Copper-catalyzed tandem synthesis of [1,2,3]triazolo[5,1-a]isoquinolines and their transformation to 1,3-disubstituted isoquinolines

Article abstract of DOI:10.1016/j.tet.2009.11.043

2-Azido-3-(2-iodophenyl)acrylates react with terminal alkynes in the presence of a copper(II) catalyst without ligands to give a wide range of [1,2,3]triazolo[5,1-a]isoquinolines in good yields. These compounds favor expulsion of N₂ in refluxed acetic acid to form 1,3-disubstituted isoquinolines. The procedure is simple, economical, and efficient.

Full text of DOI:10.1016/j.tet.2009.11.043

Tetrahedron 66 (2010) 80–86
Contents lists available at ScienceDirect
Tetrahedron
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Copper-catalyzed tandem synthesis of [1,2,3]triazolo[5,1-a]isoquinolines and their
transformation to 1,3-disubstituted isoquinolines
*
Yuan-Yuan Hu, Jie Hu, Xiang-Chuan Wang, Li-Na Guo, Xing-Zhong Shu, Yan-Ning Niu, Yong-Min Liang
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Azido-3-(2-iodophenyl)acrylates react with terminal alkynes in the presence of a copper(II) catalyst
without ligands to give a wide range of [1,2,3]triazolo[5,1-a]isoquinolines in good yields. These
compounds favor expulsion of N2 in refluxed acetic acid to form 1,3-disubstituted isoquinolines. The
procedure is simple, economical, and efficient.
Received 8 September 2009
Received in revised form 7 November 2009
Accepted 10 November 2009
Available online 12 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Herein, we wish to describe the details of the tandem synthesis
of [1,2,3]triazolo[5,1-a]isoquinolines involving the coupling
Recently, the reaction of terminal alkynes with organic azide in
the presence of transition-metal catalysts to construct N-heterocy-
cles became one of the frontier areas in organic chemistry. It has
been used to synthesize 1,4-disubstituted triazoles,1 1,5-di-
substituted triazoles,2 fully substituted triazoles,3 isoindolines fused
with triazoles,4 isoquinolones.5 In our ongoing effort to synthesize N-
heterocyclic compounds promoted by transition-metal catalysts,6
we attempted to develop a novel strategy for the synthesis of
[1,2,3]triazolo[5,1-a]isoquinolines with alkynes and organic azides as
substrates. [1,2,3]Triazolo[5,1-a]isoquinolines perhaps can be the
precursors of useful carbenes.7 The opening of triazole ring in these
structures by losing a molecular of N2 is also a promising method to
give 1,3-disubstituted isoquinolines.8 However, there are few reports
of the synthesis of isoquinolines fused with triazoles.9 Generally,
they are prepared by treating the 1-acyl isoquinolines with
4-methylphenyl sulfonohydrazide directly, or converting 1-acyl
isoquinolines to hydrazones and oxidizing with manganese dioxide.
These methods have met with significant limitations. For example,
the hazardous reagents are required and the substituted groups are
limited. In addition, the procedures involve several steps and lack
overall efficiency. These drawbacks promoted us to develop a new
method for the synthesis of isoquinolines fused with triazoles. The
isoquinoline ring system as an important building block in the
structures of plant alkaloids10 and pharmacologically valuable
compounds,11 a variety of methods for the preparation of this ring
system have been reported.12 Recently, Larock and co-workers have
developed new transition-metal catalyzed reactions to synthesize
substituted isoquinolines.12k,13
reaction catalyzed by copper14 and the [3þ2] cycloaddition. Fol-
lowed by refluxing in acetic acid, these compounds undergo
smooth denitrogenation to afford 1,3-disubstituted isoquinolines.
2. Results and discussion
Our initial studies were focused on the reaction of ethyl 2-az-
ido-3-(2-iodophenyl)acrylate 1a15 with phenylacetylene. It was
found that under the catalyst of Cu(OTf)2 at 60 ꢀC for 12 h in DMF
with K2CO3 as a base, the desired product 3aa was isolated in 19%
yield, along with 9% yield of the byproduct 4 (Table 1, entry 1).
Other copper(II) catalysts, such as Cu(acac)2, CuBr2, Cu(OAc)2,
CuCl2, CuCl2$H2O were also screened for this reaction (Table 1,
entries 2–6). CuCl2 was the most efficient catalyst. Changing the
base to KOtBu or NEt3 failed to improve the yield of the product
3aa (Table 1, entries 7 and 8). The effect of the solvents was also
investigated, and DMF was demonstrated to be the best choice
(Table 1, entries 9 and 10). Further investigation revealed that the
temperature was also a key factor in this reaction. When the re-
action was run at 100 ꢀC or room temperature, the product 3aa
was obtained in lower yield (Table 1, entries 11 and 12). The
copper(I) catalysts were also examined. However, no better result
was observed (Table 1, entries 13–15). From the above results,
Cu(II), polar solvent, and inorganic weak base are favorable to the
formation of 3, while apolar solvent promotes the formation of 4
and organic base has no selectivity. Addition of ligands,14 such as
PPh3, 1,3-diphenylpropane-1,3-dione, DMEDA, TMEDA, failed to
increase the yield (Table 1, entries 16–19). Thus, the optimum
reaction conditions were developed by employing 1a (0.2 mmol),
phenylacetylene (0.24 mmol), K2CO3 (0.4 mmol), and CuCl2
(10 mol %) in DMF at 60 ꢀC.
* Corresponding author. Tel.: þ86 931 891 2593; fax: þ86 931 891 2582.
