Facile synthesis of 3-(aminomethyl)isoquinolines by copper-catalysed domino four-component coupling and cyclisation

Article abstract of DOI:10.1039/b718201e

Copper(I)-catalysed domino four-component coupling-cyclisation using 2-ethynylbenzaldehydes, paraformaldehyde, secondary amine, and t-BuNH ₂ in DMF leads to direct and efficient formation of 3-(aminomethyl)isoquinolines in good to high yields.

Full text of DOI:10.1039/b718201e

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Facile synthesis of 3-(aminomethyl)isoquinolines by copper-catalysed
domino four-component coupling and cyclisationw
Yusuke Ohta, Shinya Oishi, Nobutaka Fujii* and Hiroaki Ohno*
Received (in Cambridge, UK) 26th November 2007, Accepted 12th December 2007
First published as an Advance Article on the web 4th January 2008
DOI: 10.1039/b718201e
Copper(I)-catalysed domino four-component coupling–cyclisa-
tion using 2-ethynylbenzaldehydes, paraformaldehyde, second-
ary amine, and t-BuNH2 in DMF leads to direct and efficient
formation of 3-(aminomethyl)isoquinolines in good to high
yields.
The isoquinoline scaffold can be found in a wide variety of
biologically active natural and synthetic compounds.1 Parti-
cularly, isoquinolines having an additional nitrogen atom
tethered by one carbon at the 3-position, including such
isoquinoline alkaloids as quinocarcin2 and ecteinascidin 597
and 583,3 and 3-(2-pyridinyl)isoquinolines,4 constitute an im-
Scheme 1 Construction of 3-(aminomethyl)isoquinolines by copper-
catalysed four-component coupling–cyclisation.
portant class of compounds with important biological activ-
ities. With a continuing interest in the development of
nucleophilic reactions in the desired order might be hampered
on one-portion reaction.10 Accordingly, after the copper-
environmentally-benign synthesis as well as multi-component
reactions in modern synthetic chemistry,5 we planned a novel
catalysed three component reaction of 1a, 2, and 3a in DMF
diversity-oriented synthetic methodology for the construction
was complete, being monitored by TLC, the N-1 synthon was
of these molecules by the use of a domino multi-component
added. Whereas ammonium nitrate 4a, perchlorate 4b, hydro-
coupling–cyclisation reaction.
xide 4c, formate 4d, chloride 4e, and sulfate 4f were ineffective
Recently, we have reported an efficient construction of
(entries 1–6), the use of acetate 4g and hydrogen carbonate 4h
2-(aminomethyl)indoles by a copper-catalysed three-compo-
gave, as expected, the desired isoquinoline 6a in moderate
nent coupling–cyclisation reaction.6 This reaction proceeds
through Mannich-type coupling followed by indole formation.
On the basis of our indole synthesis, we expected that a four-
component coupling reaction of 2-ethynylbenzaldehydes 1,
aldehyde 2, secondary amine 3, and an appropriate N-1
synthon 4, followed by cyclisation of the alkyne intermediate
5, having a nitrogen atom in proximity to the triple bond,7,8
would provide a direct route to 3-(aminomethyl)isoquinolines
6 without wasting any salts (Scheme 1). Herein, we describe a
copper-catalysed domino four-component coupling–cyclisa-
tion reaction for diversity-oriented synthesis of 3-(amino-
methyl)isoquinolines. To the best of our knowledge, this is
the first example of a four-component synthesis of an iso-
quinoline scaffold.9
yields (42–53%, entries 7 and 8).11 More promising results
were obtained with primary amines having a readily cleavable
alkyl group such as 2,4,6-trimethoxybenzylamine hydrochlor-
ide 4i and tert-butylamine 4j,7 leading to high yields of 6a
Table 1 Optimisation of the N-1 synthon 4a
Entry
N-1 synthon
Yield (%)b
1
2
3
4
5
6
7
8
9
10
a
NH4NO3 (4a)
NH4ClO4 (4b)
28% NH4OH (4c)
NH4(HCO2) (4d)
NH4Cl (4e)
(NH4)2SO4 (4f)
NH4OAc (4g)
NH4HCO3 (4h)
2,4,6-(MeO)3C6H2CH2NH2 Á HCl (4i)
t-BuNH2 (4j)
Decomp.
Decomp.
Trace
Trace
Trace
Trace
42
53
82
83
In the initial investigation, we examined the effect of the N-1
synthon on the copper-catalysed four-component synthesis of
3-(aminomethyl)isoquinoline using 2-ethynylbenzaldehyde 1a
as a model substrate, paraformaldehyde 2 and diisopropyl-
amine 3a (Table 1). Since two nucleophilic reagents coexist
with two aldehydes in the reaction system, progress of the
After a mixture of 2-ethynylbenzaldehyde 1a, paraformaldehyde 2
(2 equiv.), amine 3a (2 equiv.) and CuI (10 mol%) in DMF was stirred
at room temperature for 1 h, and N-1 synthon 4 (6 equiv.) was
added. The resulting mixture was stirred for 5 h at room temperature
Graduate School of Pharmaceutical Sciences, Kyoto University,
Sakyo-ku, Kyoto 606-8501, Japan. E-mail: nfujii@pharm.
kyoto-u.ac.jp. E-mail: hohno@pharm.kyoto-u.ac.jp
