure
MeOH 3a (10 mL); yield = 80% (271 mg); white solid; mp = from 1a (196 mg, 1.0 mmol), 2aa (165 mg, 1.0 mmol) and
167–169 °C (recrystallized from hexanes and EtOAc); HRMS MeOH 3a (10 mL); yield = 90% (319 mg); white solid; mp =
(ESI-TOF) m/z: [M + H]+ calcd for C19H18NO5 340.1185, found 192–194 °C (recrystallized from hexanes and EtOAc); HRMS
1
340.1179; H NMR (400 MHz, CDCl3): δ 7.32 (s, 1H), 7.24–7.21 (ESI-TOF) m/z: [M + H]+ calcd for C19H19N2O5 355.1294, found
(m, 2H), 6.98 (s, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.87 (s, 1H), 6.05 355.1286; 1H NMR (400 MHz, CDCl3): δ 8.40 (d, J = 1.6 Hz, 1H),
(s, 2H), 4.021 (s, 3H), 4.017 (s, 3H), 3.86 (s, 3H); 13C{1H} NMR 7.93 (dd, J = 1.6, 8.0 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.23 (s,
(100 MHz, CDCl3): δ 159.1, 155.3, 153.5, 148.4, 148.2, 147.8, 1H), 7.00 (s, 1H), 6.93 (s, 1H), 4.04 (s, 3H), 4.03 (s, 3H), 3.87 (s,
138.0, 123.9 (2x), 118.4, 110.4, 108.1, 105.3, 103.9, 101.3, 99.6, 3H), 2.71 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 159.7,
56.0, 55.9, 54.3.
3,6,7-Trimethoxy-1-(2-methoxy-5-nitrophenyl)isoquinoline (4x). 126.0, 118.3, 104.1, 104.0, 100.8, 56.1, 55.9, 54.2, 20.4.
4x was prepared according to the general synthetic procedure 3,6,7-Trimethoxy-1-(2,3,4-trimethoxyphenyl)isoquinoline (4ab).
153.4, 152.9, 149.2, 148.9, 138.3, 138.0, 134.2, 133.7, 132.7,
from 1a (196 mg, 1.0 mmol), 2x (181 mg, 1.0 mmol) and 4ab was prepared according to the general synthetic procedure
MeOH 3a (10 mL); yield = 88% (326 mg); white solid; mp = from 1a (196 mg, 1.0 mmol), 2ab (196 mg, 1.0 mmol) and
202–204 °C (recrystallized from hexanes and EtOAc); HRMS MeOH 3a (10 mL); yield = 79% (304 mg); white solid; colorless
(ESI-TOF) m/z: [M + H]+ calcd for C19H19N2O6 371.1243, found liquid; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H24NO6
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386.1604, found 386.1597; H NMR (400 MHz, CDCl3): δ 7.14 and MeOH 3a (10 mL); yield = 90% (292 mg); white solid; mp
(d, J = 8.4 Hz, 1H), 6.97 (s, 1H), 6.91 (s, 2H), 6.82 (d, J = 8.4 Hz, = 188–190 °C (recrystallized from hexanes and EtOAc); HRMS
1H), 4.014 (s, 3H), 4.013 (s, 3H), 3.954 (s, 3H), 3.949 (s, 3H), (ESI-TOF) m/z: [M + H]+ calcd for C17H13N2O5 325.0825, found
3.79 (s, 3H), 3.63 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 325.0832; 1H NMR (400 MHz, CDCl3): δ 8.37 (d, J = 8.8 Hz, 2H),
154.3, 151.9, 148.2, 142.1, 137.3, 125.8, 125.7, 123.9, 119.7, 7.86 (d, J = 8.8 Hz, 2H), 7.13 (s, 1H), 7.02 (s, 1H), 6.94 (s, 1H),
113.7, 107.3, 105.8, 103.6, 100.7, 99.7, 61.6, 61.1, 56.1, 56.0, 6.06 (s, 2H), 4.01 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
55.8, 54.5.
159.8, 153.5, 151.3, 147.8, 147.4, 145.6, 139.7, 130.9 (2x), 123.5
3,6,7-Trimethoxy-1-(3,4,5-trimethoxyphenyl)isoquinoline (4ac). (2x), 119.5, 102.4, 101.8, 101.68, 101.65, 54.2.
