Assembly of isoquinolines via CuI-catalyzed coupling of β-keto esters and 2-halobenzylamines

Article abstract of DOI:10.1021/ol800900a

(Chemical Equation Presented) CuI-catalyzed coupling of 2-halobenzylamines with β-keto esters or 1,3-diketones in i-PrOH under the action of K ₂CO₃ produced 1,2-dihydroisoquinolines as the coupling/condensative cyclization products,

Full text of DOI:10.1021/ol800900a

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2761-2763
Assembly of Isoquinolines via
CuI-Catalyzed Coupling of ꢀ-Keto Esters
and 2-Halobenzylamines
Bao Wang,† Biao Lu,‡ Yongwen Jiang,‡ Yihua Zhang,† and Dawei Ma*,‡
Center of Drug DiscoVery, China Pharmaceutical UniVersity, Nanjing 210009,
China, and State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
madw@mail.sioc.ac.cn
Received April 18, 2008
ABSTRACT
CuI-catalyzed coupling of 2-halobenzylamines with ꢀ-keto esters or 1,3-diketones in i-PrOH under the action of K2CO3 produced
1,2-dihydroisoquinolines as the coupling/condensative cyclization products, which underwent smooth dehydrogenation under air atmosphere
to afford substituted isoquinolines.
Isoquinoline ring systems have been found in numerous
natural alkaloids that display a wide range of biological
activities.1 Common approaches to assemble these ring
systems are highly dependent on Bischeler-Napieralski,2
Pictet-Spengler,3 or Pomeranz-Fritsch reactions.4 They
normally require harsh conditions (in the presence of strong
acid), which prevent the elaboration of some sensitive
isoquinolines. Consequently, considerable effort has been
devoted to the assembly of substituted isoquinolines by
employing metal-catalyzed reactions. Initial studies were
carried out by Widdowson,5 Pfeffer,6 and Heck.7 They found
that substituted isoquinolines could be obtained via annula-
tion of internal alkynes by cyclopalladated N-tert-butylaryl-
aldimines,5 cyclopalladated N,N-dimethylbenzylamine com-
plexes,6 or cyclopalladated N-tert-butylbenzaldimine tetrafluo-
roborates, respectively.7 However, these syntheses suffered
from the use of stoichiometric amounts of palladium salts,
which prompted Larock and co-workers to explore a catalytic
approach. They achieved this goal using the tert-butyl imine
† China Pharmaceutical University.
‡ Chinese Academy of Sciences.
(1) (a) Bentley, K. W. The Isoquinoline Alkaloids; Harwood Academic:
Amsterdam, The Netherlands, 1998; Vol. 1. (b) Bentley, K. W. Nat. Prod.
Rep. 2005, 22, 249. (c) Bentley, K. W. Nat. Prod. Rep. 2006, 23, 444. (d)
Arnold, N. J.; Arnold, R.; Beer, D.; Bhalay, G.; Collingwood, S. P.; Craig,
S.; Devereux, N.; Dodds, M.; Dunstan, A. R.; Fairhurst, R. A.; Farr, D.;
Fullerton, J. D.; Glen, A.; Gomez, S.; Haberthuer, S.; Hatto, J. D. I.; Howes,
C.; Jones, D.; Keller, T. H.; Leuenberger, B.; Moser, H. E.; Muller, I.;
Naef, R.; Nicklin, P. A.; Sandham, D. A.; Turner, K. L.; Tweed, M. F.;
Watson, S. J.; Zurini, M. Bioorg. Med. Chem. Lett. 2007, 17, 2376. (e)
Delcey, M. C.; Croisy, A.; Carrez, D.; Huel, C.; Chiaroni, A.; Ducrot, P.;
Bisagni, E.; Jin, L.; Leclercq, G. Bioorg. Med. Chem. 2000, 8, 2629.
(2) (a) Whaley, W. M.; Govindachari, T. R. In Organic Reactions;
Adams, R., Ed.; Wiley: New York, 1951; Vol. 6, pp 151-190. (b)
Sotomayor, N.; Dominguez, E. J. Org. Chem. 1996, 61, 4062. (c) Ishikawa,
T.; Shimooka, K.; Narioka, T.; Noguchi, S.; Saito, T.; Ishikawa, A.;
Yamazaki, E.; Harayama, T.; Seki, H.; Yamaguchi, K. J. Org. Chem. 2000,
65, 9143.
