Palladium-catalyzed, microwave-enhanced three-component synthesis of isoquinolines with aqueous ammonia

Article abstract of DOI:10.1055/s-0030-1258571

A variety of substituted isoquinoline derivatives can be synthesized in moderate yield by a palladium-catalyzed, microwave-assisted MCR starting from o-bromoarylaldehydes, terminal alkynes, and aqueous ammonia. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258571

2672
LETTER
Palladium-Catalyzed, Microwave-Enhanced Three-Component Synthesis of
Isoquinolines with Aqueous Ammonia
Multicomponent Synth
o
esis of Isoqu
n
inolines ica Dell’Acqua, Giorgio Abbiati,* Elisabetta Rossi
Dipartimento di Scienze Molecolari Applicate ai Biosistemi (DISMAB) – Sezione di Chimica Organica ‘A. Marchesini’,
Università degli Studi di Milano, Via G. Venezian 21, 20133 Milano, Italy
Fax +39(02)50314476; E-mail: giorgio.abbiati@unimi.it
Received 2 August 2010
tions on the synthesis of pyrazino[1,2-a]indole and pyrro-
Abstract: A variety of substituted isoquinoline derivatives can be
synthesized in moderate yield by a palladium-catalyzed, micro-
wave-assisted MCR starting from o-bromoarylaldehydes, terminal
alkynes, and aqueous ammonia.
lo[1,2-a]pyrazine nuclei by sequential imination–
annulation reactions of 2-carbonyl-N-propargyl-indoles22
and -pyrroles,23 respectively; the reactivity of less reactive
substrates has been promoted with TiCl4 as multifunction-
al additive. In this context, we successfully tested
microwaves24 as highly efficient nonconventional energy
source able to improve both yields and selectivity, to re-
duce reaction times and also to enhance the reactivity of
more critical substrates. In the last of these papers we also
described a selective path to the isoquinoline skeleton by
a MW-promoted domino imination–annulation cascade of
2-alkynylbenzaldehydes prepared by a Pd-catalyzed cou-
pling reaction between o-bromobenzaldehyde and various
alkynes.23 We were intrigued to further simplify and opti-
mize the approach, so, encouraged by these results, in this
paper we present a one-pot, three-component approach to
isoquinolines directly starting from simple o-bromobenz-
aldehyde, terminal alkynes, and ammonia in the presence
of a suitable catalytic system. The most interesting fea-
tures of this approach are: a) the double role of ammonia:
base for the Sonogashira coupling and amino partner for
imination–cyclization step; b) the potential multiactivity
of the metal catalyst, involved in the Sonogashira cou-
pling step and in the imination–cyclization sequence. The
suitability of ammonia as base in the Sonogashira cou-
pling has been well described by Mori and co-workers,25
whereas the ability of some late transition metals to acti-
vate the triple bond during the cyclization step has been
proven on related cyclization of carbonyl groups on
alkynes in the presence of palladium/copper,26 gold/sil-
ver,27 and also ruthenium or tungsten.28
Key words: multicomponent reaction, alkynes, aqueous ammonia,
isoquinoline, palladium
Multicomponent reactions (MCRs) are a powerful tool for
the synthesis of complex molecules starting from readily
available building blocks in a ‘well-contrived’ one-pot se-
quential procedure.1 These approaches allow an overall
reduction of the time required to obtain the desired prod-
uct with an advantageous economy of solvents and energy
and an overall reduction of waste production. MCRs have
been widely used for the preparation of heterocyclic
structures2 as well as key steps in the total synthesis of nat-
ural products.3 Moreover, the enhancing power of micro-
waves in MCRs have been recently highlighted.4
The isoquinoline nucleus is the core of well-known alka-
loids such as papaverine and local anaesthetics such as
quinisocaine, whereas saturated, functionalized, and poly-
cyclic derivatives are known to show different important
pharmacological properties.5
In the literature there are some valuable approaches to
isoquinoline6 and dihydroisoquinoline7 nuclei starting
from 2-acyl-phenylacetylenes6a–f,7a–i or from their imine
derivatives.6g–q,7j–o Some of them are MCRs leading to the
dihydroisoquinoline skeleton.7a–h Conversely, multicom-
ponent strategies to obtain isoquinolines are still scarce.6f,8
Moreover, to the best of our knowledge, in the literature
there is only one example involving a Sonogashira cou-
pling as a key step9 whereas some MCRs involving a
Sonogashira reaction have been reported for the prepara-
tion of pyrazoles,10 isoxazoles,11 halofurans,12 pyridines,13
pyrimidines,14 indoles,15 indolizines,16 furo[2,3-b]pyri-
dones,17 thiochromen-4-ones,18 thiopyran-4-ones,19 and
tetrahydro-b-carbolines.20
We screened the optimal reaction conditions with 2-bro-
mobenzadehyde (1a), ammonia solutions, and 1-ethynyl-
4-methylbenzene as model system. The results are depict-
ed in Table 1.
