A room-temperature protocol to access isoquinolines through Ag(i) catalysed annulation of o-(1-alkynyl)arylaldehydes and ketones with NH4OAc: Elaboration to berberine and palmatine

Article abstract of DOI:10.1039/c4ob02641a

An efficient and mild protocol for the direct construction of aryl- and alkyl-substituted isoquinolines has been realized through silver nitrate catalyzed aromatic annulation of o-(1-alkynyl)arylaldehydes and ketones with ammonium acetate. The salient feature of this methodology is that this annulation could be effected at room temperature leading to a wide range of isoquinoline derivatives in good to excellent yields. Additionally, this approach has been employed to the synthesis of biologically important isoquinoline alkaloids such as berberine and palmatine.

Full text of DOI:10.1039/c4ob02641a

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Organic & Biomolecular Chemistry
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PAPER
A Room-Temperature Protocol to Access Isoquinolines
through Ag(I) Catalysed Annulation of o-(1-Alkynyl)
arylaldehydes and Ketones with NH4OAc: Elaboration
to Berberine and Palmatine†
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Virsinha Reddy, Abhijeet S. Jadhav and Ramasamy Vijaya Anand*
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient and mild protocol for the direct construction of arylꢀ and alkylꢀsubstituted
isoquinolines has been realized through silver nitrate catalyzed aromatic annulation of
oꢀ(1ꢀ
alkynyl)arylaldehydes and ketones with ammonium acetate. The salient feature of this
methodology is that this annulation could be effected at room temperature leading to a wide
range of isoquinoline derivatives in good to excellent yields. Additionally, this approach has
been employed to the synthesis of biologically important isoquinoline alkaloids such as
berberine and palmatine.
Introduction
Scheme 1 comprehends all the major metal catalysed approaches to
the synthesis of the isoquinoline core. Larock’s isoquinoline
The isoquinoline core has been recognized as an important synthesis comprises intramolecular cyclization of oꢀ(1ꢀ
synthetic target due to its existence as a central core in many natural alkynyl)benzaldimines under Pdꢀcatalysed conditions at elevated
products.1 Some of the isoquinoline alkaloids exhibit antimalarial, temperature (path A).6 After this seminal contribution, many
antifungal, antitumor and antihypertensive activities (Fig 1).2 modified or alternative protocols have been developed using oꢀ(1ꢀ
Classical approaches for the construction of the isoquinoline core alkynyl)benzaldimines,7 oꢀ(1ꢀalkynyl)benzaldoximes8 and other
such as Pomeranz–Fritch,3 Pictet–Spengler4 and Bischler– derivatives9 under metal (Ag or Pd or Cu) catalysed conditions (path
Napieralski5 reactions involve either the use of highly corrosive A). Yamomoto’s group has developed iodine mediated electrophilic
reagents or harsh reaction conditions. In order to overcome these cyclisation of oꢀ(1ꢀalkynyl)benzyl azides to highly substituted iodo
hitches, many alternative methods have been developed, and out of isoquinoline derivatives (path B).10 Later, the same group has
those methods, metal catalysed approaches were found to be developed Gold catalysed cyclization of oꢀ(1ꢀalkynyl)benzyl azides
dominating as they involve relatively milder conditions.
to isoquinolines at elevated temperatures.11 Another interesting
approach to isoquinoline comprises of intermolecular annulation of
imine or hydroxylamine derivatives with internal alkynes using
Rhodium catalysts (path C).12 Apart from these methods, a few
direct approaches have been reported, where the synthesis of
isoquinolines
was
effected
by
treatment
of
oꢀ(1ꢀ
alkynyl)arylaldehydes with amine source such as ammonia, NH4Cl
etc. under TfOH mediated condition13 or microwave irradiation14 or
at high temperatures (path D).15 A few other reports have also been
reported involving microwave assisted oneꢀpot, three component
synthesis of isoquinolines from 2ꢀbromo benzaldehydes through
Sonagashira coupling with terminal alkynes followed by cyclisation
with ammonium salts.16 In addition to the above mentioned reports,
a few other different strategies have been reported for the synthesis
of isoquinoline derivatives.17
Surprisingly, the metal catalysed direct synthesis of isoquinoline
derivatives from oꢀ(1ꢀalkynyl)arylaldehydes or ketones and an amine
source at room temperature has not been reported so far. While
Figure 1: Biologically active natural isoquinolines (1 – 4)
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Organic & Biomolecular Chemistry
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working on the synthesis of isoquinoline alkaloids, we envisioned to which are known to activate alkynes,19 failed to give the desired
develop an efficient protocol for the direct synthesis isoquinolines product even after 12 h at room temperature (Entries 1 & 2,
6
from readily available precursors under mild conditions. We hereby Table 1). Astoundingly, when the reaction was performed using
report silver nitrate catalysed synthesis of isoquinoline derivatives Ag2O as a catalyst and ammonium acetate as an amine source
t
from oꢀ(1ꢀalkynyl)arylaldehydes and ketones using ammonium in BuOH, the desired product
6 was obtained in 80% yield
acetate as an amine source at room temperature.
(Entry 3). Encouraged by this result, further screening was
carried out using a variety of silver catalysts (Entries 4–9). Out
of several catalysts tried, AgOTf and AgNO3 (Entries 6 & 7)
were found to give better results. Since AgNO3 is much cheaper
compared to AgOTf, further optimisation studies were
performed using AgNO3 as a catalyst. A few experiments were
also performed using other solvents (Entries 10–13) and other
ammonia sources (Entries 14–16); but in all those cases, yield
of the product was inferior when compared to Entry 7. When
the reaction was carried out in the absence of silver catalyst, the
isoquinoline
(Entry 17).
6 was obtained only in <5% yield even after 24 h
Having optimised condition in hand, we investigated the substrate
scope of this transformation. For this purpose, a wide range of oꢀ(1ꢀ
alkynyl)arylaldehydes18 and ketones20 were prepared and subjected
to 6ꢀendoꢀdig cyclisation reaction under optimised conditions (Entry
7, Table 1), and the results are summarised in Table 2. It is evident
from Table 2 that most of the oꢀ(1ꢀalkynyl)arylaldehydes could be
converted to their corresponding isoquinoline derivatives in good to
excellent yields. The reaction worked very well in the case of oꢀ(1ꢀ
alkynyl)arylaldehydes derived from alkynes bearing electron rich
aryl substituents. For example, in the cases of alkyl or alkyloxy
phenyl substituted alkynyl aldehydes, the respective isoquinolines
(6a–6g) were obtained in very good yields. In bromo substituted
case, the product 6h was obtained only in 50% yield. For
isoquinoline precursors (5i–5n), derived from other substituted 2ꢀ
bromo benzaldehydes, the annulation reaction took place capably
leading to the products 6i to 6n in good yields. The reaction also
worked competently in the cases of isoquinoline precursors 5o and
5p, which were derived from alkynes with aliphatic substituents, and
the products 6o and 6p were obtained in 70 and 84% yields
respectively. Unfortunately, this methodology was found to be less
effective in the cases of oꢀ(1ꢀalkynyl)arylaldehydes with electron
poor aryl substituents attached to alkyne (5q–5s). For example, the
aldehydes such as 5q and 5r, gave the corresponding isoquinolines
6q and 6r in only 15–20% yields. No product (6s) was observed in
the case of oꢀ(4ꢀnitrophenylethynyl)benzaldehyde (5s). But,
gratifyingly, the extension of this methodology to oꢀ(1ꢀ
alkynyl)arylketones,15,20 gave fruitful results. As seen in Table 2,
some of the oꢀ(1ꢀalkynyl)acetophenone derivatives such as 5t and 5u
underwent 6ꢀendoꢀdig cyclisation to the respective methyl
substituted isoquinoline derivatives 6t and 6u in excellent yields.
