A tandem approach to isoquinolines from 2-azido-3-arylacrylates and α-diazocarbonyl compounds

Article abstract of DOI:10.1021/jo8003259

(Chemical Equation Presented) 2-Azido-3-arylacrylates react with α-diazocarbonyl compounds and triphenylphosphine to furnish isoquinolines in 60-92% yields. The tandem process involves a Wolff rearrangement, an aza-Wittig reaction, and an electrocyclic ri

Full text of DOI:10.1021/jo8003259

SCHEME 1. Synthesis of Isoquinoline 3a
A Tandem Approach to Isoquinolines from
2-Azido-3-arylacrylates and r-Diazocarbonyl
Compounds
Yun-Yun Yang, Wang-Ge Shou, Zheng-Bo Chen,
Deng Hong, and Yan-Guang Wang*
TABLE 1. Optimization of Reaction Conditionsa
entry solvent reaction temperature reaction time (h) yield (%)b
Department of Chemistry, Zhejiang UniVersity,
Hangzhou 310027, China
1
2
3
4
5
6
7
8
xylene
xylene
xylene
xylene
THF
DCE
toluene
toluene
140 °C
reflux
140 °C
140 °C
reflux
reflux
100 °C
reflux
5
5
2
1
5
5
5
10
82
81
82
71
0
0
0
15
orgwyg@zju.edu.cn
ReceiVed February 7, 2008
a Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), PPh3 (0.5
mmol), solvent (20 mL), N2. b The yield of the isolated product.
construction of isoquinoline rings include the Bischler-Na-
pieralski, the Pomeranz-Fritsch, and the Pictet-Spengler
reactions.5 Transition-metal-catalyzed synthesis of isoquinolines
from the tert-butylimine of 2-iodobenzaldehydes and alkynes
(or allenes) is a promising method, while it often requires the
use of base and long reaction time.4c,f,6 The intramolecular
[4 + 2] cycloaddition reaction of 4-phenyl-2-azabutadienes,
followed by dehydrogenation, can also generate isoquinolines.4e,7
We herein report a new tandem synthesis of substituted
isoquinolines.
2-Azido-3-arylacrylates react with R-diazocarbonyl com-
pounds and triphenylphosphine to furnish isoquinolines in
60-92% yields. The tandem process involves a Wolff
rearrangement, an aza-Wittig reaction, and an electrocyclic
ring closure. The procedure is efficient, rapid, and general,
and the substrates are readily available.
Our initial studies were focused on the reaction of 2-azido-
3-(4-methyloxyphenyl)-acrylate (1a), 2-diazo-1-phenylethanone
(2a), and triphenylphosphine (Scheme 1). Thus, heating a
solution of 1 equiv each of 1a, 2a, and triphenylphosphine in
xylene at 140 °C for 5 h gave isoquinoline 3a in 82% yield
(Table 1, entries 1–4). We also examined several other solvents
such as THF (Table 1, entry 5), 1,2-dichloroethane (DCE, Table
1, entry 6), and toluene (Table 1, entries 7 and 8). The best
yield (82%) was obtained when the reaction was performed in
xylene at 140 °C for 2 h (Table 1, entry 3).
Isoquinolines constitute an important class of alkaloids
commonly found in natural products.1 They also have been used
as building blocks in pharmaceutical compounds,2 as well as
chiral ligands for transition-metal catalysts.3 Due to their
substantial applicability, the synthesis of isoquinolines is an
extensively studied topic.4 The classical methods for the
(1) Bentley, K. W. The Isoquinoline Alkaloids; Hardwood Academic:
Amsterdam, 1998; Vol. 1.
Since 2-azido-3-arylacrylates8 and R-diazocarbonyl com-
pounds9 are readily available, the tandem approach to isoquino-
lines is highly appealing. We, therefore, extended the substrate
(2) (a) Kletsas, D.; Li, W.; Han, Z.; Papadopoulos, V. Biochem. Pharmacol.
