Multicatalytic tandem reaction of N′-(2-alkynylbenzylidene)hydrazide with indole

Article abstract of DOI:10.1039/b913409c

The combination of AgOTf and Dy(OTf)₃ shows high efficiency as a catalyst in the tandem reactions of N′-(2-alkynylbenzylidene)hydrazides with indoles, which generate the unexpected 1-(indol-3-yl)-2-aminoisoquinolinium triflates in good yields.

Full text of DOI:10.1039/b913409c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Multicatalytic tandem reaction of N¢-(2-alkynylbenzylidene)hydrazide
with indole†
Xingxin Yu,a Xiaodi Yangc and Jie Wu*a,b
Received 6th July 2009, Accepted 4th August 2009
First published as an Advance Article on the web 4th September 2009
DOI: 10.1039/b913409c
The combination of AgOTf and Dy(OTf)3 shows high efficiency as a catalyst in the tandem reactions
of N¢-(2-alkynylbenzylidene)hydrazides with indoles, which generate the unexpected
1-(indol-3-yl)-2-aminoisoquinolinium triflates in good yields.
reaction.5a Mg(ClO4)2 and Cu(OTf)2 were found to be highly effec-
Introduction
tive as a catalyst in the one-pot reaction of 2-alkynylbenzaldehydes,
The development of tandem reactions1,2 for the efficient gen-
amines, zinc, and allylic bromide or benzyl bromide.5d Recently, we
eration of small molecules is an important part of the field
have developed efficient strategies for accessing privileged organic
of chemical biology.3 Their operational simplicity combined
architectures.6 Prompted by the advancement of multicatalytic
with assembly efficiency make tandem reactions attractive for
synthesis,4,5 we became interested in exploring new multicatalytic
molecular complexity generation. Among the method develop-
processes to facilitate the generation of small molecules. Herein,
ment in tandem reactions, multicatalytic processes have recently
attracted growing interest.4,5 Usually, one or more catalysts
are involved in the reaction and promote two or more dis-
we disclose our recent efforts towards the tandem reaction of
N¢-(2-alkynylbenzylidene)hydrazide with indole co-catalyzed by
AgOTf and Dy(OTf)3, which unexpectedly afforded 1-(indol-3-
tinct chemical transformations in a single flask. For instance,
yl)-2-aminoisoquinolinium triflates in good yields.
Lambert and Cernak reported the multicatalytic synthesis of
Isoquinoline-based structure can be found in many natural
a-pyrrolidinyl ketones via a tandem palladium(II)/indium(III)-
catalyzed aminochlorocarbonylation/Friedel–Crafts acylation
products and pharmaceuticals that exhibit remarkable biological
activities.7 Continuous efforts have been given to the development
of new methods for their construction. In continuation of recently
developed methods for the Lewis acid-catalyzed or electrophile-
aDepartment of Chemistry, Fudan University, 220 Handan Road, Shanghai
mediated reaction of N¢-(2-alkynylbenzylidene)hydrazide 1,8
200433, China. E-mail: jie_wu@fudan.edu.cn; Fax: +86 21 6510 2412;
Tel: +86 21 5566 4619
we hypothesized that the direct synthesis of new isoquinoline
structures might occur in a one-pot reaction of N¢-(2-alkynyl-
benzylidene)hydrazide 1 with nucleophiles by sequential N–C
and C–C bond formation under appropriate conditions, such that
the intermediate isoquinolinium-2-yl amide would not have to be
isolated. Since the indole skeleton is an important substructure in
both natural products and therapeutic agents,9 at the beginning
a set of experiments was carried out using N¢-(2-alkynylbenzyl-
idene)hydrazide 1a and indole 2a as model substrates (Scheme 1).
