Synthesis of 1-aminoisoquinolines via the coinage metal cocatalyzed reaction of 2-alkynylbenzaldoximes with isocyanoacetates

Article abstract of DOI:10.1055/s-0034-1378654

An efficient reaction of 2-alkynylbenzaldoximes with 2-isocyanoacetates cocatalyzed by silver triflate and gold(I) chloride is described, providing 1-aminoisoquinolines in good to excellent yields under mild conditions. Mechanistic experiments suggest tha

Full text of DOI:10.1055/s-0034-1378654

PAPER
▌3213
paper
Synthesis of 1-Aminoisoquinolines via the Coinage Metal Cocatalyzed Reaction
of 2-Alkynylbenzaldoximes with Isocyanoacetates
1-Aminoisoquinolines via Coinage Metal Cocatalysis
Tao Wang,* Rou Li, Danhong Yu, Chenghao Gu, Fei Xiong,* Zhiyuan Chen*
National Research Center for Carbohydrate Synthesis and Key Laboratory of Chemical Biology, Jiangxi Province, Jiangxi Normal University,
99 Ziyang Road, Nanchang, Jiangxi 330022, P. R. of China
Fax +86(791)88120385; E-mail: wangtao@jxnu.edu.cn; E-mail: xiongfei@jxnu.edu.cn; E-mail: zchen@jxnu.edu.cn
Received: 25.05.2014; Accepted after revision: 27.07.2014
this ‘prefunctionalization’ strategy is obviously hindered
Abstract: An efficient reaction of 2-alkynylbenzaldoximes with 2-
by the extra preparation efforts to obtain the precursors
isocyanoacetates cocatalyzed by silver triflate and gold(I) chloride
and the formation of stoichiometric byproducts. Transi-
is described, providing 1-aminoisoquinolines in good to excellent
yields under mild conditions. Mechanistic experiments suggest that
tion-metal-catalyzed C–N bond-formation reactions,
the gold(I) cation might play a crucial role in the activation of the which are represented by Buchwald–Hartwig8 or Ullmann-
type9 amination reactions, are highly versatile, but several
isocyanide substrate. The observed reactivity and the unique path-
way of substrate activation in the cocatalyzed processes are quite in-
formative for further study.
instances continue to pose challenges since the transfor-
mations need relatively expensive metal catalysts and li-
gands, or crucial inert conditions. Although much effort
has been invested in the synthesis of functionalized iso-
Key words: 1-aminoisoquinolines, coinage metals, deformylation,
2-alkynylbenzaldoximes, isocyanoacetates
quinoline derivatives, the preparation of specific 1-amino-
isoquinolines remains highly desirable in synthetic
organic chemistry. Thus, there is still an urgent need to de-
velop new strategies for the rapid generation of diversified
aminoisoquinoline derivatives under gentle conditions.
Isoquinoline nuclei are key components of pharmacoph-
ores, natural products, and versatile synthetic building
blocks.1 In particular, 1-aminoisoquinoline derivatives
have been found to act as efficacious inhibitors of mutant
B-Raf enzyme,2 PDE4,3 adenosine A3 receptor,4 and do-
pamine D2 and D3 receptors.5 In addition, they also ex-
hibit strong cytotoxic activity against different human
cancer cell lines.6 Consequently, continuous effort has
been given to the development of methods for the rapid
synthesis of these nitrogen-containing heterocycles in
both academic and industrial laboratories. Typical 1-ami-
noisoquinolines are usually prepared starting from ha-
loisoquinolines or metalated isoquinolines.7 However,
Transition-metal-catalyzed domino reactions have been
well recognized as an efficient synthetic tool because they
can provide straightforward access to structurally diverse
molecules in a one-pot reaction process.10,11 For example,
Wu and co-workers have described a novel silver triflate
catalyzed/phosphonium salt promoted reaction of 2-
alkynylbenzaldoximes with amines for the preparation of
1-aminoisoquinoline derivatives.12 The reaction relies on
silver triflate as an effective catalyst for the formation of
the isoquinoline framework, and phosphonium salt as an
[M]+
+
N
+
[M]+
R3
N
C
H2O
R3
R3
N
R3
C–
[M]
C
[M]+
B
2
N
O
[3+2]
N
R1
O–
+
N
NOH
R1
[Ag]
R2
R1
C
R2
R2
A
– H+
HO
1
HCO2H•base
R3
R3
OH
O
R3
[M]
NH
H
N
N
H+
– [M]+
base
R1
H
O
N
R1
N
N
R1
R2
R2
R2
3
E
D
Scheme 1 Research design
SYNTHESIS 2014, 46, 3213–3220
Advanced online publication: 27.08.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0034-1378654; Art ID: ss-2014-h0322-op
© Georg Thieme Verlag Stuttgart · New York

3214
T. Wang et al.
PAPER
efficient activator of the in situ formed isoquinoline N-ox-
ide intermediate A (Scheme 1).13 Lu and co-workers have
disclosed a silver triflate catalyzed tandem reaction of 2-
alkynylbenzaldoximes with isothiocyanates to produce 1-
aminoisoquinolines in moderate to good yields.14 Despite
these more advanced strategies, the generation of a stoi-
chiometric amount of phosphorus oxide byproducts and
the availability of the isothiocyanates as starting materials
remain problematic.
Recently, we have been involved in the library construc-
tion project of natural-product-like heterocyclic small
molecules for the study of chemical genetics.15 Enlight-
ened by the results noted above and the recent advance-
ment of isocyanide chemistry,16 we envisioned that a
more straightforward method for 1-aminoisoquinoline
formation would be feasible when isocyanide derivatives
were employed in the catalytic reaction of isoquinoline N-
oxide A (Scheme 1). We reasoned that a metal–carbene
intermediate B would be formed from the isocyanide 2
when activated by a suitable catalyst cation [M]+.17 Then,
a [3+2]-cycloaddition reaction of B with isoquinoline N-
oxide A would occur to form an active metal–carbenoid
intermediate C, which would be easily trapped by a trace
amount of water through the known O–H carbenoid inser-
tion reaction to give a key species like D.18 This interme-
diate can undergo proton–metal ion exchange
transformation followed by a base-promoted aromatiza-
tion reaction to give the final product 3, along with con-
comitant regeneration of the catalyst (Scheme 1).
Described herein is our new discovery for the assemblage
of 1-aminoisoquinolines via the silver- and gold-cocata-
lyzed tandem reaction of 2-alkynylbenzaldoximes 1 with
isocyanides 2, which should shed light on transition-
metal-catalyzed isocyanide activation chemistry, and of-
fers a useful addition to the rapidly expanding, expedient
synthetic routes to complex polycyclic skeletons.
