Rapid access to 3-(aminomethyl)isoquinoline-fused polycyclic compounds by copper-catalyzed four-component coupling, cascade cyclization, and oxidation

Article abstract of DOI:10.1021/jo901090u

(Chemical Equation Presented) A novel copper-catalyzed synthesis of 3-(aminomethyl) isoquinoline-fused polycyclic compounds, through four-component coupling, cyclization, and oxidation, has been developed. AMannich-type reaction of 2-ethynylbenzaldehyde with paraformaldehyde and a secondary amine followed by treatment with a diamine component gave tricyclic isoquinolines through cascade cyclization and oxidation. Construction of fused isoquinolines of various ring sizes is also presented.

Full text of DOI:10.1021/jo901090u

pubs.acs.org/joc
Isoquinoline-fused polycyclic compounds such as pyrimi-
Rapid Access to 3-(Aminomethyl)isoquinoline-Fused
Polycyclic Compounds by Copper-Catalyzed Four-
Component Coupling, Cascade Cyclization, and
Oxidation
do[2,1-a]isoquinolines and imidazo[2,1-a]isoquinolines exert
various biological effects3 including antitumor activity.4
Considerable efforts have been made to develop efficient
methods for the synthesis of this class of compounds, in
which stepwise introduction/construction of the desired ring
system is generally required.5 As a part of our ongoing
program directed toward development of copper-catalyzed
domino multicomponent coupling and cyclization,6 we re-
ported a novel synthesis of 3-(aminomethyl)isoquinolines by
four-component coupling-cyclization (Scheme 1).7 In this
reaction, a copper-catalyzed Mannich-type reaction of a
2-ethynylbenzaldehyde 1 with paraformaldehyde 2 and a
secondary amine 3 followed by imine formation with
t-BuNH2 4 promotes isoquinoline formation to afford 7
through cleavage of a tert-butyl group.
Yusuke Ohta, Yushi Kubota, Tsuyoshi Watabe,
Hiroaki Chiba, Shinya Oishi, Nobutaka Fujii,* and
Hiroaki Ohno*
Graduate School of Pharmaceutical Sciences, Kyoto
University, Sakyo-ku, Kyoto 606-8501, Japan
nfujii@pharm.kyoto-u.ac.jp; hohno@pharm.kyoto-u.ac.jp
Received May 24, 2009
SCHEME 1. Four-Component Synthesis of 3-(Aminomethyl)
isoquinoline Using Copper Catalysis
A novel copper-catalyzed synthesis of 3-(aminomethyl)
isoquinoline-fused polycyclic compounds, through four-
component coupling, cyclization, and oxidation, has been
developed. A Mannich-type reaction of 2-ethynylbenzal-
dehyde with paraformaldehyde and a secondary amine
followed by treatment with a diamine component gave
tricyclic isoquinolines through cascade cyclization and
oxidation. Construction of fused isoquinolines of various
ring sizes is also presented.
On the basis of this chemistry, we expected that the use of a
primary amine containing a tethered nucleophilic group
instead of t-BuNH2 could bring about an intramolecular
(4) (a) Danhauser-Riedl, S.; Felix, S. B.; Houlihan, W. J.; Zafferani, M.;
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(d) Smith, L. V.; Parenty, A. D. C.; Guthrie, K. M.; Plumb, J.; Brown, R.;
Cronin, L. ChemBioChem 2006, 7, 1757–1763.
Cascade reactions1 and multicomponent reactions2 in
which several bond-forming steps take place in a single
reaction vessel play an important role in atom-economical
organic chemistry. Recently, considerable attention has been
paid to this research area since complex molecules can be
produced from readily accessible components in a simple
manner.
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DOI: 10.1021/jo901090u
r
Published on Web 07/02/2009
J. Org. Chem. 2009, 74, 6299–6302 6299
2009 American Chemical Society

Ohta et al.