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, China
cLaboratory of Advanced Materials, Fudan University, 220 Handan Road,
Shanghai 200433, China
† Electronic supplementary information (ESI) available: Experimental
details; characterization data, and 1H and 13C NMR spectra of compound
3; X-ray ORTEP illustration of compound 3j·CF3SO3. CCDC reference
number 735059. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b913409c
Scheme 1 Tandem reaction of N¢-(2-alkynylbenzylidene)hydrazide 1a with indole 2a.
4526 | Org. Biomol. Chem., 2009, 7, 4526–4530 This journal is The Royal Society of Chemistry 2009
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Table 1 AgOTf and Dy(OTf)3 co-catalyzed tandem reaction of N¢-(2-
alkynylbenzylidene)hydrazide 1 with indole
Results and discussion
N¢-(2-Alkynylbenzylidene)hydrazide 1 could be easily synthesized
via condensation of 2-alkynylbenzaldehyde with hydrazine. At
the outset of this study, our efforts were directed at discover-
ing the most appropriate catalyst and reaction conditions to
perform the proposed reaction. Thus, combinations of differ-
ent Lewis acids (10 mol%) and solvents were screened. When
AgOTf was used as the catalyst in the reaction of N¢-(2-
alkynylbenzylidene)hydrazide 1a with indole 2a in dichloroethane,
only intermediate isoquinolinium-2-yl amide B was generated via
6-endo-cyclization (99% yield, 2 hours, DCE, rt) and no further
transformation was observed under these conditions. The same
result was obtained when CuI was employed as a replacement.
When other Lewis acids (FeCl3, Sc(OTf)3, Zn(OTf)2, Cu(OTf)2,
Bi(OTf)3, Yb(OTf)3, Dy(OTf)3) were utilized in the reaction, only
a small amount of isoquinolinium-2-yl amide B was isolated with
the recovery of N¢-(2-alkynylbenzylidene)hydrazide 1a. The results
could not be improved when other solvents (MeCN, THF, toluene,
Et2O, MeNO2) were used in the reaction. Based on these results,
we conceived that additional Lewis acid might be necessary to
facilitate the next nucleophilic addition. Therefore, the reaction
of isoquinolinium-2-yl amide B with indole 2a in MeCN was
investigated. Again, no reaction occurred when AgOTf or CuI was
employed as a catalyst. A trace amount of product was observed
when Cu(OTf)2 or PdCl2 was used in the reaction. Gratifyingly, the
formation of a product was detected (16% yield) when Bi(OTf)3
was employed as the catalyst (10 mol%) at 70 ◦C. Further screening
revealed that Dy(OTf)3 was the most efficient one (28% yield) for
the transformation. However, structural identification revealed
that the product generated was compound 3a, instead of the
desired normal nucleophilic addition product C. We reasoned
that after addition of indole 2a to isoquinolinium-2-yl amide
B, the sulfonyl group might be subsequently attacked in the
presence of Dy(OTf)3 leading to the unexpected product 3a. With
this promising result in hand, we subsequently re-investigated
the tandem reaction of N¢-(2-alkynylbenzylidene)hydrazide 1a
with indole 2a. To our delight, we realized that the combination
of AgOTf (10 mol %) and Dy(OTf)3 (30 mol %) showed high
efficiency as a catalyst in MeCN in this transformation, and gave
rise to the product 3a in 83% yield. Further screening of solvents
revealed that dichloroethane (DCE) was the best choice and the
yield could be increased to 98%.
Entry
1
Compound 1
R4
Yield (%)a
1a
H (2a)
98 (3a)
2
3
4
5
1a
1a
1a
4-OMe (2b)
6-OMe (2c)
5-Br (2d)
H (2a)
97 (3b)
84 (3c)
89 (3d)
92 (3e)
1b
1c
6
7
8
H (2a)
H (2a)
H (2a)
86 (3f)
98 (3g)
96 (3h)
1d
1e
9
10
11
1e
1e
4-OMe (2b)
5-Br (2d)
H (2a)
95 (3i)
80 (3j)
82 (3k)
1f
12
13
14
1f
1f
4-OMe (2b)
6-OMe (2c)
H (2a)
93 (3l)
87 (3m)
87 (3n)
1g
15
1h
H (2a)
80 (3e)
To investigate the scope of the reaction, a variety of differently
substituted N¢-(2-alkynylbenzylidene)hydrazides 1 with indoles
2 were successfully converted to the cyclized products 3 in
good to excellent yields under the optimized conditions [AgOTf
(10 mol %), Dy(OTf)3 (30 mol %), DCE, 70 ◦C] as shown in Table 1.