4ac was prepared according to the general synthetic procedure
5-(3,4-Dimethoxyphenyl)-7-methoxy[1,3]dioxolo[4,5-g]iso-
from 1a (196 mg, 1.0 mmol), 2ac (196 mg, 1.0 mmol) and quinoline (4ag). 4ag was prepared according to the general
MeOH 3a (10 mL); yield = 82% (316 mg); white solid; mp = synthetic procedure from 1b (180 mg, 1.0 mmol), 2v (166 mg,
123–125 °C (recrystallized from hexanes and EtOAc); HRMS 1.0 mmol) and MeOH 3a (10 mL); yield = 80% (271 mg); white
(ESI-TOF) m/z: [M + H]+ calcd for C21H24NO6 386.1604, found solid; mp = 167–169 °C (recrystallized from hexanes and
386.1610; 1H NMR (400 MHz, CDCl3): δ 7.36 (s, 1H), 6.99 (s, EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H18NO5
1
1H), 6.97 (s, 2H), 6.87 (d, J = 0.4 Hz, 1H), 4.02 (s, 3H), 4.01 (s, 340.1185, found 340.1179; H NMR (400 MHz, CDCl3): δ 7.33
3H), 3.93 (s, 6H), 3.90 (s, 3H), 3.85 (s, 3H); 13C{1H} NMR (s, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 2.0, 8.0 Hz, 1H),
(100 MHz, CDCl3): δ 159.5, 155.8, 153.2, 153.1 (2x), 148.2, 7.000 (d, J = 8.0 Hz, 1H), 6.995 (s, 1H), 6.85 (s, 1H), 6.04 (s,
138.3, 137.8, 134.8, 118.3, 107.1 (2x), 105.2, 103.9, 99.5, 60.9, 2H), 4.02 (s, 3H), 3.96 (s, 3H), 3.95 (s, 3H); 13C{1H} NMR
56.2 (2x), 56.0, 55.8, 54.2.
(100 MHz, CDCl3): δ 159.6, 156.3, 151.1, 149.6, 148.9 (2x),
3,6,7-Trimethoxy-1-(5-nitrothiophen-2-yl)isoquinoline (4ad). 146.7, 139.5, 122.6, 119.7, 113.2, 110.7, 103.1, 101.6, 101.4,
4ad was prepared according to the general synthetic procedure 100.4, 56.04, 56.00, 54.2.
from 1a (196 mg, 1.0 mmol), 2ad (157 mg, 1.0 mmol) and
5-Benzo[1,3]dioxol-5-yl-7-methoxy[1,3]dioxolo[4,5-g]iso-
MeOH 3a (10 mL); yield = 83% (287 mg); red solid; mp = quinoline (4ah). 4ah was prepared according to the general
233–235 °C (recrystallized from hexanes and EtOAc); HRMS synthetic procedure from 1b (180 mg, 1.0 mmol), 2w (150 mg,
(ESI-TOF) m/z: [M + H]+ calcd for C16H15N2O5S 347.0702, found 1.0 mmol) and MeOH 3a (10 mL); yield = 80% (258 mg); white
347.0698; 1H NMR (400 MHz, CDCl3): δ 7.98 (d, J = 4.4 Hz, 1H), solid; mp = 212–214 °C (recrystallized from hexanes and
7.58 (d, J = 4.0 Hz, 1H), 7.55 (s, 1H), 6.97 (s, 2H), 4.04 (s, 3H), EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H14NO5
1
4.03 (s, 3H), 3.99 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 324.0872, found 324.0868; H NMR (400 MHz, CDCl3): δ 7.30
158.9, 153.6, 151.4, 150.0, 144.9, 138.6, 128.7 (2x), 125.9, 118.3, (s, 1H), 7.18 (d, J = 1.6 Hz, 1H), 7.15 (dd, J = 1.6, 8.0 Hz, 1H),
104.2, 103.5, 103.0, 56.1, 56.0, 54.1.
6.96 (s, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.83 (s, 1H), 6.04 (s, 2H),
6,7-Dimethoxy-1-(5-nitrothiophen-2-yl)isoquinolin-3-ol (4ad-1). 6.02 (s, 2H), 4.00 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
4ad-1 was prepared according to the general synthetic pro- 159.7, 155.9, 150.9, 147.9, 147.6, 146.6, 139.4, 133.4, 123.9,
cedure from 1a (196 mg, 1.0 mmol), 2ad (157 mg, 1.0 mmol) 119.5, 110.4, 108.1, 102.9, 101.5, 101.4, 101.2, 100.8, 54.0.
and MeOH 3a (10 mL); yield = 5% (16 mg); red solid; mp =
7-Methoxy-5-(2,3,4-trimethoxyphenyl)[1,3]dioxolo[4,5-g]iso-
213–215 °C (recrystallized from hexanes and EtOAc); HRMS quinoline (4ai). 4ai was prepared according to the general syn-
(ESI-TOF) m/z: [M + H]+ calcd for C15H13N2O5S 333.0545, found thetic procedure from 1b (180 mg, 1.0 mmol), 2ab (196 mg,
333.0540; 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 4.4 Hz, 1H), 1.0 mmol) and MeOH 3a (10 mL); yield = 75% (277 mg); white
7.73 (s, 1H), 7.58 (d, J = 4.0 Hz, 1H), 6.99 (s, 1H), 6.97 (s, 1H), solid; mp = 168–170 °C (recrystallized from hexanes and
6.00 (br s, 1H), 4.07 (s, 3H), 4.04 (s, 3H); 13C{1H} NMR EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H20NO6
1
(100 MHz, CDCl3): δ 158.7, 151.1, 146.1, 145.2, 138.1, 131.1, 370.1291, found 370.1285; H NMR (400 MHz, CDCl3): δ 7.06
128.7, 126.1, 118.7, 113.6, 106.3, 103.6 (2x), 56.2, 54.0.