2004, 67, 1927–1932. (b) Mach, U. R.; Hackling, A. E.; Perachon, S.; Ferry, S.;
Wermuth, C. G.; Schwartz, J.-C.; Sokoloff, P.; Stark, H. ChemBioChem 2004,
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Toxicol. Sci. 2003, 74, 66–73. (d) Dzierszinski, F.; Coppin, A.; Mortuaire, M.;
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Agents Chemother. 2002, 46, 3197–3207.
(5) (a) The Chemistry of Hetrocyclic Compounds: Isoquinolines; Coppola,
G. M., Schuster, H. F., Eds.; John Wiley & Sons: New York, 1981; Vol. 38,
Part 3. (b) ComprehensiVe Organic Functional Group Ttransformations, 1st ed.;
Katritzky, A. R., Cohn, O. M., Eds.; Pergamon: Chichester U.K., 1991; Vols. 2
and 3, pp 328–419.
(3) (a) Durola, F.; Sauvage, J.-P.; Wenger, O. S. Chem. Commun. 2006, 171–
173. (b) Sweetman, B. A.; Müller-Bunz, H.; Guiry, P. J. Tetrahedron Lett. 2005,
46, 4643–4646. (c) Lim, C. W.; Tissot, O.; Mattison, A.; Hooper, M. W.; Brown,
J. M.; Cowley, A. R.; Hulmes, D. I.; Blacker, A. J. Org. Process Res. DeV.
2003, 7, 379–384. (d) Alcock, N. W.; Brown, J. M.; Hulmes, G. I. Tetrahedron:
Asymmetry 1993, 4, 743–756.
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Vol. 14, Chapter 6.1. (b) Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.;
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62, 1146–1154. (c) Rodrigues, J. A. R.; Leiva, G. C.; de Sousa, J. D. F.
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3928 J. Org. Chem. 2008, 73, 3928–3930
10.1021/jo8003259 CCC: $40.75 2008 American Chemical Society
Published on Web 04/10/2008

TABLE 2. The Synthesis of Isoquinolines 3a
SCHEME 2. The Synthesis of Isoquinolines 5o and 5p
entry
R1
R2/R3
product
yield (%)b
1
2
3
4
5
6
7
8
9
4-MeO (1a)
4-MeO (1a)
4-Br (1b)
4-Br (1b)
4-NO2 (1c)
4-NO2 (1c)
H (1d)
C6H5/H (2a)
4-MeOC6H4/H (2b)
C6H5/H (2a)
4-MeOC6H4/H (2b)
C6H5/H (2a)
4-MeOC6H4/H (2b)
4-MeOC6H4/H (2b)
C6H5/H (2a)
3a
3b
3c
3d
3e
3f
3g
3h
3i
82
92
78
80
70
73
85
82
80
SCHEME 3. The Synthesis of Benzoisoquinolines 5q and 5r
H (1d)
4-MeO (1a)
Me/CO2Et (2c)
a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), PPh3 (0.5 mmol),
xylene (20 mL), 140 °C, N2, 2 h. b The yield of the isolated product.
On the basis of these results, we proposed a possible
mechanism for our cascade reaction, as shown in Scheme 4.
First, azide 1 reacts with triphenylphosphine to form phos-
phazene A via the Staudinger-Meyer reaction,10 while R-diazo-
ketone 2 transforms to ketene B through the Wolff rearrange-
ment reaction.9b,11 Then the aza-Wittig reaction between
phosphazene A and ketene B affords N-vinylic ketenemine
C.10b,12 Finally, the electrocyclic ring closure of C and a
subsequent [1,3]-H immigration led to the formation of iso-
quinolines 3. For asymmetrical substrate 2-diazo-1,3-diones
4a-e, the Wolff rearrangement results in two different ketenes,
B1 and B2, which leads to the formation of two isoquinoline
isomers 5 and 6, respectively (Scheme 5). B1 should be the major
product of the Wolff rearrangement when R2 is an aryl group
and R3 is an alkyl group, so we obtained 5 as the major product.
scope to various 2-azido-3-arylacrylates 1 and R-diazoketones
2 using the optimized conditions. As shown in Table 2, a wide
range of azides and R-diazoketones resulted in isoquinolines 3
in good yields (70-92%).