The cyclic products of the reactions were fully characterized by
1H and 13C NMR methods and mass spectroscopic data. For
instance, reaction of N¢-(2-alkynylbenzylidene)hydrazide 1a with
4-methoxyindole 2b under the standard conditions gave rise to the
desired product 3b in 97% yield (Table 1, entry 2). 84% yield of
product 3c was isolated when 6-methoxyindole 2c was employed
in the reaction of N¢-(2-alkynylbenzylidene)hydrazide 1a (Table 1,
entry 3). A similar yield was obtained when 5-bromoindole 2d was
utilized in the reaction as a partner (89% yield, Table 1, entry 4).
The reactions of N¢-(2-alkynylbenzylidene)hydrazide 1b or 1c were
meanwhile examined (Table 1, entries 5–6). The expected products
16
17
18
1i
H (2a)
H (2a)
H (2a)
93 (3g)
90 (3h)
80 (3n)
1j
1k
a Isolated yield based on N¢-(2-alkynylbenzylidene)hydrazide 1.
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were generated under our standard experimental conditions,
whatever the nature of the substituents attached to the triple bond.
The conditions have also proven to be useful for other N¢-(2-
alkynylbenzylidene)hydrazide substrates 1d–1g. The structure of
3j was also confirmed by X-ray crystallographic analysis (Fig. 1).‡
Substrates with a phenylsulfonyl group were tested as well, and
the reactions occurred smoothly to generate the corresponding
products in good yields (Table 1, entries 15–18).
chromatography plates were visualized by exposure to ultraviolet
light. Organic solutions were concentrated at ~20 Torr (house
vacuum) at 25–35 ◦C. Solvents were re-distilled prior to use in the
reactions. Other commercial reagents were used as received.
General experimental procedure for the AgOTf and Dy(OTf)3 co-
catalyzed tandem reaction of N¢-(2-alkynylbenzylidene)hydrazide 1
with indole 2. A mixture of N¢-(2-alkynylbenzylidene)hydrazide
1 (0.3 mmol), indole 2 (0.6 mmol, 2.0 equiv), AgOTf (10 mol %)
and Dy(OTf)3 (30 mol %) in 1,2-dichloroethane (1.0 mL) was
stirred at 70 ◦C. After completion of reaction as indicated by TLC,
the mixture was allowed to cool to room temperature, diluted with
ethyl acetate (5 mL), filtered through a thin pad of silica gel (eluting
with ethyl acetate), and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (eluting
with PE/EA = 1/1 to 1/10) to provide the desired product 3.
1-(Indol-3-yl)-2-amino-3-phenylisoquinolinium triflate 3a. 1H
NMR (400 MHz, CDCl3): 6.42 (s, 2H), 7.12 (t, J = 7.8 Hz,
1H), 7.19–7.23 (m, 2H), 7.56–7.57 (m, 3H), 7.60–7.66 (m, 2H),
7.75–7.77 (m, 2H), 7.89–8.00 (m, 5H), 11.17 (s, 1H); 13C NMR
(100 MHz, CDCl3) d 101.1, 113.5, 120.4 (q, 1J CF = 318 Hz), 119.4,
121.9, 123.7, 125.3, 125.7, 127.4, 128.2, 129.3, 130.0, 130.3, 130.8,
131.0, 131.4, 134.6, 135.2, 136.6, 142.8, 148.9; IR (KBr, cm-1):
3464, 1636, 1456; m/z (ESI): 336 (M+ + H); HRMS calcd for
C23H18N3 (M+ + H): 336.1501, found: 336.1518.
