Synthesis of isoquinoline derivatives via Ag-catalyzed cyclization of 2-alkynyl benzyl azides

Full text of DOI:10.1021/jo900010m

efficient synthesis of isoquinoline ring system continues to attract
the interest of synthetic chemists.5 The traditional approaches
for the synthesis of the isoquinoline ring system, including
the Bischler-Napieralski,6 the Pictet-Spengler,7 and the
Pomeranz-Fritsch8 reactions, have been frequently employed
in the total synthesis of isoquinoline alkaloids. However, all
the reactions usually required either harsh conditions or tedious
reaction procedures. Over the last two decades, there has been
growing interest to develop mild and efficient syntheses of
isoquinoline. For instance, Pfeffer,9 Heck,10 and Widdowson11
have reported palladium methodology to synthesize substituted
isoquinolines. These syntheses utilize a stoichiometric amount
of palladium salts, which is not very practical in organic
synthesis. Later, Larock and co-workers developed a palladium
catalytic revision, using the tert-butylamine, 2-iodobenzalde-
hydes, and alkynes (or allenes) as starting materials, to
synthesize a wide variety of 3,4-disubstituted isoquinolines.12
In addition, the transition metal chemistry focusing on iso-
quinoline synthesis has been expanded by exploring other
elements, such as Ni,13 Zr,14 Rh,15 and Cu.16 Due to the
importance of isoquinoline derivatives in organic chemistry, the
development of new synthetic approaches with various reaction
conditions remains an active research area.
Synthesis of Isoquinoline Derivatives via Ag-
Catalyzed Cyclization of 2-Alkynyl Benzyl Azides
Yan-Ning Niu,† Ze-Yi Yan,‡ Guo-Lin Gao,†
Hong-Li Wang,† Xing-Zhong Shu,† Ke-Gong Ji,† and
Yong-Min Liang*,†
State Key Laboratory of Applied Organic Chemistry, Lanzhou
UniVersity, Lanzhou 730000, People’s Republic of China, and
Laboratory of Radiochemistry, School of Nuclear Science and
Technology, Lanzhou UniVersity, Lanzhou 730000, People’s
Republic of China
liangym@lzu.edu.cn
ReceiVed January 10, 2009
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Ag-catalyzed cyclization of 2-alkynyl benzyl azides offers
a novel and efficient method for the synthesis of substituted
isoquinoline. The reaction proceeds smoothly in moderate
to good yields and tolerates considerable functional groups.
The reaction conditions and the scope of the process are
examined, and a plausible mechanism is proposed.
(6) (a) Ishikawa, T.; Shimooka, K.; Narioka, T.; Noguchi, S.; Saito, T.;
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The isoquinoline derivatives play an important role in organic
chemistry, not only as key structural units in many natural
products,1 but also as building blocks in important pharmaceu-
ticals.2 Isoquinoline species are also utilized as chiral ligands
for transition metal catalysts,3 and their iridium complexes are
used in organic light-emitting diodes.4 For these reasons, the
† State Key Laboratory of Applied Organic Chemistry.
‡ Laboratory of Radiochemistry.
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10.1021/jo900010m CCC: $40.75
Published on Web 03/09/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2893–2896 2893

TABLE 1. Optimization of the Reaction Conditionsa
On the other hand, silver(I) complexes are generally used as
stoichiometric oxidants for the oxidation of various organic or
inorganic substrates. Many reports used silver(I) complexes as
catalysts in oxidation or group-transfer reactions.17,18d Although
recent studies have shown that silver species exhibited interest-
ing catalytic activities functioning as a transition metal catalyst,18,19
silver “catalysts” in a “transition metal” sense are commonly
considered to have low efficiency and not to be as good as other
late transition metals. Recently, Yamamoto’s group reported the
iodine-mediated electrophilic cyclization of 2-alkynyl benzyl
azides into the corresponding 1,3,4-trisubstituted isoquinolines.20
In our ongoing efforts to develop novel and efficient methodolo-
gies for the synthesis of heterocyclic compounds promoted by
transition metal catalysts,21 we herein wish to report that Ag-
catalyzed cyclization of 2-alkynyl benzyl azides can produce
the 3-substituted or 1,3-disubstituted isoquinolines.