(3) (a) Whaley, W. M.; Govindachari, T. R. In Organic Reactions;
Adams, R., Ed.; Wiley: New York, 1951; Vol. 6, pp 74-150. (b) Youn,
S. W. J. Org. Chem. 2006, 71, 2521. (c) Chrzanowska, M.; Rozwadowska,
M. D. Chem. ReV. 2004, 104, 3341. (d) Cox, E. D.; Cook, J. M. Chem.
ReV. 1995, 95, 1797.
(4) (a) Gensler, W. J. In Organic Reactions; Adams, R., Ed.; Wiley:
New York, 1951; Vol. 6, pp 191-206. (b) Boudou, M.; Enders, D. J. Org.
Chem. 2005, 70, 9486. (c) Walker, E. R.; Leung, S. Y.; Barrett, A. G. M.
Tetrahedron Lett. 2005, 46, 6537.
(5) Girling, I. R.; Widdowson, D. A. Tetrahedron Lett. 1982, 23, 4281.
(6) Maassarani, F.; Pfeffer, M.; Le Borgne, G. J. Chem. Soc., Chem.
Commun. 1987, 8, 565.
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10.1021/ol800900a CCC: $40.75
Published on Web 05/29/2008
2008 American Chemical Society

of 2-iodobenzaldehyde and internal alkynes as annulation
substrates.8 Subsequently a series of methods for preparing
substituted isoquinolines based on palladium-catalyzed reac-
tions were reported.9 Recently, Cheng and co-workers
reported that the annulation of 2-iodobenzaldimines with
alkynes to substituted isoquinolines could be catalyzed by a
relatively inexpensive nickel complex.10 One major drawback
for these catalytic processes is the use of phosphine ligands,
which severely complicate product purification. Additionally,
for some unsymmetrical alkynes poor regioselectivities were
observed.
Scheme 1
A recent advance in Ullmann-type reactions provided the
opportunity for the development of new methodologies to
assemble heterocycles.11–15 Taking advantage of the mild
conditions applied in amino acid-promoted Ullmann-type
reactions, our group has recently established some cascade
processes for the elaboration of heterocycles, which include
benzofurans,12 benzimidazoles,13 benzimidazole-2-ones,14
and substituted indoles.15 Continuing our efforts in this area,
we became interested in the coupling reaction of 2-bro-
mobenzylamine (1) with ꢀ-keto esters and 1,3-diketones. We
envisioned that, if the copper-catalyzed coupling between
aryl bromides and these activated methylene compounds
proceeded smoothly, the resulting coupling products 3
would undergo an intramolecular condensation followed
by dehydration to afford 1,2-dihydroisoquinolines 5, which
should be easily oxidized to 3,4-disubstituted isoquinolines
6 (Scheme 1).
With this idea in mind, we investigated the reaction of
2-bromobenzylamine (1) and ethyl acetoacetate under the
catalysis of 10 mol % CuI and 20 mol % L-proline at 60 °C
in dioxane. After the scheduled reaction time a mixture of
dihydroisoquinoline 5a and isoquinoline 6a was detected,
indicating that the reaction took place in the desired manner.
The formation of 6a demonstrated that dehydrogenation of
5a might occur spontaneously under air atmosphere. To
prove this assumption we stirred the coupling mixture under
air overnight and found that only 6a was isolated in 48%
yield (Table 1, entry 1). Considering that the poor yield most
probably resulted from incomplete conversion in the coup-
Table 1. Conditions Screened for the Coupling of
2-Bromobenzylamine (1a) with Ethyl Acetoacetatea
entry ligandb
base
solvent
temp (°C) yield (%)c
1
2
3
4
5
6
7
8
A
B
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
dioxane
dioxane
dioxane
dioxane
i-PrOH
THF
DMSO
DMF
i-PrOH
i-PrOH
i-PrOH
60
60
60
90
90
90
90
90
90
90
90
48
47
51
66
76
33
50
36
88
54
42
no
no
no
no
no
no
no
no
no
d
9
10
11
d
K3PO4
Cs2CO3
d
a Reaction conditions: 2-bromobenzylamine (0.5 mmol), ethyl acetoac-
etate (1 mmol), CuI (0.05 mmol), ligand (0.1 mmol), base (2 mmol), i-PrOH
(1.5 mL), 24 h, then stirring under air, rt, 12-24 h. b Ligand: A, L-proline;
B, N,N-dimethylglycine. c Isolated yield for 6a. d 1.5 mmol of base was
used.