Fig. 1 X-ray ORTEP illustration of compound 3j·CF3SO3 (30% proba-
bility ellipsoids).
1-(4-Methoxyindol-3-yl)-2-amino-3-phenylisoquinolinium triflate
3b. 1H NMR (400 MHz, CDCl3): 3.59 (s, 3H), 6.05 (s, 2H), 6.48
(d, J = 7.9 Hz, 1H), 7.07 (t, J = 7.9 Hz, 1H), 7.17 (d, J = 9.7 Hz,
1H), 7.46–7.47 (m, 3H), 7.57–7.58 (m, 4H), 7.81–7.93 (m, 4H),
11.05 (s, 1H); 13C NMR (100 MHz, CDCl3) d 55.5, 100.0, 101.6,
Conclusion
In summary, the chemistry described herein provides a facile
and direct synthesis of novel isoquinoline-based compounds
in good yields. This multicatalytic process appears to involve
intramolecular cyclization, nucleophilic addition of indole, and
subsequent elimination of sulfonyl group. From a synthetic
point of view, the transformation involves a one-step conversion
of simple, readily available starting materials into an interest-
ing class of heterocyclic derivative. Investigation using N¢-(2-
alkynylbenzylidene)hydrazide as a substrate in other transforma-
tions is ongoing, and the results will be reported in due course.
106.8, 115.7, 120.4 (q, 1J = 318 Hz), 124.7, 125.3, 127.0, 128.6,
CF
129.1, 129.5, 129.7, 130.4, 130.5, 130.6, 131.3, 134.7, 135.4, 138.2,
143.6, 152.0, 152.1; IR (KBr, cm-1): 3447, 1636, 1457; m/z (ESI):
366 (M+ + H); HRMS calcd for C24H20N3O (M+ + H): 366.1606,
found: 366.1626.
1-(6-Methoxyindol-3-yl)-2-amino-3-phenylisoquinolinium triflate
3c. 1H NMR (400 MHz, CDCl3): 3.76 (s, 3H), 6.45 (s, 2H), 6.77
(d, J = 8.5 Hz, 1H), 7.09–7.13 (m, 2H), 7.55–7.56 (m, 3H), 7.64 (t,
J = 7.3 Hz, 1H), 7.74–7.75 (m, 3H), 7.87–7.98 (m, 4H), 11.08 (s,
1H); 13C NMR (100 MHz, CDCl3) d 55.4, 95.7, 100.9, 112.6, 119.2,
119.9, 120.4 (q, 1J = 318 Hz), 125.3, 127.1, 128.1, 129.2, 129.8,
Experimental section
CF
130.1, 130.3, 130.6, 130.7, 130.9, 134.4, 135.0, 137.6, 142.6, 148.8,
157.2; IR (KBr, cm-1): 3465, 1636, 1455; m/z (ESI): 366 (M+ + H);
HRMS calcd for C24H20N3O (M+ + H): 366.1606, found: 366.1622.
General experimental method
All reactions were performed in test tubes under a nitrogen
atmosphere at 70 ◦C. Flash column chromatography was per-
formed using silica gel (60 A pore size, 32–63 mm, standard
grade). Analytical thin-layer chromatography was performed
using glass plates pre-coated with 0.25 mm 230–400 mesh silica
gel impregnated with a fluorescent indicator (254 nm). Thin layer
1-(5-Bromoindol-3-yl)-2-amino-3-phenylisoquinolinium triflate
3d. 1H NMR (400 MHz, CDCl3): 6.44 (s, 2H), 7.23–7.25 (m,
1H), 7.32–7.33 (m, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.56–7.58 (m,
3H), 7.66 (t, J = 8.3 Hz, 1H), 7.74–7.76 (m, 2H), 7.84 (d, J =
8.8 Hz, 1H), 7.90–7.92 (m, 2H), 7.98–8.01 (m, 2H), 11.45 (s, 1H);
˚
1
13C NMR (100 MHz, CDCl3) d 100.7, 115.0, 115.1, 120.4 (q, J
CF = 318 Hz), 121.8, 126.0, 126.5, 127.1, 127.5, 128.3, 129.4, 130.0,
130.6, 131.0, 131.2, 132.3, 134.8, 135.2, 135.4, 143.0, 148.3; IR
(KBr, cm-1): 3445, 1636, 1452; m/z (ESI): 414 (M+ + H); HRMS
calcd for C23H17BrN3 (M+ + H): 414.0606, found: 414.0624.