Initially, we tested the reaction of substrate 1-(azidomethyl)-
2-(phenylethynyl)benzene 1a with 20 mol % of AgSbF6 in 1,2-
dichloroethane (DCE) at 80 °C, and the desired product 2a was
formed in 34% yield after 24 h (Table 1, entry 1). To our delight,
when the reaction was run in the presence of 1 equiv of
CF3COOH (TFA), the more satisfactory result was observed,
and the product was isolated in 55% yield (Table 1, entry 2).
By increasing the amount of TFA to 2 equiv, a significant
change occurred and the yield was 65% (Table 1, entry 3).
Common protic acids such as acetic acid, TsOH, and chloro-
acetic acid have also been examined under the same condition,
and no better results were obtained (Table 1, entries 4-6).
Changing the catalyst to AgOTf, AgBF4, CF3COOAg, and
CH3COOAg, failed to improve the yield of the product 2a (Table
1, entries 7-10). Other transition metals were also investigated
for this cyclization. However, for the reactions of 1a with PtCl2,
PtCl4, Cu(OTf)2, CuOTf, AuCl3, and PdCl2, no desired product
2a was observed (Table 1, entries 11-16). The solvent effect
on the cyclization reaction was then evaluated. This process
revealed that solvents played a significant role in the formation
of isoquinoline. In all solvents we examined, 1,2-dichloroethane
is superior. The reactions can proceed in weak polar solvents
such as toluene and benzene, although only 18% and 15% yields
were observed, respectively (Table 1, entries 17 and 18).
Disappointingly, none of product 2a was obtained in acetonitrile,
entry
catalyst
AgSbF6
additive
temp (°C) solvent yield 2a (3a)
1
2
3
4
5
6
7
8
9
none
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
toluene
benzene
THF
34 (0)
55 (0)
65 (0)
36 (0)
39 (0)
45 (0)
55 (0)
49 (0)
40 (0)
5 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
18 (0)
15 (0)
0 (0)
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgOTf
AgBF4
TFAb
TFA
CH3COOH
TsOH
ClCH2COOH
TFA
TFA
CF3COOAg TFA
10 CH3COOAg TFA
11 PtCl2
12 PtCl4
none
none
none
none
none
none
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
13 Cu(OTf)2
14 CuOTf
15 AuCl3
16 PdCl2
17 AgSbF6
18 AgSbF6
19 AgSbF6
20 AgSbF6
21 AgSbF6
22 AgSbF6
23 AgSbF6
80
80
reflux
reflux
reflux
60
CH3CN
MeOH
DCE
DCE
DCE
DCE
0 (0)
0 (0)
42c (0)
50 (25)
51 (0)
0 (0)
90
80
80
d
24 AgSbF6
25 none
a Reaction conditions: unless indicated otherwise, all reactions were
run by employing 0.25 mmol of 1a in the presence of 20 mol % of
catalysts and 2 equiv of additives in 3 mL of solvent at the indicated
temperature for 24 h. b The reaction employed 1 equiv of TFA. c The
reaction was run for 50 h. d The reaction was run by employing 10 mol
% of AgSbF6.
THF, or MeOH (Table 1, entries 19-21). Presumably, those
solvents coordinated with silver catalyst to generate complexes,
which decreased the catalytic activity of silver salt. The
temperature also is a key factor in this catalytic reaction. The
studies showed that the preferred temperature for the reaction
was 80 °C. When the reaction was conducted in 1, 2-dichlo-
roethane at 60 °C, only 42% product was obtained, even though
the reaction was prolonged to 50 h (Table 1, entry 22). By
increasing the temperature to 90 °C, a lower yield of 50% was
observed along with the Huisgen 1,3-dipolar cycloaddition
product 3a in 25% yield (Table 1, entry 23).22 A reduced yield
was also observed when the loading of AgSbF6 was lowered
(Table 1, entry 24). From these results, the role of TFA in the
reaction was doubted. Thus, the reaction without adding catalyst
in the presence of TFA was examined. However, no desired
isoquinoline was obtained (Table 1, entry 25). Thus, we chose
the following reaction conditions as optimum for all subsequent
cyclizations: 0.25 mmol of 2-alkynyl benzyl azides, 20 mol %
of AgSbF6, and 0.50 mmol of TFA in DCE were stirred at 80
°C for an appropriate amount of time.
