Diversity-oriented approach to 1,2-dihydroisoquinolin-3(4H)-imines via copper(i)-catalyzed reaction of (E)-2-ethynylphenylchalcone, sulfonyl azide and amine

Article abstract of DOI:10.1039/c1cc11176k

A three-component reaction of (E)-2-ethynylphenylchalcone, sulfonyl azide, and amine catalyzed by copper(i) chloride (5 mol%), in the presence of triethylamine, under mild conditions is described. This transformation proceeds efficiently to generate 1,2-d

Full text of DOI:10.1039/c1cc11176k

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Diversity-oriented approach to 1,2-dihydroisoquinolin-3(4H)-imines via
copper(I)-catalyzed reaction of (E)-2-ethynylphenylchalcone, sulfonyl
azide and aminewz
Zhiyuan Chen,a Chao Ye,a Liang Gaoa and Jie Wu*b
Received 28th February 2011, Accepted 25th March 2011
DOI: 10.1039/c1cc11176k
A three-component reaction of (E)-2-ethynylphenylchalcone,
sulfonyl azide, and amine catalyzed by copper(I) chloride
(5 mol%), in the presence of triethylamine, under mild conditions
is described. This transformation proceeds efficiently to generate
1,2-dihydroisoquinolin-3(4H)-imines in good to excellent yields.
have been used as an efficient route for tetrahydroisoquinoline
generation. For instance, Grigg11 reported a palladium-
catalyzed three-component process for tetrahydroisoquinoline
formation. Ferraccioli12 described a straightforward path to
1,3-substituted tetrahydroisoquinolines via
a palladium/
norbornene-catalyzed reaction of 2-iodotoluene, alkyl halides
and an electron-poor olefin. Enders13 presented one example
of organocatalytic asymmetric synthesis of trans-1,3-disubstituted
tetrahydroisoquinolines using a biphenyl-substituted benzo-
thiazoline as a hydride source. Although these approaches
have been used frequently for the synthesis of members of the
tetrahydroisoquinoline family in the last decade, less attention
has been focused on 1,2-dihydroisoquinolin-3(4H)-imines,
which have found applications in material sciences and bio-
logical studies.14
The tetrahydroisoquinoline skeleton is found in numerous
structurally diverse natural products that display a wide range
of antitumor activities, antimicrobial activities and other
biological properties.1 Moreover, the tetrahydroisoquinoline
derivatives have found applications as chiral ligands in transition
metal-catalyzed asymmetric synthesis.2,3 Additionally, they
have been demonstrated as organocatalysts in asymmetric
Diels–Alder reactions,4 and in borane-mediated hydrogena-
tion reactions.5 Consequently, continuous efforts have been
made toward methodology development for the synthesis of
tetrahydroisoquinoline derivatives. The well developed procedures
for the construction of tetrahydroisoquinoline ring systems involve
the Pictet–Spengler ring-closing reaction,6 the Pomeranz–
Fritsch–Bobbitt reaction,1f,7 and the Bischler–Napieralski
cyclization/reduction reaction.8,10b Other methods, such as
N-acyliminium ion cyclization reactions9 and transition-metal
catalyzed reactions,10 have also been recently described. These
methods, however, usually suffer from multiple synthetic
steps, harsh reaction conditions, and/or limited functional
group tolerance. In the meantime, the multicomponent reactions
During our efforts toward natural product-like compound
generation for use in different biological assays, we became
interested in exploring efficient methods for the construction
of a small library of 1,2-dihydroisoquinolin-3(4H)-imines.
Recently, we reported an efficient copper-catalyzed three-
component reaction of 2-ethynylaniline, sulfonyl azide, and
nitroolefin.15 The reaction was assumed to proceed through
the intramolecular addition of a nucleophile to a reactive
ketenimine species,16–18 followed by an intermolecular Michael
addition. Actually, this ketenimine chemistry has been well
developed and involves a Cu-catalyzed azide–alkyne cyclo-
addition. In the last few years, Chang and Wang made a great
contribution in this field. Encouraged by the ketenimine
chemistry,16–18 we envisioned that the 1,2-dihydroisoquinolin-
3(4H)-imine scaffold could also be produced via a ketenimine
intermediate. The proposed synthetic route is presented in
Scheme 1. (E)-2-ethynylphenylchalcone 1 was utilized as the
substrate for reaction development. We conceived that in
the presence of a suitable copper catalyst, the reaction of
(E)-2-ethynylphenylchalcone 1 with sulfonyl azide 2 would
generate the key ketenimine species b. The double nucleophilic
addition would occur if an amine 3 was involved in the
reaction to afford the intermediate c. This, followed by proto-
nation, would furnish the desired 1,2-dihydroisoquinolin-
3(4H)-imine 4 (Scheme 1). With these considerations in mind,
we started to explore the feasibility of this hypothesis.
