Oxidation of 1-benzyldihydroisoquinolines or 1- benzyltetrahydroisoquinolines with dioxygen to 1-benzoylisoquinolines

Article abstract of DOI:10.1016/j.tetlet.2011.01.058

An environmental-benign methodology to synthesize 1-benzoylisoquinolines from 1-benzyl-3, 4-dihydroisoquinolines or 1-benzyl-1,2,3,4- tetrahydroisoquinolines using dioxygen as an oxidant was developed. This methodology in combination with Bischler-Napieralski reaction leads to a facile synthesis of 1-benzoylisoquinolines from phenylacetic acids and phenylethanamines.

Full text of DOI:10.1016/j.tetlet.2011.01.058

Tetrahedron Letters 52 (2011) 1320–1324
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxidation of 1-benzyldihydroisoquinolines or 1-benzyltetrahydroisoquinolines
with dioxygen to 1-benzoylisoquinolines
Haifeng Gan a, Yunyu Lu a, Yue Huang a, Lijun Ni a, Jinyi Xu a, Hequan Yao a,c, , Xiaoming Wu a,b,
⇑
⇑
a Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, No. 24 Tongjiaxiang, Nanjing, Jiangsu 210009, PR China
b Center for Drug Discovery, China Pharmaceutical University, 24 TongjiaXiang, Nanjing 210009, PR China
c Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An environmental-benign methodology to synthesize 1-benzoylisoquinolines from 1-benzyl-3, 4-dihy-
droisoquinolines or 1-benzyl-1,2,3,4-tetrahydroisoquinolines using dioxygen as an oxidant was devel-
oped. This methodology in combination with Bischler-Napieralski reaction leads to a facile synthesis of
1-benzoylisoquinolines from phenylacetic acids and phenylethanamines.
Received 21 October 2010
Revised 23 December 2010
Accepted 14 January 2011
Available online 20 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
The 1-benzoylisoquinoline (BzIQ) is a common structural motif
found in a variety of naturally occurring products and pharmaceu-
ticals (Fig. 1). Some of the compounds bearing this motif display a
diverse range of biological properties including antimicrobial, anti-
malarial, antitumor, anti-HIV activities, and antioxidant capacity.1
For example, isoquinoline alkaloids lysicamine (1) and liriodenine
(2), isolated from the bark of Guatteria hispida, exhibit moderate
antimicrobial activity against S. epidermidis strain.1j Recently, liri-
odenine (2) was reported to possess anticancer activity as a potent
CDC25 inhibitor2a as well as anti-arrhythmic activity by influenc-
ing the production of nitric oxide in the cell.2b,c Up to date, various
procedures have been developed for the synthesis of this motif.3
Among them, the most general synthetic strategy includes the fol-
lowing procedures: (1) condensation between phenylacetic acids
and phenylethanamines via Bischler-Napieralski reaction to form
1-benzyl-3,4-dihydroisoquinolines (BnDHIQs).4 (2) oxidation of
BnDHIQs to 1-benzoyl-3, 4-dihydroisoquinolines (BzDHIQs) by
several oxidizing agents, such as dioxygen,5 selenium dioxide
(SeO2),1a etc. (3) Oxidation of BzDHIQs to BzIQs by sulfur,6 IBX,7
Pd/C8 or activated manganese dioxide (MnO2)9 et al. (Scheme 1).
Although such oxidations could be realized in one step by various
oxidants, such as chromium trioxide (CrO3) in pyridine,10 MnO2,11
lead (IV) acetate (LTA),12 ceric ammonium nitrate (CAN),13 periodic
acid (HIO4),14 iodine (I2),15 iodobenzene diacetate (IBD),16 and
manganese (III) acetate (MTA),17 most of the above oxidants are
toxic or hazardous metal materials, which result in waste disposal
problems (Scheme 1). Therefore, developing a novel one-step oxi-
dation using green reagent is still desirable.
and oxazoles,18 in which dioxygen was used as the sole oxidant. In
continuing our research on the environmental-benign oxidation of
heterocycles, we herein describe a one-step oxidation of BnDHIQs
and 1-benzyl-1,2,3,4-tetrahydroisoquinolines (BnTHIQs) to BzIQs
using dioxygen (Scheme 1).
MeO
MeO
MeO
MeO
O
O
N
O
N
O
N
O
MeO
OMe
3 Papaveradine
1 Lysicamine
2 Liriodenine
Figure 1. Examples of 1-arylcarbonylisoquinolines.
Two-step oxidation
R1
R2
R3
R1
R2
R1
R2
[O]
[O]
N
N
O
N
O
S, Pd/C
MnO2,
etc.
O2, SeO2
etc.
R3
R3
BzIQs
BnDHIQs
BzDHIQs
We recently reported an efficient environmental-benign meth-
od for the oxidation of 2-thiazolines and 2-oxazolines to thiazoles
MnO2 or Mn(OAc)3 etc.
O2, this work
⇑
Corresponding authors. Tel.: +86 25 83271042; fax: +86 25 83301606 (H.Y.);
tel.: +86 25 83271501; fax: +86 25 83301606 (X.W).
one-step oxidation
E-mail addresses: hyao@cpu.edu.cn (H. Yao), xmwu@cpu.edu.cn (X. Wu).
Scheme 1. Synthesis of BzIQs via a one-step oxidation of BnDHIQs using dioxygen.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.058