Figure 1 X-ray crystallographic structure of compound 3aa19
Prompted by this interesting result, we determined to op-
timize the reaction conditions further. A dramatically en-
hanced yield of 54% was observed when a weak base,
triethylamine, was added instead of cesium carbonate (Ta-
ble 1, entry 4). Since the efficiency of multicatalytic pro-
cesses has been well recognized in cascade cyclization
reactions,20 we conceived that the combination of multiple
metal catalysts in one reaction could be powerful for the
reaction activation of distinct substrates. Other Lewis acid
catalysts [Fe(OTf)2, CuI, Bi(OTf)3, Pd(OAc)2] were
shown to be less efficient, and no reaction occurred when
boron trifluoride–diethyl ether complex was used (Table
1, entries 5–9). A promising result was obtained when
gold(I) catalyst was added to the reaction mixture; the
yield increased to 77% when gold(I) chloride was em-
ployed (Table 1, entries 10 and 11). However, considering
that the gold(I) cation is well known as a stronger π-acid
than silver(I) for the activation of alkyne, and also that
gold(I) chloride would be transferred to gold(I) triflate in
situ in the presence of silver triflate, we also tried using
gold(I) triflate as the sole catalyst in the whole process,
and found that 3aa was only isolated in 59% yield in this
reaction (Table 1, entry 12).13,21 Increasing the amount of
triethylamine to 3.0 equivalents did not facilitate the reac-
tion (Table 1, entry 13).
The initial investigations were carried out on the reaction
of 2-alkynylbenzaldoxime 1a with phenyl isocyanide or
an alkyl isocyanide (t-BuNC). Since it was known that sil-
ver triflate is an efficient catalyst for the formation of iso-
quinoline N-oxide A via 6-endo-dig cyclization of 2-
alkynylbenzaldoxime 1a, the preliminary reaction was
undertaken with 10 mol% of silver triflate as catalyst in
the presence of cesium carbonate in tetrahydrofuran at
70 °C. However, to our surprise, no desired product 3 was
obtained, as detected by TLC and crude NMR analysis;
the starting materials were fully consumed and the reac-
tion quickly turned black (Table 1, entries 1 and 2). Pleas-
ingly, the desired product 3aa was isolated in 5% yield
when ethyl isocyanoacetate (2a), which contains an elec-
tron-withdrawing ester group in the molecule, was em-
ployed as a test substrate (Table 1, entry 3). The structure
of compound 3aa was confirmed by X-ray diffraction
analysis (Figure 1).19 This result demonstrated that the de-
signed reaction was theoretically feasible, although the
detailed reaction mechanism with such a particular elec-
tron-deficient isonitrile 2a workable in this process re-
mains a puzzle at present.
Next, different bases were examined; however, only infe-
rior results were obtained when other organic or inorganic
bases were used (Table 1, entries 14–16). We further ex-
plored the reaction carried out in various solvents; tetrahy-
drofuran was demonstrated as the best choice (Table 1,
entries 17–20 vs entry 11).
The scope of this silver triflate and gold(I) chloride cocat-
alyzed reaction was then investigated under the optimized
conditions (10 mol% AgOTf, 5 mol% AuCl, 1.2 equiv
Et3N, THF, 70 °C); the results are summarized in Table 2.
In the meantime, methyl isocyanoacetate (2b) was also
examined in the reaction with 1a, and the corresponding
product 3ab was isolated in good yield without difficulty
Synthesis 2014, 46, 3213–3220
© Georg Thieme Verlag Stuttgart · New York

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1-Aminoisoquinolines via Coinage Metal Cocatalysis
3215
the desired products 3ga and 3gb were isolated in 56%
and 70% yield, respectively (Table 2, entries 13 and 14).
However, the reactions failed to proceed with substrates 1
bearing a tert-butyl group, a terminal hydrogen, or a
trimethylsilyl group attached at the R2 position (data not
shown in Table 2).
Table 1 Initial Studies on the Reaction of 2-Alkynylbenzaldoxime
1a with Isocyanides 2a
R3
AgOTf (10 mol%)
[M] (5 mol%)
base (1.2 equiv)
HN
NOH
R3NC
+
N
2
solvent, 70 °C, N2
Ph
Ph
1a
3
Table 2 Silver Triflate and Gold(I) Chloride Cocatalyzed Reaction
of 2-Alkynylbenzaldoximes 1 with 2-Isocyanoacetates 2
Entry R3
[M]
Base
Solvent
Yieldb
(%)
AgOTf (10 mol%)
R3
NH
AuCl (5 mol%)
Et3N (1.2 equiv)
NOH
R1
1
2
3
Ph
t-Bu
–
–
Cs2CO3 THF
Cs2CO3 THF
Cs2CO3 THF
messy
messy
5 (3aa)
N
R3NC
2
R1
+
THF, 70 °C
R2
R2
1
3
CH2CO2Et –
(2a)
Entry
R1, R2 (1)
R3 (2)
Yielda (%)
4
5
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
–
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
54 (3aa)
15 (3aa)
trace
1
2
H, Ph (1a)
CH2CO2Et (2a)
77 (3aa)
86 (3ab)
88 (3ba)
88 (3bb)
72 (3ca)
78 (3cb)
90 (3da)
88 (3db)
78 (3ea)
74 (3eb)
73 (3fa)
76 (3fb)
56 (3ga)
70 (3gb)
77 (3ha)
80 (3hb)
75 (3ia)
63 (3ib)
57 (3ja)
66 (3jb)
72 (3ka)
57 (3kb)
69 (3la)
88 (3lb)
74 (3ma)
86 (3mb)
Fe(OTf)2
CuI
1a
CH2CO2Me (2b)
6
3
H, 4-Tol (1b)
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
7
Bi(OTf)3
Pd(OAc)2
BF3·OEt2
trace
4
1b
8
37 (3aa)
n.r.
5
H, 4-MeOC6H4 (1c)
9
6
1c
10
11
12
13
AuCl(PPh3) Et3N
56 (3aa)
77 (3aa)
59c (3aa)
66 (3aa)
7
H, 3-FC6H4 (1d)
AuCl
Et3N
Et3N
8
1d
AuOTf c
AuCl
9
H, 4-FC6H4 (1e)
Et3N
(3.0 equiv)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
1e
H, 4-ClC6H4 (1f)
14
15
16
17
18
19
20
2a
2a
2a
2a
2a
2a
2a
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
K3PO4
DBU
THF
THF
54 (3aa)
messy
1f
H, cyclopropyl (1g)
DABCO THF
26 (3aa)
1g
Et3N
Et3N
Et3N
Et3N
1,4-dioxane 44 (3aa)
5-Me, Ph (1h)
toluene
MeCN
CCl4
20 (3aa)
25 (3aa)
41 (3aa)
1h
4-MeO, Ph (1i)
1i
a Unless otherwise indicated, all reactions were run under the follow-
ing conditions: 1a (0.20 mmol), isocyanide 2 (1.2 equiv), base (1.2
equiv), solvent (1 mL), 70 °C, under N2.