(d, J = 8.4 Hz, 1H), 6.96 (s, 1H), 6.89 (s, 1H), 6.87 (d, J = 0.4 Hz,
7-Methoxy-5-(3-nitrophenyl)[1,3]dioxolo[4,5-g]isoquinoline 1H), 6.79 (d, J = 8.4 Hz, 1H), 5.99 (s, 2H), 3.99 (s, 3H), 3.95 (s,
(4ae). 4ae was prepared according to the general synthetic pro- 3H), 3.93 (s, 3H), 3.65 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3):
cedure from 1b (180 mg, 1.0 mmol), 2f (151 mg, 1.0 mmol) δ 159.7, 154.3, 154.0, 151.8, 151.1, 146.4, 142.2, 138.7, 126.4, 125.5,
and MeOH 3a (10 mL); yield = 90% (292 mg); white solid; mp 121.0, 107.3, 103.2, 101.3, 101.2, 100.9, 61.5, 61.0, 56.1, 54.2.
= 197–199 °C (recrystallized from hexanes and EtOAc); HRMS
7-Methoxy-5-(3,4,5-trimethoxyphenyl)[1,3]dioxolo[4,5-g]iso-
(ESI-TOF) m/z: [M + H]+ calcd for C17H13N2O5 325.0825, found quinoline (4aj). 4aj was prepared according to the general syn-
325.0830; 1H NMR (400 MHz, CDCl3): δ 8.55 (t, J = 2.0 Hz, 1H), thetic procedure from 1b (180 mg, 1.0 mmol), 2ac (196 mg,
8.32 (ddd, J = 1.2, 2.4, 8.0 Hz, 1H), 8.01 (dt, J = 1.6, 7.6 Hz, 1H), 1.0 mmol) and MeOH 3a (10 mL); yield = 87% (321 mg); white
7.68 (t, J = 7.6 Hz, 1H), 7.12 (s, 1H), 7.01 (s, 1H), 6.92 (s, 1H), solid; mp = 145–147 °C (recrystallized from hexanes and
6.05 (s, 2H), 4.01 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H20NO6
1
159.9, 153.4, 151.2, 148.2, 147.3, 141.2, 139.5, 135.8, 129.3, 370.1291, found 370.1286; H NMR (400 MHz, CDCl3): δ 7.31
124.8, 123.2, 119.4, 102.2, 101.7, 101.6, 101.5, 54.1.
(s, 1H), 7.02 (s, 1H), 6.89 (s, 3H), 6.06 (s, 2H), 4.03 (s, 3H), 3.93
7-Methoxy-5-(4-nitrophenyl)[1,3]dioxolo[4,5-g]isoquinoline (s, 3H), 3.91 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 159.2,
(4af). 4af was prepared according to the general synthetic pro- 153.8, 153.1 (2x), 147.1, 139.8, 119.6, 107.4, 107.2, 103.1, 102.1,
cedure from 1b (180 mg, 1.0 mmol), 2m (151 mg, 1.0 mmol) 101.8, 101.7 (2x), 100.7, 99.1, 61.0, 56.3 (2x), 54.5.
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1-(3,4-Dimethoxyphenyl)-3-methoxy-6,7-dipropoxyisoquino- 3b (10 mL); yield = 80% (283 mg); white solid; mp =
line (4ak). 4ak was prepared according to the general synthetic 184–186 °C (recrystallized from hexanes and EtOAc); HRMS
procedure from 1c (252 mg, 1.0 mmol), 2v (166 mg, 1.0 mmol) (ESI-TOF) m/z: [M + H]+ calcd for C19H19N2O5 355.1294, found
and MeOH 3a (10 mL); yield = 80% (329 mg); white solid; mp 355.1297; 1H NMR (400 MHz, CDCl3): δ 8.53 (t, J = 2.0 Hz, 1H),
= 110–112 °C (recrystallized from hexanes and EtOAc); HRMS 8.39 (ddd, J = 1.2, 2.4, 8.4 Hz, 1H), 8.11 (dt, J = 1.2, 8.0 Hz, 1H),
(ESI-TOF) m/z: [M + H]+ calcd for C24H30NO5 412.2124, found 7.64 (t, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.26 (s, 1H), 6.86 (s, 1H),
1
412.2118; H NMR (400 MHz, CDCl3): δ 7.36 (s, 1H), 7.31–7.29 4.06 (q, J = 7.2 Hz, 2H), 4.02 (s, 3H), 3.94 (s, 3H), 1.08 (t, J = 7.2
(m, 2H), 7.01 (d, J = 8.8 Hz, 1H), 6.95 (s, 1H), 6.81 (s, 1H), 4.08 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 165.2, 152.6, 149.9,
(t, J = 6.8 Hz, 2H), 4.01 (s, 3H), 3.96 (s, 3H), 3.93 (s, 3H), 3.90 148.4, 140.8, 139.2, 134.4, 134.1, 129.7, 127.1, 123.7, 121.7,
(t, J = 6.4 Hz, 2H), 1.95–1.82 (m, 4H), 1.09 (t, J = 7.6 Hz, 3H), 112.3 (2x), 110.1, 61.5, 56.31, 56.30, 13.8.