Scheme 1: Major approaches toward isoquinoline core
Results and Discussion
The optimisation studies were carried out using
oꢀ
18
(phenylethynyl)benzaldehyde (
5
)
under various conditions.
Our initial studies focused on the selection of a suitable catalyst
for this transformation. The preliminary screening of the
catalysts gave disappointing results as Bi(OTf)3 and Yb(OTf)3,
Table 1. Optimisation studiesa
"NH3" Source
Cat (10 mol %)
O
N
Solvent, rt
Ph
6
5
Ph
Catalyst
“NH3”
Solvent
Time
[h]
Yield
[%]c
Entry
1
Sourceb
Bi(OTf)3
NH4OAc
tBuOH
12
--
2
Yb(OTf)3
Ag2O
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4HCO3
NH4OH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
CH2Cl2
CH3CN
THF
12
8
--
80
80
84
95
95
92
92
57
45
33
65
70
70
ꢀꢀ
3
4
AgClO4
Ag(OCOCF3)
AgOTf
AgNO3
Ag2CO3
AgSbF6
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
ꢀꢀ
8
5
8
6
6
At this stage, we were interested in elucidating a reasonable
mechanism of this transformation. It is well documented in the
literature that the uncatalysed reaction between 5 and an ammonia
source at higher temperature proceeds through imine intermediate,
which on cyclisation leads to isoquinoline derivative 6.15 On the
other hand; Swager’s group found that TfOH promotes the formation
of pyrylium intermediate, which on exposure with ammonia gives
the isoquinoline derivative.13 To understand whether our
methodology proceeds through imine or pyrylium intermediate, a
few experiments were performed. In one of the experiments, oꢀ(1ꢀ
alkynyl)benzaldehyde 5 was treated with ammonium acetate in the
absence of silver catalyst at room temperature and the progress of
7
6
8
8
9
8
10
11
12
13
14
15
16
17
15
15
15
15
9
EtOH
tBuOH
tBuOH
tBuOH
tBuOH
24
24
24
NH4Cl
1
the reaction was monitored by H NMR spectroscopy (in CD3CN).
NH4OAc
<5
a Reaction conditions: 0.12 M solution of 5 in solvent b 1.5 equiv. of NH3
In this case, the characteristic peak that corresponds to CH=N proton
was not observed even after 12 h, and most the aldehyde 5 remained
source was used in all the reactions c Isolated yields. rt = 27–30 °C
2 | Org. Biomol. Chem., 2014, 00, 1-3
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DOI: 10.1039/C4OBA02R6T4I1CALE
Table 2: Substrate scope:
Nucleophilic attack of ammonia to the pyrylium C=O leads to the
formation of intermediate III, which presumably rearranges to
hemiaminal IV under acidic condition. Finally, hemiaminal IV
decomposes to isoquinoline 6 (Scheme 2).
R
R
AgNO3 (10 mol %)
NH4OAc (1.5 equiv)
O
N
R1
R1
R2
tBuOH, rt
R2
5a-t
6a-t
R = H or Me
R1 = Alkyl, halo, Oalkyl, etc
R2 = Alkyl or aryl
6a
, 2 h, 80%
6b
, 4 h, 70%
6c
, 6 h, 88%
N
N
N
OPh
OMe
OMe
6d
6e
6f
, 5 h, 95%
N
, 12 h, 98%
, 7 h, 91%
N
Scheme 2: Plausible mechanism for isoquinoline formation
O
N
O
To portray its synthetic application, this protocol was elaborated to
the total synthesis of berberine (3) and palmatine (4). Berberine (3),
isolated from a plant Coptis chinensis, is a member of protoberberine
class of isoquinoline alkaloids.21 Berberine has been used as a drug
for the treatment of diarrhea in China for many decades. Berberine
possesses a wide range of biological activities such as antimalarial,22
Br
NMe2
6h
, 24 h, 50%
6g
6i,
, 3 h, 85%
N
6 h, 91%
N
O
O
MeO
MeO
N
antifungal,23
antibacterial,24
antiviral,25
anticancer,26
6j, 24 h, 77%
6k, 24 h, 79%
6l, 12 h, 89%
antileishmanial27 etc. Recent studies showed that 3 also exhibits
cholesterol lowering activity in animals and patients with
hypercholesterolemia without any sign of side effects.28 It was found
that the cholesterol lowering activity increased further if 3 was used
in combination with statins.29 Palmatine (4), a structural analog of
berberine (3), also exhibits interesting biological properties.
Palmatine has been used for the treatment of dysentery, jaundice,
hypertension etc.,30 and its derivatives are known to possess
antimalarial and antimicrobial activities.31 Only two reports are
available in the literature for the total synthesis of berberine (3). In
1969, Kametani’s group reported the first synthesis of berberine
iodide.32 While working on this manuscript, a research article has
been appeared, from Donohoe’s group, for the synthesis of berberine
and palmatine through palladium catalysed enolate arylation
reaction.33 A few other reports are available for the synthesis of
berberine (3) and palmatine (4) analogues.21,34
OMe
MeO
F
N
N
N
6m,
6n
6o
, 3 h, 70%
6 h, 60%
N
, 6 h, 90%
N
N
CO2Ph
CN
6q
6r
, 24 h, 20%
, 24 h, 15%
6p
, 4 h, 84%
N
N
N
NO2
6s
, 12 h, 0%
6t, 24 h, 87%
6u, 8 h, 93%
a
t
Reaction conditions: 0.12 M solution of 5 in BuOH. Yields reported are
isolated yields. rt = 27–30 °C.
OMe O
OH
OH
O
O
O
O
unreacted. In another experiment, 5 was treated with stoichiometric
amounts of AgNO3 in CD3CN at room temperature and the 1H NMR
was recorded after 12 h. In this case, along with the aldehyde signal,
a new singlet appeared at 10.01 ppm. We presume that the signal at
10.01 ppm corresponds to the CH=O proton of the pyrylium salt
because this δ value approximately matches with the δ value (10.14
ppm) of the pyrylium CH=O proton reported by the Swager’s group
though the reaction conditions are different (please see SI for
spectra).13 When ammonium acetate was added to this reaction
mixture, the signal at 10.01 disappeared and a new signal at 9.35
ppm, which corresponds to the CH=N proton of isoquinoline,
appeared after 5 h. The signal that corresponds to aldimine CH=N
b
a
MeO
+
H
65%
88%
Br
SiMe3
8
7
9
OMe O
OMe
OH
MeO
OH
H
MeO
N
c
d
3
78%
72%
O
O
10
11
O
O
1
proton was not observed in H NMR during the reaction. The above
Reaction conditions: (a) TBAF, THF, rt, 1 h (b) PdCl2(PPh3)2, CuI, Et3N, 70
oC, 3 h (c) NH4OAc, AgNO3, tBuOH, rt, 15 h (d) PPh3, CH2Cl2:CCl4 (1:2), rt,
12 h.
experiments indicate that our methodology proceeds through
pyrylium intermediate and not through imine. Based on the above
observations, a possible mechanism has been proposed (Scheme 2).
In the initial step, AgNO3 coordinates with the alkyne and the
oxygen of aldehyde group attacks the alkyne in an 6ꢀendoꢀdig
fashion to give the pyrylium intermediate I, which undergoes
protonation with acetic acid (which was produced during the
decomposition of ammonium acetate) gives intermediate II.
Scheme 3. Total synthesis of berberine (3)
Scheme 3 represents our strategy for the synthesis of berberine (3).