E-mail address: liangym@lzu.edu.cn (Y.-M. Liang).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.043

Y.-Y. Hu et al. / Tetrahedron 66 (2010) 80–86
81
Table 1
Table 2
Optimization of the reaction conditionsa
The synthesis of [1,2,3]triazolo[5,1-a]isoquinolinesa
CO2Et
CO2Et
CO2Et
CO2Et
catalyst, Ar
R1
CO2Et
10 mol % CuCl2, Ar
K2CO3, DMF, 60 °C
+
Ph
R2
R1
N
+
N
N3
N
+
I
I
base, solvent
N
N
N
N3
X
N
N
N
R2
Ph
3aa
Ph
1
3
2
1a
2
4
Entry
1
R2
2
Product (3) Yieldb (%)
Entry
Catalyst
Cu(OTf)2
Cu(acac)2
CuBr2
Cu(OAc)2
CuCl2
CuCl2$H2O
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuI
CuBr
CuCl
CuCl2/PPh3
CuCl2/L
CuCl2/DMEDA
CuCl2/TMEDA
Base
Solvent
Yieldb
(%) of 3aa
Yieldb
(%) of 4
1
2
3
4
5
6
7
8
R1¼H, X¼I, 1a
Ph
2a
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
75
60
42
32
29
59
68
42
63
71
75
65
93
28
58
57
90
16
33
61
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
4-MeO–C6H4
4-Me–C6H4
4-Br–C6H4
4-Cl–C6H4
2b
2c
2d
2e
1
2
3
4
5
6
7
8
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOtBu
NEt3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Toluene
THF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
19
35
58
68
75
55
0
45
14
67
34
35
0
9
Trace
34
19
13
16
0
54
56
10
21
37
40
31
14
7
4-MeCO–C6H4 2f
CH3CH2CH2
CH3(CH2)4
HOCH2
HO(CH3)CH
HO(CH3)2C
THPOCH2
HO(Ph)CH
HO(Ph)CH
Ph
2g
2h
2i
2j
2k
2l
9c
10c
11c
12c
13c
14
15
16
17
18
19
20
3aj
3ak
3al
9
10
11c
12d
13
14
15
16e
17e
18e
19e
2m 3am
2m 3bm
2a
2l
2m 3cm
2a
2l
R1¼H, X¼Br, 1b
R1¼4-Me, X¼I, 1c
3ca
3cl
0
1c
1c
THPOCH2
HO(Ph)CH
35
47
73
31
0
R1¼5-MeO,X¼I, 1d Ph
3da
3dl
10
5
0
1d
1d
THPOCH2
HO(Ph)CH
2m 3dm
a
All reactions were run under the following conditions (unless otherwise spec-
ified):1 (0.2 mmol), 2 (0.24 mmol), CuCl2(10 mol %), K2CO3 (0.4 mmol), DMF (2 mL)
at 60 ꢀC under argon atmosphere for 12 h, and the byproducts observed in the re-
actions were trace amount.
a
Reactions conditions (unless otherwise specified): 1a (0.2 mmol), phenyl-
acetylene (0.24 mmol), catalyst (10 mol %), base (0.4 mmol), solvent (2 mL) at 60 ꢀC
under an argon atmosphere for 12 h.
b
Isolated yields.
b
Isolated yields.
The reactions were run for 8 h.
c
The reaction was run at 100 ꢀC.
c
d
The reaction was run at rt for 24 h.
L¼1,3-diphenylpropane-1,3-dione. DMEDA¼N,N0-dimethylethane-1,2-diamine.
e
isoquinolines. As R is the group with more strong electron-donating
or electron-withdrawing effect, the yield of isolated 5 is lower. To
our surprise, the reaction of 3ai and 3an furnished the same
product 5e in 34% and 81% yield, respectively (Scheme 1).
TMEDA¼N,N,N0,N0-tetramethylethane-1,2-diamine.
With the optimized reaction conditions in hand, we further
explored the scope of this transformation, as shown in Table 2. The
reaction of substrate 1a with a variety of aryl acetylenes was first
explored (Table 2, entries 1–6). The electronic effect of the
substituted groups is not apparent. The electron-rich aryl acetylene
2b reacted with 1a to afford the desired product in 60% yield, and
the reaction using the electron-deficient aryl acetylene 2f also
provided the desired product in 59% yield. The reaction also pro-
ceeded well with aliphatic acetylenes such as pent-1-yne 2g and
hept-1-yne 2h (Table 2, entries 7 and 8). Furthermore, homo-
propargyl alcohols were compatible under the optimized reaction
conditions (Table 2, entries 9–11). Protecting the hydroxyl group of
prop-2-yn-1-ol with dihydropyrane had not significant influence
on the yield (Table 2, entry 12). Interestingly, in the case of phenyl
propargyl alcohol 2m, an excellent yield was obtained (93%, Table 2,
entry 13).
Table 3
The synthesis of isoquinolinesa
CO2Et
CO2Et
AcOH
N
N
O
N
O
reflux, 8 h
N
R
R
3
5
Entry
R
Product (5)
Yieldb (%)
1
2
3
4
5
6
Ph (3aa)
4-MeO–C6H4 (3ab)
4-Br–C6H4 (3ad)
4-MeCO–C6H4 (3af)
CH3CH2CH2 (3ag)
CH3(CH2)3CH2 (3ah)
5a
5b
5c
5d
5e
5f
99
55
75
64
66
62
a
The scope of the functionalized halides was also examined.
Unfortunately, bromide 1b reacted with 2m to afford 3bm in a poor
yield (Table 2, entry 14). The substituent R1 on the aromatic ring
was also investigated. The reaction proceeded smoothly when Me-
and MeO-substituents were introduced at R1 position (Table 2,
entries 15–20). The electronic effect of the substituent on the aro-
matic ring is very obvious. The results show that strong donating-
electron substituent on the aromatic ring leads to the sharply de-
creased yield.
At last, we were interested in converting triazoloisoquinolines
into isoquinolines. Fortunately, the corresponding 1,3-disubstituted
isoquinolines 5 could easily be formed from compounds 3 via loss
of N2 in refluxed acetic acid. Both phenyl and alkyl groups at R
position were all suitable for this reaction (Table 3, entries 1–6).
Notably, the electronic effect of R influences the formation of
All reactions were run under the following conditions: 3 (0.20 mmol), refluxed
acetic acid (2 mL) for 8 h.
b
Isolated yield.
CO2Et
N
CO2Et
AcOH
N
N
O
reflux, 8 h
N
R
3
5g
R = HOCH2, 3ai
R = AcOCH2, 3an
34 %
81 %
Scheme 1.

82
Y.-Y. Hu et al. / Tetrahedron 66 (2010) 80–86
R
R2
R2
R2
2
2K2CO3
2
Cu2
To clarify this reaction process, the following reactions were
2KHCO3
performed, as shown in Scheme 2. No 3aa was observed when
byproduct 4 was treated under the standard conditions. On the
other hand, compound 6 easily gave the Huisgen 1,3-dipolar
cycloadditive product 3aa without CuCl2 in almost quantitative
yield. On the basis of these results, we consider compound 6 is the
key intermediate in this tandem reaction.
H
C
C
R2
N
N
N
reductive
elimination
Cu
C
CO2Et
Huisgen 1,3-dipolar
cycloaddition
R2
C
CO2Et
N3
CO2Et
Cu
CO2Et
N
Cu
R2
C
CO2Et
N
I
10 mol % CuCl2, K2CO3
N
N
N
N
A
I
N
0%
R2
DMF, 12 h,
Ar
60 °C
N
N
oxidative
addition
3
Ph
4
B
Ph
Ph
3aa
CO2Et
N3
path a
CO2Et
CO2Et
N3
CO2Et
N
I
DMF, K2CO3
60°C, 4 h
CO2Et
N
N
99%
N
N
R2
N2
R2
N2
Ph
6
3aa
D
Scheme 2.
