Gold-catalyzed synthesis of isoquinolines via intramolecular cyclization of 2-alkynyl benzyl azides

Article abstract of DOI:10.1016/j.tetlet.2009.03.129

Intramolecular cyclization of 2-alkynyl benzyl azides in the presence of AuCl₃ and AgSbF₆ in THF under a pressured vial at 100 °C gives the corresponding isoquinolines in good yields. Similarly, the five-membered analogs afford the c

Full text of DOI:10.1016/j.tetlet.2009.03.129

Tetrahedron Letters 50 (2009) 3651–3653
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Gold-catalyzed synthesis of isoquinolines via intramolecular cyclization
of 2-alkynyl benzyl azides
*
Zhibao Huo, Yoshinori Yamamoto
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Intramolecular cyclization of 2-alkynyl benzyl azides in the presence of AuCl3 and AgSbF6 in THF under a
pressured vial at 100 °C gives the corresponding isoquinolines in good yields. Similarly, the five-mem-
bered analogs afford the corresponding isoquinolines.
Received 4 February 2009
Revised 9 March 2009
Accepted 16 March 2009
Available online 21 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Gold catalyst
Azide
Cyclization
Heterocycle
Isoquinoline
Isoquinolines are an important class of alkaloids and many bio-
logically active natural products contain the isoquinoline frame-
work.1 Their biological activities have made them useful in
pharmaceutical compounds, and their physical properties make
them beneficial as functional materials.2 Furthermore, they are uti-
lized as chiral ligands for transition metal catalysts.3 Accordingly, a
number of synthetic methods for isoquinolines have been devel-
oped. For example, (1) classic methods such as the Pomeranz–Frit-
sch,4 Bischler–Napieralski,5 and Pictet–Spengler6 reactions,
although all have considerable drawbacks such as the use of strong
acids and elevated temperatures, and (2) transition metal-cata-
lyzed synthesis of substituted isoquinolines from phenylacetylene
substrates (Eq. 1).7 These reactions have proven to be extremely
efficient in the synthesis of a wide variety of isoquinolines. How-
ever, the development of additional synthetic methods is still
highly desirable.
the gold-catalyzed intramolecular cyclization of 2-alkynyl benzyl
azides 1 using AuCl3 and AgSbF6 in THF at 100 °C gives isoquino-
lines 2 in good yields (Eq. 5).
5 % Pd(dba)2
10% PPh3
R
R1
R
R1-X
Nu-
+
ð1Þ
Na2CO3
DMF, 100 ºC
N
N
N
N
tBu
R
R
Cat. Pd, Ag
+
ð2Þ
ð3Þ
R1
R
R1
R
Nu
Nu
4 Å MS
+
R1NH2+ H-Nu
N
R1
CH2Cl2
CHO
Recently, we reported the synthesis of 1,2-dihydroisoquin-
olines via palladium- or AgOTf-catalyzed direct addition of nucleo-
philes to o-alkynylarylaldimines (Eq. 2).8 Asao et al. reported the
three-component coupling reaction with ortho-alkynylbenzalde-
hydes, primary amines, and pronu-cleophiles in the presence of
molecular sieves (Eq. 3).9 More recently, we reported an entirely
new method for the synthesis of 1,3,4-trisubstituted isoquinolines
through iodine-mediated electrophilic cyclization of 2-alkynyl
benzyl azides (Eq. 4).10 It occurred to us that cyclization of 1 may
take place using coinage metal catalysts. Herein, we report that
I
R1
5 equiv I2
X
R1
X
1 equiv base
ð4Þ
ð5Þ
N
N
N3
CH2Cl2, rt, 24 h
R2
R2
X = C, N
R1
R1
30% AuCl3
90% AgSbF6
N3
THF, 100 ºC
R2
R2
1
* Corresponding author. Tel.: +81 22 795 6581; fax: +81 22 795 6784.
E-mail address: yoshi@mail.tains.tohoku.ac.jp (Y. Yamamoto).
2
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.129