This unprecedented synthetic approach involves four direct steps to
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access 3 from readily available silylated alkynyl aryl ethanol
derivative 7.35 Deprotection of 7 with TBAF gave the 2ꢀalkynyl aryl
ethanol derivative 8 in 88% yield. The Sonagashira coupling
between 8 and 2,3ꢀdimethoxyꢀ5ꢀbromo benzaldehyde (9)36 gave the
isoquinoline precursor 10 in 65% yield. The annulation reaction of
10 was carried out under our optimised reaction condition (Table 2)
and the isoquinoline derivative 11 was obtained in 78% yield.
Finally, the isoquinoline 11 was subjected to cyclisation under Appel
condition37 to provide berberine (3) in 72% yield (32% overall yield
from 7).
General procedure:
Aryl acetylene (1.2 equiv) was added to a stirred solution of
PdCl2(PPh3)2 (0.02 equiv), CuI (0.01 equiv), and 2ꢀbromoꢀ
arylaldehyde (1 equiv) or 2′ꢀbromo acetophenone (1 equiv) in
triethylamine (0.27 M) at room temperature and the reaction mixture
was heated to 70 °C under inert atmosphere. After completion (by
TLC), triethylamine was removed under reduced pressure. The
residue was then diluted with dichloromethane and water. Organic
layer was separated and aqueous layer was extracted two times with
DCM. Combined organic layer was dried over anhydrous sodium
sulphate, filtered and concentrated under reduced pressure. The
residue was purified through silica gel column chromatography
using hexane/EtOAc to get pure (2ꢀarylethynyl)arylaldehyde or
ketone derivatives.
In a similar mode, palmatine (4) was synthesised from the 2ꢀalkynyl
aryl ethanol derivative 1238 in three linear steps as shown in Scheme
4. The starting material 12 was subjected to Sonagashira coupling
with 9 to give the arylated alkyne 13 in 65% yield. On exposure to
ammonium acetate under our optimised condition, 13 underwent 6ꢀ
endoꢀdig cyclisation to give the isoquinoline derivative 14, which
was then converted to palmatine (4) under Appel condition (35%
overall yield from 12).
2-[(4-Pentylphenyl)ethynyl]benzaldehyde (5b): Yield: 70%; brown
1
liquid; H NMR (400 MHz, CDCl3) δ 10.66 (s, 1H), 7.95–7.94 (m,
1H), 7.64–7.62 (m, 1H), 7.59–7.55 (m, 1H), 7.48 (d, J = 8.0 Hz, 2H),
7.46–7.41 (m, 1H), 7.20 (d, J = 7.9 Hz, 2H), 2.63 (t, J = 7.5 Hz, 2H),
1.66–1.59 (m, 2H), 1.37–1.28 (m, 4H), 0.90 (t, J = 6.9 Hz, 3H); 13
C
OMe O
MeO
OH
NMR (100 MHz, CDCl3) δ 192.0, 144.6, 135.9, 133.9, 133.3, 131.7,
128.8, 128.5, 127.33, 127.30, 119.6, 96.8, 84.4, 36.1, 31.6. 31.0,
22.6, 14.2; HRMS (ESI): m/z calcd for C20H21O [M+H]+: 277.1592;
found: 277.1576.
H
MeO
MeO
OH
a
65%
12
13
OMe
OMe
2-[(2,4,5-Trimethylphenyl)ethynyl]benzaldehyde (5c): Yield: 86%;
yellow solid; mp = 87–89 °C; 1H NMR (400 MHz, CDCl3) δ 10.68
(d, J = 0.9 Hz, 1H), 7.95 (ddd, J = 7.8, 1.4, 0.6 Hz, 1H), 7.63 (ddd, J
= 7.8, 1.4, 0.7 Hz, 1H), 7.60–7.56 (m, 1H), 7.46–7.41 (m, 1H), 7.32
(s, 1H), 7.03 (s, 1H), 2.46 (s, 3H), 2.26 (s, 3H), 2.24 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 192.1, 138.3, 137.9, 135.8, 134.2, 133.9,
133.3, 133.2, 131.2, 128.4, 127.7, 127.3, 119.4, 96.1, 88.0, 20.4,
19.9, 19.2; HRMS (ESI): m/z calcd for C18H17O [M+H]+: 249.1279;
found: 249.1295.
OMe
OH
MeO
N
b
c
4
77%
70%
14
OMe
OMe
o
Reaction conditions: (a) 9, PdCl2(PPh3)2, CuI, Et3N, 70 C, 4 h (b) NH4OAc,
AgNO3, tBuOH, rt, 14 h (c) PPh3, CH2Cl2:CCl4 (1:2), rt, 24 h.
Scheme 4. Total synthesis of palmatine (4)
Experimental
2-[(6-Methoxynaphthalen-2-yl)ethynyl]benzaldehyde (5e): Yield:
90%; colourless solid; mp = 117–119 °C; 1H NMR (400 MHz,
CDCl3) δ 10.72 (d, J = 0.8 Hz, 1H), 8.03 (d, J = 0.9 Hz, 1H), 7.97
(ddd, J = 7.8, 1.4, 0.5 Hz, 1H), 7.75 (d, J = 2.9 Hz, 1H), 7.73 (d, J =
2.8 Hz, 1H), 7.69–7.67 (m, 1H), 7.62–7.58 (m, 1H), 7.57 (dd, J =
8.5, 1.6 Hz, 1H), 7.48–7.44 (m, 1H), 7.20 (dd, J = 8.9, 2.6 Hz, 1H ),
7.14 (d, J = 2.5 Hz, 1H), 3.95 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 192.0, 158.8, 135.9, 134.7, 134.0, 133.3, 132.9, 131.9, 129.6,
128.9, 128.6, 127.5, 127.3, 127.2, 127.1, 119.8, 117.3, 106.0, 84.8,
55.5; HRMS (ESI): m/z calcd for C20H15O2 [M+H]+: 287.1072;
found: 287.1081.
I. General methods
All reactions were carried out under argon atmosphere in an oven
dried round bottom flask. Triethylamine was dried over calcium
hydride, distilled and stored with molecular sieves. Melting points
were recorded on SMP20 melting point apparatus and are
uncorrected. Most of the reagents and starting materials were
purchased from commercial sources and used as such. H and 13C
1
2-[(4-(Dimethylamino)phenyl)ethynyl]benzaldehyde (5g): Yield:
60%; crystalline yellow solid; mp = 100–102 °C; 1H NMR (400
MHz, CDCl3) δ 10.67 (d, J = 0.8 Hz, 1H), 7.93–7.91 (m, 1H), 7.61–
7.58 (m, 1H), 7.56–7.52 (m, 1H), 7.45–7.42 (m, 2H), 7.40–7.36 (m,
1H), 6.69–6.65 (m, 2H), 3.01 (s, 6H); 13C NMR (100 MHz, CDCl3)
δ 192.4, 150.7, 135.5, 133.9, 133.1, 132.9, 128.3, 127.8, 127.2,
111.9, 108.9, 98.4, 83.4, 40.3; HRMS (ESI): m/z calcd for C17H16NO
[M+H]+: 250.1232; found: 250.1237.
spectra were recorded in CDCl3 or DMSOꢀd6 (400, 100 MHz
respectively) on Bruker FTꢀNMR spectrometer. Chemical shifts (δ)
values are reported in parts per million relative to TMS and the
coupling constants (J) are reported in Hz. High resolution mass
spectra were recorded on Waters QꢀTOF PremierꢀHAB213
spectrometer. Thin layer chromatography was performed on Merck
silica gel 60 F254 TLC plates. Column chromatography was carried
out through silica gel (100ꢀ200 mesh) using EtOAc/hexane as an
eluent.