‡ Crystal data and structure refinement for compound 3j. Empirical
formula: C26H20BrClF4N3O4S (Molecular weight: 661.87), Crystal system:
˚
Monoclinic. Unit cell dimensions: a = 11.839(2) A a = 90 deg., b =
˚
˚
10.8146(18) A b = 99.293(2) deg., c = 21.529(4) A g = 90 deg. Volume:
3
˚
2720.3(8) A , refine_1s_shift/su_max 0.041 mean 0.002, Temperature:
296(2) K, space group: P2(1)/n, Z, Calculated density: 4, 1.616 Mg/m3, Re-
flections collected/unique: 14327 / 5342 [R(int) = 0.0248], FinalRindices
[I2sigma(I)]: R1 = 0.0410, wR2 = 0.1018, R indices (all data): R1 = 0.0663,
wR2 = 0.1151.
1-(Indol-3-yl)-2-amino-3-(4-methoxyphenyl)isoquinolinium tri-
flate 3e. 1H NMR (400 MHz, CDCl3): 3.86 (s, 3H), 6.41 (s,
2H), 7.06–7.14 (m, 3H), 7.18–7.23 (m, 2H), 7.59–7.62 (m, 2H),
4528 | Org. Biomol. Chem., 2009, 7, 4526–4530
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7.68–7.71 (m, 2H), 7.86–7.89 (m, 3H), 7.93 (s, 1H), 7.97 (d, J =
8.3 Hz, 1H), 11.05 (s, 1H); 13C NMR (100 MHz, CDCl3) d 55.6,
3H), 7.85 (s, 1H), 8.03 (s, 1H), 8.05–8.09 (m, 1H), 11.31 (s, 1H);
2
13C NMR (100 MHz, CDCl3) d 55.3, 100.3, 113.0 (d, J
= 24
CF
101.2, 113.6, 114.8, 119.4, 120.4 (q, 1J = 318 Hz), 121.8, 122.6,
Hz), 114.6, 114.8, 114.9, 120.4 (d, 1J CF = 318 Hz), 121.7, 124.9 (d,
CF
123.6, 125.3, 125.5, 127.2, 128.1, 130.4, 130.6, 131.4, 131.6, 134.4,
135.2, 136.6, 142.8, 148.6, 161.6; IR (KBr, cm-1): 3449, 1636, 1450;
m/z (ESI): 366 (M+ + H); HRMS calcd for C24H20N3O (M+ + H):
366.1606, found: 366.1622.
2J CF = 25 Hz), 125.7, 126.3, 129.4 (d, 3J CF = 9 Hz), 130.5, 131.3,
1
131.6, 132.2, 135.1, 142.0, 146.1, 146.2, 161.4, 162.6 (d, J
=
CF
254 Hz); IR (KBr, cm-1): 3447, 1628, 1456; m/z (ESI): 462 (M+ +
H); HRMS calcd for C24H18BrFN3O (M+ + H): 462.0617, found:
462.0630.