w Electronic supplementary information (ESI) available: Experimental
details and NMR spectra. See DOI: 10.1039/b718201e
b
and for an additional 45 min at 140 1C. Isolated yield.
ꢀc
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Table 2 Synthesis of 3-(aminomethyl)isoquinolinesa
Table 3 Reactions with substituted 2-ethynylbenzaldehydesa
Entry Substrate
1
Product
Yield (%)b
83
1b
7
Yield
(%)d
Entry Amine
Conditionsb Product
rt, 1 h
2
79
87
84
1
2
3
i-Pr2NH
83
3a
6a
1c
8
9
Bn2NH
100 1C, 1 h
0
3
3b
6b
100 1C, 1 h
73
1d
4
3c
6c
4
5
(allyl)2NH
rt, 1 hc
60
88
1e
10
3d
3e
6d
a
After the three-component reaction of 1, 2 (2 equiv.), and 3a (2 equiv.) in the
presence of CuI (10 mol%) in DMF was completed on TLC, t-BuNH2
(4j, 6 equiv.) was added and the reaction mixture was stirred for 5 h at room
rt, 1 hc
b
temperature and for an additional 45 min at 140 1C. Isolated yield.
6e
6
rt, 1 hc
79
nylbenzaldehydes were next investigated (Table 3). The use of
2-ethynyl-4-fluorobenzaldehyde 1b in the presence of CuI (10
mol%) gave the desired 3-(aminomethyl)-6-fluoroisoquinoline
derivative 7 in high yield (83%, entry 1). Benzaldehyde 1c,
which has a fluorine atom at the meta-position to the formyl
group, afforded the corresponding isoquinoline 8 (79%, entry
2). Also, in the cases of 2-ethynylbenzaldehydes containing an
electron-donating group such as a methyl or a methoxy group
at the para- or meta-position to the formyl group (1d and 1e,
respectively), the copper-catalysed four-component isoquino-
line formation proceeded smoothly (87 and 84% yield, respec-
tively, entries 3 and 4). Thus, this isoquinoline formation was
proven to be widely applicable to 2-ethynylbenzaldehydes
having an electron-withdrawing and -donating group.
In conclusion, we have developed a novel copper-catalysed
domino four-component coupling–cyclisation reaction for the
synthesis of 3-(aminomethyl)isoquinolines, which form one
carbon–carbon and three carbon–nitrogen bonds. This meth-
odology could be applied to the construction of a highly
potent isoquinoline library in terms of diversity and biological
activity.
3f
6f
a
After the three-component reaction of 1a, 2 (2 equiv.), and 3 (2 equiv.) in the
presence of CuI (10 mol%) in DMF was completed on TLC, t-BuNH2 (4j, 6
equiv.) was added and the reaction mixture was stirred for 5 h at room
b
temperature and for an additional 45 min at 140 1C. Conditions for the
c
three-component coupling. Before 1a was added, a mixture of 2, 3 and CuI
d
in DMF was stirred for 30 min at room temperature. Isolated yield.
(entries 9 and 10).12 Taking the atom economy of the reaction into
consideration, we regarded 4j as the most potent N-1 synthon.
Next, various secondary amines were employed to deter-
mine the scope of this reaction (Table 2). Although dibenzyl-
amine 3b showed lower reactivity toward Mannich-type cou-
pling with 1a and 2, leading to recovery of the unchanged
starting material (entry 2),13 the reaction with more bulky
bis(1-phenylethyl)amine 3c led to successful conversion into
the corresponding isoquinoline 6c (73%, entry 3). Unfortu-
nately, the initial Mannich type reaction with highly nucleo-
philic diallylamine, piperidine, or pyrrolidine was unsuccessful,
producing a complex mixture, presumably due to the simulta-
neous presence of two aldehydes (2-ethynylbenzaldehyde 1a
and paraformaldehyde 2) and a reactive amine. Extensive
optimisation of the reaction conditions brought about addition
of 2-ethynylaldehyde 1a after the formation of iminium ions
between secondary amines 3d–f and paraformaldehyde 2. As a
result, the corresponding 3-(aminomethyl)isoquinolines 6d–f
were obtained in moderate to high yields (entries 4–6).
Notes and references
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The copper-catalysed domino four-component syntheses of
3-(aminomethyl)isoquinolines with some substituted 2-ethy-
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10 Actually, one-portion addition of all the four components using 4j
gave a complex mixture of unidentified products without produ-
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11 For isoquinoline formation with such ammonium salts as formate,
carbonate, and ammonia, see ref. 8c.
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12 In the reaction using 4i, a hydrogen atom at the 4-position of 6a
would come from H2O generated in imine formation.
6 H. Ohno, Y. Ohta, S. Oishi and N. Fujii, Angew. Chem., Int. Ed.,
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13 At the present stage of our understanding, the reason for this
unsatisfactory result is unclear.
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