a Key Laboratory of Functional Small Organic Molecules,
Ministry of Education and College of Chemistry & Chemical
Engineering, Jiangxi Normal University, Nanchang,
Jiangxi 330022, China
b Department of Chemistry, Fudan University, 220 Handan Road,
Shanghai 200433, China. E-mail: jie_wu@fudan.edu.cn;
Fax: 86 21 6564 1740; Tel: 8621 6510 2412
w Electronic supplementary information (ESI) available: Experimental
methods and characterization data.. CCDC 815165. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c1cc11176k
z Crystal data and structure refinement for compound 4a. Empirical
formula: C32H30N2O5S (molecular weight: 554), Crystal system:
Monoclinic, unit cell dimensions: a = 24.277(10) A, a = 90 deg.,
b = 10.347(4) A, b = 99.370(5) deg., c = 23.279(10) A, g = 90 deg.
Volume: 5769(4) A3, refine_1s_shift/su_max = 0.003 mean = 0.000,
temperature: 293(2) K, space group: C2/c, Z, calculated density: 8,
1.314 mg mꢀ3, Reflections collected/unique: 11615/5070 [R(int) =
0.0370], Final R indices [I > 2s(I)]: R1 = 0.0570, wR2 = 0.1711,
R indices (all data): R1 = 0.0859, wR2 = 0.1922. CCDC 815165.
Our studies commenced with the reaction of (E)-2-ethynyl-
phenylchalcone 1a, tosyl azide 2a, and p-anisidine 3a (Scheme 2).
c
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Table 1 Copper(I)-catalyzed three-component reactions of (E)-2-ethynyl-
phenylchalcone 1, sulfonyl azide 2, and p-anisidine 3aa
Scheme 1 The proposed synthetic route for a three-component
reaction of (E)-2-ethynylphenylchalcone, sulfonyl azide, and amine.
Scheme
2 Initial studies for the copper-catalyzed reaction of
(E)-2-ethynylphenylchalcone 1a, tosyl azide 2a, and p-anisidine 3a.
Initially, the reaction occurred in the presence of CuI (10 mol%)
and triethylamine (3.0 equiv.) in anhydrous CH3CN. To our
delight, the desired product 4a was successfully isolated in
62% yield. The structure of 4a was confirmed by X-ray
diffraction analysis (see ESIw). Other copper sources with the
potential for use as the catalyst in the reaction were then
screened. Copper(I) bromide (78% yield) and copper(I) chloride
(81% yield) were proved to be more effective than copper(I)
iodide, whereas copper(II) triflate (16% yield) or IPr/CuCl
(7% yield) gave only low yield. The catalyst loading of
copper(I) chloride could be reduced to 5 mol% without loss
of efficiency (82% yield). A blank experiment, without the
addition of a copper catalyst, indicated that the reaction was
inert. We next examined the effect of base in the reaction. The
reaction worked efficiently when triethylamine acted as the
base (for details, please see ESIw). A similar yield was isolated
when the reaction was carried out in the presence of 1.5 equiv.
of triethylamine (81% yield), while no reaction took place in
the absence of base. This result indicated that a combination
of a copper catalyst and a base is indispensable to afford the
target product. Additionally, we realized that THF was the
most suitable solvent for the reaction, giving rise to the desired
product in 92% yield. Inferior results were produced when
the reaction proceeded in other solvents (DMSO, toluene,
1,4-dioxane, and dichloromethane).
a
Isolated yield based on (E)-2-ethynylphenylchalcone 1.