1-(Indol-3-yl)-2-amino-3-butylisoquinolinium triflate 3f. 1H
NMR (400 MHz, CDCl3): 1.02 (t, J = 7.3 Hz, 3H), 1.54–1.56
(m, 2H), 1.89–1.91 (m, 2H), 3.24–3.28 (m, 2H), 6.80 (s, 2H), 7.12–
7.20 (m, 3H), 7.55 (t, J = 7.3 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H),
7.76–7.77 (m, 2H), 7.86 (t, J = 7.3 Hz, 1H), 7.95 (t, J = 8.3 Hz,
1-(Indol-3-yl)-2-amino-3-butyl-7-fluoroisoquinolinium
triflate
3k. 1H NMR (400 MHz, CDCl3): 1.00 (t, J = 7.2 Hz, 3H),
1.47–1.57 (m, 2H), 1.85–1.92 (m, 2H), 3.16–3.30 (m, 2H), 6.86 (s,
2H), 7.10–7.22 (m, 3H), 7.37 (dd, J = 9.2, 2.0 Hz, 1H), 7.58–7.64
(m, 2H), 7.78 (d, J = 2.4 Hz, 1H), 7.96 (s, 1H), 7.99–8.03 (m, 1H),
11.09 (s, 1H); 13C NMR (100 MHz, CDCl3) d 12.8, 22.1, 28.8,
2H), 11.08 (s, 1H); 13C NMR (100 MHz, CDCl3) d 13.7, 22.2,
1
28.8, 31.5, 100.8, 113.5, 118.6, 120.4 (q, J
= 318 Hz), 121.9,
CF
31.4, 101.4, 112.4, 112.6, 118.8, 120.4 (q, 1J = 318 Hz), 121.6,
122.8, 123.7, 125.3, 126.6, 127.6, 129.9, 134.3, 135.4, 136.6, 146.3,
149.5; IR (KBr, cm-1): 3446, 1636, 1452; m/z (ESI): 316 (M+ + H);
HRMS calcd for C21H22N3 (M+ + H): 316.1814, found: 316.1817.
CF
2
3
123.4, 123.5, 124.6 (d, J
= 25 Hz), 125.4, 129.2 (d, J
=
CF
CF
10 Hz), 129.9, 130.5 (d, 3J = 9 Hz), 133.1, 136.9, 145.9, 148.7,
CF
162.5 (d, 1J CF = 251 Hz); IR (KBr, cm-1): 3446, 1638, 1536, 1450;
m/z (ESI): 334 (M+ + H); HRMS calcd for C21H21FN3 (M+ + H):
334.1720, found: 334.1730.
1-(Indol-3-yl)-2-amino-3-phenyl-7-fluoroisoquinolinium triflate
3g. 1H NMR (400 MHz, CDCl3): 6.37 (s, 2H), 7.11 (t, J = 7.3 Hz,
1H), 7.18 (t, J = 7.3 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.48–7.53
(m, 4H), 7.57–7.62 (m, 2H), 7.71–7.74 (m, 2H), 7.85–7.86 (m, 1H),
1-(4-Methoxyindol-3-yl)-2-amino-3-butyl-7-fluoroisoquinolinium
triflate 3l. 1H NMR (400 MHz, CDCl3): 0.98 (t, J = 6.9 Hz,
3H), 1.44–1.52 (m, 2H), 1.82–1.89 (m, 2H), 3.11–3.18 (m, 1H),
3.31–3.37 (m, 1H), 3.58 (s, 3H), 6.53 (s, 1H), 6.55 (s, 2H), 7.12 (t,
J = 8.3 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.39 (d, J = 7.8 Hz,
1H), 7.56–7.63 (m, 2H), 8.00 (s, 1H), 8.03–8.07 (m, 1H), 11.15 (s,
1H); 13C NMR (100 MHz, CDCl3) d 13.8, 22.3, 29.5, 32.0, 55.5,
7.97 (s, 1H), 8.01–8.05 (m, 1H), 11.12 (s, 1H); 13C NMR (100 MHz,
2
CDCl3) d 100.8, 113.4, 113.9 (d, J
= 24 Hz), 119.2, 120.4 (q,
CF
2
1J
= 318 Hz), 121.9, 123.6, 124.9, 125.0 (d, J
= 25 Hz),
CF
CF
125.4, 129.2, 129.7 (d, 3J = 10 Hz), 129.9, 130.3, 130.4, 131.0,
CF
1
132.2, 136.5, 142.2, 147.6, 147.7, 162.7 (d, J
= 254 Hz); IR
CF
(KBr, cm-1): 3445, 1636, 1450; m/z (ESI): 354 (M+ + H); HRMS
2
1
calcd for C23H17FN3 (M+ + H): 354.1407, found: 354.1415.