H. Gan et al. / Tetrahedron Letters 52 (2011) 1320–1324
1321
Table 1
Table 2
The screening of the reaction conditions as the sole oxidanta
One-step oxidation of BnDHIQs using dioxygena,19
MeO
MeO
N
conditions
N
O
MeO
R1
MeO
MeO
MeO
R1
N
N
O
NaHCO3/DMF
O2
5a
4a
Conditions
R2
R2
5a-n
4a-n
Entry
T (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
DMF, K2CO3,O2
DMF, K2CO3,O2
DMF, K2CO3,O2
DMF, NaHCO3,O2
DMF, NaHCO3,O2
DMF, NaHCO3, O2
DMF, NaHCO3, air
EtOH, NaHCO3, O2
CH3CN, NaHCO3, O2
Pyridine, O2
80
100
120
80
100
120
120
Reflux
Reflux
Reflux
22
22
6
23
5
3
6
22
22
27
55 (32c)
69 (19c)
85 (0c)
88 (0c)
Entry
Product
Yieldb (%)
87 (0c)
MeO
MeO
88 (0c)
78 (0c)
N
O
6 (29c, 51d)
7 (86d)
26 (41d)
1
88 (3 h)
52 (7 h)
59 (3 h)
67 (3 h)
68 (3 h)
76 (4 h)
70 (3 h)
10
a
All reactions were performed on a 0.5 mmol scale with inorganic or organic
bases (3 equiv).
5a
5b
5c
5d
5e
5f
MeO
MeO
b
Isolated yields after flash chromatography.
The recovery of the starting material.
Isolated yields of the mono-oxidation of benzylic carbon.
c
N
O
d
2
3
4
5
6
7
O2N
We initiated our investigation using BnDHIQ 4a as the model
MeO
substrate to establish a general procedure. 4a was synthesized
through Bischler–Napieralski reaction from 3,4-dimethoxylpheny-
lethanamine and phenylacetic acid. A series of reaction conditions
were then screened and the results were summarized in Table 1.
When the reaction was conducted in DMF at 80 °C and 100 °C for
22 h, the desired product BzIQ 5a was obtained in 55% and 69%
yields, respectively, and most of the unreacted 4a could be recov-
ered (entries 1 and 2). Higher temperature remarkably shortened
the reaction time to 6 h and the yield of 5a was increased to 85%
(entry 3). Interestingly, the yields of 5a were even better when
K2CO3 was replaced by NaHCO3 (entries 4–6). Compound 4a could
be fully consumed in 3 h at 120 °C and 5a was acquired in 88%
yields (entry 6). It is worth noting that the reaction also proceeded
smoothly in air under the same condition, although prolongated
reaction time was needed (entry 7). Using EtOH, CH3CN or pyridine
as solvent generated the desired product 5a in low yield, together
with the corresponding mono-oxidative product as a major prod-
uct (entries 8–10).
With the optimized condition in hand, the substrate scope of
BnDHIQs with various substituents was explored (Table 2). As
can be seen, a series of substrates (4a–4n) could be converted into
the corresponding products (5a–5n) under the optimized condi-
tion in less than 8 h (entries 1–12). Moderate to good yields of
the corresponding products could be obtained for the substrates
bearing various benzyl groups (entries 1, 3–8, 10–14). However,
relatively low yields of the corresponding products were obtained
for the substrates with 4-nitrobenzyl group at 1-postion (entries 2
and 9).
N
O
MeO
F3C
MeO
N
O
MeO
Cl
MeO
N
O
MeO
Br
MeO
N
O
MeO
H3C
MeO
N
O
MeO
Having demonstrated that BnDHIQs could be oxidized to BzIQs,
we continued to exploit the one-step oxidation of BnTHIQs to
BzIQs with dioxygen. First, we synthesized twelve BnTHIQs
MeO
MeO
5g
(6a–6n) from BnDHIQs (5a–5n) through
a reduction using
NaBH4.20 We then tested the oxidation of BnTHIQs. To our delight,
all substrates could be oxidized to the corresponding products un-
der the same condition in moderate yields. The results in Table 3
indicate a similar pattern about the influence of substitutions on
the 1-benzyl group.21
N
8
77 (7 h)
O
5h
(continued on next page)