1.03 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
3-Isopropoxy-6,7-dimethoxy-1-(3-nitrophenyl)isoquinoline
159.4, 155.7, 153.2, 149.3, 148.7, 148.0, 137.8, 132.2, 122.5, (5b). 5b was prepared according to the general synthetic pro-
118.4, 113.1, 110.7, 107.1, 104.7, 98.9, 70.3, 70.1, 55.90, 55.88, cedure from 1a (196 mg, 1.0 mmol), 2f (151 mg, 1.0 mmol)
54.0, 22.3, 22.2, 10.41, 10.40.
and iPrOH 3c (10 mL); yield = 80% (295 mg); colorless liquid;
1-(3,4-Dimethoxyphenyl)-3,6,7,8-tetramethoxyisoquinoline HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H21N2O5 369.1451,
1
(4al). 4al was prepared according to the general synthetic pro- found 369.1455; H NMR (400 MHz, CDCl3): δ 8.62 (t, J = 2.0
cedure from 1d (226 mg, 1.0 mmol), 2v (166 mg, 1.0 mmol) Hz, 1H), 8.34 (ddd, J = 0.8, 2.4, 8.0 Hz, 1H), 8.10 (dt, J = 1.2, 7.6
and MeOH 3a (10 mL); yield = 78% (300 mg); colorless liquid; Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.15 (s, 1H), 6.99 (s, 1H), 6.93
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H24NO6 386.1604, (s, 1H), 5.29–5.23 (m, 1H), 4.04 (s, 3H), 3.84 (s, 3H), 1.42 (d, J =
found 386.1598; 1H NMR (400 MHz, CDCl3): δ 7.13–7.11 (m, 6.4 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 158.5, 153.6,
2H), 6.94 (d, J = 8.8 Hz, 1H), 6.86 (s, 1H), 6.83 (s, 1H), 4.02 (s, 152.7, 149.0, 148.2, 140.8, 138.2, 135.9, 129.4, 124.9, 123.4,
3H), 4.01 (s, 3H), 3.95 (s, 3H), 3.91 (s, 3H), 3.88 (s, 3H), 3.35 (s, 118.1, 104.0, 103.9, 102.4, 69.2, 56.1, 55.9, 22.2 (2x).
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 158.9, 156.0, 150.3,
149.0, 147.6, 140.8, 140.0, 124.0, 122.1, 114.3, 113.0, 109.9, 5c was prepared according to the general synthetic procedure
104.1, 100.3, 99.1, 61.2, 61.0, 56.04, 55.97, 55.9, 54.7. from 1a (196 mg, 1.0 mmol), 2f (151 mg, 1.0 mmol) and
3-n-Butoxy-6,7-dimethoxy-1-(3-nitrophenyl)isoquinoline (5c).
1-(3,4-Dimethoxyphenyl)-3,6-dimethoxyisoquinoline (4am). nBuOH 3d (10 mL); yield = 82% (313 mg); white solid; mp =
4am was prepared according to the general synthetic pro- 89–91 °C (recrystallized from hexanes and EtOAc); HRMS
cedure from 1e (166 mg, 1.0 mmol), 2v (166 mg, 1.0 mmol) (ESI-TOF) m/z: [M + H]+ calcd for C21H23N2O5 383.1607, found
and MeOH 3a (10 mL); yield = 78% (254 mg); white solid; mp 383.1601; 1H NMR (400 MHz, CDCl3): δ 8.62 (t, J = 2.0 Hz, 1H),
= 78–80 °C (recrystallized from hexanes and EtOAc); HRMS 8.33 (ddd, J = 1.2, 2.4, 8.4 Hz, 1H), 8.10 (dt, J = 1.2, 8.0 Hz, 1H),
(ESI-TOF) m/z: [M + H]+ calcd for C19H20NO4 326.1392, found 7.70 (t, J = 8.0 Hz, 1H), 7.15 (s, 1H), 7.00 (s, 1H), 6.94 (s, 1H),
326.1388; 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 9.6 Hz, 1H), 4.33 (t, J = 6.8 Hz, 2H), 4.03 (s, 3H), 3.84 (s, 3H), 1.87–1.80 (m,
7.30 (d, J = 2.0 Hz, 1H), 7.26 (dd, J = 2.0, 8.4 Hz, 1H), 7.00 (d, J 2H), 1.58–1.50 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H); 13C{1H} NMR
= 8.4 Hz, 1H), 6.97 (d, J = 2.8 Hz, 1H), 6.94 (dd, J = 2.4, 9.2 Hz, (100 MHz, CDCl3): δ 159.5, 153.5, 152.9, 148.9, 148.2, 140.9,
1H), 6.86 (s, 1H), 4.04 (s, 3H), 3.96 (s, 3H), 3.94 (s, 3H), 3.93 (s, 138.1, 135.9, 129.4, 124.9, 123.3, 118.2, 104.0, 103.9, 101.1,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 160.8, 160.6, 158.2, 66.8, 56.1, 55.8, 31.3, 19.3, 13.9.
149.6, 148.8, 142.8, 131.7, 129.5, 122.9, 118.8, 117.7, 113.3,
110.6, 103.2, 99.0, 55.99, 55.96, 55.3, 54.2.