JOCNote
SCHEME 2. Four-Component Construction of an Isoquinoline-
Fused Tricyclic Ring System
TABLE 1. Optimization of Reaction Conditions Using 1,3-Diamino-
propanea
entry CuX
condition A
condition B
yieldd (%)
1
2
3
4
5
6
7
8
CuI
CuI
CuBr
CuBr2
CuCl2
CuF2
rt, 0.5 h
rt, 0.5 h
rt, 1.5 h
rt, 1.0 h
rt, 2.3 h
120 °C, 15 h
38
29
42
38
42
27
20
43
52
72
MW, 200 °C, 0.33 h
120 °C, 15 h
nucleophilic attack onto the isoquinolinium ion 10 without
causing cleavage (Scheme 2).8-10 In this paper, we describe a
novel approach to 3-(aminomethyl)isoquinoline-fused poly-
cyclic compounds utilizing four-component coupling and
cascade cyclization in the presence of a copper catalyst.
To the best of our knowledge, this is the first example of
multicomponent sequential construction of an isoquinoline-
fused heterocyclic ring system including imidazo[2,1-a]iso-
quinolines and pyrimido[2,1-a]isoquinolines.
120 °C, 15 h
120 °C, 10 h
100 °C, 0.5 h 120 °C, 16 h
Cu(OAc)2 rt, 2.5 h
120 °C, 12 h
120 °C, 12 h
120 °C, 20 h
120 °C, 1 h
CuCl
CuCl
CuCl
rt, 1.5 h
rt, 1.5 h
rt, 1.5 h
9b
10b,c
aAfter the Mannich-type reaction of 1a, 2 (2 equiv), and 3a (2 equiv) in
the presence of copper salt (10 mol %) was completed under conditions
A (monitored by TLC), 8a (3 equiv) was added. The reaction mixture
was stirred under conditions B. b8a with MS 4 A was added. Under
c
We envisioned that 1,3-diaminopropane would be an ap-
propriate primary amine as it has an additional nucleophilic
group that could sequentially form isoquinoline and pyrimi-
dinerings.11 Thus, our attemptstoconstructthe pyrimido[2,1-
a]isoquinoline framework were initiated with 2-ethynylben-
zaldehyde 1a, paraformaldehyde 2, diisopropylamine 3a, and
1,3-diaminopropane 8a (Table 1). Coexistence of two amines
with two aldehydes in one portion of the reaction would
hamper the effective Mannich-type reaction of 1a, 2, and 3a
and subsequent imine formation with 8a in the desired order.
Therefore, the copper-catalyzed Mannich-type reaction of 1a,
oxygen atmosphere. dIsolated yields.
2 (2 equiv), and 3a (2 equiv) in DMF was completed and
monitored by TLC, and then the reaction mixture was treated
with 8a (3 equiv) at 120 °C to afford the expected product of
the oxidized form 12a in 38% yield (entry 1).12 The elevated
reaction temperature (200 °C) under microwave irradiation
in the ring formation step led to a lower yield of 12a (29%,
entry2). When othercopper saltssuchasCuBr, CuBr2, CuCl2,
CuF2, Cu(OAc)2, and CuCl (entries 3-8) were used in the
reaction, it was revealed that CuCl was the most effective
catalyst for this transformation (43% yield, entry 8). Use of
MS 4 A slightly improved the yield of 12a (52%, entry 9).
Further optimization demonstrated that the cyclization reac-
tion under an oxygen atmosphere, which would facilitate the
oxidation step, realized rapid formation of 12a in 72% yield
(entry 10).
Several substituted 2-ethynylbenzaldehydes were then ap-
plied to this copper-catalyzed four-component synthesis of
3,4-dihydro-2H-pyrimido[2,1-a]isoquinoline under optimized
conditions (Table 1, entry 10). The results are summarized in
Table 2. The substitution by a fluorine atom at the para-
position to the formyl group slightly decreased the yield of
12b (55%, entry 1). The reaction with 2-ethynylbenzalde-
hydes 1c and 1d containing a fluorine atom at the meta-
position or methyl group at the para-position to the formyl
group showed a good conversion to yield the desired tricyclic
compounds 12c and 12d (74 and 71%, respectively, entries
2 and 3). The use of 2-ethynyl-5-methoxybenzaldehyde 1e
also gave tricyclic compound 12e (55%, entry 4). Overall,
this four-component construction of 3,4-dihydro-2H-pyri-
mido[2,1-a]isoquinoline having an aminomethyl group was
found to be applicable to 2-ethynylbenzaldehydes containing
an electron-donating or electron-withdrawing group.