In first instance, we ran the reaction under typical
Sonogashira cross-coupling conditions [PdCl2(PPh3)2,
CuI, 50 °C], under microwave irradiation and in the pres-
ence of a solution of ammonia in DMF. After four hours
the reaction gave only traces of the desired product 3a, be-
side a complex mixture of unidentified products (Table 1,
entry 1). At higher temperatures, a modest rise in yields
was observed (Table 1, entries 2 and 3). When the reac-
tion was performed in ammonia in methanol, the desired
product was obtained in a encouraging 39% yield in one
For many years we devoted our studies to the synthesis of
nitrogen-containing rings by sequential addition–annula-
tion reactions of g- and d-ketoalkynes in the presence of
ammonia.21 In particular, we reported in-depth investiga-
SYNLETT 2010, No. 17, pp 2672–2676
x
x
.x
x
.2
0
1
0
Advanced online publication: 23.09.2010
DOI: 10.1055/s-0030-1258571; Art ID: G23310ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Multicomponent Synthesis of Isoquinolines
2673
hour (Table 1, entry 4). Next, we move our attention to the time gave worse results, and a little amount of the o-alky-
use of aqueous solution of ammonia.
nylbenzaldehyde 2a intermediate was isolated (Table 1,
entry 9). Likewise, a rise in temperature to 160 °C resulted
in lower yields (Table 1, entry 10). The concentration of
ammonia solution was found to be critical in Sonogashira
coupling reaction with aqueous ammonia.25 According to
this, an increasing as well as a reduction of the ammonia
concentration gave worse results (Table 1, entries 11 and
12). We also tried a different water-soluble co-solvent
such as DMF, but also in this case a slightly lowering of
the reaction yield was observed (Table 1, entry 13). The
studies on copper-free Sonogashira coupling are widely
reported in the literature,29 but when we tested these fa-
vorable conditions we observed a reduction of reaction
yield (Table 1, entry 14). We also tried a different basic
co-catalyst such as silver oxide30 with scarce results
(Table 1, entry 15). Finally, the reaction was performed in
This readily available and inexpensive reagent has been
successfully used in some examples of Sonogashira cou-
pling reactions25 and the possibility to use it in our MCR
could be a further improvement of the method. Neverthe-
less, probably due to the low water solubility of the re-
agents, the reaction was sluggish, the yield was still low,
and the workup was troublesome (Table 1, entry 5). In the
presence of THF as co-solvent and under conventional
heating at 100 °C for eight hours the reaction yield
jumped to 50% (Table 1, entry 6), whereas under micro-
wave irradiation at the same temperature the reaction gave
the same yield in an half time (Table 1, entry 7). By in-
creasing the temperature of microwave oven to 130 °C the
desired product was obtained in a satisfying 58% yield in
one hour only (Table 1, entry 8). A further reduction of
Table 1 Screening of Optimal Reaction Conditions
p-Tol
Br
catalytic
p-Tol
system
NH3
+
+
p-Tol
H
solvent
energy
N
H
O
O
1a
2a
3a
Entry NH3, solvent
Catalyst
(mol%)
Co-catalyst/
additive
Energy
Temp
(°C)
Time Yield (%)b Yield (%)b
(h)a
of 3a
trace
10
of 2a
1
2
2.3 M in DMFc
2.3 M in DMF
2.3 M in DMF
PdCl2(PPh3)2 (0.02)
PdCl2(PPh3)2 (0.02)
PdCl2(PPh3)2 (0.02))
PdCl2(PPh3)2 (0.02)
PdCl2(PPh3)2 (0.01)
PdCl2(PPh3)2 (0.01)
PdCl2(PPh3)2 (0.01)
PdCl2(PPh3)2 (0.01)
PdCl2(PPh3)2 (0.01)
PdCl2(PPh3)2 (0.01)
PdCl2(PPh3)2 (0.01)
CuI (0.02 mol%)
CuI (0.02 mol%)
CuI (0.02 mol%)
CuI (0.02 mol%)
CuI (0.02 mol%)
CuI (0.02 mol%)
CuI (0.02 mol%)
CuI (0.02 mol%)
CuI (0.02 mol%)
CuI (0.02 mol%)
CuI (0.02 mol%)
CuI (0.02 mol%)
CuI (0.02 mol%)
–
MW
MW
MW
MW
oil bath
oil bath
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
50
80
4
–
0.5
2
–
3
130
130
100
100
100
130
130
160
130
130
130
130
130
130
26
trace
–
4
2.0 M in MeOHd
2.5 M in H2Oe
1
39
5
16
8
30
–
6
2.5 M in H2O–THF (3:1)
2.5 M in H2O–THF (3:1)
2.5 M in H2O–THF (3:1)
2.5 M in H2O–THF (3:1)
2.5 M in H2O–THF (3:1)
5 M in H2Of–THF (3:1)
50
–
7
4
50
–
8
1
58
–
9
0.5
0.34
1
48
10
–
10
11
12
13
14
15
16
48
47
–
1.25 M in H2O–THFg (3:1) PdCl2(PPh3)2 (0.01)
2.5
1
44
20
–
2.5 M in H2O–DMF (3:1)
2.5 M in H2O–THF (3:1)
2.5 M in H2O–THF (3:1)
2.5 M in H2O–THF (3:1)
PdCl2(PPh3)2 (0.01)
PdCl2(PPh3)2 (0.02)
PdCl2(PPh3)2 (0.02)
PdCl2(PPh3)2 (0.02)
46
1
39
11
20
15
Ag2O (0.2 mol%)
KOH (5 equiv)
1
25
1.5
30
a Not including 10 min ‘ramp time’ (10 °C/min).