General synthetic procedure of 6a–6g
H2O (180 mg, 10 mmol) was added to PCl5 (2.1 g, 10 mmol) to
generate gaseous HCl. Excess HCl gas was added to a solution
General synthetic procedure of 5a–5d
NH2OH-HCl (75 mg, 1.1 mmol) was added to a solution of of substituted benzaldehydes 2a, 2b, 2e, 2i, 2o, 2p or 2t
3-nitrobenzaldehyde 2f (151 mg, 1.0 mmol) in alcohols 3b–3e (1.0 mmol) in methanol 3a (5 mL) at 25 °C. The reaction
(5 mL) at 25 °C. The reaction mixture was stirred at 25 °C for mixture was stirred at 25 °C for 15 min. A solution of 3,4-
15 min. A solution of 3,4-dimethoxyphenylacetic acid 1a dimethoxyphenylacetic acid 1a (196 mg, 1.0 mmol) in metha-
(196 mg, 1.0 mmol) in alcohols 3b–3e (5 mL) was added to the nol 3a (5 mL) was added to the reaction mixture at 25 °C. The
reaction mixture at 25 °C. The reaction mixture was stirred at reaction mixture was stirred at reflux for 20 h. The reaction
reflux for 20 h. The reaction mixture was cooled to 25 °C and mixture was cooled to 25 °C and the solvent was concentrated.
the solvent was concentrated. The residue was diluted with The residue was diluted with water (10 mL) and the mixture
water (10 mL) and the mixture was extracted with CH2Cl2 (3 × was extracted with CH2Cl2 (3 × 20 mL). The combined organic
20 mL). The combined organic layers were washed with brine, layers were washed with brine, dried, filtered and evaporated
dried, filtered and evaporated to afford the crude product to afford the crude product under reduced pressure.
under reduced pressure. Purification on silica gel (hexanes/ Purification on silica gel (hexanes/EtOAc = 15/1–8/1) afforded
EtOAc = 8/1–4/1) afforded 5a–5d.
3-Ethoxy-6,7-dimethoxy-1-(3-nitrophenyl)isoquinoline (5a).
6a–6g.
[4,5-Dimethoxy-2-(methoxyphenylmethyl)phenyl]acetic acid
5a was prepared according to the general synthetic procedure methyl ester (6a). 6a was prepared according to the general
from 1a (196 mg, 1.0 mmol), 2f (151 mg, 1.0 mmol) and EtOH synthetic procedure from 1a (196 mg, 1.0 mmol), 2a (106 mg,
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1.0 mmol) and MeOH 3a (10 mL); yield = 73% (241 mg); color- 114.1, 111.2, 111.0, 81.3, 57.0, 55.9, 55.8, 51.9, 37.6. Single-
less liquid; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H23O5 crystal X-ray diagram: the crystal of compound 6e was grown
331.1546, found 331.1540; 1H NMR (400 MHz, CDCl3): δ by slow diffusion of EtOAc into a solution of compound 6e in
7.32–7.21 (m, 5H), 6.92 (s, 1H), 6.74 (s, 1H), 5.43 (s, 1H), 3.86 CH2Cl2 to yield colorless prisms. The compound crystallizes in
(s, 3H), 3.82 (s, 3H), 3.58 (s, 3H), 3.57 (s, 2H), 3.36 (s, 3H); 13C the monoclinic crystal system, space group P21/n, a = 8.6565(2)
{1H} NMR (100 MHz, CDCl3): δ 171.8, 148.0, 140.9, 132.0, 128.1 Å, b = 9.9527(2) Å, c = 20.7506(5) Å, V = 1777.20(7) Å3, Z = 4,
(2x), 127.3, 127.1 (3x), 124.6, 113.9, 110.8, 82.0, 56.9, 55.73, dcalcd = 1.328 g cm−3, F(000) = 752, 2θ range 4.54–52°, R
55.72, 51.7, 37.6.
indices (all data) R1 = 0.0728, wR2 = 0.1550.
{2-[(2-Bromophenyl)methoxymethyl]-4,5-dimethoxyphenyl}-
[2-(Biphenyl-4-ylmethoxymethyl)-4,5-dimethoxyphenyl]acetic
acetic acid methyl ester (6b). 6b was prepared according to the acid methyl ester (6f). 6f was prepared according to the
general synthetic procedure from 1a (196 mg, 1.0 mmol), 2b general synthetic procedure from 1a (196 mg, 1.0 mmol), 2p
(184 mg, 1.0 mmol) and MeOH 3a (10 mL); yield = 78% (182 mg, 1.0 mmol) and MeOH 3a (10 mL); yield = 80%
(318 mg); colorless liquid; HRMS (ESI-TOF) m/z: [M + H]+ calcd (325 mg); colorless liquid; HRMS (ESI-TOF) m/z: [M + H]+ calcd
1
for C19H22BrO5 409.0651, found 409.0645; H NMR (400 MHz, for C25H27O5 407.1859, found 407.1862; 1H NMR (400 MHz,
CDCl3): δ 7.58 (dd, J = 1.2, 8.0 Hz, 1H), 7.31–7.23 (m, 2H), 7.15 CDCl3): δ 7.60–7.55 (s, 4H), 7.45–7.32 (m, 5H), 7.00 (s, 1H),
(dt, J = 2.0, 8.0 Hz, 1H), 6.80 (s, 1H), 6.78 (s, 1H), 5.74 (s, 1H), 6.78 (s, 1H), 5.49 (s, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.62 (s, 2H),
3.88 (s, 3H), 3.77 (s, 3H), 3.60 (s, 2H), 3.59 (s, 3H), 3.42 (s, 3H); 3.61 (s, 3H), 3.41 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
13C{1H} NMR (100 MHz, CDCl3): δ 171.7, 148.3, 148.0, 139.5, 171.9, 148.2, 140.7, 140.3, 140.1, 131.9, 128.7 (2x), 127.6 (2x),
133.0, 130.5, 129.3, 129.3, 127.5, 125.3, 124.7, 114.1, 110.6, 127.2 (2x), 126.9 (4x), 124.6, 114.0, 110.9, 81.9, 57.0, 55.9, 55.8,
80.7, 57.6, 55.9, 55.8, 51.9, 37.9.