4,5-(MeO)2, Ph (1j)
b Isolated yield based on 1a.
1j
c Using AuOTf as the sole catalyst.
4-F, Ph (1k)
1k
(Table 2, entry 2). In most cases, the 2-alkynylbenzaldox-
imes 1 reacted with the 2-isocyanoacetates 2 smoothly to
give the corresponding products 3 in good to excellent
yields. For example, when R1 = H, reactions of 1 with the
R2 group attached to the triple bond with electron-donat-
ing or electron-withdrawing functionalities, such as meth-
yl, methoxy, chloro, or fluoro, all worked well to afford
the desired products 3b–f in yields ranging from 72–90%
(Table 2, entries 3–12). It was found that the intrinsically
strained cyclopropyl group of 1g could also be tolerated;
5-F, Ph (1l)
1l
5-Cl, Ph (1m)
1m
a Isolated yield based on 2-alkynylbenzaldoximes 1.
© Georg Thieme Verlag Stuttgart · New York
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3216
T. Wang et al.
PAPER
To further assess the feasibility of using 2-isocyanoace- played good functional group compatibility under mild
tates as an efficient agent to introduce amines onto the iso- conditions. Mechanistic experiments have suggested that
quinoline nucleus, we next attempted the process with the gold(I) cation might play a crucial role in the activa-
different R1 groups attached to the aromatic ring of 2- tion process of the isonitrile substrate into a metal–carben-
(phenylethynyl)benzaldoximes 1 (R2 = Ph). As can be oid reactive species. The observed reactivity and the
seen from Table 2, all reactions worked well to produce unique pathway of substrate activation in the cocatalyzed
the expected 1-aminoisoquinolines 3h–m in good yields processes are quite informative for further understanding.
(entries 15–26); the phenyl group attached to the triple Further studies, including mechanistic studies, to extend
bond did not affect the efficiency of the transformation, the scope of this chemistry are being carried out in our lab-
and R1 substitutions including electron-donating or elec- oratory.
tron-withdrawing groups afforded the desired outcomes.
To gain an insight into the reaction mechanism, we syn-
thesized the isoquinoline N-oxide compound A_1a from
readily available starting material 1a according to the lit-
erature procedure.13 Compound A_1a could be recrystal-
lized as a white floccular solid from a solvent mixture of
dichloromethane–petroleum ether (1:3, v/v). We then
subjected this compound as a starting material in the reac-
tion with ethyl isocyanoacetate (2a) (Scheme 2). Com-
pound 3aa could be isolated in 81% yield with gold(I)
chloride (5 mol%) catalysis and in the presence of tri-
ethylamine, whereas only a trace amount of product 3aa
was observed when no gold(I) chloride was added. These
results indicate that the gold(I) cation is an important ac-
tivator of the isocyanoacetate in the reaction, thus giving
some insight into the research design of isocyanide activa-
tion in the synthesis of N-containing heterocycles and the
related mechanistic studies. Interestingly, no desired 1-
aminoisoquinoline product was obtained in the reaction of
isoquinoline N-oxide A_1a with phenyl isocyanide, n-bu-
tyl isocyanide, or tert-butyl isocyanide, which suggests
the crucial importance of the ester group in the starting
isocyanide substrates.
Unless otherwise stated, all commercial reagents were used as re-
ceived. All solvents were dried and distilled according to standard
procedures. Flash column chromatography was performed using
silica gel (60-Å pore size, 32–63 μm, standard grade). Melting
points were determined on an x-4 digital display microscope appa-
ratus. IR spectra were recorded on a Nicolet 6700 spectrophotome-
ter. 1H and 13C NMR spectra were recorded in CDCl3 on a Bruker
DRX-400 instrument at 400 MHz and 100 MHz, respectively, with
TMS as an internal standard. 1H NMR signals are described as fol-
lows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet).
The number of protons (n) for a given resonance is indicated as n H.
Coupling constants are reported as J values in Hz. 13C NMR signals
are reported as δ (ppm) downfield from TMS and relative to the sig-
nal of CDCl3 (δ 77.00, triplet). EI-MS data were measured on a
Shimadzu GC/MS-QP2010Ultra (single quadrupole MS filter)
mass spectrometer. High-resolution mass spectrometry (HRMS)
spectra were obtained on a Bruker micrOTOF II instrument.
1-Aminoisoquinolines 3 via the Gold-Catalyzed 1,3-Dipolar Cy-
cloaddition Reaction; General Procedure
A THF solution (1.0 mL) containing a 2-alkynylbenzaldoxime 1
(0.20 mmol, 1.0 equiv) and AgOTf (0.02 mmol, 10 mol%) was
heated to 70 °C for about 3 h under N2; then, AuCl (0.01 mmol, 5
mol%) and Et3N (0.24 mmol, 1.2 equiv) were added to the solution,
followed by the addition of a 2-isocyanoacetate 2 (0.24 mmol, 1.2
equiv) in THF (0.5 mL) solution. The resulting mixture was stirred
at 70 °C for a further 18–26 h. After completion of the reaction, as
indicated by TLC, the reaction mixture was cooled to r.t., concen-
trated on a rotary evaporator, and purified by flash column chroma-
tography (EtOAc–n-hexane, 1:6 to 1:10) to give the desired product
3 as a white or light yellow solid.
NOH
Ph
1a
Ethyl (3-Phenylisoquinolin-1-ylamino)acetate (3aa)
Yield: 47 mg (77%); mp 123–125 °C.
AgOTf (10 mol%)
DCE, 70 °C, 3 h
98% isolated yield
IR (KBr): 3430, 2988, 1729, 1622, 1530, 1212, 1179, 766 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.32 (t, J = 7.2 Hz, 3 H), 4.27 (q,
J = 7.2 Hz, 2 H), 4.47 (d, J = 5.2 Hz, 2 H), 5.89 (br s, 1 H), 7.36 (t,
J = 7.2 Hz, 1 H), 7.41–7.48 (m, 4 H), 7.58 (t, J = 7.2 Hz, 1 H), 7.73
(d, J = 8.4 Hz, 1 H), 7.85 (d, J = 8.4 Hz, 1 H), 8.15 (d, J = 7.2 Hz, 2
H).
CO2Et
AuCl (5 mol%)
Et3N (1.2 equiv)
HN
O–
+
N
CO2Et
+
N
THF, 70 °C, 12 h
NC
Ph
Ph
13C NMR (100 MHz, CDCl3): δ = 14.2, 44.0, 61.2, 107.6, 117.5,
121.6, 125.8, 126.6, 127.6, 128.1, 128.4, 129.9, 138.0, 139.8, 148.4,
153.8, 171.8.