(9) For related three-component monocyclizations, see: (a) Asao, N.;
Iso, K.; Yudha, S., S. Org. Lett. 2006, 8, 4149–4151. (b) Ding, Q.; Wang, B.;
Wu, J. Tetrahedron 2007, 63, 12166–12171. (c) Ding, Q.; Wu, J. Org. Lett.
2007, 9, 4959–4962. (d) Gao, K.; Wu, J. J. Org. Chem. 2007, 72, 8611–8613.
(e) Ye, Y.; Ding, Q.; Wu, J. Tetrahedron 2008, 64, 1378–1382.
(10) For related two-component monocyclizations using aldimines, see:
(a) Ohtaka, M.; Nakamura, H.; Yamamoto, Y. Tetrahedron Lett. 2004, 45,
7339–7341. (b) Asao, N.; Yudha, S.; Nogami, S.; Yamamoto, T. Angew.
Chem. Int. Ed 2005, 44, 5526–5528. (c) Yanada, R.; Obika, S.; Kono, H.;
Takemoto, Y. Angew. Chem., Int. Ed. 2006, 45, 3822–3825. (d) Obika, S.;
Kono, H.; Yasui, Y.; Yanada, R.; Takemoto, Y. J. Org. Chem. 2007, 72,
4462–4468.
(11) The reaction using 3-aminopropanol as the amine component 8
showed a promising result. However, the main product of this reaction was
unstable and decomposed during purification.
(12) The unambiguous structure assignment for 12a was made by X-ray
analysis (for CIF, see the Supporting Information).
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Ohta et al.
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TABLE 2. Reaction with Substituted 2-Ethynylbenzaldehydesa
TABLE 3. Reaction with Secondary Amines 3b-da
aThe reactions were conducted as described in Table 2. bIsolated
yields. cBefore addition of 1a, a mixture of 2 and 3b or 3c in DMF was
stirred at rt for 1 h in the presence of CuCl. dOne-portion Mannich-type
reaction of 1a, 2, and 3d was conducted at 100 °C for 1 h.
TABLE 4. Synthesis of (Aminomethyl)isoquinoline-Fused Polycyclic
Compoundsa
aAfter the Mannich-type reaction of 1, 2 (2 equiv), and 3a (2 equiv) in
the presence of CuCl (10 mol %) in DMF under O2 was completed (rt,
within 1.5 h, monitored by TLC), 8a (2 equiv) and MS 4 A were added
and the reaction mixture was stirred at 120 °C for 1 h. bIsolated yields.
Next, investigation with several secondary amines 3 was
conducted (Table 3). A one-portion Mannich-type reaction
with 2-ethynylbenzaldehyde 1a, paraformaldehyde 2, and
piperidine 3b was very sluggish. Therefore, a mixture of 2 and
3b in DMF was allowed to react at rt for 1 h in the presence of
CuCl before successive addition of 1a and 1,3-diaminopro-
pane 8a. This stepwise addition was successful to give the
desired 3,4-dihydro-2H-pyrimido[2,1-a]isoquinoline 12f in
61% yield (entry 1). Diallylamine 3c and bis(1-phenylethyl)
amine 3d showed relatively low reactivity to give 12g and 12h
in 30 and 38% respective yields (entries 2 and 3).
Finally, we examined preparation of 3-(aminomethyl)iso-
quinolines fused with various heterocycles by changing the
carbon tether of the diamine component 8 (Table 4). Use of
1,2-diaminoethane 8b in the reaction of 2-ethynylbenzalde-
hyde 1a, paraformaldehyde 2, and diisopropylamine 3a in
the presence of CuCl under an oxygen atmosphere gave the
desired 2,3-dihydroimidazo[2,1-a]isoquinoline 13 in 56%
yield (entry 1). The reaction using 1,4-diaminobutane 8c
afforded the tricyclic compound 14 with a tetrahydro[1,3]-
diazepine structure in 50% yield (entry 3). The limitation of
this reaction can be seen in the reaction with 1,5-diamino-
pentane 8d, which produced 1,3-diazocine-fused isoquino-
line 15 in only 12% yield (entry 5). This strategy was also
aThe reactions were conducted as described in Table 2. bThe reaction
under argon required 15 h for the cyclization/oxidation step. cIsolated
yields.
applicable to the synthesis of tetracyclic benzimidazo[2,1-a]-
isoquinoline 16 (entry 7).8a In the case of entries 4 and 8, the
increased yields of 14 and 16 were observed under an argon
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Ohta et al.