3652
Z. Huo, Y. Yamamoto / Tetrahedron Letters 50 (2009) 3651–3653
Table 1
Table 2
Effect of catalysts and solvents on formation of isoquinoline 2a from 1aa
Gold-catalyzed synthesis of isoquinolines 2a
Ph
R1
Ph
R1
Ph
+
Catalyst (10 mol%)
Solvent, T ºC
30 mol% AuCl3,
90 mol% AgSbF6,
N
N
N
N
N
N3
N3
THF, 100 ºC
R2
1a
2a
3a
R2
1
2
Entry
Catalyst
Time (h)
Solvent
Yieldb of (%)
Entry
R1
R2
Product 2
Yieldb of 2 mp (°C)
2a
3a
1a
1
2
3
4
5
6
7
Ph
1a
1b
1c
1d
1e
1f
H
H
H
H
OAc
Hex
Ph
2a
2b
2c
2d
2e
2f
67 (97–98)
80 (97–99)
77
1
2
3
4
5
6
7
8
AgSbF6
AgNTf2
AgOTf
In(OTf)3
Cu(OTf)2
TfOH
12
12
12
12
12
3
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
30
28
32
0
0
0
10
31
36
(43)
(48)
31
31
28
(52)
(67)
58
55
37
33
94
90
97
80
46
38
0
10
8
10
0
0
0
5
6
0
0
0
0
0
0
0
0
0
p-MeOC6H4
n-Butyl
1-Cyclohexenyl
Ph
Ph
Ph
59 (104–106)
36
60
51
1g
2g
PtBr2
7
AuCl/AgSbF6
AuCl3/AgSbF6
AuCl3/AgSbF6
AuCl3/AgSbF6
AuCl3/AgSbF6
AuCl3/AgSbF6
AuCl3/AgSbF6
AuCl3/AgSbF6
AuCl3/AgSbF6
AuCl3/AgSbF6
12
12
5
Ph
9
DCE
DCE
O
O
10
11
12
13
14
15
16c
17c,d
1h
N3
8
2h
48 (92–93)
5
CH3NO2
Toluene
1,4-Dioxane
CH3CN
THF
0
12
12
12
12
12
24
18
20
34
(18)
0
Me
a
The reaction of 1 (0.2 mmol) in the presence of 30 mol % AuCl3 and 90 mol %
AgSbF6 was carried out at 100 °C in THF under a pressured vial for 12 h.
THF
THF
10
b
Isolated yield.
a
The reaction of 1a in a pressured vial was carried out in the presence of the
catalyst at reflux (entries 1–10) and at 100 °C (entries 11–16).
1H NMR yield was determined using CH2Br2 as an internal standard. Isolated
b
The scope of the intramolecular cyclization of 2-alkynyl benzyl
azides 1 is summarized in Table 2.12 An arylacetylene bearing a
methoxy group on the aromatic ring afforded the corresponding
cyclized product 2b in 80% yield (entry 2). The reactions of sub-
strates having n-butyl and 1-cyclohexenyl groups at the alkyne ter-
minus, under the standard conditions, proceeded smoothly to give
the desired products 2c and 2d, respectively, in good yields (entries
3 and 4). For secondary azides, the yields of the isoquinolines 2e–g
were lower than those of the primary azides (entries 5–7). Azide
1h gave the corresponding isoquinoline 2h in 48% yield (entry 8).
With five-membered heterocyclic derivatives, the cyclization pro-
ceeded similarly, although the yields of the desired products were
lower than those of the corresponding six-membered derivatives;
the furan and pyrrole substrates 1i and 1j gave the products 2i
and 2j in 34% and 41% yields, respectively (Eqs. 6 and 7).
yield is shown in parentheses.
c
30 mol % AuCl3/90 mol % AgSbF6 was used.
Reaction temperature was 80 °C.
d
Initially, we tested the reaction of substrate 1a in order to opti-
mize the reaction conditions, and the results are summarized in
Table 1. Treatment of azide 1a with 10 mol % of silver catalysts in
1,2-dichloroethane (DCE) at reflux for 12 h gave a mixture of the
desired product 2a and triazole 3a (entries 1–3). Other Lewis acid
and protic acid catalysts, such as In(OTf)3, Cu(OTf)2, and TfOH, were
ineffective for the production of 2a, instead, only triazole 3a was
obtained in high yields (entries 4–6). Surprisingly, PtBr2,11 which
was reported as an effective catalyst for the synthesis of isoquino-
lines, gave only trace amounts of the product 2a along with triazole
3a in 80% NMR yield (entry 7). The use of AuCl/AgSbF6 and AuCl3/
AgSbF6, afforded 2a in moderate yields (entries 8 and 9). Increasing
the catalyst loading up to 20 mol % enhanced the yield of 2a (entry
10). Various solvents such as CH3NO2, toluene, 1,4-dioxane, CH3CN,
and THF, instead of 1,2-dichloroethane (DCE), were examined; we
found that THF gave the best result among the solvents tested and
the product 2a was obtained in 52% yield along with triazole 3a in
18% yield (entries 11–15). To our delight, increasing the amount of
catalyst gave the best result, the product was obtained in 67% yield
without formation of 3a (entry 16). Decreasing the reaction tem-
perature led to a lower yield of the product even after prolonged
reaction time (entry 17).
A plausible mechanism for the gold-catalyzed cyclization of 1 is
shown in Scheme 1. Initially, coordination of the triple bond of 1 to
the gold catalyst enhances the electrophilicity of the alkyne to gen-
R
R
N
AuL3
N3
2
1
H+
AuL3
L3Au
R
Ph
R
30 mol% AuCl3,
90 mol% AgSbF6,
Ph
N
N2
N
N
ð6Þ
ð7Þ
O
N3
THF, 100 ºC, 12 h
C
A
O
1i
2i
, 34% (Mp: 61-63 ºC)
AuL3
Ph
Ph
- N2
- H+
30 mol% AuCl3,
90 mol% AgSbF6,
R
N
N
N
N3
N
N2
THF, 100 ºC,12 h
Ts
Hex
Ts
B
H
Hex
1j
2j
, 41%
Scheme 1. A plausible mechanism for the formation of 2.