MS (EI): m/z (%) = 306 (34) [M+], 233 (100), 204 (45).
HRMS (ESI): m/z [M + H]+ calcd for C19H18N2O2: 307.1447;
A_1a
(white floccular solid)
recrystallized from CH2Cl2–PE
2a
3aa
with AuCl: 81%
without AuCl: trace
Scheme 2 Reaction of isoquinoline N-oxide A_1a with isocyanide
2a
found: 307.1478.
Methyl (3-Phenylisoquinolin-1-ylamino)acetate (3ab)
In conclusion, we have described an interesting silver
triflate and gold(I) chloride cocatalyzed reaction of 2-
alkynylbenzaldoximes with electron-deficient isocyano-
acetates, to give 1-aminoisoquinolines in good to excel-
lent yields. The reaction performed well when a weak
organic base such as triethylamine was used, and dis-
Yield: 50 mg (86%); mp 157–159 °C (Lit.14 158–159 °C).
1H NMR (400 MHz, CDCl3): δ = 3.83 (s, 3 H), 4.48 (d, J = 5.2 Hz,
2 H), 5.94 (br s, 1 H), 7.40 (t, J = 7.2 Hz, 2 H), 7.47 (d, J = 7.2 Hz,
3 H), 7.56 (t, J = 7.2 Hz, 1 H), 7.72 (d, J = 8.0 Hz, 1 H), 7.82 (d, J =
8.4 Hz, 1 H), 8.16 (d, J = 7.6 Hz, 2 H).
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1-Aminoisoquinolines via Coinage Metal Cocatalysis
3217
13C NMR (100 MHz, CDCl3): δ = 43.9, 52.2, 107.7, 117.4, 121.6,
125.9, 126.6, 127.6, 128.2, 128.5, 129.9, 137.9, 139.8, 148.4, 153.8,
172.3.
MS (EI): m/z (%) = 292 (37) [M+], 233 (100), 204 (43).
HRMS (ESI): m/z [M + Na]+ calcd for C18H16N2O2: 315.1109;
MS (EI): m/z (%) = 322 (32) [M+], 263 (100), 234 (43).
HRMS (ESI): m/z [M + Na]+ calcd for C19H18N2O3: 345.1215;
found: 345.1203.
Ethyl [3-(3-Fluorophenyl)isoquinolin-1-ylamino]acetate (3da)
Yield: 58 mg (90%); mp 158–160 °C.
IR (KBr): 3428, 2984, 1727, 1603, 1508, 1238, 1154, 768 cm–1.
found: 315.1121.
1H NMR (400 MHz, CDCl3): δ = 1.35 (t, J = 7.2 Hz, 3 H), 4.31 (q,
J = 7.2 Hz, 2 H), 4.43 (d, J = 4.4 Hz, 2 H), 6.10 (br s, 1 H), 7.06 (t,
J = 8 Hz, 1 H), 7.34–7.41 (m, 2 H), 7.43 (s, 1 H), 7.53 (t, J = 7.6 Hz,
1 H), 7.68 (d, J = 8 Hz, 1 H), 7.79 (t, J = 8.4 Hz, 1 H), 7.90 (t, J = 8
Hz, 2 H).
Ethyl (3-p-Tolylisoquinolin-1-ylamino)acetate (3ba)
Yield: 56 mg (88%); mp 158–160 °C.
IR (KBr): 3426, 2985, 1727, 1603, 1508, 1276, 1154, 768 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.34 (t, J = 7.2 Hz, 3 H), 2.43 (s,
3 H), 4.30 (q, J = 7.2 Hz, 2 H), 4.47 (d, J = 4.8 Hz, 2 H), 5.95 (br s,
1 H), 7.28 (d, J = 8 Hz, 2 H), 7.39 (t, J = 7.2 Hz, 1 H), 7.45 (s, 1 H),
7.55 (t, J = 7.2 Hz, 1 H), 7.71 (d, J = 8 Hz, 1 H), 7.82 (d, J = 8.4 Hz,
1 H), 8.07 (d, J = 7.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 14.3, 21.3, 44.0, 61.2, 107.1,
117.3, 121.6, 125.6, 126.3, 126.5, 127.5, 129.2, 129.8, 137.1, 138.0,
148.5, 153.8, 171.9.
13C NMR (100 MHz, CDCl32): δ = 14.2, 44.0, 61.3, 107.9, 113.6 (d,
2JCF = 22.8 Hz), 114.8 (d, JCF = 21.3 Hz), 117.7, 121.6, 121.8,
126.1, 127.6, 129.7 (d, 3JCF = 8.2 Hz), 129.9, 137.7, 142.3 (d, 3JCF
=
7.9 Hz), 146.9, 153.9, 163.4 (d, 1JCF = 242.5 Hz), 171.9.
MS (EI): m/z (%) = 324 (36) [M+], 251 (100), 222 (41).
HRMS (ESI): m/z [M + Na]+ calcd for C19H17FN2O2: 347.1172;
MS (EI): m/z (%) = 320 (38) [M+], 247 (100), 218 (47).
found: 347.1192.
HRMS (ESI): m/z [M + H]+ calcd for C20H20N2O2: 321.1603;
found: 321.1603.
Methyl [3-(3-Fluorophenyl)isoquinolin-1-ylamino]acetate
(3db)
Yield: 55 mg (88%); mp 187–189 °C.
IR (KBr): 3427, 2983, 1724, 1614, 1508, 1275, 1178, 766 cm–1.
Methyl (3-p-Tolylisoquinolin-1-ylamino)acetate (3bb)
Yield: 54 mg (88%); mp 140–142 °C.
1H NMR (400 MHz, CDCl3): δ = 3.84 (s, 3 H), 4.45 (d, J = 5.2 Hz,
2 H), 5.96 (br s, 1 H), 7.05 (t, J = 8.4 Hz, 1 H), 7.37–7.44 (m, 2 H),
7.45 (s, 1 H), 7.57 (t, J = 7.2 Hz, 1 H), 7.71 (d, J = 8 Hz, 1 H), 7.82
(d, J = 8 Hz, 1 H), 7.88 (d, J = 8.4 Hz, 2 H).
IR (KBr): 3427, 2984, 1727, 1614, 1524, 1277, 1105, 768 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.43 (s, 3 H), 3.83 (s, 3 H), 4.48
(d, J = 4.8 Hz, 2 H), 5.92 (br s, 1 H), 7.29 (d, J = 8.0 Hz, 2 H), 7.38
(t, J = 8.0 Hz, 1 H), 7.46 (s, 1 H), 7.55 (t, J = 7.2 Hz, 1 H), 7.71 (d,
J = 8.0 Hz, 1 H), 7.81 (d, J = 8.0 Hz, 1 H), 8.06 (d, J = 7.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.3, 43.9, 52.1, 107.2, 117.3,
121.6, 125.6, 126.5, 127.5, 129.0, 129.2, 129.8, 137.1, 138.0, 148.5,
153.7, 172.3.