JOCNote
atmosphere, although a prolonged reaction time was re-
quired (15 h for the cyclization/oxidation step).13
propanediamine 8a (48.1 μL, 0.58 mmol) and MS 4 A (37.5 mg)
were added, and the mixture was additionally stirred at 120 °C for
1 h. The mixture was concentrated in vacuo and purified by column
chromatography over alumina with CHCl3/CH3OH (15:1) as the
eluent to give 12a (41.3 mg, 72%) as a colorless solid: mp 128-
129 °C; 1H NMR (400 MHz, CDCl3) δ 1.04 (d, J = 6.6 Hz, 12H, 4
ꢀ CH3), 1.91-1.96 (m, 2H, 3-CH2), 3.06-3.16 (m, 2H, 2 ꢀ CH
(CH3)2), 3.49 (s, 2H, NCH2), 3.64 (t, J = 5.6 Hz, 2H, NCH2), 4.13
(t, J = 5.9 Hz, 2H, NCH2), 6.05 (s, 1H, 7-H), 7.19 (d, J = 7.8 Hz,
1H, Ar), 7.23-7.27 (m, 1H, Ar), 7.36-7.40 (m, 1H, Ar), 8.26 (d, J
= 8.0 Hz, 1H, Ar); 13C NMR (100 MHz, CDCl3) δ 20.3 (4C), 21.0,
43.5, 44.4, 47.2 (2C), 48.0, 105.3, 124.9, 125.6, 126.1, 127.2, 130.2,
134.0, 140.7, 149.9; MS (FAB) m/z 298 (MHþ, 100); HRMS (FAB)
calcd for C19H28N3 (MHþ) 298.2284, found 298.2285.
In conclusion, we have developed a novel route to iso-
quinoline-fused polycyclic compounds by a four-component
coupling and cascade cyclization strategy. In this reaction,
the cyclization/oxidation step can be accelerated by use of an
oxygen atmosphere, giving rise to improved yields of the
cyclized products in many cases. Because this four-compo-
nent reaction catalytically forms one carbon-carbon and
four carbon-nitrogen bonds producing only H2O and H2 as
the theoretical waste products, it would be useful for diver-
sity-oriented synthesis of various isoquinolines in an atom-
economical manner.
Acknowledgment. This work was supported by a Grant-
in-Aid for Encouragement of Young Scientists (A) (H.O.)
from the Ministry of Education, Culture, Sports, Science and
Technology of Japan, the Program for Promotion of Funda-
mental Studies in Health Sciences of the National Institute of
Biomedical Innovation (NIBIO), and Targeted Proteins
Research Program. Y.O. is grateful for Research Fellow-
ships of the Japan Society for the Promotion of Science
(JSPS) for Young Scientists.
Experimental Section
General Procedure for Synthesis of 3-(Aminomethyl)isoquinoline-
Fused Polycyclic Compounds by Domino Mannich-Type Reaction
and Cascade Cyclization: Synthesis of 6-[(N,N-Diisopropylamino)
methyl]-3,4-dihydro-2H-pyrimido[2,1-a]isoquinoline (12a) (Table 1,
Entry 10). A mixture of 2-ethynylbenzaldehyde 1a (25.0 mg, 0.19
mmol), paraformaldehye 2 (11.5 mg, 0.38 mmol), diisopropyla-
mine 3a (53.8 μL, 0.38 mmol), and CuCl (1.9 mg, 0.019 mmol) in
DMF (1.5 mL) was stirred under O2 at rt for 1.5 h. After the
Mannich-type reaction was completed and monitored by TLC,
Supporting Information Available: Experimental proce-
1
dures, full characterization, and H and 13C NMR charts of
(13) The exact reason for the increased yields of 14 and 16 under argon
atmosphere is unclear. One plausible explanation is instability of 14 and 16
under the oxidative reaction conditions, which would decrease their yields
under O2 in the presence of a copper salt.
the 2-ethynylbenzaldehydes and cyclization products and a
crystallographic information file for 12a. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
6302 J. Org. Chem. Vol. 74, No. 16, 2009