CO2Et
OAc
H
N
5a-5f
N2
R2
OAc
To further investigate the origin of the hydrogen atom in-
corporated into the product 5, two reactions were performed with
CH3CH2OD as the solvent (Scheme 3). The corresponding product of
5a–d was isolated in 70% yield with 95% D incorporation at the
benzyl carbon position. The product of 5g–d was isolated in 81%
CO2Et
N
R2
N2
CO2Et
CO2Et
H
CO2Et
E
1,2-H shift
N
N2
N
N
O
H
yield with 99% D incorporation at the
a
-carbonyl carbon position. It
-carbonyl carbon is
H
5g
OH
should be noted that the hydrogen at the
a
OH
F
G
acidic, so three H atoms of the methyl group of 5g–d are easily
replaced by D atoms when the reaction is carried out in refluxed
CH3CH2OD. This result suggests that the hydrogen atom originates
from the acidic proton.
CO2Et
H-OAc
N
H
5a-5f
CO2Et
path b
N
R2
OAc
CO2Et
N
N
CO2Et
CO2Et
N
N
R2
CO2Et
R2
CO2Et
AcOD
N
D
O
N
H
3
1,2-H shift
N
N
O
reflux, 8 h
5a-d
70%
H
D/H = 95/5
N
5g
H
Ph
Ph
3aa
I
O
O
D
Scheme 4. Proposed mechanism.
CO2Et
CO2Et
N
AcOD
N
N
5g-d
81% D/H = 99/1
N
reflux, 8 h
D
D
3. Conclusion
O
OAc
3an
In conclusion, we have developed a novel method for the
synthesis of various [1,2,3]triazolo[5,1-a]isoquinolines and iso-
quinolines derivatives from terminal alkynes and organic azides.
The tandem reaction proceeds under mild conditions and tol-
erates various functional groups. Further investigation of the
reaction mechanism and application of the reaction is in prog-
ress in our laboratory and the results will be reported in
due course.
Scheme 3. Deuterium labeling experiments.
A possible reaction mechanism for the reaction process is pro-
posed in Scheme 4. CuCl2 can oxidize terminal alkynes to give
diynes, and itself transforms to a catalytical copper(I) species,16
which is more active than other copper(I) species, such as CuI, CuBr,
and CuCl, for this reaction. Under the copper catalyst, the coupling
intermediate C is formed,14 which subsequently undergoes Huisgen
1,3-dipolar cycloaddition to afford triazoloisoquinoline 3. Followed
two possible paths of the transformation from 3 to 5 are proposed.
Path a: compound 3 undergoes closed/open form equilibrium to
produce small amounts of diazo compound D.7 After protonation,
followed by loss of N2 along with a nucleophilic attack of acetate
anion to E, the isoquinoline (5a–f) is formed. For the substrates 3an
and 3ai, the intermediate F is produced when E was attacked by
hydroxyl group of itself, and then 1,2-H shift and leaving the proton
leads to 5g.
4. Experimental
4.1. General procedure for synthesis of [1,2,3]triazolo[5,1-
a]isoquinolines
To a solution of 1 (0.20 mmol) in DMF (2.0 mL) were added 2
(1.2 equiv, 0.24 mmol), CuCl2 (2.7 mg, 0.02 mmol, 10 mol %), K2CO3
(55.2 mg, 0.40 mmol). The resulting mixture was then heated
under an argon atmosphere at 60 ꢀC. When the reaction was
considered complete, as determined by TLC analysis, the reaction
mixture was cooled to room temperature, quenched with a satu-
rated aqueous solution of ammonium chloride, and extracted with
Path b: compound 3 loses a molecular of N2 to give a carbene
species H, and it undergoes insertion to the H–O bond of a acetic
acid or itself. At last, the isoquinoline is formed.

Y.-Y. Hu et al. / Tetrahedron 66 (2010) 80–86
83
EtOAc. The combined organic extracts were washed with water
and saturated brine. The organic layers were dried over Na2SO4
and filtered. The solvents were evaporated under reduced pres-
sure. The residue was purified by chromatography on silica gel to
afford 3.
124.8, 123.2, 122.1, 62.7, 14.2; IR (neat, cmꢁ1) 3069, 2925, 1737, 1635,
1474, 1250, 109.5. Anal. Calcd for C19H14ClN3O2: C, 64.87; H, 4.01; N,
11.94. Found: C, 64.69; H, 4.00; N, 11.91.
4.1.6. Ethyl-1-(4-acetylphenyl)-[1,2,3]triazolo[5,1-a]isoquinoline-5-
carboxylate 3af. The reaction mixture was chromatographed using
5:1 hexanes/EtOAc to afford 42.4 mg (59%) of the indicated com-
pound as a pale yellow solid: mp 150–154 ꢀC; 1H NMR (300 MHz,
4.1.1. Ethyl-1-phenyl-[1,2,3]triazolo[5,1-a]isoquinoline-5-carboxylate
3aa. The reaction mixture was chromatographed using 5:1 hex-
anes/EtOAc to afford 47.6 mg (75%) of the indicated compound as
CDCl3)
d 8.19–8.15 (m, 3H), 7.99 (s, CH]), 7.93–7.89 (m, 3H), 7.69–
a brown solid: mp 165–167 ꢀC; 1H NMR (300 MHz, CDCl3)
d
8.18–
7.65 (t, J¼7.6 Hz, 1H), 7.61–7.57 (t, J¼7.6 Hz, 1H), 4.65–4.60 (q,
8.15 (d, J¼8.1 Hz, 1H), 7.94 (s, CH]), 7.88–7.85 (d, J¼7.5 Hz, 1H),
7.75–7.73(d, J¼6.9 Hz, 2H), 7.63–7.51 (m, 5H), 4.64–4.57 (q,
J¼6.9 Hz, 2H), 1.54–1.50 (t, J¼7.2 Hz, 3H); 13C NMR (75 MHz,
J¼7.2 Hz, 2H), 2.71 (s, CH3CO), 1.55–1.51 (t, J¼7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 197.7, 160.5, 139.8, 137.2, 136.7,130.6, 130.0, 129.6,
129.5, 129.2, 128.8, 128.3, 126.1, 124.7, 123.3, 122.2, 62.7, 26.7, 14.2;
IR (neat, cmꢁ1) 3070, 2983, 1737, 1682, 1609, 1424, 1252, 1015. Anal.
Calcd for C21H17N3O3: C, 70.18; H, 4.77; N, 11.69. Found: C, 69.93; H,
4.79; N, 11.66.
CDCl3)
d 160.5, 140.9, 131.9, 130.4, 129.7, 129.2, 128.9, 128.7, 128.8,
128.0, 125.9, 125.0, 123.2, 122.0, 88.3, 62.5, 14.2; IR (neat, cmꢁ1
)
3053, 2926, 1727, 1631, 1495, 1256, 1065. Anal. Calcd for
C19H15N3O2: C, 71.91; H, 4.76; N, 13.24. Found: C, 71.83; H, 4.73; N,
13.18.