1322
H. Gan et al. / Tetrahedron Letters 52 (2011) 1320–1324
Table 3
Table 2 (continued)
One-step oxidation of BnTHIQs using dioxygena,22
Entry
Product
Yieldb (%)
64 (6 h)
MeO
MeO
R1
MeO
NH
N
O
R1
NaHCO3/DMF
O2
N
O
9
10
11
12
13
R2
R2
O2N
5a-l
6a-l
5i
Yieldb (%)
MeO
Entry
Product
N
O
MeO
69 (3 h)
72 (5 h)
65 (5 h)
65 (6 h)
N
O
MeO
1
53 (9 h)
23 (23 h)
29 (6 h)
54 (10 h)
45 (7 h)
47 (10 h)
49 (11 h)
F3C
5j
MeO
5a
5b
5c
5d
5e
5f
N
O
MeO
MeO
N
O
2
3
4
5
6
7
Cl
5k
5l
O2N
MeO
N
O
MeO
N
O
MeO
Br
F3C
MeO
N
O
MeO
N
O
MeO
H3C
5m
Cl
MeO
N
O
MeO
14
60 (7 h)
N
O
MeO
MeO
5n
Br
a
All reactions were performed in DMF on
a
0.5 mmol scale with NaHCO3
(3 equiv) at 120 °C.
MeO
b
Isolated yields after flash chromatography.
N
O
MeO
Finally, we combined this methodology with Bischler–
Napieralski reaction to lead to facile synthesis of BzIQs
a
H3C
(Scheme 2). Condensation between phenylacetic acid and phenyle-
thanamines to form BnDHIQs (without purification), subsequent
oxidation using dioxygen smoothly afforded 5a, 5h, and papavera-
dine (3)23 in acceptable total yields. Thus, this procedure offers a
simple route in the synthesis of BzIQs from phenylacetic acids
and phenylethanamines.
In summary, we have developed the one-step oxidation of
BnDHIQs and BnTHIQs to BzIQs with dioxygen as a sole oxidant
in moderate to good yields. This process is milder, safer, and more
environmental-benign than the established ones. This methodol-
ogy combined with Bischler–Napieralski reaction could lead to a
facile method for the synthesis of BzIQs from phenylacetic acids
and phenylethanamines. Further investigation and synthetic appli-
cation of this protocol is now underway and will be reported in due
course.
MeO
N
O
MeO
MeO
MeO
5g
N
8
58 (8 h)
O
5h