b Yields refer to pure isolated product.
c Molar ratio 1/NH3 = 1:10.
d Molar ratio 1/NH3 = 1:16.
e Molar ratio 1/NH3 = 1:7.5.
f Molar ratio 1/NH3 = 1:15.
g Molar ratio 1/NH3 = 1:3.75.
Synlett 2010, No. 17, 2672–2676 © Thieme Stuttgart · New York

2674
M. Dell’Acqua et al.
LETTER
the presence of a stronger water-soluble base such as rise to a complex mixture of unidentified byproducts.
KOH to restrict the role of ammonia to a simple amino Then, the effect of the presence of electron-withdrawing
partner for the imination–annulation process, nevertheless and electron-donating groups on the 2-bromobenzalde-
the result was still unsatisfactory (Table 1, entry 16).
hyde was briefly investigated (Table 2, entries 10 and 11).
In the first trial the reaction yield was satisfying under
standard conditions (Table 2, entry 10), whereas in the
presence of EDG best results were obtained in a twofold
reaction time (Table 2, entry 11). Finally, starting from
the electron-poor 2-bromonicotinaldehyde (1d) the ap-
proach demonstrated to be a little less effective (Table 2,
entry 12).
With the best conditions in hand31 (Table 1, entry 8), we
briefly investigated the scope and the limitation of the ap-
proach by changing the substitution pattern on the alkyne,
on the benzaldehyde framework, and modifying the na-
ture of the aromatic aldehyde. The reactions proceeded
with complete 6-endo-dig regioselectivity, leading to the
formation of the corresponding isoquinolines in moderate
yields. It is interesting to note that, although also under the The suggested reaction mechanism involves a well-or-
best reaction conditions the yields are not excellent, the dered set of three different events: a) an imination step, b)
overall yields of this multicomponent process are in most a Sonogashira coupling (these two steps could also occur
cases better than those obtained in the two-step domino simultaneously), c) a final intramolecular annulation reac-
sequence.23 The results are depicted in the Table 2.
tion. As mentioned above, the ammonia play the double
role of base in the cross-coupling and amino partner in the
addition–cyclization sequence. Regarding the role of the
metals (Pd and Cu), obviously involved in the cross-cou-
pling between the o-bromobenzaldehyde and the alkyne,
we cannot ‘a priori’ exclude their involvement as Lewis
acids in the imination and in the cyclization steps.32 This
fact could explain the higher overall yields observed in
this multicomponent approach, with respect to the domino
synthesis.23
Electron-rich phenylacetylenes gave the corresponding
isoquinolines in good yields (Table 2, entries 2–4), also
when the substituent is in a sterically demanding ortho po-
sition (Table 2, entries 2 and 4), but in extended reaction
times. The presence of an acetal group on the triple bond
is tolerated too (Table 2, entry 5). Conversely, in the pres-
ence of an electron-withdrawing group on the phenylacet-
ylene, despite a quantitative conversion of 1 in one hour
only, the reaction yields are slightly lower (Table 2, entry
6 and 7). Unfortunately, the reaction failed in the presence In summary, we developed an unprecedented multicom-
of aliphatic linear alkynes (Table 2, entries 8 and 9) giving ponent synthesis of isoquinoline skeleton starting from
Table 2 Scope and Limitation of the Three-Component Approach to Isoquinolines
R2
PdCl2(PPh3)2 (0,01 mol%)
CuI (0,02 mol%)
X
X
Br
O
R2
+
N
H
NH3 (2.5 M aq), THF
MW, 130 °C
R1
R1
3
1
Entry
1
X
R1
H
H
H
H
H
H
H
H
H
F
Aldehyde
R2
Ph
Time (h)a
Product
3b
3c
Yield (%)b
C
C
C
C
C
C
C
C
C
C
C
N
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1
2
2
3
1
1
1
3
3
1
2
1
50
46
56
64
42
32
33
2
2-MeOC6H4
4-MeOC6H4
3
3d
3e
4
4-MeO-2-MeC6H4
(EtO)2CH
3-F3CC6H4
3-FC6H4
5
3f
6
3g
7
3h
3i
c
8
C5H11
–
c
9
SiMe3
3j
–
10
11
12
4-MeC6H4
4-MeC6H4
4-MeC6H4
3k
3l
59
57
35
OMe
H
1c
1d
3m
a Not including 10 min ‘ramp time’ (ca. 10 °C/min).