ling step, we next tried to optimize the conditions for this
step to improve the overall transformation. Switching the
ligand to N,N-dimethylglycine or omitting the ligand both
gave similar results (entries 1-3), which illustrated that
the ligand might be unnecessary for this process. This
result is consistent with our previous report on the syn-
thesis of benzofurans.12 Increasing the reaction temper-
ature gave a higher yield (entry 4), while further improve-
ment was achieved by using i-PrOH as solvent (entry 5).
Other solvents like THF, DMSO, or DMF gave worse
results (entries 6-8). We were pleased to find that 6a
was obtained in 88% yield (entry 9) after decreasing the
amount of K2CO3 from 4 equiv to 3 equiv. Under the same
conditions, other bases such as K3PO4 or Cs2CO3 provided
lower yields (entries 10 and 11).
(8) Roesch, K. R.; Larock, R. C. J. Org. Chem. 1998, 63, 5306.
(9) (a) Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1, 553. (b) Dai,
G.; Larock, R. C. Org. Lett. 2001, 3, 4035. (c) Roesch, K. R.; Zhang, H.;
Larock, R. C. J. Org. Chem. 2001, 66, 8042. (d) Huang, Q.; Hunter, J. A.;
Larock, R. C. J. Org. Chem. 2002, 67, 3437. (e) Dai, G.; Larock, R. C. J.
Org. Chem. 2002, 67, 7042. (f) Huang, Q.; Hunter, J. A.; Larock, R. C. J.
Org. Chem. 2003, 68, 980. (g) Konno, T.; Chae, J.; Miyabe, T.; Ishihara,
T. J. Org. Chem. 2005, 70, 10172.
(10) Korivi, R. P.; Cheng, C.-H. Org. Lett. 2005, 7, 5179.
(11) For selected examples, see: (a) Evindar, G.; Batey, R. A. Org. Lett.
2003, 5, 133. (b) Altenhoff, G.; Glorius, F. AdV. Synth. Catal. 2004, 346,
1661. (c) Klapars, A.; Parris, S.; Anderson, K. W.; Buchwald, S. L. J. Am.
Chem. Soc. 2004, 126, 3529. (d) Yang, T.; Lin, C.; Fu, H.; Jiang, Y.; Zhao,
Y. Org. Lett. 2005, 7, 4781. (e) Evindar, G.; Batey, R. A. J. Org. Chem.
2006, 71, 1802. (f) Martin, R.; Rodr´ıguez, R.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2006, 45, 7079. (g) Lu, B.; Ma, D. Org. Lett. 2006, 8,
6115. (h) Rivero, M. R.; Buchwald, S. L. Org. Lett. 2007, 9, 973. (i) Yuan,
X.; Xu, X.; Zhou, X.; Yuan, J.; Mai, L.; Li, Y. J. Org. Chem. 2007, 72,
These optimized reaction conditions were applied to a
variety of aryl halides and activated methylene compounds;
the results are summarized in Table 2. Ethyl propionylacetate
worked well to provide the corresponding isoquinoline in
90% yield (entry 1). However, ethyl isobutyrylacetate only
gave 53% yield (entry 2), indicating that the steric bulk of
1510
(12) Lu, B.; Wang, B.; Zhang, Y.; Ma, D. J. Org. Chem. 2007, 72, 5337
(13) Zou, B.; Yuan, Q.; Ma, D. Angew. Chem., Int. Ed. 2007, 46, 2598
(14) Zou, B.; Yuan, Q.; Ma, D. Org. Lett. 2007, 9, 4291
.
.
.
.
(15) (a) Liu, F.; Ma, D. J. Org. Chem. 2007, 72, 4844. (b) Chen, Y.;
Xie, X. Ma. D. J. Org. Chem. 2007, 72, 9329. (c) Chen, Y.; Wang, Y.;
Sun, Z.; Ma, D. Org. Lett. 2008, 10, 625
.