H. Gan et al. / Tetrahedron Letters 52 (2011) 1320–1324
1323
Table 3 (continued)
Acknowledgments
Entry
Product
Yieldb (%)
Financial support from the National Natural Science Foundation
(Grant no. 20902111), Program for New Century Excellent Talents
in University (NCET-2008) by the Ministry of Education of China,
the State Key Laboratory of Drug Research (SIMM0901KF-04) and
Fundamental Research Funds for the Central Universities
(JKZ2009002 for H. Yao and JKY2009013 for Y. Huang) are
appreciated.
MeO
N
O
9
10
11
12
13
24 (7 h)
49 (4 h)
60 (11 h)
59 (11 h)
42 (11 h)
O2N
5i
MeO
Supplementary data
N
O
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.01.058.
F3C
5j
References and notes
MeO
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(e) Yu, X.; Wu, J. J. Comb. Chem. 2009, 11, 895.
N
O
Cl
5k
5l
MeO
N
O
Br
MeO
N
O
4. (a) Bischler, A.; Napieralski, B. Ber. Dtsch. Chem. Ges. 1893, 26, 1903; (b)
Bergstrom, F. W. Chem. Rev. 1944, 35, 77.
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6. Still, W. J.; McNulty, J. J. Chem. Soc., Perkin Trans. 1 1994, 1329.
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8. (a) Buchs, P.; Brossi, A. Helv. Chim. Acta 1981, 64, 681; (b) Bembenek, M. E.;
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Chem. 1990, 33, 147; (c) Batra, S.; Sabnis, Y. A.; Rosenthal, P. J.; Avery, M. A.
Bioorg. Med. Chem. 2003, 11, 2293.
H3C
5m
5n
MeO
N
O
14
41 (11 h)
MeO
9. Janin, Y. L.; Roulland, E.; Beurdeley-Thomas, A.; Decaudin, D.; Monneret, C.;
Poupon, M. F. J. Chem. Soc., Perkin Trans. 1 2002, 529.
a
10. (a) Granchelli, F. E.; Neumeyer, J. L. Tetrahedron 1974, 30, 3701; (b) Pai, B. R.;
Shanmugasundaram, G. Tetrahedron 1965, 21, 2579.
11. Yang, S. S.; Huang, W. Y.; Lin, L. C.; Yeh, P. Y. Chemistry (Taipei) 1961, 144.
12. LTA Lenz, G. R.; Costanza, C. J Org. Chem. 1988, 53, 1176.
All reactions were performed in DMF on
a
0.5 mmol scale with NaHCO3
(3 equiv) at 120 °C.
b
Isolated yields after flash chromatography.
13. Kuo, R. Y.; Chang, F. R.; Wu, C. C.; Patnam, R.; Wang, W. Y.; Du, Y. C.; Wu, Y. C.
Bioorg. Med. Chem. Lett. 2003, 13, 2789.
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16. Reddy, G. C. Tetrahedron Lett. 1995, 36, 1001.
17. Singh, O. V.; Huang, W.; Chen, C.; Lee, S. S. Tetrahedron Lett. 2007, 48, 8166.
18. Oxidation of 2-thiazolines, see: (a) Huang, Y.; Gan, H.; Li, S.; Xu, J.; Wu, X.; Yao,
H. Tetrahedron Lett. 2010, 51, 1751; (b) Oxidation of 2-oxazolines, 2010,
submitted.
MeO
MeO
R1
MeO
R1
N
N
NH2
R1
NaHCO3
DMF
POCl3
19. Typical experimental procedure for oxidation of BnDHIQs by dioxygen. To
a
+
O
solution of BnDHIQ 4a (141 mg, 0.5 mmol) in anhydrous DMF (2 mL) was
added NaHCO3 (126 mg, 1.5 mmol). The reaction mixture was heated to 120 °C
with an O2 balloon and stirred for 3 h. The resulting solution was diluted with
ethyl acetate and the solution was washed with water and brine, dried over
sodium sulfate, filtered, and concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel to afford 128 mg (88%) of
BzIQ 5a as a white solid. Mp: 131–132 °C; 1H NMR (CDCl3, 300 MHz) d 8.47 (d,
J = 5.5 Hz, 1H), 7.96 (d, J = 7.6 Hz, 2H), 7.67 (d, J = 5.5 Hz, 1H), 7.64–7.58 (m,
2H), 7.48 (t, J = 7.6 Hz, 2H), 7.15 (s, 1H), 4.06 (s, 3H), 3.97 (s, 3H); 13C NMR
(CDCl3, 75 MHz) d 195.4, 153.2, 153.0, 151.2, 140.1, 137.1, 134.1, 133.4, 130.9,
128.4, 123.0, 121.6, 104.9, 104.0, 56.1; MS(ESI) m/z 294.1 [M+H]+.
Toluene
O2
R2
COOH
R2
R3
R3
R2
R3
1
2
3
5a
5h
R =OMe, R =R =H (65%)
1
2
3
R =R =R =H (54%)
3 R1=R2=R3=OMe (57%)
Scheme 2. Facile synthesis of BzIQs from phenylacetic acids and arylethanamines.
20. Huang, W. J.; Singh, O. V.; Chen, C. H.; Lee, S. S. Helv. Chim. Acta 2004, 87, 167.

1324
H. Gan et al. / Tetrahedron Letters 52 (2011) 1320–1324
21. The relatively low yields of the corresponding products were due to the
decomposition of the BnTHIQs. For example,
22. Typical experimental procedure for oxidation of BnTHIQs by dioxygen. To a
solution of BnTHIQ 6a (142 mg, 0.5 mmol) in anhydrous DMF (2 mL) was
added NaHCO3 (126 mg, 1.5 mmol). The reaction mixture was heated to 120 °C
with an O2 balloon and stirred for 9 h. The resulting solution was diluted with
ethyl acetate and the solution was washed with water and brine, dried over
sodium sulfate, filtered, and concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel to provide 78 mg (53%) of
BzIQ 5a as a white solid.
MeO
MeO
Me
NH
N
O
R
R
NaHCO3/DMF
O2
+
NO2
23. Wu, W. N.; Huang, C. H. Chin. Pharm. J. 2006, 58, 41.
O2N
O2N
5b R=MeO (23%)
5i R=H( 24%)
35% for 6b
34% for 6i
6b R=MeO
6i R=H