5-(Phenylethynyl)benzo[d][1,3]dioxole-4-carbaldehyde (5i): Yield:
96%; yellow solid; mp = 138–140 °C; 1H NMR (400 MHz, CDCl3) δ
10.56 (s, 1H), 7.54–7.51 (m, 2H), 7.38–7.35 (m, 3H), 7.16 (d, J = 8.0
Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.19 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 190.2, 149.2, 148.0, 131.6, 128.9, 128.6, 127.6, 122.6,
119.2, 118.8, 113.0, 103.4, 94.3, 85.2; HRMS (ESI): m/z calcd for
C16H11O3 [M+H]+: 251.0708; found: 251.0696.
II. Synthesis of 2-(arylethynyl)arylaldehydes and ketones
All the known compounds 539,, 5a14a, 5d40, 5e41, 5f14a, 5h42, 5j39,
5k39, 5l39, 5n39, 5o39, 5p6c, 5s42, 5t14b were synthesised according to
the literature procedure. Other precursors were prepared by adapting
the following procedure.
4 | Org. Biomol. Chem., 2014, 00, 1-3
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DOI: 10.1039/C4OB02641A
2,3-Dimethoxy-6-(phenylethynyl)benzaldehyde (5m): Yield: 87%; 130.6, 129.7(3C), 127.8, 127.7, 127.0, 116.4, 21.4; HRMS (ESI):
brown solid; mp = 95–97 °C 1H NMR (400 MHz, CDCl3) δ 10.61 (s, m/z calcd for C16H13N [M+H]+: 220.1126; found: 220.1122.
1H), 7.58ꢀ7.55 (m, 2H), 7.35–7.33 (m, 3H), 7.07 (d, J = 8.6 Hz, 1H),
3.94 (s, 3H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.5, 3-(4-Pentylphenyl)isoquinoline (6b): Yield: 70%; brown solid; mp
1
153.4, 151.3, 131.8, 130.3, 130.0, 128.6, 128.5, 123.2, 116.8, 116.6, = 62–64 °C; H NMR (400 MHz, CDCl3) δ 9.33 (t, J = 0.8 Hz,1H),
93.4, 86.8, 62.2, 56.2; HRMS (ESI): m/z calcd for C17H15O3 [M+H]+: 8.06ꢀ8.03 (m, 3H), 7.98 (dd, J = 8.2, 0.8 Hz, 1H), 7.86 (dd, J = 8.2,
267.1021; found: 267.1032.
0.6 Hz, 1H), 7.69 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.57 (ddd, J = 8.1,
6.9 1.2 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 2.68 (t, J = 7.6 Hz, 2H),
1.72–1.64 (m, 2H), 1.38–1.33 (m, 4H), 0.93–0.89 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 152.3, 151.3, 143.8, 136.9, 136.8, 130.8, 129.1,
127.8, 127.7, 127.1, 127.1, 127.0, 116.3, 35.8, 31.6, 31.3, 22.7, 14.2;
HRMS (ESI): m/z calcd for C20H22N [M+H]+: 276.1752; found:
276.1740.
4-[(2-Formylphenyl)ethynyl]benzonitrile (5q): Yield: 85%; off
white solid; mp = 110–112 °C; 1H NMR (400 MHz, CDCl3) δ 10.59
(d, J = 0.7 Hz, 1H), 7.99–7.96 (m, 1H), 7.70–7.61 (m, 6H), 7.54–
7.50 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 191.2, 136.2, 134.0,
133.6, 132.4, 132.3, 129.6, 128.0, 127.3, 125.5, 118.4, 112.5, 94.2,
89.3; HRMS (ESI): m/z calcd for C16H10NO [M+H]+: 232.0762;
found:.332.0771.
3-(2,4,5-Trimethylphenyl)isoquinoline (6c): Yield: 88%; off white
1
solid; mp = 82–84 °C; H NMR (400 MHz, CDCl3) δ 9.34 (s, 1H),
8.01 (dd, J = 8.2, 0.88 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.73–7.68
(m, 2H), 7.61 (ddd, J = 8.1, 6.8, 1.1 Hz, 1H), 7.31 (s, 1H), 7.10 (s,
1H), 2.37 (s, 3H), 2.30 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
153.7, 151.8, 137.9, 136.6, 136.4, 134.1, 133.3, 132.3, 131.5, 130.6,
127.7, 127.2, 127.1, 126.8, 120.2, 20.0, 19.6, 19.4; HRMS (ESI): m/z
calcd for C18H18N [M+H]+: 248.1439; found: 248.1441.
Phenyl 4-((2-formylphenyl)ethynyl)benzoate (5r): Yield: 66%; off
wihite solid; mp = 122–124 °C; 1H NMR (400 MHz, CDCl3) δ 10.65
(s, 1H), 8.22 (d, J = 8.1 Hz, 2H), 7.98 (d, J = 7.8 Hz, 1H), 7.71–7.68
(m, 3H), 7.63 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.45 (t, J =
7.8 Hz, 2H), 7.31–7.22 (m, 3H); 13C NMR (100 MHz, CDCl3) δ
191.5, 164.7, 150.9, 136.1, 134.0, 133.6, 131.9, 130.4, 129.8, 129.7,
129.4, 127.8, 127.7, 126.2, 121.8, 116.5, 100.6, 88.5; HRMS (ESI):
m/z calcd for C22H15O3 [M+H]+: 327.1021; found: 327.1031.
3-(4-Phenoxyphenyl)isoquinoline (6d): Yield: 95%; brown solid;
mp = 106–108 °C; 1H NMR (400 MHz, CDCl3) δ 9.32 (t, J = 0.8 Hz,
1H), 8.12–8.10 (m, 2H), 8.03 (s,1H), 8.0 (dd, J = 8.2, 0.9 Hz, 1H),
7.86 (dd, J = 8.3, 0.7 Hz, 1H), 7.70 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H),
7.58 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.39–7.35 (m, 2H), 7.16–7.12
(m, 3H), 7.11–7.07 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 158.1,
157.1, 152. 2, 137.0, 131.1, 130.0, 128.7, 127.9, 127.6, 127.3, 127.0,
123.7, 122.0, 119.3, 119.1, 118.9, 116.4; HRMS (ESI): m/z calcd for
C21H16NO [M+H]+: 298.1232; found: 298.1231.
1-[2-(Cyclohexylethynyl)phenyl]ethanone (5u): Yield: 50%; yellow
1
oil; H NMR (400 MHz, CDCl3) δ 7.65 (ddd, J = 7.8, 1.4, 0.4 Hz,
1H), 7.48–7.46 (m, 1H), 7.38 (td, J = 7.4, 1.5 Hz, 1H), 7.31 (td, J =
7.7, 1.4 Hz, 1H), 2.73 (s, 3H), 2.66–2.60 (m, 1H), 1.91–1.88 (m,
2H), 1.78–1.71 (m, 2H), 1.58–1.49 (m, 3H), 1.37–1.31 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 201.3, 141.2, 134.0, 131.2, 128.4, 127.6,
122.6, 100.9, 79.8, 32.5, 30.4, 30.1, 26.0, 25.0; HRMS (ESI): m/z
calcd for C16H19O [M+H]+: 227.1436; found: 227.1439.