51.8, 37.7.
{4,5-Dimethoxy-2-[methoxy-(3-methoxyphenyl)methyl]-
{2-[(3,4-Difluorophenyl)methoxymethyl]-4,5-dimethoxy-
phenyl}acetic acid methyl ester (6c). 6c was prepared phenyl}acetic acid methyl ester (6g). 6g was prepared
according to the general synthetic procedure from 1a (196 mg, according to the general synthetic procedure from 1a (196 mg,
1.0 mmol), 2e (136 mg, 1.0 mmol) and MeOH 3a (10 mL); 1.0 mmol), 2t (142 mg, 1.0 mmol) and MeOH 3a (10 mL); yield
yield = 74% (267 mg); colorless liquid; HRMS (ESI-TOF) m/z: = 73% (267 mg); colorless liquid; HRMS (ESI-TOF) m/z: [M +
[M + H]+ calcd for C20H25O6 361.1651, found 361.1648; 1H H]+ calcd for C19H21F2O5 367.1357, found 367.1362; 1H NMR
NMR (400 MHz, CDCl3): δ 7.21 (dt, J = 0.4, 8.0 Hz, 1H), 6.90 (s, (400 MHz, CDCl3): δ 7.14–7.05 (m, 2H), 6.99–6.95 (m, 1H), 6.83
1H), 6.86–6.84 (m, 2H), 6.80–6.77 (m, 1H), 6.74 (s, 1H), 5.39 (s, (s, 1H), 6.75 (s, 1H), 5.37 (s, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.61
1H), 3.86 (s, 3H), 3.82 (s, 3H), 3.76 (s, 3H), 3.61 (s, 3H), 3.58 (s, (s, 3H), 3.58 (d, J = 16.0 Hz, 1H), 3.53 (d, J = 15.6 Hz, 1H), 3.34
2H), 3.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 171.9, (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 171.8, 151.2 (dd, J =
159.6, 148.2, 148.1, 142.6, 132.0, 129.2, 124.7, 119.6, 114.0, 12.9, 246.4 Hz), 149.5 (dd, J = 12.9, 246.4 Hz), 148.5, 148.4,
112.8 (2x), 110.9, 81.9, 57.0, 55.83, 55.81, 55.1, 51.8, 37.7.
138.5 (t, J = 4.6 Hz), 131.1, 124.8, 123.1 (dd, J = 3.0, 6.0 Hz),
{2-[(4-Chlorophenyl)methoxymethyl]-4,5-dimethoxyphenyl}- 116.9 (d, J = 17.4 Hz), 116.2 (d, J = 18.2 Hz), 114.1, 110.9, 80.9,
acetic acid methyl ester (6d). 6d was prepared according to the 57.0, 56.0, 55.9, 51.9, 37.7.
general synthetic procedure from 1a (196 mg, 1.0 mmol), 2i
6,7-Dimethoxy-3-(methoxy-d3)-1-(3-nitrophenyl)isoquino-
(140 mg, 1.0 mmol) and MeOH 3a (10 mL); yield = 76% line-4-d (7). NH2OH-HCl (75 mg, 1.1 mmol) was added to a
(277 mg); colorless liquid; HRMS (ESI-TOF) m/z: [M + H]+ calcd solution of 3-nitrobenzaldehyde 2f (151 mg, 1.0 mmol) in
1
for C19H22ClO5 365.1156, found 365.1150; H NMR (400 MHz, CD3OD 3f (5 mL) at 25 °C. The reaction mixture was stirred at
CDCl3): δ 7.28 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 6.86 25 °C for 15 min. A solution of 3,4-dimethoxyphenylacetic acid
(s, 1H), 6.74 (s, 1H), 5.39 (s, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.59 1a (196 mg, 1.0 mmol) in CD3OD 3f (5 mL) was added to the
(s, 3H), 3.56 (d, J = 16.0 Hz, 1H), 3.54 (d, J = 16.0 Hz, 1H), 3.35 reaction mixture at 25 °C. The reaction mixture was stirred at
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 171.8, 148.4, 148.3, reflux for 20 h. The reaction mixture was cooled to 25 °C and
139.8, 133.2, 131.5, 128.6 (2x), 128.4 (2x), 124.8, 114.1, 111.0, the solvent was concentrated. The residue was diluted with
81.4, 57.0, 55.93, 55.89, 51.9, 37.7.