Table 2 Copper(I)-catalyzed three-component reactions of (E)-2-ethynyl-
phenylchalcone 1a, tosyl azide 2a, and amine 3a
With the conditions highlighted above (5 mol% of CuCl,
1.5 equiv. of triethylamine, THF, room temperature), the
scope of the three-component reaction was studied. Table 1
and Table 2 show the summary of results for the evaluation of
various substituted (E)-2-ethynylphenylchalcones 1, sulfonyl
azides 2, and amines 3. In Table 1, (E)-2-ethynylphenylchalcone
1 reacted with sulfonyl azide 2 and p-anisidine 3a, leading to
the corresponding 1,2-dihydroisoquinolin-3(4H)-imines 4 in
good to excellent yields. Substrates bearing either electron-rich
or electron-poor aryl substituents in the R2 position were
converted to the desired products with excellent reactivity.
Noticeably, the reaction was also workable when an alkyl
a
Isolated yield based on (E)-2-ethynylphenylchalcone1.
group was used as a replacement in the R2 position, affording
product 4h in 76% yield. The effect of the electronic variation
in the R1 position was examined in the meantime. As expected,
no influence was observed on the output. We next tested the
reactions of (E)-2-ethynylphenylchalcone 1a, sulfonyl azides 2,
and p-anisidine 3a under the standard conditions. Several
sulfonyl azides (R3 = Ph, 4-NO2C6H4, and Me) were present
in the reaction, which were proved to be excellent partners for
the transformation.
c
5624 Chem. Commun., 2011, 47, 5623–5625
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We next investigated the three-component reactions of
(E)-2-ethynylphenylchalcone 1a and tosyl azide 2a with
various amines 3 under the optimized conditions (Table 2).
As shown in Table 2, the desired products 4 were generated in
high yields. A series of para-substituted anilines with electron-
donating groups or electron-withdrawing groups attached to
the aromatic ring worked well. It is noteworthy that an
ester group and a nitro group were all tolerated in this
transformation, which indicated that this diversity could easily
be incorporated into the 1,2-dihydroisoquinolin-3(4H)-imine
scaffold. Interestingly, little impact was observed on the reac-
tion outcome when a sterically bulky aniline (2,6-diethyl-
aniline) was employed in the reaction. Aliphatic amines (tert-butyl
amine, benzyl amine, and 1-octyl amine) were also demonstrated
as effective nucleophiles in the above reaction. Additionally,
heterocyclic amines, such as piperidin-1-amine, showed good
reactivity under the standard conditions, leading to 1,2-dihydro-
isoquinolin-3(4H)-imine 4v in 86% yield.
7 (a) A. G"uszyn
´
ska and M. Rozwadowska, Tetrahedron: Asymmetry,
2000, 11, 2359; (b) M. Boudou and D. Enders, J. Org. Chem., 2005,
70, 9486; (c) A. G"uszynska and M. Rozwadowska, Tetrahedron:
Asymmetry, 2004, 15, 3289.
8 N. Aouad, I. Berenguer, V. Romero, P. Marin, A. Serrano,
S. Andujar, F. Suvire, A. Bermejo, M. Ivorra, R. Enriz,
N. Cabedo and D. Cortes, Eur. J. Med. Chem., 2009, 44, 4616.
9 (a) A. Padwa, M. D. Danca, K. Hardcastle and M. McClure,
J. Org. Chem., 2003, 68, 929; (b) A. Padwa and M. D. Danca, Org.
Lett., 2002, 4, 715; (c) E. Garcia, E. Lete and N. Sotomayor,
J. Org. Chem., 2006, 71, 6776.
10 (a) K. Shimizu, M. Takimoto and M. Mori, Org. Lett., 2003, 5,
2323; (b) L. Evanno, J. Ormala and P. Pihko, Chem.–Eur. J., 2009,
15, 12963.
+
11 (a) X. Gai, R. Grigg, I. Koppen, J. Marchbank and V. Sridharan,
Tetrahedron Lett., 2003, 44, 7445; (b) R. Grigg, M. Inman,
´
+
C. Kilner, I. Koppen, J. Marchbank, P. Selby and V. Sridharan,
Tetrahedron, 2007, 63, 6152.
12 (a) R. Ferraccioli, D. Carenzi and M. Catellani, Tetrahedron Lett.,
2004, 45, 6903; (b) R. Ferraccioli, C. Giannini and G. Molteni,
Tetrahedron: Asymmetry, 2007, 18, 1475; (c) R. Ferraccioli and
A. Forni, Eur. J. Org. Chem., 2009, 3161.
13 D. Enders, J. Liebich and G. Raabe, Chem.–Eur. J., 2010, 16,
9763.