(18) For selected recent examples of Ag-catalyzed reviews, see: (a) Yama-
moto, Y. Chem. ReV. 2008, 108, 3199–3222. (b) Weibel, J.-M.; Blanc, A.; Pale,
´
P. Chem. ReV. 2008, 108, 3149–3173. (c) Alvarez-Corral, M.; Mun˜oz-Dorado,
M.; Rodr´ıguez-Garc`ıa, I. Chem. ReV. 2008, 108, 3174–3198. (d) Li, Z.; He, C.
Eur. J. Org. Chem. 2006, 4313–4322.
(19) For selected examples of Ag-catalyzed reactions, see: (a) Umeda, R.;
Studer, A. Org. Lett. 2008, 10, 993–996. (b) Mandai, H.; Mandai., K.; Snapper,
M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130, 17961–17969. (c) Yong,
S. W.; Eom, J. I. J. Org. Chem. 2006, 71, 6705–6707. (d) Cho, G. Y.; Bolm, C.
Org. Lett. 2005, 7, 4983–4985. (e) Yang, C.-G.; Reich, N. W.; Shi, Z.; He, C.
Org. Lett. 2005, 7, 4553–4556. (f) Yao, X.; Li, C.-J. Org. Lett. 2005, 7, 4395–
4398. (g) Patil, N. T.; Pahadi, N. K.; Yamamoto, Y. J. Org. Chem. 2005, 70,
10096–10098. (h) Yao, X.; Li, C.-J. J. Org. Chem. 2005, 70, 5752–5755. (i)
Harrison, T. J.; Dake, G. R. Org. Lett. 2004, 6, 5023–5026. (j) Sweis, R. F.;
Schramm, M. P.; Kozmin, S. A. J. Am. Chem. Soc. 2004, 126, 7442–7443. (k)
Wei, C.; Li, Z.; Li, C.-J. Org. Lett. 2003, 5, 4473–4475.
(20) (a) Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Huo, Z.;
Yamamoto, Y. J. Am. Chem. Soc. 2008, 130, 15720–15725. (b) Fischer, D.;
Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Yamamoto, Y. Angew. Chem., Int. Ed.
2007, 46, 4764–4766.
(21) (a) Shu, X.-Z.; Liu, X.-Y.; Ji, K.-G.; Xiao, H.-Q.; Liang, Y.-M. Chem.
Eur. J. 2008, 14, 5282–5289. (b) Ji, K.-G.; Shen, Y.-W.; Shu, X.-Z.; Xiao, H.-
Q.; Bian, Y.-J.; Liang, Y.-M. AdV. Synth. Catal. 2008, 350, 1275–1280. (c) Zhao,
L.-B.; Guan, Z.-H.; Han, Y.; Xie, Y.-X.; He, S.; Liang, Y.-M. J. Org. Chem.
2007, 72, 10276–10278. (d) Shu, X.-Z.; Liu, X.-Y.; Xiao, H.-Q.; Ji, K.-G.; Guo,
L.-N.; Qi, C.-Z.; Liang, Y.-M. AdV. Synth. Catal. 2007, 349, 2493–2498. (e)
Duan, X.; Liu, X.; Guo, L.; Liao, M.; Liu, W.; Liang, Y. J. Org. Chem. 2005,
70, 6980–6983.
With the optimized conditions in hand, the scope of this
reaction was then investigated, and the results are summarized
in Table 2. The scope of this reaction is quite general. When
R1 was a phenyl with an electron-donating -CH3 group (Table
2, entries 2-4), the yields of 2 were higher than those substrates
(22) Huisgen R., 1,3-Dipolar Cycloaddition Chemistry; Wiley: New York,
1984; Vol. 1, pp 1-176.