2762
Org. Lett., Vol. 10, No. 13, 2008

to 4 equiv for γ-aryl-ꢀ-keto esters bearing electron-
withdrawing groups (entries 7 and 9).
Table 2. Synthesis of Isoquinolines via CuI-Catalyzed Coupling
of 2-Halobenzylamines with ꢀ-Keto Esters and 1,3-Diketonesa
Several substituted 2-halobenzylamines with both electron-
donating and electron-withdrawing groups were compatible
with the present process, providing polysubstituted isoquino-
lines in good yields (entries 12-15). Two cyclic 1,3-
diketones also worked for this process, affording tricyclic
compounds in moderate yields (entries 16 and 17). However,
when acetoacetone was utilized the desired isoquinoline was
isolated in only 23% yield (entry 18). The major side product
was found to be imine 7 (Scheme 2) in this case. This phe-
nomenon implied that first the coupling reaction must occur
in an intermolecular manner as depicted in Scheme 1, but
not go through the condensation/coupling process. Further
evidence came from the fact that the CuI-catalyzed coupling
reaction of imine 8 (formed by condensation of 1a with ethyl
acetoacetate at 60 °C) did not afford any coupling products.
entry
X
Y
Z
R
R′
yield (%)b
1
2
3
4
5
6
7
8
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
I
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
Et
i-Pr
But-3-enyl
Bn
Ph
4-ClC6H4
4-ClC6H4
4-NO2C6H4
4-NO2C6H4
4-(EtCONH)-C6H4 OMe
4-MeOC6H4
OMe
OMe
OEt
OMe
OEt
OMe
OMe
OEt
OEt
90
53
80
59
74
51
73c
53
72c
79
83
73
76
72
76
61
51
23
H
H
H
H
H
H
H
H
H
H
9
10
11
12
13
14
15
16
17
18
OMe
OEt
OEt
OMe
OMe
Scheme 2
OMe Me
H
Me
Me
4-MeOC6H4
Br
Br
Br
Br
Br
OCH2O
OCH2O
H
H
H
H
H
H
(CH2)3
CH2C(CH3)2CH2
Me
Me
a Reaction conditions: aryl halide 1 (0.5 mmol), ꢀ-keto ester (1.0 mmol),
CuI (0.05 mmol), K2CO3 (1.5 mmol), i-PrOH (1.5 mL), 90 °C, 24 h, then
stirring under air, rt, 12-24 h. b Isolated yield. c 2 mmol of ꢀ-keto ester
was used.
In conclusion, we have developed a CuI-catalyzed cascade
process for the assembly of substituted isoquinolines from
o-halobenzylamines and ꢀ-keto esters. A number of func-
tional groups in both the benzylamine and the ꢀ-keto ester
moieties are tolerated by the reaction conditions. Thus, our
process provides a versatile access to substituted isoquino-
lines and a useful tool for the synthesis of biologically active
molecules.
the ꢀ-keto ester is unfavorable for the process. But-3-enyl,
benzyl, and phenyl groups could be introduced in the
3-position of isoquinolines by choosing suitable ꢀ-keto esters
(entries 3-5). When γ-(4-chlorophenyl)- or γ-(4-nitrophe-
nyl)-substituted ꢀ-keto esters were used, the reaction yields
were only moderate (entries 6 and 8). However, good yields
were still observed when two γ-aryl-ꢀ-keto esters bearing
electron-donating groups were employed (entries 10 and 11).
These results demonstrated that the electronic nature of the
aryl moiety has an influence on this transformation; an elec-
tron-rich aryl group can significantly enhance the nucleo-
philicity of the ꢀ-keto esters. Noteworthy is that satisfactory
yields were obtained by increasing the amount of ꢀ-keto ester
Acknowledgment. The authors are grateful to the Chinese
Academy of Sciences, National Natural Science Foundation
of China (grant nos. 20621062 and 20572119) for their
financial support.
Supporting Information Available: Experimental pro-
cedures and copies of 1H NMR and 13C NMR spectra for all
new products. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL800900A
Org. Lett., Vol. 10, No. 13, 2008
2763