13C NMR (100 MHz, CDCl3): δ = 43.8, 52.1, 108.0, 110.9 (d, 2JCF
=
2
22.7 Hz), 114.8 (d, JCF = 21.4 Hz), 117.7, 121.6, 121.8, 126.2,
3
3
127.6, 129.7 (d, JCF = 7.9 Hz), 130.0, 137.8, 142.3 (d, JCF = 7.8
Hz), 147.0, 153.8, 163.3 (d, 1JCF = 242.4 Hz), 172.2.
MS (EI): m/z (%) = 310 (29) [M+], 251 (100), 222 (37).
HRMS (ESI): m/z [M + Na]+ calcd for C18H15FN2O2: 333.1015;
MS (EI): m/z (%) = 306 (38) [M+], 247 (100), 218 (42).
HRMS (ESI): m/z [M + Na]+ calcd for C19H18N2O2: 329.1266;
found: 333.1033.
found: 329.1263.
Ethyl [3-(4-Fluorophenyl)isoquinolin-1-ylamino]acetate (3ea)
Ethyl [3-(4-Methoxyphenyl)isoquinolin-1-ylamino]acetate
Yield: 51 mg (78%); mp 174–176 °C.
(3ca)
Yield: 48 mg (72%); mp 150–152 °C.
IR (KBr): 3428, 2985, 1727, 1603, 1508, 1276, 1154, 768 cm–1.
IR (KBr): 3427, 2982, 1724, 1614, 1576, 1276, 1105, 755 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.33 (t, J = 7.2 Hz, 3 H), 4.29 (q,
J = 7.2 Hz, 2 H), 4.45 (d, J = 5.2 Hz, 2 H), 5.94 (br s, 1 H), 7.14 (t,
J = 8.4 Hz, 2 H), 7.41 (d, J = 10.8 Hz, 2 H), 7.56 (t, J = 7.2 Hz, 1
H), 7.70 (t, J = 8.4 Hz, 1 H), 7.82 (t, J = 8.4 Hz, 1 H), 8.12 (t, J =
8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 14.2, 44.0, 61.2, 107.2, 115.2 (d,
2JCF = 21 Hz), 117.3, 121.6, 125.8, 127.5, 128.2 (d, 3JCF = 8.2 Hz),
129.9, 135.9, 137.9, 147.5, 153.8, 163.1 (d, 1JCF = 245.5 Hz), 171.7.
1H NMR (400 MHz, CDCl3): δ = 1.34 (t, J = 7.2 Hz, 3 H), 3.88 (s,
3 H), 4.30 (q, J = 7.2 Hz, 2 H), 4.48 (d, J = 4.8 Hz, 2 H), 5.98 (br s,
1 H), 7.01 (d, J = 8.8 Hz, 2 H), 7.41 (t, J = 5.2 Hz, 2 H), 7.57 (t, J =
7.2 Hz, 1 H), 7.71 (d, J = 8.4 Hz, 1 H), 7.86 (d, J = 8.4 Hz, 1 H),
8.11 (d, J = 8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 14.3, 44.1, 55.4, 61.3, 106.6,
113.9, 114.1, 117.2, 121.8, 125.6, 127.4, 127.9, 132.5, 138.2, 153.8,
159.9, 171.9.
MS (EI): m/z (%) = 324 (33) [M+], 251 (100), 222 (38).
MS (EI): m/z (%) = 336 (30) [M+], 263 (100), 234 (48).
HRMS (ESI): m/z [M + Na]+ calcd for C19H17FN2O2: 347.1172;
found: 347.1179.
HRMS (ESI): m/z [M + Na]+ calcd for C20H20N2O3: 359.1372;
found: 359.1371.
Methyl [3-(4-Fluorophenyl)isoquinolin-1-ylamino]acetate (3eb)
Yield: 46 mg (74%); mp 179–181 °C.
Methyl [3-(4-Methoxyphenyl)isoquinolin-1-ylamino]acetate
(3cb)
IR (KBr): 3427, 2983, 1724, 1613, 1525, 1276, 1178, 755 cm–1.
Yield: 50 mg (78%); mp 133–135 °C.
1H NMR (400 MHz, CDCl3): δ = 3.82 (s, 3 H), 4.46 (d, J = 4.8 Hz,
2 H), 5.92 (br s, 1 H), 7.14 (t, J = 8.8 Hz, 2 H), 7.41 (d, J = 11.2 Hz,
2 H), 7.56 (t, J = 7.2 Hz, 1 H), 7.80 (d, J = 8 Hz, 1 H), 7.81 (t, J =
8.4 Hz, 1 H), 8.16 (t, J = 6.8 Hz, 2 H).
IR (KBr): 3428, 2984, 1726, 1603, 1509, 1276, 1154, 768 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.81 (s, 3 H), 3.87 (s, 3 H), 4.47
(d, J = 4.8 Hz, 2 H), 5.89 (br s, 1 H), 7.01 (d, J = 8.8 Hz, 2 H), 7.39
(d, J = 6.4 Hz, 2 H), 7.55 (t, J = 7.6 Hz, 1 H), 7.70 (d, J = 8.4 Hz, 1
H), 7.81 (d, J = 8.4 Hz, 1 H), 8.10 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 43.9, 52.2, 55.3, 106.5, 113.8,
117.1, 121.6, 125.5, 127.4, 127.8, 129.8, 132.5, 138.1, 148.2, 153.7,
159.9, 172.3.
13C NMR (100 MHz, CDCl3): δ = 43.8, 52.1, 107.3, 115.2 (d, 2JCF
=
21.2 Hz), 117.3, 121.6, 125.9, 127.5, 128.2 (d, 3JCF = 8 Hz), 130.0,
135.9, 137.9, 147.5, 153.8, 163.1 (d, 1JCF = 245.5 Hz), 172.2.
MS (EI): m/z (%) = 310 (33) [M+], 251 (100), 222 (41).
Synthesis 2014, 46, 3213–3220
© Georg Thieme Verlag Stuttgart · New York

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T. Wang et al.
PAPER
HRMS (ESI): m/z [M + H]+ calcd for C18H15FN2O2: 311.1196;
found: 311.1227.
13C NMR (100 MHz, CDCl3): δ = 14.3, 21.9, 44.1, 61.3, 107.6,
117.6, 121.0, 126.5, 127.4, 128.0, 128.5, 131.9, 135.8, 136.0, 140.0,
147.5, 153.5, 172.1.