b Yields refer to pure isolated product.
c Complex mixture of unidentified byproducts.
Synlett 2010, No. 17, 2672–2676 © Thieme Stuttgart · New York

LETTER
Multicomponent Synthesis of Isoquinolines
2675
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This work was supported by Ministero dell’Istruzione, Università e
Ricerca, Roma.
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(28) Gulías, M.; Rodríguez, J. R.; Castedo, L.; Mascareñas, J. L.
Org. Lett. 2003, 5, 1975.
microwave oven (Microsinth Milestone®) for 2 h. The
reaction mixture was diluted with H2O (70 mL) and
extracted with EtOAc (3 × 70 mL). The organic layer dried
with Na2SO4, was evaporated to dryness, and the crude
material was purified by flash chromatography over a silica
gel column (hexane–EtOAc = 96:4) yielding the
(29) For some representative examples, see: (a) Alami, M.;
Ferri, F.; Linstrumelle, G. Tetrahedron Lett. 1993, 34, 6403.
(b) Leadbeater, N. E.; Tominack, B. J. Tetrahedron Lett.
2003, 44, 8653. (c) Gil-Moltó, J.; Nájera, C. Eur. J. Org.
Chem. 2005, 4073. (d) Bakherad, M.; Keivanloo, A.;
Bahramian, B.; Mihanparast, S. Tetrahedron Lett. 2009, 50,
6418.
(30) Mori, A.; Kawashima, J.; Shimada, T.; Suguro, M.;
Hirabayashi, K.; Nishihara, Y. Org. Lett. 2000, 2, 2935.
(31) Synthesis of 3-(4-Methoxyphenyl)isoquinoline (3d)
In a sealed MW test tube, to a solution of 2-bromobenz-
aldehyde (1a, 185 mg, 0.116 mL, 1 mmol) in THF (1 mL),
4-ethynylanisole (159 mg, 0.156 mL, 1.2 mmol), and trans-
dichlorobis(triphenylphosphine)palladium (7.02 mg, 0.01
mmol) were added. The solution was stirred at r.t. for 10
min, then NH3 (2.5 M aq, 3 mL) and CuI (3.81 mg, 0.02
mmol) were added. The stirred reaction mixture was heated
isoquinoline 3d (132 mg, 56%) as brown solid; mp 85–
87 °C. IR (KBr): 1626, 1606, 1584, 1512, 1447, 1292, 1249,
1179, 1024, 834 cm–1. 1H NMR (200 MHz, CDCl3): d = 3.88
(s, 3 H, CH3), 7.04 (d, 2 H, arom, J = 8.8 Hz), 7.57 (ddd, 1
H, arom, J = 8.1, 7.0, 1.1 Hz), 7.67 (ddd, 1 H, arom, J = 8.4,
7.0, 1.5 Hz), 7.85 (d, 1 H, arom, J = 8.1 Hz), 7.95–7.99 (m,
2 H, arom), 8.08 (d, 2 H, arom, J = 8.8 Hz), 9.31 (s, 1 H,
arom). 13C NMR (50.3 MHz, CDCl3): d = 55.6 (CH3), 114.5,
115.5, 126.8, 126.9, 127.8, 128.4, 130.6, 152.5 (CH arom),
127.7, 132.6, 137.0, 151.4, 160.5 (C quat.). ESI-MS: m/z
(%) = 236 (100) [M + 1]+. Anal. Calcd for C16H13NO
(235.28): C, 81.68; H, 5.57; N, 5.95. Found: C, 81.77; H,
5.60; N, 5.93.
(32) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817.
Synlett 2010, No. 17, 2672–2676 © Thieme Stuttgart · New York

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