4.1.7. Ethyl-1-propyl-[1,2,3]triazolo[5,1-a]isoquinoline-5-carboxylate
3ag. The reaction mixture was chromatographed using 10:1 hex-
anes/EtOAc to afford 38.5 mg (68%) of the indicated compound as
4.1.2. Ethyl-1-(4-methoxyphenyl)-[1,2,3]triazolo[5,1-a]isoquinoline-
5-carboxylate 3ab. The reaction mixture was chromatographed
using 5:1 hexanes/EtOAc to afford 41.7 mg (60%) of the indicated
compound as a pale yellow solid: mp 150–152 ꢀC; 1H NMR
a pale yellow solid: mp 68–70 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.18–
8.16 (d, J¼8.4 Hz, 1H), 7.85–7.83 (m, 2H), 7.76–7.72 (t, J¼7.2 Hz, 1H),
7.63–7.60 (t, J¼7.6 Hz, 1H), 4.61–4.55 (q, J¼7.2 Hz, 2H), 3.27–3.23 (t,
J¼7.6 Hz, 2H), 1.96–1.91 (m, 2H), 1.52–1.49 (t, J¼7.2 Hz, 3H), 1.12–
(400 MHz, CDCl3)
d
8.18–8.16 (d, J¼8.0 Hz, 1H), 7.93 (s, CH]), 7.87–
7.85 (d, J¼8.0 Hz, 1H), 7.66–7.64 (m, 2H), 7.62–7.59 (t, J¼7.6 Hz, 1H),
7.56–7.52 (t, J¼7.6 Hz, 1H), 7.09–7.07 (m, 2H), 4.63–4.58 (q,
J¼7.2 Hz, 2H), 3.91 (s, CH3O), 1.54–1.50 (t, J¼7.2 Hz, 3H); 13C NMR
1.09 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 160.5, 140.6,
130.6, 128.9, 128.7, 128.4, 127.5, 125.8, 125.4, 123.0, 121.6, 62.3, 29.1,
21.8, 14.1, 13.8; IR (neat, cmꢁ1) 3093, 2930, 1734, 1628, 1459, 1249,
1043. Anal. Calcd for C16H17N3O2: C, 67.83; H, 6.05; N, 14.83. Found:
C, 67.55; H, 6.07; N, 14.80.
(100 MHz, CDCl3)
d 160.6, 160.1, 140.7, 131.0, 130.4, 129.1, 128.9,
128.0, 126.0, 125.2, 124.1, 123.2, 122.0, 114.2, 62.6, 55.3, 14.2; IR
(neat, cmꢁ1) 3068, 2933, 1737, 1613, 1475, 1250, 1021. Anal. Calcd for
C20H17N3O3: C, 69.15; H, 4.93; N, 12.10. Found: C, 69.28; H, 4.90; N,
12.04.
4.1.8. Ethyl-1-pentyl-[1,2,3]triazolo[5,1-a]isoquinoline-5-carboxylate
3ah. The reaction mixture was chromatographed using 10:1 hex-
anes/EtOAc to afford 26.2 mg (42%) of the indicated compound as
4.1.3. Ethyl-1-p-tolyl-[1,2,3]triazolo[5,1-a]isoquinoline-5-carboxylate
3ac. The reaction mixture was chromatographed using 5:1 hex-
anes/EtOAc to afford 27.8 mg (42%) of the indicated compound as
a yellow solid: mp 38–40 ꢀC; 1H NMR (300 MHz, CDCl3)
d 8.19–8.17
(d, J¼8.1 Hz, 1H), 7.85–7.83 (m, 2H), 7.76–7.71 (t, J¼6.9 Hz, 1H),
7.63–7.58 (t, J¼6.9 Hz, 1H), 4.59–4.52 (q, J¼7.2 Hz, 2H), 3.28–3.23 (t,
J¼7.8 Hz, 2H), 1.93–1.83 (m, 2H), 1.50–1.23 (m, 7H), 0.92–0.87 (t,
a yellow solid: mp 109–111 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.20–
8.18 (d, J¼8.0 Hz, 1H), 7.93 (s, CH]), 7.86–7.84 (d, J¼7.6 Hz, 1H),
7.63–7.58 (m, 3H), 7.55–7.51 (t, J¼7.6 Hz, 1H), 7.37–7.35 (m, 2H),
4.63–4.58 (q, J¼7.2 Hz, 2H), 2.47 (s, CH3), 1.53–1.50 (t, J¼7.2 Hz, 3H);
J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 160.6, 141.0, 130.7, 129.0,
128.8, 128.4, 127.7, 126.1, 125.6, 123.2, 121.7, 62.4, 31.6, 28.2, 27.3,
22.4, 14.2, 13.9; IR (neat, cmꢁ1) 3071, 2931, 1739, 1633, 1463, 1248,
1137, 1032. Anal. Calcd for C18H21N3O2: C, 69.43; H, 6.80; N, 13.49.
Found: C, 69.13; H, 6.79; N, 13.46.
13C NMR (100 MHz, CDCl3)
d 160.6, 140.9, 138.7, 130.4, 129.6, 129.5,
129.1, 128.9, 128.0, 126.0, 125.1, 123.2, 121.9, 62.5, 21.4, 14.2; IR (neat,
cmꢁ1) 3052, 2923, 1737, 1631, 1460, 1251, 1064. Anal. Calcd for
C20H17N3O2: C, 72.49; H, 5.17; N, 12.68. Found: C, 72.31; H, 5.15; N,
12.63.
4.1.9. Ethyl-1-(hydroxymethyl)-[1,2,3]triazolo[5,1-a]isoquinoline-5-
carboxylate 3ai. The reaction mixture was chromatographed using
1:1 hexanes/EtOAc to afford 34.2 mg (63%) of the indicated com-
pound as a white solid: mp 137–139 ꢀC; 1H NMR (300 MHz, CDCl3)
4.1.4. Ethyl-1-(4-bromophenyl)-[1,2,3]triazolo[5,1-a]isoquinoline-5-
carboxylate 3ad. The reaction mixture was chromatographed using
5:1 hexanes/EtOAc to afford 25.4 mg (32%) of the indicated com-
pound as a pale yellow solid: mp 174–176 ꢀC; 1H NMR (400 MHz,
d
8.51–8.48 (d, J¼8.1 Hz, 1H), 7.89 (s, CH]), 7.85–7.82 (d, J¼7.8 Hz,
1H), 7.79–7.74 (t, J¼7.5 Hz, 1H), 7.67–7.62 (t, J¼7.4 Hz, 1H), 5.28 (s,
CH2), 4.58–4.51 (q, J¼7.2 Hz, 2H), 3.77 (s, OH), 1.50–1.45 (t, J¼7.5 Hz,
CDCl3)
d
8.15–8.13 (d, J¼8.0 Hz, 1H), 7.97 (s, CH]), 7.91–7.89 (d,
3H); 13C NMR (75 MHz, CDCl3)
d 160.2, 139.6, 131.2, 130.9, 129.2,
J¼7.6 Hz, 1H), 7.71–7.67 (m, 2H), 7.65–7.57 (m, 4H), 4.64–4.59 (q,
128.6, 127.7, 125.5, 125.1, 124.7, 122.5, 62.5, 57.1, 14.1; IR (neat, cmꢁ1
)
J¼7.2 Hz, 2H),1.54–1.51 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
3420, 3074, 2979, 1732, 1632, 1464, 1246, 1137, 1027. Anal. Calcd for
C14H13N3O3: C, 61.99; H, 4.83; N, 15.49. Found: C, 61.85; H, 4.84; N,
15.52.