2894 J. Org. Chem. Vol. 74, No. 7, 2009

a
TABLE 2. Cyclization Reaction Catalyzed by AgSbF6
SCHEME 2. A Plausible Mechanism for the Formation of
Isoquinolines
substrate
entry
1
R1
R2
X
product 2 yield (%)
1
2
3
4
5
6
7
8
1a
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
65
75
78
72
56
62
60
48
46
57
55
80
78
85
31
60
63
76
1b 4-CH3C6H4
1c 3-CH3C6H4
1d 2-CH3C6H4
1e
1f
4-ClC6H4
3-ClC6H4
2-ClC6H4
1g
1h 4-CH3COC6H4
9
1i
1j
4-CH3OOCC6H4
10
11
12
13
14
15
16
17
18
pentyl
b
1k R1
1l
Ph
1m pentyl
1n 3-CH3C6H4
1o
1p Ph
1q Ph
We continued to elucidate the scope of the reaction by
replacing the hydrogen atom at the R2 position with ethyl and
phenyl groups (Table 2, entries 16-18). The reactions of 1p
and 1q having aliphatic substituents at the R2 position proceeded
smoothly and gave the desired 1,3-disubstituted isoquinolines
2p and 2q in 60% and 63% yields (Table 2, entries 16 and 17),
respectively. Very interestingly, in the case of R2 changing as
phenyl group (Table 2, entry 18), the more satisfactory result
was obtained in 76% yield.
Ph
3-CH3
ethyl
butyl
Ph
H
H
H
1r
Ph
a Reaction conditions: unless indicated otherwise, all reactions were
run by employing 0.25 mmol of 1a in the presence of 20 mol % of
b
AgSbF6 and 0.50 mmol of TFA in 3 mL of DCE at 80 °C. R1
CH2O-(4-CH3OOCC6H4).
)
From the results shown in Tables 1 and 2, the reactions
showed very high regioselectivity. Only the six-membered-ring
isoquinoline from 6-endo-dig cyclization was obtained, and no
five-membered exocyclic product was detected by TLC moni-
toring from the reaction mixture (Scheme 2, path b). Presumably,
the reaction via 6-endo-dig cyclization can produce stable
product and undergo a similar mechanism, which has been
supported in the literature.20
SCHEME 1. Explanation of the Electronic Effects of the
Substituents on the Aromatic Ring
On the base of the above results, we propose the following
plausible mechanism for this process (Scheme 2, path a): (i)
the alkynyl moiety of A is coordinated to the silver catalyst to
generate complex B, (ii) the nitrogen atom undergoes regiose-
lective attack at the electron-deficient triple bonds via 6-endo-
dig cyclization, leading to the intermediate C, (iii) the inter-
mediate C loses N2 and H+ and the organosilver isoquinoline
D is formed, (iv) D then undergoes subsequent reaction with
TFA and H+ to afford isoquinoline salt E and to regenerate the
silver catalyst, which enters the next catalytic cycle, and (v)
finally, E reacts with saturated NaHCO3 to afford the corre-
sponding isoquinoline F.
In summary, we have described a novel and efficient method
for the synthesis of substituted isoquinoline via Ag-catalyzed
cyclization of 2-alkynyl benzyl azides. The reaction proceeds
smoothly in moderate to good yields and tolerates considerable
functional groups. Further application of the methodology to
synthesize some natural alkaloids and pharmaceutical com-
pounds is in progress in our laboratory and the results will be
reported in due course.
with electron-withdrawing groups such as -Cl, -COCH3, or
-COOCH3 (Table 2, entries 5-9). As can be seen, the position
of the substituent on R1 had only a slight influence in the yield
of the products (Table 2, entries 2-4 and 5-7). Cyclization
still proceeds when the terminus of the carbon-carbon triple
bond is substituted by an alkyl group. Thus, 3-pentylisoquinoline
2j can be synthesized in a moderate yield by the cyclization of
benzyl azides 1j (Table 2, entry 10). The reaction also proceeded
smoothly when the -CH2O-(4-CH3OOCC6H4) substituent was
introduced on the alkyne terminus. Therefore, substrate 1k was
successfully converted to methyl 4-(isoquinolin-3-ylmethoxy)-
benzoate in 55% yield (Table 2, entry 11). We were also
interested in investigating substituents on the aromatic ring.