Encouraged by these results, we investigated the reaction of
2-diazo-1,3-diones 4 with azides and triphenylphosphine (Table
3). We found that all reactions could take place at lower
temperature (100 °C) in toluene, resulting in isoquinolines 5 or
a mixture of 5 and their isomers 6. In most cases, good
regioselectivity was obtained (Table 3, entries 1-5 and 7-14),
while 2-azido-3-(4-fluorophenyl)acrylate gave equal amounts
of 5f and 6f (Table 3, entry 6). Moreover, electron-rich azides
(Table 3, entries 7-12) gave higher yields than electron-deficient
azides (Table 3, entries 1-6).
In summary, we have developed an efficient synthesis of
isoquinolines via a tandem reaction of 2-azido-3-arylacrylates,
R-diazocarbonyl compounds, and triphenylphosphine. The
procedure is rapid and general, and the substrates are readily
available.8,9,13 Further application of the methodology to
synthesize some natural alkaloids and pharmaceutical com-
pounds is in progress in our laboratory.
We also examined the symmetrical 2-diazo-1,3-diones 4f and
4g using the established procedure and obtained 5o and 5p in
87 and 82% yields, respectively (Scheme 2).
Next, our attention was directed toward the construction of
the benzoisoquinoline framework using azide 7 as a substrate
(Scheme 3). It was found that the reaction afforded the desired
benzoisoquinolines 5q and 5r in 88 and 90% yields, respectively.
TABLE 3. The Synthesis of Isoquinolines 5 and 6a
entry
R1
R2/R3
Ph/Et (4a)
Ph/Me (4b)
Ph/Me (4b)
5/6 (ratio)b
yield (%)c
1
2
3
4
5
6
7
8
4-Cl (1e)
2-Cl (1f)
4-Br (1b)
4-Br (1b)
4-Br (1b)
4-F (1g)
4-PhCH2O (1h)
4-PhCH2O (1h)
4-PhCH2O (1h)
4-PhCH2O (1h)
4-MeO (1a)
4-MeO (1a)
4-Ph (1i)
5a/6a (100:0)
5b/6b (100:0)
5c/6c (100:0)
5d/6d (100:0)
5e/6e (>95:5)
5f/6f (50:50)
5g/6g (91:9)
5h/6h (100:0)
5i/6i (>95:5)
5j/6j (>95:5)
5k/6k (>95:5)
5l/6l (100:0)
5m/6m (88:12)
5n/6n (>95:5)
79
75
68
72
71
60
86
84
88
86
85
83
78
89
Ph/Et (4a)
4-MeC6H4/Me (4c)
4-MeC6H4/Me (4c)
Ph/Me (4b)
Ph/Et (4a)
9
4-MeOC6H4/Me (4d)
4-MeC6H4/Me (4c)
Ph/Me (4b)
Ph/Et (4a)
2-ClC6H4/Et (4e)
4-MeOC6H4/Me (4d)
10
11
12
13
14
H (1d)
b
a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), PPh3 (0.5 mmol), toluene (20 mL), 100 °C, N2, 2 h. Determined by H NMR. c The yield of the
1
isolated product.
J. Org. Chem. Vol. 73, No. 10, 2008 3929

SCHEME 4. A Plausible Mechanism for the Synthesis of
Isoquinolines
MS m/z ([M + H]+) 352; HRMS m/z calcd for (C21H21NO4 + Na)
374.1363; found 374.1370.
General Procedure for the Synthesis of Isoquinolines 5. To a
solution of PPh3 (0.5 mmol) in anhydrous toluene (10 mL) was added
dropwise a solution of 1 (0.5 mmol) and 4 (0.5 mmol) in anhydrous
toluene (10 mL) under the nitrogen atmosphere at 100 °C over 30
min. After the mixture was stirred for 2 h, the solvent was evaporated
in vacuum, and residual oil was purified by silica gel column
chromatography using hexane/EtOAc (8:1) as the eluent. The product
was rescrystallized from hexane/EtOAc (6:1).