d
160.5, 139.7, 132.1, 131.4, 130.9, 130.6, 129.4, 129.1, 128.2, 126.1,
124.9, 123.2, 122.1, 62.7, 14.2; IR (neat, cmꢁ1) 3075, 2923, 1737, 1634,
1471, 1250, 1061. Anal. Calcd for C19H14BrN3O2: C, 57.59; H, 3.56; N,
10.60. Found: C, 57.36; H, 3.55; N, 10.58.
4.1.10. Ethyl-1-(1-hydroxyethyl)-[1,2,3]triazolo[5,1-a]isoquinoline-5-
carboxylate 3aj. The reaction mixture was chromatographed using
1:1 hexanes/EtOAc to afford 40.5 mg (71%) of the indicated com-
pound as a pale yellow solid: mp 148–150 ꢀC; 1H NMR (400 MHz,
4.1.5. Ethyl-1-(4-chlorophenyl)-[1,2,3]triazolo[5,1-a]isoquinoline-5-
carboxylate 3ae. The reaction mixture was chromatographed using
5:1 hexanes/EtOAc to afford 20.4 mg (29%) of the indicated com-
pound as a yellow solid: mp 173–175 ꢀC; 1H NMR (400 MHz, CDCl3)
CDCl3)
d
8.64–8.62 (d, J¼8.1 Hz, 1H), 7.84–7.82 (m, 2H), 7.79–7.74 (t,
J¼7.8 Hz, 1H), 7.67–7.62 (t, J¼7.5 Hz, 1H), 5.59 (s, CH), 4.58–4.51 (q,
d
8.14–8.12 (d, J¼8.0 Hz, 1H), 7.97 (s, CH]), 7.91–7.89 (d, J¼7.6 Hz,
J¼7.2 Hz, 2H), 3.33 (s, OH), 1.85–1.83 (d, J¼6.9 Hz, 3H), 1.51–1.46 (t,
1H), 7.70–7.63 (m, 3H), 7.60–7.53 (m, 3H), 4.64–4.59 (q, J¼7.2 Hz,
J¼6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 160.4, 142.7, 130.9,
2H), 1.54–1.51 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
160.5,
128.9, 128.7, 127.8, 125.8, 125.6, 124.7, 122.3, 63.9, 62.5, 22.3, 14.1; IR
139.7,135.0,131.1,130.6, 130.4,129.4,129.2,129.1,129.0,128.2,126.1,
(neat, cmꢁ1) 3431, 3071, 2981, 1729, 1635, 1460, 1253, 1034. Anal.

84
Y.-Y. Hu et al. / Tetrahedron 66 (2010) 80–86
Calcd for C15H15N3O3: C, 63.15; H, 5.30; N, 14.73. Found: C, 63.44; H,
5.28; N, 14.69.
19.5, 14.2; IR (neat, cmꢁ1) 3069, 2942, 1739, 1637, 1446, 1211, 1032.
Anal. Calcd for C20H23N3O4: C, 65.03; H, 6.28; N, 11.37. Found: C,
65.32; H, 6.27; N, 11.34.
4.1.11. Ethyl-1-(2-hydroxypropan-2-yl)-[1,2,3]triazolo[5,1-a]iso-
quinoline-5-carboxylate 3ak. The reaction mixture was chromato-
graphed using 1:1 hexanes/EtOAc to afford 44.9 mg (75%) of the
indicated compound as a yellow solid: mp 106–108 ꢀC; 1H NMR
4.1.16. Ethyl1-(hydroxy(phenyl)methyl)-9-methyl-[1,2,3] triazolo[5,1-
a]isoquinoline-5-carboxylate 3cm. The reaction mixture was chro-
matographed using 1:1 hexanes/EtOAc to afford 65.1 mg (90%) of the
indicated compound as a yellow solid: mp 5658 ꢀC; 1H NMR
(400 MHz, CDCl3)
d
9.29–9.27 (d, J¼8.0 Hz, 1H), 7.76–7.72 (m, 2H),
7.66–7.61 (m, 2H), 4.57–4.51 (q, J¼7.2 Hz, 2H), 3.03 (s, OH), 1.89 (s,
(400 MHz, CDCl3)
d
7.82 (s, CH]), 7.69–7.67 (d, J¼7.2 Hz, 1H), 7.56–
2CH3), 1.51–1.48 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
7.50 (m, 2H), 7.41–7.39 (d, J¼7.6 Hz, 2H), 7.31–7.25 (m, 3H), 6.53 (s,
d
160.5, 146.6, 130.5, 129.7, 128.6, 128.6, 128.3, 128.0, 125.5, 124.8,
CH), 4.60–4.54 (q, J¼7.2 Hz, 2H), 3.95 (s, OH), 2.74 (s, CH3), 1.50–1.47
122.3, 70.1, 62.5, 29.8, 14.2; IR (CDCl3, cmꢁ1) 3427, 3089, 2982, 1735,
1632, 1458, 1238, 1025. Anal. Calcd for C16H17N3O3: C, 64.20; H,
5.72; N, 14.04. Found: C, 64.01; H, 5.74; N, 14.08.
(t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 160.7, 142.6, 134.7,
133.8, 129.8, 129.0, 128.6, 128.4, 127.8, 127.4, 127.2, 126.5, 125.5, 124.7,
122.8, 70.4, 62.6, 23.5, 14.2; IR (neat, cmꢁ1) 3425, 3063, 2927, 1733,
1634, 1449, 1214, 1032. Anal. Calcd for C21H19N3O3: C, 69.79; H, 5.30;
N, 11.63. Found: C, 69.65; H, 5.32; N, 11.66.