water (10 mL) and the mixture was extracted with CH2Cl2 (3 ×
{4,5-Dimethoxy-2-[methoxy(4-cyanophenyl)methyl]phenyl}- 20 mL). The combined organic layers were washed with brine,
acetic acid methyl ester (6e). 6e was prepared according to the dried, filtered and evaporated to afford the crude product
general synthetic procedure from 1a (196 mg, 1.0 mmol), 2o under reduced pressure. Purification on silica gel (hexanes/
(131 mg, 1.0 mmol) and MeOH 3a (10 mL); yield = 70% EtOAc = 8/1–4/1) afforded 7. Yield = 88% (303 mg); white solid;
(249 mg); white solid; mp = 123–125 °C (recrystallized from mp = 189–191 °C (recrystallized from hexanes and EtOAc);
hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H13D4N2O5
1
C20H22NO5 356.1498, found 356.1493; 1H NMR (400 MHz, 345.1385, found 3445.1379; H NMR (400 MHz, CDCl3): δ 8.63
CDCl3): δ 7.58 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 6.76 (t, J = 2.0 Hz, 1H), 8.33 (dd, J = 1.2, 8.0 Hz, 1H), 8.11 (d, J = 7.6
(s, 1H), 6.74 (s, 1H), 5.45 (s, 1H), 3.86 (s, 3H), 3.80 (s, 3H), Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.17 (s, 1H), 7.01 (s, 1H), 4.03
3.583 (d, J = 16.0 Hz, 1H), 3.579 (s, 3H), 3.53 (d, J = 16.0 Hz, (s, 3H), 3.84 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 159.7,
1H), 3.34 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 171.6, 153.4, 152.8, 149.0, 148.3, 141.1, 138.0, 135.9, 129.4, 124.8,
148.6, 148.4, 146.8, 132.0 (2x), 130.6, 127.6 (2x), 125.0, 118.7, 123.3, 118.3, 104.0, 103.9, 100.9 (t, J = 19.6 Hz, CD), 56.0, 55.8,
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55.5 (septet, J = 18.3 Hz, CD3); 2H NMR (92 MHz, CH2Cl2): δ 2a (530 mg, 5.0 mmol) in methanol 3a (30 mL) at 25 °C. The
6.99 (s, 1D), 3.96 (s, 3D). reaction mixture was stirred at 25 °C for 15 min. A solution of
Methyl-d3 2-(4,5-dimethoxy-2-((methoxy-d3)(3-nitrophenyl)- homoveratric acid 1a (980 mg, 5.0 mmol) in methanol 3a
methyl)phenyl)acetate-d2 (8). D2O (200 mg, 10 mmol) was (30 mL) was added to the reaction mixture at 25 °C. The reac-
added to PCl5 (2.1 g, 10 mmol) to generate gaseous DCl. tion mixture was stirred at reflux for 30 h. The reaction
Excess freshly prepared DCl gas was added to a solution of mixture was cooled to 25 °C and the solvent was concentrated.
3-nitrobenzaldehyde 2f (151 mg, 1.0 mmol) in CD3OD 3f The residue was diluted with water (20 mL) and the mixture
(5 mL) at 25 °C. The reaction mixture was stirred at 25 °C for was extracted with CH2Cl2 (3 × 40 mL). The combined organic
15 min. A solution of 3,4-dimethoxyphenylacetic acid 1a layers were washed with brine, dried, filtered and evaporated
(196 mg, 1.0 mmol) in CD3OD 3f (5 mL) was added to the reac- to afford the crude product under reduced pressure.
tion mixture at 25 °C. The reaction mixture was stirred at Purification on silica gel (hexanes/EtOAc = 8/1–4/1) afforded 4a
reflux for 20 h. The reaction mixture was cooled to 25 °C and (1.21 g, 82%).
the solvent was concentrated. The residue was diluted with
water (10 mL) and the mixture was extracted with CH2Cl2 (3 ×
20 mL). The combined organic layers were washed with brine, Conflicts of interest
dried, filtered and evaporated to afford the crude product
under reduced pressure. Purification on silica gel (hexanes/
There are no conflicts of interest to declare.
EtOAc = 15/1–8/1) afforded 8. Yield = 70% (268 mg); colorless
liquid; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H14D8NO7
384.1890, found 384.1883; H NMR (400 MHz, CDCl3): δ 8.21
1
Acknowledgements
(t, J = 1.2 Hz, 1H), 8.11 (dd, J = 0.8, 7.6 Hz, 1H), 7.59 (d, J = 8.4
Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 6.82 (s, 1H), 6.77 (s, 1H), 5.52
(s, 1H), 3.89 (s, 3H), 3.83 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 171.7, 148.8, 148.6, 148.3, 144.0, 133.0, 130.7, 129.1,
124.9, 122.4, 122.0, 114.1 (d, J = 3.9 Hz), 111.0, 80.8, 56.3
(septet, J = 18.3 Hz, CD3), 56.0, 55.9, 51.3 (septet, J = 19.0 Hz,
CD3), 37.5 (quintet, J = 17.0 Hz, CD2); 2H NMR (92 MHz,
CH2Cl2): δ 3.54 (s, 5D), 3.31 (s, 3D).
The authors would like to thank the Ministry of Science and
Technology of the Republic of China (Taiwan) for its financial
support (MOST 109-2113-M-037-014-MY3).
Notes and references
1 (a) M. Chrzanowska, A. Grajewska and M. D. Rozwadowska,
Chem. Rev., 2016, 116, 12369–12465; (b) M. Chrzanowska
and M. D. Rozwadowska, Chem. Rev., 2004, 104, 3341–3370.