14 For selected examples: (a) H. Li, J. L. Petersen and K. K. Wang,
J. Org. Chem., 2003, 68, 5512; (b) J. Qian, X. Qian and Y. Xu,
Chem.–Eur. J., 2009, 15, 319; (c) M. Jaggi, C. Blum, N. Dupont,
J. Grilj, S.-X. Liu, J. Hauser, A. Hauser and S. Decurtins, Org.
Lett., 2009, 11, 3096; (d) H. Langhals and T. Pust, Eur. J. Org.
Chem., 2010, 3140.
15 Z. Chen, D. Zheng and J. Wu, Org. Lett., 2011, 13, 848.
16 For a recent review, see: (a) P. Lu and Y.-G. Wang, Synlett, 2010,
165; (b) E. J. Yoo and S. Chang, Curr. Org. Chem., 2009, 13, 1766.
17 (a) E. J. Yoo, I. Bae, S. H. Cho, H. Han and S. Chang, Org. Lett.,
2006, 8, 1347; (b) S. H. Cho and S. Chang, Angew. Chem., Int. Ed.,
2007, 46, 1897; (c) S. H. Cho and S. Chang, Angew. Chem., Int. Ed.,
2008, 47, 2836; (d) E. J. Yoo, M. Ahlquist, I. Bae, K. B. Sharpless,
V. V. Fokin and S. Chang, J. Org. Chem., 2008, 73, 5520; (e) I. Bae,
H. Han and S. Chang, J. Am. Chem. Soc., 2005, 127, 2038;
(f) S. H. Cho, E. J. Yoo, I. Bae and S. Chang, J. Am. Chem.
Soc., 2005, 127, 16046; (g) J. Y. Kim, S. H. Kim and S. Chang,
Tetrahedron Lett., 2008, 49, 1745; (h) S. Chang, M. Lee,
D. Y. Jung, E. J. Yoo, S. H. Cho and S. K. Han, J. Am. Chem.
Soc., 2006, 128, 12366; (i) E. J. Yoo and S. Chang, Org. Lett., 2008,
10, 1163; (j) J. Kim, Y. Lee, J. Lee, Y. Do and S. Chang, J. Org.
Chem., 2008, 73, 9454; (k) E. J. Yoo, S. H. Park, S. H. Lee and
S. Chang, Org. Lett., 2009, 11, 1155.
In summary, a novel and efficient reaction of (E)-2-ethynyl-
phenylchalcone, sulfonyl azide, and amine catalyzed by copper(I)
chloride has been successfully developed. Diverse 1,2-dihydro-
isoquinolin-3(4H)-imines are generated in good to excellent
yields. This reaction proceeds with a wide substrate scope
under extremely mild conditions. Library construction and
subsequent biological assays are in progress in our laboratory.
Financial support from National Natural Science Founda-
tion of China (No. 21032007) is gratefully acknowledged.
Notes and references
1 For reviews: (a) K. W. Bentley, The Isoquinoline Alkaloids,
Hardwood Academic, Amsterdam, 1998, vol. 1; (b) The Chemistry
and Biology of Isoquinoline Alkaloids, ed. J. D. Phillipson,
M. F. Roberts and M. H. Zenk, Springer Verlag, Berlin, 1985;
(c) M. D. Rozwadowska, Heterocycles, 1994, 39, 903; (d) D. Jack
and R. Williams, Chem. Rev., 2002, 102, 1669; (e) M. Chrzanowska
and M. D. Rozwadowska, Chem. Rev., 2004, 104, 3341;
(f) P. Siengalewicz, U. Rinner and J. Mulzer, Chem. Soc. Rev.,
2008, 37, 2676; For selected examples: (g) B. Zhou, J. Guo and
S. Danishefsky, Org. Lett., 2002, 4, 43; (h) A. Endo,
A. Yanagisawa, M. Abe, S. Tohma, T. Kan and T. Fukuyama,
J. Am. Chem. Soc., 2002, 124, 6552; (i) K. W. Bentley, Nat. Prod.
Rep., 2006, 23, 444; (j) X. Fang, Y. Yin, Y. Chen, L. Yao, B. Wang,
M. Caneron, L. Lin, S. Khan, P. LoGrasso and Y. Feng, J. Med.
Chem., 2010, 53, 5727; (k) C. Razafindrabe, S. Aubry, B. Bourdon,
M. Andriantsiferana, S. Pellet-Rostaing and M. Lemaire,
Tetrahedron, 2010, 66, 9061.