4.1.12. Ethyl-1-((tetrahydro-2H-pyran-2-yloxy)methyl)-[1,2,3]tri-
azolo[5,1-a]isoquinoline-5-carboxylate 3al. The reaction mixture
was chromatographed using 2:1 hexanes/EtOAc to afford 46.2 mg
(65%) of the indicated compound as a pale yellow solid: mp 76–
4.1.17. Ethyl 8-methoxy-1-phenyl-[1,2,3]triazolo[5,1-a]isoquinoline-
5-carboxylate 3da. The reaction mixture was chromatographed
using 5:1 hexanes/EtOAc to afford 11.1 mg (16%) of the indicated
compound as a yellow solid: mp 116–118 ꢀC; 1H NMR (400 MHz,
78 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.57–8.55 (d, J¼8.0 Hz, 1H), 7.96
(s, CH]), 7.91–7.89 (d, J¼8.0 Hz, 1H), 7.82–7.79 (t, J¼7.2 Hz, 1H),
7.71–7.67 (t, J¼7.6 Hz, 1H), 5.41–5.38 (d, J¼12.4 Hz, 1H), 5.25–5.22
(d, J¼12.8 Hz, 1H), 4.84–4.82 (m, 1H), 4.62–4.57 (q, J¼7.2 Hz, 2H),
4.04–3.99 (m, 1CH2), 3.64–3.59 (m, 1CH2), 1.82–1.47 (m, 9H); 13C
CDCl3)
d
8.10–8.07 (d, J¼9.2 Hz, 1H), 7.87 (s, CH]), 7.73–7.72 (d,
J¼6.8 Hz, 2H), 7.57–7.50 (m, 3H), 7.25–7.24 (d, J¼2.8 Hz, 1H), 7.15–
7.12 (d, J¼9.6 Hz, 1H), 4.63–4.58 (q, J¼7.2 Hz, 2H), 3.92 (s, CH3O),
NMR (100 MHz, CDCl3)
d
160.5, 137.0, 131.4, 131.0, 129.2, 128.7,
1.54–1.50 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 160.7,
128.0, 125.9,125.1,124.9,122.2, 98.2, 62.9, 62.5, 61.3, 30.5, 25.3, 19.6,
14.2; IR (neat, cmꢁ1) 3072, 2927, 1738, 1634, 1463, 1248, 1135, 1029.
Anal. Calcd for C19H21N3O4: C, 64.21; H, 5.96; N, 11.82. Found: C,
64.37; H, 5.95; N, 11.77.
160.0, 139.7, 132.1, 129.9, 129.8, 129.3, 128.8, 128.7, 126.4, 124.9,
121.6, 119.8, 118.9, 110.1, 62.6, 55.6, 14.2; IR (neat, cmꢁ1) 3065, 2929,
1738, 1608,1464,1256,1031. Anal. Calcd for C20H17N3O3: C, 69.15; H,
4.93; N, 12.10. Found: C, 69.41; H, 4.92; N, 12.07.
4.1.13. Ethyl-1-(hydroxy(phenyl)methyl)-[1,2,3]triazolo
[5,1-a]iso-
4.1.18. Ethyl 8-methoxy-1-((tetrahydro-2H-pyran-2-yloxy) methyl)-
[1,2,3]triazolo[5,1-a]isoquinoline-5-carboxylate 3dl. The reaction
mixture was chromatographed using 5:1 hexanes/EtOAc to afford
25.4 mg (33%) of the indicated compound as a pale yellow solid: mp
quinoline-5-carboxylate 3am. The reaction mixture was chroma-
tographed using 1:1 hexanes/EtOAc to afford 64.6 mg (93%) of the
indicated compound as a pale yellow solid: mp 122–124 ꢀC; 1H
NMR (400 MHz, CDCl3)
d
8.34–8.32 (d, J¼8.0 Hz, 1H), 7.85 (s, CH]),
146–148 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.48–8.45 (d, J¼9.2 Hz,
7.78–7.76 (d, J¼6.4 Hz,1H), 7.61–7.53 (m, 2H) 7.44–7.42 (d, J¼7.2 Hz,
2H), 7.30–7.24 (m, 2H), 7.22–7.18 (m, 1H), 6.65 (s, CH), 4.58–4.52 (q,
J¼7.2 Hz, 2H), 4.23–4.22 (d, J¼4.0 Hz, OH), 1.50–1.47 (t, J¼7.2 Hz,
1H), 7.9 (s, CH]), 7.40–7.37 (d, J¼8.8 Hz,1H), 7.28–7.27 (d, J¼5.2 Hz,
1H), 5.37–5.34 (d, J¼12.4 Hz, 1H), 5.22–5.19 (d, J¼12.4 Hz, 1H),
4.82–4.80 (m, 1H), 4.61–4.56 (q, J¼7.2 Hz, 2H), 4.05–3.96 (m,
1CH2þCH3O), 3.63–3.58 (m, 1CH2), 1.81–1.49 (m, 9H); 13C NMR
3H); 13C NMR (100 MHz, CDCl3)
d 160.4, 142.4, 141.0, 130.7, 129.9,
129.0, 128.6, 128.3, 127.9, 127.5, 126.5, 126.1, 125.7, 124.4, 122.6, 69.7,
62.6, 14.2; IR (neat, cmꢁ1) 3402, 3065, 2983, 1734, 1633, 1461, 1251,
1135, 1027. Anal. Calcd for C20H17N3O3: C, 69.15; H, 4.93; N, 12.10.
Found: C, 69.37; H, 4.91; N, 12.05.
(100 MHz, CDCl3) d 160.5, 160.1, 135.7, 131.6, 129.8, 126.7, 126.3,
121.7, 120.4, 118.8, 109.8, 98.2, 63.0, 62.5, 61.3, 55.8, 30.6, 25.3, 19.7,
14.2; IR (CDCl3, cmꢁ1) 3076, 2942, 1739, 1633, 1609, 1464, 1254,
1031. Anal. Calcd for C20H23N3O5: C, 62.33; H, 6.01; N, 10.90. Found:
C, 62.17; H, 6.03; N, 10.95.
4.1.14. Ethyl 9-methyl-1-phenyl-[1,2,3]triazolo[5,1-a]isoquinoline-5-
carboxylate 3ca. The reaction mixture was chromatographed using
5:1 hexanes/EtOAc to afford 38.4 mg (58%) of the indicated com-
pound as a yellow solid: mp 156–158 ꢀC; 1H NMR (400 MHz, CDCl3)
4.1.19. Ethyl-1-(hydroxy(phenyl)methyl)-8-methoxy-[1,2,3]tri-
azolo[5,1-a]isoquinoline-5-carboxy-late 3dm. The reaction mixture
was chromatographed using 1:1 hexanes/EtOAc to afford 46.0 mg
(61%) of the indicated compound as a pale yellow solid: mp 179–
d
7.84 (s, CH]), 7.71–7.69 (d, J¼7.6 Hz, 1H), 7.57–7.53 (m, 3H), 7.47–
7.41 (m, 4H), 4.62–4.57 (q, J¼7.2 Hz, 2H), 1.99 (s, CH3), 1.52–1.49 (t,
181 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.22–8.19 (d, J¼9.2 Hz,1H), 7.80
J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
160.8, 143.1, 135.3, 134.1,
(s, CH]), 7.44–7.42 (d, J¼7.6 Hz, 2H), 7.30–7.22 (m, 3H), 7.18–7.16
(m, 2H), 6.63–6.62 (d, J¼3.6 Hz, 1H), 4.59–4.53 (q, J¼7.2 Hz, 2H),
3.88 (s, OHþCH3), 1.51–1.47 (t, J¼7.2 Hz, 3H); 13C NMR (75 MHz,
133.6, 130.0, 129.6, 129.2, 128.9, 128.4, 128.3, 126.5, 125.6, 124.9,
122.5, 62.5, 23.5, 14.2; IR (neat, cmꢁ1) 3062, 2982, 1736, 1632, 1443,
1214, 1013. Anal. Calcd for C20H17N3O2: C, 72.49; H, 5.17; N, 12.68.