MS (EI): m/z (%) = 320 (38) [M+], 247 (100), 218 (49).
HRMS (ESI): m/z [M + Na]+ calcd for C20H20N2O2: 343.1422;
Ethyl [3-(4-Chlorophenyl)isoquinolin-1-ylamino]acetate (3fa)
Yield: 50 mg (73%); mp 202–204 °C.
IR (KBr): 3428, 2962, 1729, 1622, 1529, 1260, 1128, 766 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.34 (t, J = 7.2 Hz, 3 H), 4.30 (q,
J = 7.2 Hz, 2 H), 4.45 (d, J = 5.2 Hz, 2 H), 5.98 (br s, 1 H), 7.42–
7.44 (d, J = 9.2 Hz, 4 H), 7.58 (t, J = 7.2 Hz, 1 H), 7.72 (t, J = 8 Hz,
1 H), 7.84 (d, J = 8.4 Hz, 1 H), 8.10 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 14.3, 44.1, 61.3, 107.6, 117.6,
121.7, 126.1, 127.6, 127.9, 128.6, 130.1, 134.1, 137.9, 138.3, 147.3,
153.9, 171.8.
found: 343.1396.
Methyl (7-Methyl-3-phenylisoquinolin-1-ylamino)acetate (3hb)
Yield: 49 mg (80%); mp 167–169 °C.
IR (KBr): 3427, 2984, 1724, 1603, 1508, 1276, 1154, 768 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.41 (s, 3 H), 3.85 (s, 3 H), 4.48
(d, J = 5.2 Hz, 2 H), 6.04 (br s, 1 H), 7.33–7.41 (m, 2 H), 7.44 (s, 1
H), 7.49 (t, J = 7.2 Hz, 2 H), 7.57 (d, J = 8.8 Hz, 2 H), 8.17 (d, J =
8.0 Hz, 2 H).
MS (EI): m/z (%) = 340 (28) [M+], 305 (14), 267 (100), 238 (39).
HRMS (ESI): m/z [M + Na]+ calcd for C19H17ClN2O2: 363.0876;
found: 363.0884.
13C NMR (100 MHz, CDCl3): δ = 21.8, 43.9, 52.2, 107.6, 117.5,
121.0, 126.4, 127.3, 128.0, 128.4, 131.8, 135.8, 135.9, 140.0, 147.4,
153.4, 172.7.
MS (EI): m/z (%) = 306 (31) [M+], 247 (100), 218 (46).
HRMS (ESI): m/z [M + H]+ calcd for C19H18N2O2: 307.1447;
Methyl [3-(4-Chlorophenyl)isoquinolin-1-ylamino]acetate (3fb)
Yield: 50 mg (76%); mp 173–175 °C.
IR (KBr): 3428, 2981, 1725, 1613, 1529, 1275, 1178, 755 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.83 (s, 3 H), 4.46 (d, J = 4.8 Hz,
2 H), 5.85 (br s, 1 H), 7.38 (t, J = 7.2 Hz, 1 H), 7.42–7.49 (m, 4 H),
7.63 (t, J = 8.8 Hz, 1 H), 7.80 (s, 1 H), 8.11 (t, J = 7.6 Hz, 2 H).
found: 307.1467.
Ethyl (6-Methoxy-3-phenylisoquinolin-1-ylamino)acetate (3ia)
Yield: 50 mg (75%); mp 161–163 °C.
13C NMR (100 MHz, CDCl3): δ = 43.8, 52.2, 107.1, 117.9, 121.2,
126.5, 128.4, 128.5, 129.0, 130.6, 131.2, 136.3, 139.4, 148.9, 152.9,
172.1.
MS (EI): m/z (%) = 326 (26) [M+], 291 (12), 267 (100), 238 (37).
HRMS (ESI): m/z [M + Na]+ calcd for C18H15ClN2O2: 349.0720;
IR (KBr): 3427, 2930, 1729, 1621, 1517, 1251, 1145, 766 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.35 (t, J = 7.2 Hz, 3 H), 3.90 (s,
3 H), 4.30 (q, J = 7.2 Hz, 2 H), 4.45 (d, J = 5.6 Hz, 2 H), 5.94 (br s,
1 H), 7.00 (d, J = 2.0 Hz, 2 H), 7.40 (d, J = 4.8 Hz, 2 H), 7.48 (t, J =
7.2 Hz, 2 H), 7.72 (d, J = 9.2 Hz, 1 H), 8.16 (d, J = 7.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 14.3, 44.1, 55.4, 61.3, 106.2,
107.5, 117.5, 123.5, 126.7, 127.4, 128.2, 128.5, 140.0, 149.0, 153.8,
153.8, 160.6, 172.1.
found: 349.0756.
Ethyl (3-Cyclopropylisoquinolin-1-ylamino)acetate (3ga)
Yield: 30 mg (56%); mp 112–114 °C.
IR (KBr): 3428, 2983, 1727, 1613, 1509, 1275, 1178, 767 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.86–0.90 (m, 2 H), 1.06–1.10 (m,
2 H), 1.34 (t, J = 7.2 Hz, 3 H), 2.00 (s, 1 H), 4.25–4.30 (m, 4 H),
5.78 (br s, 1 H), 6.90 (s, 1 H), 7.34 (t, J = 7.6 Hz, 1 H), 7.52 (t, J =
7.2 Hz, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 7.77 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 8.3, 14.3, 16.8, 43.9, 61.2, 108.0,
116.6, 121.6, 124.6, 126.3, 129.8, 137.8, 153.7, 154.0, 171.9.
MS (EI): m/z (%) = 336 (30) [M+], 263 (100), 234 (44).
HRMS (ESI): m/z [M + H]+ calcd for C20H20N2O3: 337.1552;
found: 337.1563.
Methyl (6-Methoxy-3-phenylisoquinolin-1-ylamino)acetate
(3ib)
Yield: 41 mg (63%); mp 138–140 °C.
IR (KBr): 3427, 2984, 1726, 1603, 1508, 1277, 1154, 768 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.82 (s, 3 H), 3.90 (s, 3 H), 4.45
(d, J = 5.2 Hz, 2 H), 5.83 (br s, 1 H), 7.00 (d, J = 8.4 Hz, 2 H), 7.35–
7.40 (m, 2 H), 7.46 (t, J = 7.6 Hz, 2 H), 7.71 (d, J = 8.4 Hz, 1 H),
8.13 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 43.8, 52.1, 55.3, 106.1, 107.5,
112.4, 117.5, 123.4, 126.7, 128.1, 128.4, 139.9, 139.9, 149.1, 153.7,
160.6, 172.4.
MS (EI): m/z (%) = 270 (46) [M+], 197 (100), 168 (43).
HRMS (ESI): m/z [M + H]+ calcd for C16H18N2O2: 271.1447;
found: 271.1466.