99.9, 101.7, 106.7, 113.6 (d, J
= 24 Hz), 115.6, 120.4 (q, J
CF
= 318 Hz), 123.3, 125.0, 125.2 (d, 2J = 25 Hz), 128.5, 129.6
CF
CF
(d, 3J = 11 Hz), 129.9, 133.1, 138.4, 146.6, 151.8, 152.2, 162.3
1-(Indol-3-yl)-2-amino-3-(4-methoxyphenyl)-7-fluoroisoquinoli-
nium triflate 3h. 1H NMR (400 MHz, CDCl3): 3.82 (s, 3H), 6.48
(s, 2H), 7.03 (d, J = 7.3 Hz, 2H), 7.11 (t, J = 7.3 Hz, 1H), 7.18 (t,
J = 6.8 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 9.2 Hz,
1H), 7.57–7.63 (m, 2H), 7.69 (d, J = 8.3 Hz, 2H), 7.87 (s, 1H), 7.97
(s, 1H), 8.01–8.04 (m, 1H), 11.16 (s, 1H); 13C NMR (100 MHz,
CDCl3) d 55.4, 100.9, 113.4, 113.8 (d, 2J CF = 25 Hz), 114.7, 119.2,
CF
(d, 1J = 253 Hz); IR (KBr, cm-1): 3446, 1638, 1507, 1456; m/z
CF
(ESI): 364 (M+ + H); HRMS calcd for C22H23FN3O (M+ + H):
364.1825, found: 364.1839.
1-(6-Methoxyindol-3-yl)-2-amino-3-butyl-7-fluoroisoquinolinium
triflate 3m. 1H NMR (400 MHz, CDCl3): 0.99 (t, J = 7.2 Hz,
3H), 1.46–1.53 (m, 2H), 1.81–1.87 (m, 2H), 3.13–3.26 (m, 2H),
3.75 (s, 3H), 6.77 (d, J = 8.4 Hz, 1H), 6.87 (s, 2H), 7.00 (d, J =
8.8 Hz, 1H), 7.14 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.58 (t, J =
8.4 Hz, 1H), 7.63 (s, 1H), 7.87 (s, 1H), 7.93–7.97 (m, 1H), 10.94 (s,
1H); 13C NMR (100 MHz, CDCl3) d 13.8, 22.3, 28.8, 31.5, 55.6,
95.9, 100.7, 113.0, 113.4 (d, 2J CF = 25 Hz), 119.1, 119.4, 120.4 (q,
1J = 318 Hz), 122.7, 125.0 (d, 2J = 26 Hz), 128.6, 129.0 (d,
120.4 (q, 1J = 318 Hz), 121.8, 122.2, 123.6, 124.6, 124.9, 125.3,
CF
129.5, 130.3, 131.0, 131.5, 132.2, 136.5, 142.2, 147.4, 161.5, 162.6
(d, 1J = 254 Hz); IR (KBr, cm-1): 3463, 1636, 1455; m/z (ESI):
CF
384 (M+ + H); HRMS calcd for C24H19FN3O (M+ + H): 384.1512,
found: 384.1526.