Introducing an electron-withdrawing Cl- group onto the
aromatic ring significantly increased the yields to 85% (Table
2, entries 12-14). However, when the electron-donating CH3-
group was used, the yield of desired product was lowered to
only 31% (Table 2, entry 15). The electronic effect of substit-
uents on the aromatic ring can be explained as shown in Scheme
1. For intermediate 4a, the positive charge on the alkyne carbon
bearing the phenyl ring is better stabilized, and therefor closure
to a six-membered ring and formation of the isoquinoline
product are favored. For intermediate 4b, more of the partial
positive charge is located on the alkyne carbon bearing the (2-
(azidomethyl)-6-methyl)phenyl ring, which disfavors the forma-
tion of a six-membered ring and results in a decrease in yield.
Experimental Section
General Produce for the Silver-Catalyzed Cyclization of
2-Alkynyl Benzyl Azide. To a stirred solution of 2-alkynyl benzyl
azides 1 (0.25 mmol) in 1,2-dichloroethane (3.0 mL) was added
AgSbF6 (17 mg, 20 mol %) and TFA (57 mg, 0.5 mmol) at 80 °C.
J. Org. Chem. Vol. 74, No. 7, 2009 2895

When the reaction was considered complete as determined by TLC
analysis, saturated NaHCO3 (15 mL) was added to the reaction
mixture which was then stirred for 30 min. The mixtures were
extracted with CH2Cl2 (3 × 15 mL). The organic layer was washed
with saturated NaCl solution (2 × 20 mL) and dried with Na2SO4,
the solvent was evaporated, and the residue was purified by column
chromatography, eluting with hexanes/EtOAc (5:1) to affod
pure 2.
3-Phenylisoquinoline (2a): yield 33.4 mg (65%), white solid,
mp 96-98 °C; 1H NMR (400 MHz, CDCl3) δ 9.20 (s, 1 H),
8.01-7.99 (d, J ) 7.6 Hz, 2 H), 7.89 (s, 1 H), 7.81-7.79 (d, J )
8.4 Hz, 1 H), 7.69-7.67 (d, J ) 8.0 Hz, 1 H), 7.53-7.49 (t, J )
7.2 Hz, 1 H), 7.42-7.36 (m, 3 H), 7.30-7.26 (t, J ) 7.2 Hz, 1 H);
13C NMR (100 MHz, CDCl3) δ 152.3, 151.1, 139.5, 136.5, 130.4,
128.6, 128.4, 127.6, 127.4, 126.9, 126.7, 116.3; IR (KBr) 3352,
3033, 2925, 2854, 2251, 1624, 1584, 1452, 1279, 1199, 909, 883,
785, 760, 738, 686 cm-1. Anal. Calcd for C15H11N: C, 87.77; H,
5.40; N, 6.82. Found: C, 87.79; H, 5.47; N, 6.75.
3-p-Tolylisoquinoline (2b): yield 41.2 mg (75%), white solid,
mp 94-96 °C; 1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1 H),
8.03-8.00 (m, 3 H), 7.94-7.92 (d, J ) 8.4 Hz, 1 H), 7.82-7.79
(d, J ) 8.4 Hz, 1 H), 7.65-7.61 (t, J ) 7.6 Hz, 1 H), 7.54-7.50
(t, J ) 7.6 Hz, 1 H), 7.30-7.28 (d, J ) 8.0 Hz, 2 H), 2.40 (s, 3 H);
13C NMR (100 MHz, CDCl3) δ 152.2, 151.1, 138.3, 136.7, 136.6,
130.3, 129.4, 127.5, 127.4, 126.8, 126.7, 126.7, 115.8, 21.2; IR
(KBr) 3053, 3032, 2914, 2856,1914, 1623, 1584, 1565, 1448, 1281,
1196, 943, 884, 822, 744 cm-1. Anal. Calcd for C16H13N: C, 87.64;
H, 5.98; N, 6.39. Found: C, 87.59; H, 6.04; N, 6.43.
Acknowledgment. We thank the National Science Founda-
tion (NSF-20672049, NSF-20732002) for financial support.
Supporting Information Available: Experimental procedure,
1
characterization details, and copies of H NMR and 13C NMR
spectra of all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO900010M
2896 J. Org. Chem. Vol. 74, No. 7, 2009