2 E. L. Larghi, M. L. Bohn and T. S. Kaufman, Tetrahedron,
2009, 65, 4257–4282.
3 R. Gujjarappa, N. Vodnala and C. C. Malakar, Adv. Synth.
Catal., 2020, 362, 4896–4990.
4 E. Awuah and A. Capretta, J. Org. Chem., 2010, 75, 5627–
5634 and references cited therein.
5 N. Todorovic, E. Awuah, S. Albu, C. Ozimok and
A. Capretta, Org. Lett., 2011, 13, 6180–6183 and references
cited therein.
6 T. Noguchi, Y. Nishii and M. Miura, Chem. Lett., 2017, 46,
1512–1514.
7 X.-C. Li, C. Du, H. Zhang, J.-L. Niu and M.-P. Song, Org.
Lett., 2019, 21, 2863–2866.
8 C. Zhou, J. Jiang and J. Wang, Org. Lett., 2019, 21, 4971–
4975.
[4,5-Dimethoxy-2-(3-nitrobenzyl)phenyl]acetic acid ethyl
ester (9). H2O (180 mg, 10 mmol) was added to PCl5 (2.1 g,
10 mmol) to generate gaseous HCl. Excess freshly prepared
HCl gas was added to a solution of 3-nitrobenzaldehyde 2f
(151 mg, 1.0 mmol) in EtOH 3b (5 mL) at 25 °C. The reaction
mixture was stirred at 25 °C for 15 min. A solution of 3,4-
dimethoxyphenylacetic acid 1a (196 mg, 1.0 mmol) in EtOH 3b
(5 mL) was added to the reaction mixture at 25 °C. The reac-
tion mixture was stirred at reflux for 20 h. The reaction
mixture was cooled to 25 °C. The reaction could be monitored
by TLC. NaBH4 (114 mg, 3.0 mmol) was added to the reaction
mixture at 25 °C. Then, the reaction mixture was stirred at
25 °C for 5 h, and the solvent was concentrated. The residue
was diluted with water (10 mL) and the mixture was extracted
with CH2Cl2 (3 × 20 mL). The combined organic layers were
washed with brine, dried, filtered and evaporated to afford the
crude product under reduced pressure. Purification on silica
gel (hexanes/EtOAc = 15/1–8/1) afforded 9. Yield = 46%
9 A. Nikbakht, S. Balalaie and B. Breit, Org. Lett., 2019, 21,
7645–7648.
(165 mg); colorless liquid; HRMS (ESI-TOF) m/z: [M + H]+ calcd
1
for C19H22NO6 360.1447, found 360.1440; H NMR (400 MHz, 10 M. Y. Chang, K.-T. Chen, Y.-T. Hsiao and S.-M. Chen, J. Org.
CDCl3): δ 8.07–8.03 (m, 1H), 7.98 (s, 1H), 7.46–7.42 (m, 2H),
7.90 (s, 1H), 6.63 (s, 1H), 4.09 (s, 2H), 4.06 (q, J = 7.2 Hz, 2H), 11 CCDC 2000637 (4r), 2000638 (4x) and 2000639 (6e) contain
3.89 (s, 3H), 3.82 (s, 3H), 3.49 (s, 2H), 1.20 (t, J = 7.2 Hz, 3H); the supplementary crystallographic data for this paper.†
13C{1H} NMR (100 MHz, CDCl3): δ 171.4, 148.3, 148.0, 142.8, 12 T. Misawa, K. Dodo, M. Ishikawa, Y. Hashimoto,
Chem., 2020, 85, 3605–3616.
134.7, 129.5, 129.3, 128.3, 125.0, 123.3, 121.3, 114.1, 113.7,
60.9, 56.0, 55.9, 38.5, 38.2, 14.1.
M. Sagawa, M. Kizaki and H. Aoyama, Bioorg. Med. Chem.,
2015, 23, 2241–2246.
Gram-scale synthesis of compound 4a. NH2OH-HCl 13 O. S. Taskin, B. A. Temel, M. A. Tasdelen and Y. Yagci, Eur.
(380 mg, 5.5 mmol) was added to a solution of benzaldehyde
Polym. J., 2015, 62, 304–311.
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Paper
14 J. D. Keighron, J. C. Quarterman, J. Cao, E. M. De Marco, 16 H. Tsuchihashi, T. Sasaki, S. Kojima and T. Nagatomo,
M. A. Coggiano, A. Gleaves, R. D. Slack, C. Zanettini, J. Pharm. Pharmacol., 1992, 44, 911–914.
A. H. Newman and O. G. Tanda, ACS Chem. Neurosci., 2019, 17 B. M. Ahmed and G. Mezei, J. Org. Chem., 2018, 83, 1649–
10, 2012–2021. 1653.
15 A. D. Volgin, O. A. Yakovlev, K. A. Demin, P. A. Alekseeva, 18 CD3OD with 100 mol% DCl was a commercially available
E. J. Kyzar, C. Collins, D. E. Nichols and A. V. Kalueff, ACS
Chem. Neurosci., 2019, 10, 143–154.
deuterated solvent, and could be purchased from Sigma-
Aldrich and CIL companies.
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