Z. Huo, Y. Yamamoto / Tetrahedron Letters 50 (2009) 3651–3653
3653
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nitrogen atom on the electron-deficient alkyne forms the interme-
diate B. Elimination of N2 and H+ forms C. Protonolysis of C then re-
sults in the formation of isoquinoline 2 and regenerates the gold
catalyst.
In conclusion, we have developed an efficient method for the
synthesis of isoquinolines from 2-alkynyl benzyl azides. The cycli-
zation proceeds very smoothly in the presence of AuCl3 and
AgSbF6. Further studies to extend the scope of this procedure are
in progress in our laboratory.
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References and notes
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12. General procedure for the synthesis of isoquinoline 2a from 2-alkynyl benzyl azide
1a: To a THF (2 mL, 0.1 M) solution of AuCl3 (18.2 mg, 0.06 mmol) and AgSbF6
(61.8 mg, 0.18 mmol) which were weighed in a glove box, was added 2-alkynyl
benzyl azide 1a (46.6 mg, 0.2 mmol) at room temperature under an Ar
atmosphere in a pressured vial. The mixture was stirred at 100 °C for 12 h. The
reaction progress was monitored by TLC (hexane/ethyl acetate; 2:1). After
consumption of 1a, the reaction mixture was cooled to room temperature and
filtered through
a short Florisil pad using ethyl acetate as eluent. After
concentration, the residue was purified by column chromatography (silica gel,
hexane/ethyl acetate; 20:1–5:1) to afford product 2a in 67% yield as a white
solid (27.5 mg). Mp: 97–98 °C; 1H NMR (300 MHz, CDCl3): d 9.35 (s, 1H), 8.13
(d, J = 7.5 Hz, 2H), 8.08 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H),
7.70 (t, J = 7.5 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 7.42 (t,
J = 7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3): 152.3, 151.1, 139.2, 136.4, 130.3,
128.6, 128.4, 127.6, 127.4, 126.8, 126.6, 126.5, 116.0; IR (KBr) 3346, 2859,
1626, 1455, 684 cmꢀ1; HRMS (EI) Calcd for C15H11NNa ([M+Na]+) 228.0784.
Found 228.0783.
Data for 3a. See: Chowdhury, C.; Mandal, S. B.; Achari, B. Tetrahedron Lett. 2005,
46, 8531.
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