3-(6-Methoxynaphthalen-2-yl)isoquinoline (6e):14c Yield: 98%; off
1
white solid; 166–168 °C; H NMR (400 MHz, CDCl3) δ 9.39 (s,
III. General procedure for the synthesis of isoquinolines:
1H), 8.59 (d, J = 1.6 Hz, 1H), 8.21 (dd, J = 8.6, 1.8 Hz, 1H), 8.18 (s,
1H), 8.01 (dd, J = 8.2, 0.7 Hz, 1H), 7.91–7.86 (m, 3H), 7.72 (ddd, J
= 8.1, 6.9, 1.2 Hz, 1H), 7.60 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.21–
7.18 (m, 2H), 3.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.3,
152.5, 151.2, 137.0, 134.9, 134.6, 130.9, 130.4, 129.3, 127.8, 127.7,
127.5, 127.2, 127.1, 126.4, 125.3, 119.3, 116.6, 105.8, 55.5; HRMS
(ESI): m/z calcd for C20H16NO [M+H]+: 286.1232; found: 286.1223.
tBuOH (1 ml) was added to a mixture of AgNO3 (0.01 mmol, 0.1
equiv.), ammonium acetate (0.18 mmol, 1.5 equiv.) and 2ꢀethynyl
arylaldehyde or ketone (0.12 mmol,
1 equiv.) under inert
atmosphere. The resultant mixture was stirred at room temperature
and the reaction was monitored by TLC. After completion, the
reaction was quenched by the addition of NaHCO3 (0.48 mmol, 4
equiv.) at room temperature and stirring was continued for additional
4 h. The mixture was then filtered through a cotton plug, washed
with EtOAc (5–10 mL) and dried over anhydrous Na2SO4. The
filtrate was evaporated under reduced pressure and the residue was
purified through silica gel column chromatography (EtOAc in
hexane) to get the pure isoquinoline derivative.
3-(4-Methoxy-2-methylphenyl)isoquinoline (6f):14a Yield: 91%;
1
pale yellow gummy solid; H NMR (400 MHz, CDCl3) δ 9.34 (s,
1H), 8.03–8.00 (m, 1H), 7.86–7.84 (m, 1H), 7.74–7.70 (m, 2H), 7.61
(ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.47–7.45 (m, 1H), 6.87–6.84 (m,
2H), 3.86 (s, 3H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
159.6, 153.8, 151.7, 137.6, 136.5, 133.2, 131.5, 130.8, 127.8, 127.2,
126.8, 120.3, 116.3, 112.4, 111.4, 55.5, 21.0; HRMS (ESI): m/z
calcd for C17H16NO [M+H]+: 250.1232; found: 250.1236.
3-Phenyisoquinoline (6):9b Yield: 95%; brown solid; mp = 101–
1
103 °C; H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 8.15–8.12 (m,
4-(Isoquinolin-3-yl)-N,N-dimethylaniline (6g):9b Yield: 85%; pale
2H), 8.07 (s, 1H), 7.99 (dd, J = 8.2, 0.9 Hz, 1H), 7.87 (d, J = 8.3 Hz,
1H), 7.70 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.59 (ddd, J = 8.1, 6.9, 1.1
Hz, 1H), 7.55–7.50 (m, 2H), 7.45–7.40 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 152.6, 151.4, 139.7, 136.8, 130.7, 128.9, 128.6,
127.9, 127.7, 127.2, 127.1, 127.0, 116.7; HRMS (ESI): m/z calcd for
C15H12N [M+H]+: 206.0970; found: 206.968.
1
yellow solid; mp = 140–142 °C; H NMR (400 MHz, CDCl3) δ 9.31
(s, 1H), 8.05 (d, J = 9.0 Hz, 2H), 7.97–7.94 (m, 2H), 7.84–7.82 (m,
1H), 7.66 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.52 (ddd, J = 8.0, 6.8, 1.2
Hz, 1H), 6.85 (d, J = 9.0 Hz, 2H), 3.04 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 152.3, 151.7, 150.9, 137.1, 130.4, 127.9, 127.7, 127.6,
127.3, 126.8, 126.3, 114.4, 112.6, 40.6; HRMS (ESI): m/z calcd for
C17H17N2 [M+H]+: 249.1392; found: 249.1404.
3-(p-Tolyl)isoquinoline (6a):13 Yield: 80%; yellow solid; mp = 72–
1
74 °C; H NMR (400 MHz, CDCl3) δ 9.33 (s, 1H), 8.04–8.02 (m,
3-(4-Bromophenyl)isoquinoline (6h): Yield: 50%; brown solid; mp
3H), 7.98 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.70–7.66
(m, 1H), 7.59–7.55 (m, 1H), 7.32 (d, J = 8.0 Hz, 2H), 2.43 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 152.5, 151.4, 138.6, 136.9, 136.8,
1
= 158–160 °C; H NMR (400 MHz, CDCl3) δ 9.34 (s, 1H), 8.06 (s,
1H), 8.04–7.99 (m, 3H), 7.88 (dd, J = 8.1, 0.6 Hz, 1H), 7.72 (ddd, J
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2014, 00, 1-3 | 5

Organic & Biomolecular Chemistry
Page 6 of 10
ARTICLE
VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C4OB02641A
1
= 8.2, 6.8, 1.2 Hz, 1H), 7.66–7.60 (m, 3H); 13C NMR (100 MHz, 3-Cyclohexylisoquinoline (6p):6c Yield: 84%; yellow oil; H NMR
CDCl3) δ 152.7, 150.2, 138.6, 136.7, 132.0, 130.9, 128.7, 128.0, (400 MHz, CDCl3) δ 9.20 (s, 1H), 7.92 (dd, J = 8.2, 0.9 Hz, 1H),
127.8, 127.5, 127.1, 123.0, 116.6; HRMS (ESI): m/z calcd for 7.75 (dd, J = 8.2, 0.7 Hz, 1H), 7.64 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H),
C15H11BrN [M+H]+: 284.0075; found: 284.0067.
7.51 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.46 (s, 1H), 2.85 (tt, J = 11.7,
3.3 Hz, 1H), 2.08–2.04 (m, 2H), 1.92–1.87 (m, 2H), 1.81–1.75 (m,
7-Phenyl-[1,3]dioxolo[4,5-h]isoquinoline (6i): Yield: 91%; off 1H), 1.66–1.56 (m, 2H), 1.52–1.41 (m, 2H), 1.37–1.30 (m, 2H); 13
C
1
white solid; mp = 122–124 °C; H NMR (400 MHz, CDCl3) δ 9.37 NMR (100 MHz, CDCl3) δ 160.2, 152.0, 136.8, 130.3, 127.6, 127.4,
(s, 1H), 8.10–8.07 (m, 2H), 7.98 (s, 1H), 7.52–7.48 (m, 2H), 7.43– 126.5, 126.4, 116.3, 46.3, 33.3, 26.9, 26.3; HRMS (ESI): m/z calcd
6.36 (m, 3H), 6.24 (s, 2H); 13C NMR(100 MHz, CDCl3) δ 149.3, for C15H18N [M+H]+: 212.1439; found: 212.1442.
145.7, 144.7, 141.9, 139.7, 132.5, 128.5, 128.4, 126.9, 120.8, 116.9,
115.2, 114.4, 102.6; HRMS (ESI): m/z calcd for C16H12NO2 [M+H]+: 4-(Isoquinolin-3-yl)benzonitrile (6q): Yield: 20%; brown solid; mp
250.0868; found: 250.0867.
= 122–124 °C; 1H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 8.26 (d, J
= 7.9 Hz, 2H), 8.13 (s, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 8.2
7-Phenyl-[1,3]dioxolo[4,5-g]isoquinoline (6j):9b Yield: 77%; white Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7. 75 (t, J = 7.1 Hz, 1H), 7.66 (t, J
solid; mp = 135–137 °C; 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), = 7.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 152.9, 149.1, 143.9,
8.08–8.06 (m, 2H), 7,91 (s, 1H), 7.52–7.47 (m, 2H), 7.42–7.38 (m, 136.5, 132.7, 131.1, 128.4, 128.2, 127.8, 127.6, 127.3, 119.1, 117.8,
1H), 7.22 (s, 1H), 7.13 (s, 1H), 6.11 (s, 2H); 13C NMR (100 MHz, 112.0; HRMS (ESI): m/z calcd for C16H11N2 [M+H]+: 231.0922;
CDCl3) δ 151.4, 150.6, 150.2, 148.6, 139.6, 135.3, 128.9, 128.5, found: 231.0915.