18 (a) Y. Shen, S. Cui, J. Wang, X. Chen, P. Lu and Y.-G. Wang, Adv.
Synth. Catal., 2010, 352, 1139; (b) W. Yao, L. Pan, Y. Zhang,
G. Wang, X. Wang and C. Ma, Angew. Chem., Int. Ed., 2010, 49,
9210; (c) Y. Shang, K. Ju, X. He, J. Hu, S. Yu, M. Zhang, K. Liao,
L. Wang and P. Zhang, J. Org. Chem., 2010, 75, 5743; (d) I. Cano,
E. Alvarez, M. C. Nicasio and P. J. Perez, J. Am. Chem. Soc., 2011,
´
133, 191; (e) R. Husmann, Y. S. Na, C. Bolm and S. Chang, Chem.
Commun., 2010, 46, 5494; (f) H. Jin, X. Xu, J. Gao, J. Zhong and
Y.-G. Wang, Adv. Synth. Catal., 2010, 352, 347; (g) W. Song,
W. Lu, J. Wang, P. Lu and Y.-G. Wang, J. Org. Chem., 2010, 75,
3481; (h) W. Lu, W. Z. Song, D. Hong, P. Lu and Y.-G. Wang,
Adv. Synth. Catal., 2009, 351, 1768; (i) S. L. Cui, J. Wang and
Y.-G. Wang, Org. Lett., 2008, 10, 1267; (j) S. L. Cui, X. F. Lin and
Y.-G. Wang, Org. Lett., 2006, 8, 4517; (k) X. Xu, D. Cheng, J. Li,
H. Guo and J. Yan, Org. Lett., 2007, 9, 1585; (l) M. Whiting and
V. V. Fokin, Angew. Chem., Int. Ed., 2006, 45, 3157; (m) S. L.
Cui, J. Wang and Y.-G. Wang, Org. Lett., 2007, 9, 5023;
(n) S. L. Cui, J. Wang and Y.-G. Wang, Tetrahedron, 2008, 64,
487; (o) S. L. Cui, J. Wang and Y.-G. Wang, Org. Lett., 2008, 10,
13; (p) J. She, Z. Jiang and Y.-G. Wang, Synlett, 2009, 2023;
(q) V. V. Rostovtsev, L. G. Green, V. V. Fokin and K. B.
Sharpless, Angew. Chem., Int. Ed., 2002, 41, 2596; (r) F. Wang,
H. Fu, Y. Jiang and Y. Zhao, Adv. Synth. Catal., 2008, 350, 1830;
(s) Y. Shang, X. He, J. Hu, J. Wu, M. Zhang, S. Yu and Q. Zhang,
Adv. Synth. Catal., 2009, 351, 2709.
2 (a) S. K. Chakka, P. G. Andersson, G. E. M. Maguire,
H. G. Kruger and T. Govender, Eur. J. Org. Chem., 2010, 972;
(b) B. Peters, S. Chakka, T. Naicker, G. Maguire, H. Kruger,
P. Andersson and T. Govender, Tetrahedron: Asymmetry, 2010,
21, 679.
3 S. Chakka, B. Peters, P. Andersson, G. Maguire, H. Kruger and
T. Govender, Tetrahedron: Asymmetry, 2010, 21, 2295.
4 T. Naicker, K. Petzold, T. Singh, P. Arvidsson, H. Kruger,
G. Maguire and T. Govender, Tetrahedron: Asymmetry, 2010,
21, 2859.
5 (a) D. Basavaiah, U. Das and S. Roy, J. Chem. Sci., 2009, 121,
1003; (b) K. Stingl, J. Martens and S. Wallbaum, Tetrahedron:
Asymmetry, 1992, 3, 223.
6 (a) E. Cox and J. Cook, Chem. Rev., 1995, 95, 1797; (b) P. Magnus,
K. Matthews and V. Lynch, Org. Lett., 2003, 5, 2181;
(c) M. J. Eynden and J. P. Stambuli, Org. Lett., 2008, 10, 5289;
(d) P. Cheng, N. Huang, Z. Jiang, Q. Zhang, Y. Zheng, J. Chen,
X. Zhang and Y. Ma, Bioorg. Med. Chem. Lett., 2008, 18, 2475.
c
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Chem. Commun., 2011, 47, 5623–5625 5625