Methyl (3-Cyclopropylisoquinolin-1-ylamino)acetate (3gb)
Yield: 36 mg (70%); mp 185–187 °C (Lit.14 187–188 °C).
1H NMR (400 MHz, CDCl3): δ = 0.83–0.88 (m, 2 H), 1.03–1.06 (m,
2 H), 1.97 (s, 1 H), 3.79 (s, 3 H), 4.27 (d, J = 5.4 Hz, 2 H), 5.74 (br
s, 1 H), 6.89 (s, 1 H), 7.32 (t, J = 7.6 Hz, 1 H), 7.50 (t, J = 7.2 Hz, 1
H), 7.56 (d, J = 8.0 Hz, 1 H), 7.73 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 8.2, 16.8, 43.7, 52.1, 108.1,
116.5, 121.5, 124.6, 126.2, 129.7, 137.8, 153.7, 153.9, 172.3.
MS (EI): m/z (%) = 256 (45) [M+], 197 (100), 168 (41).
HRMS (ESI): m/z [M + Na]+ calcd for C15H16N2O2: 279.1109;
MS (EI): m/z (%) = 322 (29) [M+], 263 (100), 234 (43).
HRMS (ESI): m/z [M + Na]+ calcd for C19H18N2O3: 345.1215;
found: 345.1231.
Ethyl (6,7-Dimethoxy-3-phenylisoquinolin-1-ylamino)acetate
(3ja)
Yield: 41 mg (57%); mp 135–137 °C.
IR (KBr): 3424, 2982, 1725, 1612, 1508, 1276, 1154, 755 cm–1.
found: 279.1096.
1H NMR (400 MHz, CDCl3): δ = 1.38 (t, J = 6.8 Hz, 3 H), 3.47 (s,
3 H), 3.95 (s, 3 H), 4.30 (q, J = 7.2 Hz, 2 H), 4.38 (d, J = 5.2 Hz, 2
H), 6.71 (br s, 1 H), 6.83 (d, J = 5.2 Hz, 2 H), 7.35 (d, J = 8.8 Hz, 2
H), 7.43–7.47 (t, J = 7.8 Hz, 2 H), 8.15 (d, J = 7.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 14.4, 44.4, 55.5, 55.8, 61.3,
101.1, 105.8, 107.1, 112.3, 126.3, 127.7, 128.4, 133.7, 140.1, 146.5,
148.7, 151.7, 152.9, 174.0.
Ethyl (7-Methyl-3-phenylisoquinolin-1-ylamino)acetate (3ha)
Yield: 49 mg (77%); mp 144–146 °C.
IR (KBr): 3426, 2984, 1725, 1603, 1508, 1276, 1154, 769 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.36 (t, J = 7.2 Hz, 3 H), 2.46 (s,
3 H), 4.32 (q, J = 7.2 Hz, 2 H), 4.48 (d, J = 4.8 Hz, 2 H), 6.01 (br s,
1 H), 7.39 (t, J = 8.0 Hz, 2 H), 7.46–7.50 (t, J = 8.0 Hz, 3 H), 7.61
(d, J = 7.6 Hz, 2 H), 8.17 (d, J = 7.6 Hz, 2 H).
MS (EI): m/z (%) = 366 (28) [M+], 293 (100), 264 (42).
Synthesis 2014, 46, 3213–3220
© Georg Thieme Verlag Stuttgart · New York

PAPER
1-Aminoisoquinolines via Coinage Metal Cocatalysis
3219
HRMS (ESI): m/z [M + Na]+ calcd for C21H22N2O4: 389.1477;
found: 389.1485.
Methyl (7-Fluoro-3-phenylisoquinolin-1-ylamino)acetate (3lb)
Yield: 55 mg (88%); mp 164–166 °C.
IR (KBr): 3426, 2985, 1725, 1605, 1508, 1274, 1154, 768 cm–1.
Methyl (6,7-Dimethoxy-3-phenylisoquinolin-1-ylamino)acetate
(3jb)
1H NMR (400 MHz, CDCl3): δ = 3.83 (s, 3 H), 4.45 (d, J = 5.2 Hz,
2 H), 5.79 (br s, 1 H), 7.30–7.39 (m, 2 H), 7.41–7.50 (m, 4 H), 7.68–
7.71 (t, J = 7.2 Hz, 1 H), 8.11 (d, J = 7.8 Hz, 2 H).
Yield: 46 mg (66%); mp 177–179 °C (Lit.14 176–177 °C).
1H NMR (400 MHz, CDCl3): δ = 3.53 (s, 3 H), 3.85 (s, 3 H), 3.96
(s, 3 H), 4.40 (q, J = 5.2 Hz, 2 H), 6.54 (br s, 1 H), 6.85 (d, J = 6.0
Hz, 2 H), 7.36 (d, J = 5.6 Hz, 2 H), 7.46 (t, J = 7.2 Hz, 2 H), 8.13 (d,
J = 7.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 44.2, 52.2, 55.6, 55.8, 101.1,
105.9, 107.2, 112.2, 126.2, 127.8, 128.4, 133.8, 140.0, 146.6, 148.8,
151.9, 152.8, 174.1.
13C NMR (100 MHz, CDCl3): δ = 43.8, 52.1, 106.1 (d, 2JCF = 21.4
Hz), 107.2, 117.8 (d, 3JCF = 6.5 Hz), 119.8 (d, 2JCF = 24.2 Hz), 126.4,
3
128.2, 128.4, 129.9 (d, JCF = 8 Hz), 134.8, 139.5, 148.0, 153.3,
160.4 (d, 1JCF = 245.3 Hz), 172.1.
MS (EI): m/z (%) = 310 (28) [M+], 251 (100), 222 (41).
HRMS (ESI): m/z [M + Na]+ calcd for C18H15FN2O2: 333.1015;
MS (EI): m/z (%) = 352 (31) [M+], 293 (100), 264 (45).
found: 333.1035.
HRMS (ESI): m/z [M + Na]+ calcd for C20H20N2O4: 375.1321;
found: 375.1334.
Ethyl (7-Chloro-3-phenylisoquinolin-1-ylamino)acetate (3ma)
Yield: 50 mg (74%); mp 164–166 °C.
Ethyl (6-Fluoro-3-phenylisoquinolin-1-ylamino)acetate (3ka)
IR (KBr): 3427, 2983, 1722, 1613, 1525, 1274, 1177, 754 cm–1.
Yield: 47 mg (72%); mp 176–178 °C.