126.9, 125.2, 116.6, 103.3, 103.0, 101.8; HRMS (ESI): m/z calcd for
C16H12NO2 [M+H]+: 250.0868; found: 250.0868.
Phenyl 4-(isoquinolin-3-yl)benzoate (6r): Yield: 15%; off white
solid; mp = 163–165 °C; 1H NMR (400 MHz, CDCl3) δ 9.38 (s, 1H),
6,7-Dimethoxy-3-phenylisoquinoline (6k):43 Yield: 79%; brown 8.36–8.33 (m, 2H), 8.31–8.28 (m, 2H), 8.19 (s, 1H), 8.05–8.02 (m,
solid; mp = 129–131 °C; 1H NMR (400 MHz, CDCl3) δ 9.13 (s,1H), 1H), 7.94–7.92 (m, 1H), 7.75 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.65
8.09–8.06 (m, 2H), 7.94 (s, 1H), 7.52–7.47 (m, 2H), 7.42–7.37 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.48–7.44 (m, 2H), 7.32–7.29 (m,
(m,1H), 7.23 (s, 1H), 7.13 (s, 1H), 4.05 (s, 3H), 4.04 (s, 3H); 13C 1H), 7.28–7.27 (m,1H), 7.26–7.25 (m, 1H); 13C NMR (100 MHz,
NMR (100 MHz, CDCl3) δ 153.3, 150.5, 150.4, 150.0, 140.0, 133.5, CDCl3) δ 165.3, 152.9, 151.1, 150.0, 144.6, 136.6, 131.0, 130.9,
128.9, 128.3, 126.9, 123.9, 115.7, 105.4, 105.1, 56.3, 56.2; HRMS 130.4, 129.7, 129.6, 127.9, 127.8, 127.1, 126.1, 121.9, 121.8, 117.8;
(ESI): m/z calcd for C17H16NO2 [M+H]+: 266.1181; found: 266.1184. HRMS (ESI): m/z calcd for C22H16NO2 [M+H]+: 326.1181; found:
326.1189.
6-Methyl-3-phenylisoquinoline (6l):44 Yield: 89%; brown solid; mp
1
= 176–178 °C; H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 8.13– 1-Methyl-3-(p-tolyl)isoquinoline (6t):14b Yield: 87%; brown liquid;
8.10 (m, 2H), 8.00 (s, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 0.4 1H NMR (400 MHz, CDCl3) δ 8.12 (dq, J = 8.3, 0.9 Hz, 1H), 8.04
Hz, 1H), 7.53–7.49 (m, 2H), 7.44–7.39 (m, 2H). 2.57 (s, 3H); 13C (d, J = 8.2 Hz, 1H), 7.89 (s, 1H), 7.85–7.83 (m, 1H), 7.66 (ddd, J =
NMR (100 MHz, CDCl3) δ 152.1, 151.4, 141.1, 139.8, 137.1, 129.6, 8.1, 6.9, 1.2 Hz, 1H), 7.55 (ddd, J = 8.3, 6.9, 1.3 Hz), 7.32–7.30 (m,
128.9, 128.6, 127.5, 127.1, 126.4, 126.0, 116.3, 22.3; HRMS (ESI): 2H), 3.04 (s, 3H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
m/z calcd for C16H14N [M+H]+: 220.1126; found: 220.1121.
158.6, 150.2, 138.3, 137.1, 136.9, 130.1, 129.1, 127.7, 127.0, 126.7,
126.6, 125.8, 114.9, 22.8, 21.4; HRMS (ESI): m/z calcd for C17H16N
7,8-Dimethoxy-3-phenylisoquinoline (6m): Yield: 60%; brown [M+H]+: 234.1283; found: 234.1282.
1
solid; mp = 102–104 °C; H NMR (400 MHz, CDCl3) δ 9.62 (t, J =
0.8 Hz, 1H), 8.12–8.10 (m, 2H), 8.0 (d, J = 0.9 Hz, 1H), 7.63 (d, J = 3-Cyclohexyl-1-methylisoquinoline (6u):47 Yield: 93%; yellow oil;
8.9 Hz, 1H), 7.52–7.48 (m, 3H), 7.42–7.38 (m, 1H), 4.09 (s,3H), 1NMR (400 MHz, CDCl3) δ 8.08–8.05 (m, 1H), 7.74 (d, J = 8.2 Hz,
4.02 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 149.8, 148.9, 147.5, 1H), 7.61 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 7.50 (ddd, J = 8.3, 6.9, 1.3
144.1, 139.8, 132.6, 128.9, 128.4, 126.9, 123.3, 123.3, 120.4, 116.1, Hz, 1H), 7.31, (s, 1H), 2.95 (d, J = 0.4 Hz, 3H), 2.84–2.77 (m, 1H),
61.9, 57.2; HRMS (ESI): m/z calcd for C17H16NO2 [M+H]+: 2.10–2.08 (m, 2H), 1.89–1.86 (m, 4H), 1.59–1.42 (m, 4H); 13C NMR
266.1181; found: 266.1178.
(100 MHz, CDCl3) δ 159.2, 136.9, 134.2, 129.8, 127.2, 126.2, 126.1,
125.7, 114.5, 46.2, 33.4, 26.9, 26.4, 22.5; HRMS (ESI): m/z calcd
7-Fluoro-3-phenylisoquinoline (6n):45 Yield: 90%; brown solid; mp for C16H20N [M+H]+: 226.1596; found: 226.1598.
1
= 136–138 °C; H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.12–
8.09 (m, 2H), 8.06, (s, 1H), 7.88 (dd, J = 9.0, 5.2 Hz, 1H), 7.60 (dd,
IV. Synthesis of Berberine
J = 8.7, 2.6 Hz, 1H), 7.54–7.48 (m, 3H), 7.46–7.40 (m, 1H). 13C 2ꢀ(6ꢀIodobenzo[d][1,3]dioxolꢀ5ꢀyl)ethanol48
and
6ꢀbromoꢀ2,3ꢀ
NMR (100 MHz, CDCl3) δ 160.9 (d, JCF = 247.9 Hz), 151.7 (d, JCF dimethoxybenzaldehyde (9)36 were synthesized according to the
= 5.9 Hz), 151.1 (d, JCF = 2.9 Hz), 139.3, 133.9, 129.7 (d, JCF = 7.9 literature procedure.
Hz), 129.0, 128.7, 128.4 (d, JCF = 7.9 Hz), 121.3, (d, JCF = 25.3 Hz),
2-(6-{(Trimethylsilyl)ethynyl}benzo[d][1,3]dioxol-5-yl)ethanol
116.4 (d, JCF = 2.0 Hz), 110.8, 110.6; HRMS (ESI): m/z calcd for (7):35An oven dried round bottom flask was charged with
C15H11FN [M+H]+: 224.0876; found: 224.0865.