1-(4-Methoxyindol-3-yl)-2-amino-3-(4-methoxyphenyl)-7-fluo-
roisoquinolinium triflate 3i. 1H NMR (400 MHz, CDCl3): 3.64 (s,
3H), 3.81 (s, 3H), 6.27 (s, 2H), 6.53 (d, J = 8.0 Hz, 1H), 7.03 (d, J =
8.8 Hz, 2H), 7.11 (t, J = 8.0 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.47
(dd, J = 9.6, 2.4 Hz, 1H), 7.59–7.64 (m, 4H), 8.00 (s, 1H), 8.03–8.07
CF
CF
3J CF = 11 Hz), 129.9 (d, 3J = 9 Hz), 132.6, 137.9, 145.8, 148.4,
CF
157.6, 162.4 (d, 1J CF = 253 Hz); IR (KBr, cm-1): 3446, 1638, 1473,
1456; m/z (ESI): 364 (M+ + H); HRMS calcd for C22H23FN3O
(M+ + H): 364.1825, found: 364.1843.
(m, 1H), 11.03 (s, 1H); 13C NMR (100 MHz, CDCl3) d 55.5, 55.6,
1-(Indol-3-yl)-2-amino-3-phenyl-5,6,7-trimethoxyisoquinolinium
triflate 3n. 1H NMR (400 MHz, CDCl3): 3.66 (s, 3H), 4.07 (s,
3H), 4.08 (s, 3H), 6.31 (s, 2H), 7.00 (s, 1H), 7.13 (t, J = 7.3 Hz,
1H), 7.20–7.26 (m, 2H), 7.56–7.57 (m, 3H), 7.63 (d, J = 8.3 Hz,
1H), 7.73–7.74 (m, 2H), 8.02 (d, J = 3.0 Hz, 1H), 8.12 (s, 1H),
11.19 (s, 1H); 13C NMR (100 MHz, CDCl3) d 56.3, 61.4, 61.8,
2
100.0, 101.7, 106.8, 113.8 (d, J
= 25 Hz), 114.8, 115.7, 120.4
CF
(q, 1J = 318 Hz), 122.9, 124.9, 125.1, 125.4, 128.9, 130.1 (d, 3J
CF
3
= 10 Hz), 130.4 (d, J
= 9 Hz), 131.4, 132.6, 138.3, 142.8,
CF
CF
1
150.0, 152.3, 161.5, 162.7 (d, J
= 253 Hz); IR (KBr, cm-1):
CF
3446, 1618, 1514, 1464; m/z (ESI): 414 (M+ + H); HRMS calcd
for C25H21FN3O2 (M+ + H): 414.1618, found: 414.1636.
101.1, 104.2, 113.5, 119.2, 119.5, 120.4 (q, 1J
= 318 Hz),
CF
1-(5-Bromoindol-3-yl)-2-amino-3-(4-methoxyphenyl)-7-fluoro-
isoquinolinium triflate 3j. 1H NMR (400 MHz, CDCl3): 3.78 (s,
3H), 6.50 (s, 2H), 7.00 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.8 Hz,
1H), 7.37–7.39 (m, 2H), 7.45 (d, J = 8.8 Hz, 1H), 7.59–7.67 (m,
121.4, 123.4, 125.0, 125.4, 127.4, 129.1, 129.9, 130.6, 130.8, 131.3,
136.6, 141.0, 146.2, 146.3, 147.0, 156.4; IR (KBr, cm-1): 3445,
1636, 1540, 1456; m/z (ESI): 426 (M+ + H); HRMS calcd for
C26H24N3O3 (M+ + H): 426.1818, found: 426.1837.
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Acknowledgements
Financial support from National Natural Science Foundation of
China (20772018), Shanghai Pujiang Program, and Program for
New Century Excellent Talents in University (NCET-07-0208)
is gratefully acknowledged. This paper is dedicated to Professor
Li-Xin Dai on the occasion of his 85th birthday.
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4530 | Org. Biomol. Chem., 2009, 7, 4526–4530
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