Ethyl 7-chloro-1-(2-oxo-1-phenylbutyl)isoquinoline-3-carbox-
ylate (5a):. White solid, mp 136–137 °C; IR (KBr) 1716, 1705, 1423,
1241, 1232, 821, 707 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.46 (s,
1 H), 7.96 (s, 1 H), 7.90 (d, J ) 8.5 Hz, 1 H), 7.63 (d, J ) 8.4 Hz, 1
H), 7.33–7.25 (m, 5 H), 5.82 (s, 1 H), 4.50–4.43 (m, 2 H), 2.87–2.83
(m, 1 H), 2.48–2.43 (m, 1 H), 1.45 (t, J ) 7.2 Hz, 3 H), 1.15 (t, J )
7.1 Hz, 3 H) ppm; 13C NMR (125 MHz, CDCl3) δ 208.7, 165.7, 158.6,
141.1, 137.3, 135.8, 135.0, 132.0, 130.8, 129.5, 129.1, 127.9, 124.8,
123.1, 64.0, 61.9, 35.9, 14.5, 8.4 ppm; MS m/z ([M + Na]+) 404;
HRMS m/z calcd for (C22H20ClNO3 + Na) 404.1024; found 404.1021.
Ethyl 5-chloro-1-(2-oxo-1-phenylpropyl)isoquinoline-3-car-
boxylate (5b): Yellow solid, mp 123–124 °C; IR (KBr) 1709, 1670,
1358, 1240, 1213, 746 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.89 (s,
1 H), 7.92 (d, J ) 8.5 Hz, 1 H), 7.77 (d, J ) 7.5 Hz, 1 H), 7.50 (t, J
) 8.1 Hz, 1 H), 7.32–7.23 (m, 5 H), 5.86 (s, 1 H), 4.51–4.48 (m, 2
H), 2.37 (s, 3 H), 1.47 (t, J ) 7.1 Hz, 3 H) ppm; 13C NMR (125
MHz, CDCl3) δ 206.0, 165.6, 159.4, 141.8, 137.4, 134.8, 133.8, 130.9,
129.6, 129.5, 129.4, 129.1, 127.9, 124.5, 119.8, 65.1, 61.9, 29.8, 14.5
ppm; MS m/z ([M + Na]+) 390; HRMS m/z calcd for (C21H18ClNO3
+ Na) 390.0867; found 390.0861.
SCHEME 5. Reaction of Asymmetrical 2-Diazo-1,3-diones
Ethyl 7-methoxy-1-(3-oxobutan-2-yl)isoquinoline-3-carbox-
ylate (5p):. White solid, mp 115–116 °C; IR (KBr) 1713, 1699, 1623,
1313, 1228, 903 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.42 (s, 1 H),
7.89 (d, J ) 9 Hz, 1 H), 7.40 (dd, J ) 9, 2 Hz, 1 H), 7.35 (d, J ) 2
Hz, 1 H), 4.61 (q, J ) 7 Hz, 1 H), 4.52–4.48 (m, 2 H), 3.95 (s, 3 H),
2.06 (s, 3 H), 1.71 (d, J ) 7 Hz, 3 H), 1.47 (t, J ) 7 Hz, 3 H) ppm;
13C NMR (125 MHz, CDCl3) δ 209.0, 166.1, 160.7, 158.2, 139.6,
131.8, 130.8, 129.8, 123.8, 123.5, 103.3, 61.7, 55.9, 55.5, 28.0, 15.5,
14.6 ppm; MS m/z ([M + Na]+) 324; HRMS m/z calcd for (C17H19NO4
+ Na) 324.1206; found 324.1210.