1H NMR (400 MHz, CDCl3): δ = 1.35 (t, J = 7.2 Hz, 3 H), 4.31 (q,
J = 7.2 Hz, 2 H), 4.46 (d, J = 4.8 Hz, 2 H), 5.91 (br s, 1 H), 7.39 (t,
J = 7.2 Hz, 1 H), 7.44–7.51 (m, 4 H), 7.65 (d, J = 8.8 Hz, 1 H), 7.83
(s, 1 H), 8.14 (d, J = 7.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 14.3, 44.1, 61.4, 107.1, 118.0,
121.3, 126.6, 128.4, 128.5, 129.1, 130.7, 131.2, 136.3, 139.5, 149.0,
153.0, 171.8.
IR (KBr): 3427, 2981, 1721, 1613, 1526, 1276, 1178, 768 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.37 (t, J = 7.2 Hz, 3 H), 4.32 (q,
J = 7.2 Hz, 2 H), 4.44 (d, J = 5.2 Hz, 2 H), 6.23 (br s, 1 H), 7.00 (dt,
J = 8.8, 2.4 Hz, 1 H), 7.24 (m, 1 H), 7.40 (t, J = 7.2 Hz, 2 H), 7.49
(t, J = 7.2 Hz, 2 H), 7.76 (dd, J = 5.2, 8.8 Hz, 1 H), 8.15 (d, J = 7.8
Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 14.3, 44.0, 61.4, 107.2 (d, 4JCF
=
MS (EI): m/z (%) = 340 (26) [M+], 305 (15), 267 (100), 238 (42).
HRMS (ESI): m/z [M + Na]+ calcd for C19H17ClN2O2: 363.0876;
2
3.9 Hz), 110.9 (d, JCF = 20.4 Hz), 114.4, 115.2, 115.4, 124.5 (d,
3
3JCF = 9.6 Hz), 126.7, 128.5, 139.5, 139.8 (d, JCF = 9 Hz), 149.6,
found: 363.0896.
153.8, 163.2 (d, 1JCF = 248.5 Hz), 172.2.
MS (EI): m/z (%) = 324 (26) [M+], 251 (100), 222 (40).
HRMS (ESI): m/z [M + Na]+ calcd for C19H17FN2O2: 347.1172;
Methyl (7-Chloro-3-phenylisoquinolin-1-ylamino)acetate
(3mb)
Yield: 56 mg (86%); mp 178–180 °C.
found: 347.1177.
IR (KBr): 3428, 2919, 1728, 1618, 1516, 1252, 1103, 768 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.82 (s, 3 H), 4.46 (d, J = 5.2 Hz,
2 H), 5.94 (br s, 1 H), 7.42 (d, J = 6.8 Hz, 4 H), 7.57 (t, J = 7.6 Hz,
1 H), 7.70 (d, J = 8.0 Hz, 1 H), 7.81 (d, J = 8.8 Hz, 1 H), 8.06 (d, J =
8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 43.8, 52.2, 107.6, 117.5, 121.6,
126.1, 127.6, 127.8, 128.6, 130.0, 134.0, 137.8, 138.3, 147.2, 153.8,
172.2.
Methyl (6-Fluoro-3-phenylisoquinolin-1-ylamino)acetate (3kb)
Yield: 35 mg (57%); mp 172–174 °C (Lit.14 178–179 °C).
1H NMR (400 MHz, CDCl3): δ = 3.84 (s, 3 H), 4.45 (d, J = 5.2 Hz,
2 H), 6.10 (br s, 1 H), 7.02 (t, J = 8.8 Hz, 1 H), 7.26 (d, J = 9.2 Hz,
1 H), 7.39 (t, J = 7.2 Hz, 2 H), 7.47 (d, J = 7.2 Hz, 2 H), 7.75 (dd,
J = 5.6, 8.4 Hz, 1 H), 8.12 (t, J = 8 Hz, 2 H).
4
13C NMR (100 MHz, CDCl3): δ = 43.8, 52.2, 107.2 (d, JCF = 3.9
2
2
Hz), 108.2, 110.9 (d, JCF = 20.5 Hz), 114.3, 115.3 (d, JCF = 24.6
MS (EI): m/z (%) = 326 (24) [M+], 291 (12), 267 (100), 238 (40).
HRMS (ESI): m/z [M + Na]+ calcd for C18H15ClN2O2: 349.0720;
Hz), 124.4 (d, 3JCF = 9.5 Hz), 126.6, 128.5, 139.5, 139.7 (d, 3JCF
10 Hz), 149.6, 153.7, 163.2 (d, 1JCF = 248.3 Hz), 172.5.
=
found: 349.0741.
MS (EI): m/z (%) = 310 (25) [M+], 251 (100), 222 (38).
HRMS (ESI): m/z [M + Na]+ calcd for C18H15FN2O2: 333.1015;
found: 333.1037.
Acknowledgment
We thank Prof. Jie Wu at Fudan University for valuable discussions
during the course of this research. Financial support from the Natio-
nal Natural Science Foundation of China (Nos. 21262018,
20862007, 21202065) and the Natural Science Foundation of
Jiangxi Province (2010GZH0070) is gratefully acknowledged.
Ethyl (7-Fluoro-3-phenylisoquinolin-1-ylamino)acetate (3la)
Yield: 45 mg (69%); mp 180–182 °C.
IR (KBr): 3428, 2984, 1725, 1604, 1508, 1276, 1107, 767 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.35 (t, J = 7.2 Hz, 3 H), 4.11 (q,
J = 7.2 Hz, 2 H), 4.50 (d, J = 5.2 Hz, 2 H), 5.84 (br s, 1 H), 7.32–
7.40 (m, 2 H), 7.46–7.50 (m, 4 H), 7.70–7.73 (m, 1 H), 8.13 (s, 1 H),
8.15 (d, J = 1.6 Hz, 1 H).
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
13C NMR (100 MHz, CDCl3): δ = 14.2, 44.0, 61.3, 106.2 (d, 2JCF
=
2
10.1055/s-00000084.SunogIpimrfiantoSuIpg
n
fonirtat
ori
21.6 Hz), 107.2, 117.9, 119.8 (d, JCF = 24.2 Hz), 126.5, 128.2,
128.4, 129.8 (d, 3JCF = 8 Hz), 134.8, 139.5, 148.0, 153.4 (d, 4JCF
=
4.3 Hz), 160.4 (d, 1JCF = 245.8 Hz), 171.8.
Primary Data for this article are available online at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084 and can be cited using the following DOI:
MS (EI): m/z (%) = 324 (30) [M+], 251 (100), 222 (43).
HRMS (ESI): m/z [M + Na]+ calcd for C19H17FN2O2: 347.1172;
10.4125/pd0059th.mPirDayrmaPitrDyra104at.1p2d50/m0P59hri.tayrDaZtaheln101
C
hemyrt
found: 347.1208.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3213–3220

3220
T. Wang et al.
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Synthesis 2014, 46, 3213–3220
© Georg Thieme Verlag Stuttgart · New York