PdCl2(PPh)3 (15 mg, 0.014 mmol), CuI (2 mg, 0.010 mmol) and 2ꢀ
(6ꢀIodobenzo[d][1,3]dioxolꢀ5ꢀyl)ethanol (250 mg, 0.87 mmol) in
1
3-Cyclopropylisoquinoline (6o):46 Yield: 70%; yellow oil; H NMR Et3N (2 ml) under inert atmosphere. After stirring for 2ꢀ3 minutes,
(400 MHz, CDCl3) δ 9.11 (s, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.70 (d, trimethylsilylacetylene (128 mg, 1.30 mmol) was added at room
J = 8.3 Hz, 1H), 7.61 (t, J = 8.1 Hz, 1H), 7.48–7.45 (m, 2H), 2.20– temperature under inert atmosphere and reaction mixture was heated
2.16 (m, 1H), 1.11–1.08 (m, 2H), 1.06–1.00 (m, 2H); 13C NMR (100 to 50 °C. After completion of reaction (monitored by TLC) solvent
MHz, CDCl3) 156.2, 152.2, 136.5, 130.4, 127.7, 127.2, 126.0, 125.9, was concentrated under reduced pressure and the residue was diluted
116.5, 17.2, 9.4; HRMS (ESI): m/z calcd for C12H12N [M+H]+: with EtOAc (30 mL) and water (15 mL). Organic layer was
170.0970; found: 170.0973.
separated and the aqueous layer was washed two times with EtOAc
(20 mL). The combined organic layer was dried over Na2SO4 and
6 | Org. Biomol. Chem., 2014, 00, 1-3
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ARTICLE
DOI: 10.1039/C4OB02641A
concentrated under reduced pressure. Yield: 90%; brown oil; 1H 110.1, 101.4, 64.0, 61.9, 57.2, 35.4; HRMS (ESI): m/z calcd for
NMR (400 MHz, CDCl3) δ 6.90 (s, 1H), 6,71 (s, 1H), 5.94 (s, 2H), C20H20NO5 [M+H]+: 354.1341; found: 354.1350.
3.86 (t, J = 6.4 Hz, 2H), 2.98 (t, J = 6.4 Hz, 2H), 0.02 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 148.3, 146.0, 136.3, 115.7, 112.0, 110.1, Synthesis of berberine (3):33 A mixture of Isoquinoline derivative 11
103.9, 101.5, 96.9, 63.0, 38.0, 0.1; HRMS (ESI): m/z calcd for (10 mg, 0.028 mmol), PPh3 (16 mg, 0.056 mmol) in CH2Cl2ꢀCCl4
C14H19O3Si: 263.1103 [M+H]+; found: 263.1116.
mixture (1:2) (0.5 mL) was stirred at room temperature until the
starting material got completely consumed (12 h, by TLC). The
2-(6-Ethynylbenzo[d][1,3]dioxol-5-yl)ethanol (8): TBAF solution reaction mixture was carefully filtered and the solid was washed
(1.0 M in THF, 1.26 mL, 1.26 mmol) was added in a dropꢀwise with EtOAc (5 mL x 4) to get berberine (3). Yield: 72%; yellow
manner to a stirred solution of 7 (166 mg, 0.63 mmol) in THF (1.3 solid; mp = 204–206 °C; 1H NMR (400 MHz, DMSOꢀd6) δ 9.89 (s,
mL) at rt. Thr reaction mixture immediately turned to dark brown in 1H), 8.94 (s, 1H), 8,21 (d, J = 9.2 Hz, 1H), 7.99 (d, J = 9.0 Hz, 1H),
colour. After completion of the reaction (monitored by TLC), 1M 7.80 (s, 1H), 7.09 (s, 1H), 6.18 (s, 2H), 4.93 (t, J = 6.2 Hz, 2H), 3.20
aqueous HCl (15 mL) was added to the reaction mixture and (t, J = 6.5 Hz, 2H); 13C NMR (100 MHz, DMSOꢀd6) δ 150.4, 149.9,
extracted with diethyl ether (20 mL). Aqueous layer was washed two 147.7, 145.5, 143.7, 137.5, 133.0, 130.7, 126.8, 123.6, 121.4, 120.5,
times with diethyl ether (20 mL) and combined organic layer was 120.2, 108.5, 105.5, 102.1, 62.0, 57.1, 55.2, 26.3; HRMS (ESI): m/z
dried over anhydrous Na2SO4, filtered and concentrated under calcd for C20H19NO4 [M+H]+: 337.1314; found: 337.1323.
reduced pressure. The residue was purified through a short pad of
silica gel column using EtOAc/hexane as an eluent to get pure
V. Synthesis of Palmatine
compound. Yield: 88%; brown liquid; 1H NMR (400 MHz, CDCl3) δ
6.92 (s, 1H), 6.73 (s, 1H), 5.95 (s, 2H), 3.85 (t, J = 6.6 Hz, 2H), 3.17 The starting material, 2ꢀ(2ꢀEthynylꢀ4,5ꢀdimethoxyphenyl)ethanol
(s, 1H), 2.99 (t, J = 6.6 Hz, 2H); 13C NMR δ (100 MHz, CDCl3) (12), was prepared according to the literature procedure.38
146.0, 136.4, 112.4, 110.0, 109.5, 101.5, 82.4, 79.7, 63.1, 39.0, 37.7;
HRMS (ESI): m/z calcd for C11H11O3 [M+H]+: 191.0708; found:
2-{[2-(2-Hydroxyethyl)-4,5-dimethoxyphenyl]ethynyl}-4,5-
191.0704.
dimethoxybenzaldehyde (13): Triethylamine (2 mL) was added to a
mixture of PdCl2(PPh)3 (9.6 mg, 0.014 mmol), CuI (1.3 mg, 0.007
mmol), 12 (144 mg, 0.71 mmol) and 9 (135 mg, 0.55 mmol) under
6-{[6-(2-Hydroxyethyl)benzo[d][1,3]dioxol-5-yl]ethynyl}-2,3-
dimethoxybenzaldehyde (10): Triethylamine (1.2 mL) was added to inert atmosphere. The reaction mixture was heated to reflux for 3 h.
a mixture of PdCl2(PPh)3 (18 mg, 0.0125 mmol), CuI (1.1 mg, 0.006 After completion of the reaction (monitored by TLC), solvent was
mmol), 9 (122 mg, 0.5 mmol) and 8 (124 mg, 0.65 mmol) under removed under reduced pressure. The residue was then diluted with
inert atmosphere. The reaction mixture was heated to reflux for 3 h. EtOAc (20 mL) and water (10 mL). Organic layer was separated and
After completion of the reaction (monitored by TLC), Et3N was aqueous layer was washed with EtOAc (10 mL x 2). The combined
removed under reduced pressure. The residue was then diluted with organic layer was dried over anhydrous Na2SO4, filtered and
EtOAc (10 mL) and water (5 mL). Organic layer was separated and concentrated under reduced pressure. The residue was purified
aqueous layer was washed two times with EtOAc (10 mL). The through silica gel column using EtOAc/hexane to get pure 13. Yield:
1
combined organic layer was dried over anhydrous Na2SO4, filtered 65%; yellow gummy solid; H NMR (400 MHz, CDCl3) δ 10.53 (d,
and concentrated under reduced pressure. The residue was purified J = 0.6 Hz, 1H), 7.38 (dd, J = 8.5, 0.7 Hz, 1H), 7.11 (d, J = 8.7 Hz,
by silica gel column chromatography using EtOAc/hexane to get 1H), 7.03, (s, 1H), 6.76 (s, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 3.92–3.91
pure 10. Yield: 65%; pale yellow solid; mp = 104–106 °C; 1H NMR (m, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.18 (t, J = 7.3 Hz, 2H); 13C
(400 MHz, CDCl3) δ 10.51 (s, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.11 (d, NMR (100 MHz, CDCl3) δ 190.6, 152.8, 149.8, 147.3, 135.1, 132.2,
J = 8.5 Hz, 1H), 6.99 (s, 1H), 6.75 (s, 1H), 5.96 (s, 2H), 3.97 (s, 3H), 130.4, 129.7, 117.3, 115.6, 115.1, 114.9, 112.5, 92.1, 89.7, 64.1,
3.93 (s, 3H), 3.87 (t, J = 7.2 Hz, 2H), 3.17 (t, J = 7.3 Hz, 2H); 13C 62.5, 56.2, 56.1, 56.0, 38.4; HRMS (ESI): m/z calcd for C21H23O6
NMR (100 MHz, CDCl3) δ 190.6, 152.8, 152.7, 148.4, 146.1, 136.7, [M+H]+: 371.1495; found: 371.1491.