Ethyl 1-(2-oxo-1-p-tolylpropyl)benzo[g]isoquinoline-3-carbox-
ylate (5q):. White solid, mp 129–130 °C; IR (KBr) 1743, 1707, 1257,
1213, 746 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.52 (d, J ) 8.5 Hz,
1 H), 8.49 (s, 1 H), 7.94–7.90 (m, 2 H), 7.76 (d, J ) 8.7 Hz, 1 H),
7.63–7.60 (m, 1 H), 7.54–7.51 (m, 1 H), 7.36 (d, J ) 7.7 Hz, 2 H),
7.21 (d, J ) 7.7 Hz, 2 H), 6.00 (s, 1 H), 4.51–4.47 (m, 2 H), 2.34 (s,
3 H), 2.22 (s, 3 H), 1.46 (t, J ) 7.1 Hz, 3 H) ppm; 13C NMR (125
MHz, CDCl3) δ 207.2, 165.7, 157.2, 141.8, 138.8, 137.6, 134.9, 134.4,
132.7, 130.1, 129.6, 129.4, 128.6, 128.1, 127.9, 127.7, 127.6, 126.4,
123.0, 68.0, 61.8, 30.2, 21.4, 14.5 ppm; MS m/z ([M + Na]+) 420;
HRMS m/z calcd for (C26H23NO3 + Na) 420.1570; found 420.1569.
Experiment Section
General Procedure for the Synthesis of Isoquinolines 3. To a
solution of PPh3 (0.131 g, 0.5 mmol) in anhydrous xylene (10 mL)
was added dropwise a solution of 1 (0.5 mmol) and 2 (0.5 mmol) in
anhydrous xylene (10 mL) at 140 °C under the nitrogen atmosphere
over 30 min. The mixture was stirred for 2 h. The solvent was
evaporated in vacuum, and the residual oil was purified by silica gel
column chromatography using hexane/EtOAc (4:1) as the eluent. The
product was recrystallized from hexane/EtOAc (4:1).
Ethyl 1-benzyl-7-methoxyisoquinoline-3-carboxylate (3a):
White solid, mp 117–118 °C; IR (KBr) 1724, 1617, 1498, 1408,
1229, 1205, 1028, 845 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.42
(s, 1 H), 7.82 (d, J ) 8.6 Hz, 1 H), 7.32–7.22 (m, 6 H), 7.17–7.16
(m, 1 H), 4.74 (s, 2 H), 4.53 (q, J ) 7.1 Hz, 2 H), 3.78 (s, 3 H),
1.48 (t, J ) 7.1 Hz, 3 H) ppm; 13C NMR (125 MHz, CDCl3) δ
167.6, 161.3, 160.3, 140.6, 140.5, 132.9, 131.6, 131.4, 130.0, 129.9,
127.7, 124.6, 124.5, 105.9, 63.0, 56.8, 44.5, 15.9 ppm; MS m/z
([M + H]+) 322; RMS m/z calcd for (C20H19NO3 + Na) 344.1257;
found 344.1267.
Acknowledgment. We thank the National Natural Science
Foundation of China (No. 20672093) and the Specialized Research
Fund for Doctoral Program of Higher Education (20050335101).
Ethyl 7-methoxy-1-(4-methoxybenzyl)isoquinoline-3-carbox-
ylate (3b):. White solid, mp 120–121 °C; IR (KBr) 1728, 1618,
1514, 1500, 1291, 1229, 1207, 1032, 850 cm-1; H NMR (500
1
MHz, CDCl3) δ 8.41 (s, 1 H), 7.82 (d, J ) 8.8 Hz, 1 H), 7.34–7.27
(m, 2 H), 7.19 (d, J ) 8.6 Hz, 2 H), 6.78 (d, J ) 8.6 Hz, 2 H),
4.67 (s, 2 H), 4.53 (q, J ) 7.1 Hz, 2 H), 3.80 (s, 3 H), 3.73 (s, 3
H), 1.48 (t, J ) 7.1 Hz, 3 H) ppm; 13C NMR (125 MHz, CDCl3)
δ 166.4, 160.1, 159.4, 158.2, 139.3, 131.7, 131.5, 130.4, 130.2,
129.7, 123.3, 123.2, 114.1, 104.7, 61.8, 55.6, 55.4, 42.3, 14.7 ppm;
Supporting Information Available: Detailed experimental
1
procedures, characterization data, copies of H and 13C NMR
spectra for all products. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO8003259
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3930 J. Org. Chem. Vol. 73, No. 10, 2008