Found: C, 72.25; H, 5.18; N, 12.71.
DMSO-d6)
d 160.3, 159.5, 142.5, 141.9, 129.7, 128.0, 127.0, 126.2,
125.6, 121.4, 119.8, 117.7, 110.6, 68.2, 62.2, 55.6, 14.1; IR (neat, cmꢁ1
)
3426,1657,1251, 1051,1004. Anal. Calcd for C21H19N3O4: C, 66.83; H,
5.07; N, 11.13. Found: C, 66.74; H, 5.08; N, 11.15.
4.1.15. Ethyl 9-methyl-1-((tetrahydro-2H-pyran-2-yloxy) methyl)-
[1,2,3]triazolo[5,1-a]isoquinoline-5-carboxylate 3cl. The reaction
mixture was chromatographed using 5:1 hexanes/EtOAc to afford
42.1 mg (57%) of the indicated compound as a yellow oil: 1H NMR
4.2. General procedure for the synthesis of the isoquinolines
derivatives
(400 MHz, CDCl3)
d
7.79 (s, CH]), 7.69–7.67 (d, J¼7.2 Hz, 1H), 7.61–
7.54 (m, 2H), 5.44–5.41 (d, J¼12.4 Hz, 1H), 5.18–5.15 (d, J¼12.4 Hz,
1H), 4.79–4.77 (m, 1H), 4.60–4.54 (q, J¼7.2 Hz, 2H), 3.97–3.92 (m,
1CH2), 3.59–3.54 (m, 1CH2), 3.01 (s, CH3), 1.76–1.47 (m, 9H); 13C
A solution of 3a (0.2 mmol) in acetic acid (2.0 mL) was heated
to reflux. When the reaction was considered complete as de-
termined by TLC analysis, the reaction mixture was cooled to room
temperature, neutralized with a saturated aqueous solution of
NaHCO3, and extracted with EtOAc. The combined organic extracts
NMR (100 MHz, CDCl3)
128.9, 127.0, 125.7, 125.0, 122.4, 98.1, 63.1, 62.6, 62.5, 30.6, 25.3, 22.6,
d 160.8, 138.2, 135.7, 133.6, 131.3, 129.7,

Y.-Y. Hu et al. / Tetrahedron 66 (2010) 80–86
85
were washed with water and saturated brine. The organic layers
were dried over Na2SO4 and filtered. The solvents were evapo-
rated under reduced pressure. The residue was purified by chro-
matography on silica gel to afford corresponding isoquinolines
derivatives 5.
1266, 1237, 1019. Anal. Calcd for C23H21NO5: C, 69.64; H, 5.58; N,
3.69. Found: C, 69.45; H, 5.62; N, 3.71.
4.2.5. Ethyl-1-(1-acetoxybutyl)isoquinoline-3-carboxylate 5e. The
reaction mixture was chromatographed using 20:1 hexanes/EtOAc
to afford 41.6 mg (66%) of the indicated compound as a pale yellow
4.2.1. Ethyl-1-(acetoxy(phenyl)methyl)isoquinoline-3-carboxylate
5a. The reaction mixture was chromatographed using 20:1 hex-
anes/EtOAc to afford 69.2 mg (99%) of the indicated compound as
a pale yellow solid: mp 172–174 ꢀC; 1H NMR (400 MHz, CDCl3)
oil: 1H NMR (400 MHz, CDCl3)
d 8.48 (s, CH]), 8.38–8.36 (m, 1H),
7.99–7.97 (m, 1H), 7.78–7.72 (m, 2H), 6.58–6.55 (m, 1H), 4.53–4.48
(m, 2H), 2.25–2.09 (m, 5H), 1.60–1.55 (m, 1H), 1.50–1.44 (m, 4H),
1.01–0.97 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 170.8,
d
8.50 (s, CH]), 8.20–8.18 (d, J¼8.4 Hz, 1H), 7.95–7.93 (d, J¼8.0 Hz,
165.6, 158.5, 140.8, 136.3, 130.5, 129.4, 128.9, 127.2, 124.7, 123.8, 74.1,
61.5, 36.1, 21.1, 19.2, 14.3, 13.8; IR (neat, cmꢁ1) 3069, 2962, 1739,
1708, 1447, 1371, 1243, 1023. Anal. Calcd for C18H21NO4: C, 70.58; H,
5.41; N, 3.58. Found: C, 70.50; H, 5.43; N, 3.57.
1H), 7.69–7.65 (t, J¼7.2 Hz, 1H), 7.61–7.57 (t, J¼7.6 Hz, 1H), 7.55 (s,
CH), 7.45–7.43 (m, 2H), 7.32–7.26 (m, 3H), 4.52–4.48 (q, J¼7.2 Hz,
2H), 2.26 (s, CH3COO), 1.48–1.45 (t, J¼6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3)
d 170.4, 165.6, 157.1, 140.6, 137.8, 136.5, 130.4,
129.3, 128.9, 128.5, 128.3, 127.9, 127.1, 125.2, 124.0, 76.8, 61.5, 21.1,
14.3; IR (neat, cmꢁ1) 3069, 2982, 1733, 1449, 1373, 1239, 1017. Anal.
Calcd for C21H19NO4: C, 72.19; H, 5.48; N, 4.01. Found: C, 71.43; H,
5.41; N, 3.99.