130.5, 129.7, 117.3, 116.1, 115.4, 112.0, 110.0, 101.5, 92.0, 89.7,
64.1, 62.5, 56.3, 38.5; HRMS (ESI): m/z calcd for C20H19O6 [M+H]+:
355.1182; found: 355.1185.
2-[2-(6,7-Dimethoxyisoquinolin-3-yl)-4,5-
dimethoxyphenyl]ethanol (14): BuOH (2 mL) was added to a
t
mixture of AgNO3 (3.4 mg, 0.02 mmol), ammonium acetate (23 mg,
2-{6-[(7,8-Dimethoxyisoquinolin-3-yl]methyl)benzo[d][1,3]dioxol-
5-yl}ethanol (11): tBuOH (5 mL) was added to a mixture of AgNO3 0.3 mmol) and 13 (76 mg 0.20 mmol) under inert atmosphere. The
(9.0 mg, 0.054 mmol), ammonium acetate (62 mg, 0.81 mmol) and resultant mixture was stirred at room temperature and the reaction
10 (190, 0.54 mmol) under inert atmosphere. The resultant mixture was monitored by TLC. After completion, the reaction was
was stirred at room temperature and the reaction was monitored by quenched by the addition of NaHCO3 (83 mg, 1.0 mmol, 4) at room
TLC. After completion, the reaction was quenched by the addition of temperature and stirring was continued for additional 4 h. The
NaHCO3 (180 mg, 2.12 mmol) at room temperature and stirring was mixture was then filtered through a cotton plug, washed with EtOAc
continued for additional 4 h. The mixture was then filtered through a (10 mL) and dried over anhydrous Na2SO4. The filtrate was
cotton plug, washed with EtOAc (10 mL) and dried over anhydrous evaporated under reduced pressure and the residue was purified
Na2SO4. The filtrate was evaporated under reduced pressure and the through silica gel column chromatography (EtOAc/hexane) to get
residue was purified through silica gel column chromatography the pure isoquinoline (14). Yield: 70%; brown solid; mp = 164–166
(EtOAc/hexane) to get the pure isoquinoline (11). Yield: 78%; °C; 1H NMR (400 MHz, CDCl3) δ 9.53 (t, J = 0.9 Hz, 1H), 7.76 (d, J
1
brown solid; mp = 137–139 °C; H NMR (400 MHz, CDCl3) δ 9.52 = 0.9 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.54 (d, J = 9.0 Hz, 1H),
(t, J = 0.8 Hz, 1H), 7.72 (d, J = 0.8 Hz, 1H), 7.61 (d, J = 9.0, Hz,1H), 6.95 (s, 1H), 6.89 (s, 1H), 4.08 (s, 3H), 4.02 (s, 3H), 4.01 (t, J = 5.8
7.54 (d, J = 9.0 Hz, 1H), 6.92 (s, 1H), 6.88 (s, 1H), 6.0 (s, 2H), 4.09 Hz, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 2.86 (t, J = 5.8 Hz, 2H); 13C
(s, 3H), 4.03 (s, 3H), 3.99 (t, J = 5.8 Hz, 2H), 2.82 (t, J = 5.7 Hz, NMR (100 MHz, CDCl3) δ 150.7, 149.6, 149.0, 147.4, 145.6, 144.1,
2H); 13C NMR (100 MHz, CDCl3) δ 150.5, 149.1, 148.2, 146.2, 132.8, 132.6, 131.4, 122.9, 122.7, 121.0, 120.0, 113.4, 113.1, 64.1,
145.6, 144.1, 133.6, 132.9, 132.7, 122.9, 122.8, 121.0, 120.2, 110.2, 61.9, 57.2, 56.3, 56.1, 35.3; HRMS (ESI): m/z calcd for C21H24NO5
[M+H]+: 370.1654; found: 370.1658.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2014, 00, 1-3 | 7

Organic & Biomolecular Chemistry
Page 8 of 10
VJieowuArrtnicalelONnlainme e
ARTICLE
DOI: 10.1039/C4OB02641A
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Synthesis of Palmatine (4):33 A mixture of Isoquinoline derivative
14 (10 mg, 0.027 mmol), PPh3 (15 mg, 0.054 mmol) in CH2Cl2ꢀCCl4
mixture (1:2) (0.5 mL) was stirred at room temperature until the
starting material got completely consumed (24 h, by TLC). The
reaction mixture was carefully filtered and the solid was washed
with EtOAc (5 mL x 4) to get palmatine (4). Yield: 70%; yellow
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1
solid; mp = 195ꢀ197°C; H NMR (400 MHz, DMSOꢀd6) δ 9.90 (s,
1H), 9.06 (s, 1H), 8.22 (d, J = 9.2 Hz, 1H), 8.03, (d, J = 9.1 Hz, 1H),
7.72 (s, 1H), 7.10 (s, 1H), 4.95 (t, J = 6.0 Hz, 2H), 4.10 (s, 3H), 4.07
(s, 3H), 3.94 (s, 3H), 3.87 (s, 3H), 3.23 (t, J = 6.2 Hz, 2H); 13C NMR
(100 MHz, DMSOꢀd6) δ 151.5, 150.3, 148.8, 145.5, 143.7, 137.8,
133.1, 128.7, 126.8, 123.5, 121.4, 119.9, 117.3, 111.3, 108.7, 62.0,
57.1, 56.2, 55.9, 55.4, 26.01; HRMS (ESI): m/z calcd for C21H23NO4
[M+H]+: 353.1627; found: 353.1644.
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Conclusions
In conclusion, a silver catalysed room temperature protocol for the
synthesis of a wide range of isoquinoline derivatives from oꢀ(1ꢀ
alkynyl)arylaldehydes and ketones has been developed. This mild
protocol has been successfully utilized in the total synthesis of
biologically active isoquinoline alkaloids such as berberine and
palmatine. Since only a few steps are involved, the total synthesis of
these alkaloids 3 and 4 were accomplished in a very high overall
yield.
Acknowledgements
The authors gratefully acknowledge IISER Mohali for financial
support and infrastructure. VR and ASJ thank the CSIR, New Delhi
for a research fellowship. The NMR and HRMS facilities at IISER
Mohali are gratefully acknowledged.
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Notes and references
Department of Chemical Sciences, Indian Institute of Science Education
and Research (IISER) Mohali, Sector 81, Knowledge City, S. A. S. Nagar,
Manauli (PO), Punjab – 140306, India.
Email: rvijayan@iisermohali.ac.in
1
† Electronic Supplementary Information (ESI) available: [Copies of H
and 13C NMR spectra of all new compounds]. See
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DOI: 10.1039/C4OB02641A
Table of Contents
A Room Temperature Protocol to Access Isoquinolines through Silver (I) Catalysed
Annulation of o-(1-Alkynyl)arylaldehydes and Ketones with NH4OAc: Elaboration
to Berberine and Palmatine
Virsinha Reddy, Abhijeet S. Jadhav and R. Vijaya Anand*
A silver catalysed protocol for the synthesis of a wide range of isoquinoline derivatives from o-
(1-alkynyl)arylaldehydes and ketones has been developed under mild conditions. This protocol
has been elaborated to the synthesis of two important isoquinoline alkaloids, berberine and
palmatine, which were obtained in 32 and 35% overall yield respectively.