4.2.6. Ethyl-1-(1-acetoxyhexyl)isoquinoline-3-carboxylate 5f. The
reaction mixture was chromatographed using 20:1 hexanes/EtOAc
to afford 42.6 mg (62%) of the indicated compound as a pale yellow
oil: 1H NMR (400 MHz, CDCl3)
d 8.48 (s, CH]), 8.38–8.36 (d,
Compounds 5a–d: 1H NMR (400 MHz, CDCl3)
d
8.50 (s, CH]),
J¼7.6 Hz, 1H), 7.98–7.96 (d, J¼7.2 Hz, 1H), 7.75–7.73 (m, 2H),
6.57–6.54 (m, 1H), 4.53–4.46 (m, 2H), 2.23–2.10 (m, 5H), 1.56–1.52
(m, 1H), 1.48–1.44 (t, J¼7.2 Hz, 3H), 1.42–1.31 (m, 5H), 0.89–0.86 (t,
8.21–8.19 (d, J¼8.4 Hz, 1H), 7.95–7.93 (d, J¼8.4 Hz, 1H), 7.70–7.66 (t,
J¼8.0 Hz, 1H), 7.62–7.59 (t, J¼8.4 Hz, 1H), 7.58 (s, 0.05H, CH), 7.46–
7.43 (m, 2H), 7.33–7.26 (m, 3H), 4.52–4.48 (q, J¼7.2 Hz, 2H), 2.26 (s,
CH3COO), 1.49–1.45 (t, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 170.7, 165.6, 158.5, 140.7,
136.3, 130.4, 129.4, 128.9, 127.2, 124.6, 123.7, 74.3, 61.4, 33.9, 31.4,
25.5, 22.4, 21.0, 14.3, 13.9; IR (neat, cmꢁ1) 3069, 2931, 1739, 1448,
1371, 1242, 1023. Anal. Calcd for C20H25NO4: C, 69.95; H, 7.34; N,
4.08. Found: C, 69.76; H, 7.41; N, 4.10.
d
170.4, 165.7, 157.1, 140.6, 137.8, 136.5, 130.4, 129.3, 128.9, 128.5,
128.4, 127.9, 127.1, 125.2, 124.0, 77.0, 61.5, 21.3, 14.3.
4.2.2. Ethyl-1-(acetoxy(4-methoxyphenyl)methyl)
isoquinoline-3-
carboxylate 5b. The reaction mixture was chromatographed using
4.2.7. Ethyl-1-acetylisoquinoline-3-carboxylate 5g. The reaction
mixture was chromatographed using 20:1 hexanes/EtOAc to afford
39.4 mg (81%) of the indicated compound as a white solid: mp
20:1 hexanes/EtOAc to afford 41.7 mg (55%) of the indicated com-
pound as a pale yellow oil: 1H NMR (400 MHz, CDCl3)
d 8.50 (s,
CH]), 8.17–8.15 (d, J¼8.8 Hz, 1H), 7.95–7.93 (d, J¼8.0 Hz, 1H), 7.70–
7.66 (t, J¼7.2 Hz, 1H), 7.62–7.58 (t, J¼7.2 Hz, 1H), 7.49 (s, CH), 7.37–
7.35 (d, J¼8.4 Hz, 2H), 6.85–6.82 (d, J¼8.8 Hz, 2H) , 4.53–4.48 (m,
104–106 ꢀC; 1H NMR (400 MHz, CDCl3)
d 9.00–8.98 (m, 1H), 8.69 (s,
CH]), 8.03–8.00 (m, 1H), 7.82–7.80 (m, 2H), 4.55–4.53 (q, J¼7.2 Hz,
2H), 2.94 (s, CH3CO),1.52–1.48 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz,
2H), 3.75 (s, CH3O), 2.26 (s, CH3COO), 1.49–1.45 (t, J¼7.2 Hz, 3H); 13
C
CDCl3) d 202.2, 165.1, 152.8, 140.0, 136.9, 131.2, 131.0, 128.4, 127.2,
NMR (100 MHz, CDCl3)
d
170.6, 165.7, 159.6, 157.2, 140.6, 136.4,
127.1, 126.7, 61.8, 28.5, 14.3; IR (neat, cmꢁ1) 3068, 2991, 2922, 1712,
1447, 1362, 1215, 1022. Anal. Calcd for C14H13NO3: C, 69.12; H, 5.39;
N, 5.76. Found: C, 69.46; H, 5.33; N, 5.73.
130.4, 129.9, 129.6, 129.3, 128.9, 127.0, 125.2, 123.9, 113.9, 76.1, 61.5,
55.2, 21.2, 14.3; IR (neat, cmꢁ1) 3069, 2981, 1737, 1513, 1446, 1370,
1239, 1030. Anal. Calcd for C22H21NO5: C, 69.64; H, 5.58; N, 3.69.
Found: C, 69.45; H, 5.62; N, 3.71.
Compounds 5g–d: 1H NMR (400 MHz, CDCl3)
d 9.018.99 (m, 1H),
8.67 (s, CH]), 8.01–7.99 (m, 1H), 7.81–7.78 (m, 2H), 4.56–4.51 (q,
J¼7.2 Hz, 2H), 2.90 (s, 0.21H, CH3CO), 1.52–1.48 (t, J¼7.2 Hz, 3H); 13
C
4.2.3. Ethyl-1-(acetoxy(4-bromophenyl)methyl) isoquinoline-3-car-
boxylate 5c. The reaction mixture was chromatographed using
20:1 hexanes/EtOAc to afford 64.1 mg (75%) of the indicated com-
pound as a pale yellow solid: mp 45–47 ꢀC; 1H NMR (400 MHz,
NMR (100 MHz, CDCl3) d 202.3, 165.1, 152.8, 140.1, 137.0, 131.1, 131.0,
128.4, 127.2, 127.2, 126.8, 61.8, 22.6, 14.3.
Acknowledgements
CDCl3)
d
8.51 (s, CH]), 8.18–8.16 (d, J¼8.4 Hz, 1H), 7.98–7.96 (d,
J¼8.0 Hz, 1H), 7.74–7.70 (t, J¼7.2 Hz, 1H), 7.66–7.62 (t, J¼7.2 Hz, 1H),
We thank the NSF (NSF-20872052) and the ‘111 project’ for
financial support.
7.50 (s, CH), 7.45–7.43 (d, J¼8.4 Hz, 2H), 7.34–7.32 (d, J¼8.4 Hz, 2H),
4.52–4.49 (m, 2H), 2.24 (s, CH3COO), 1.49–1.45 (t, J¼7.2 Hz, 3H); 13
C
NMR (100 MHz, CDCl3)
d 170.3, 165.6, 156.7, 140.7, 136.9, 136.6,
Supplementary data
131.7, 130.6, 129.6, 129.0, 127.0, 125.0, 124.2, 122.6, 76.0, 61.6, 21.1,
14.4; IR (neat, cmꢁ1) 3066, 2925, 1738, 1370, 1237, 1015. Anal. Calcd
for C21H18BrNO4: C, 58.89; H, 4.24; N, 3.27. Found: C, 58.75; H, 4.26;
N, 3.28.
Experimental procedure, characterization details, copies of 1H
NMR and 13C NMR spectra of 1, 3, 4, 5, 5a–d, 5g–d, 6 are provided.
Supplementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2009.11.043.
4.2.4. Ethyl-1-(acetoxy(4-acetylphenyl)methyl) isoquinoline-3-car-
boxylate 5d. The reaction mixture was chromatographed using
20:1 hexanes/EtOAc to afford 51.6 mg (64%) of the indicated com-
pound as a pale yellow solid: mp 53–55 ꢀC; 1H NMR (400 MHz,
References and notes
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