A concise synthesis of nornitidine via nickel- or palladium-catalyzed annulation

Article abstract of DOI:10.1016/j.tet.2006.07.048

A concise method to synthesize benzo[c]phenanthridine alkaloid, nornitidine, was developed utilizing nickel- or palladium-catalyzed iminoannulation of an internal alkyne. The advantages of this strategy included readily available starting materials, inexp

Full text of DOI:10.1016/j.tet.2006.07.048

Tetrahedron 62 (2006) 9131–9134
A concise synthesis of nornitidine via nickel- or
palladium-catalyzed annulation
a
Yu Luo,a,b Yuhua Mei,a Jianbo Zhang,a Wei Lua, and Jie Tang
*
aInstitute of Medicinal Chemistry, Shanghai Key Laboratory of Green Chemistry and Chemical Process, Department of Chemistry,
East China Normal University, Shanghai 200062, China
bShanghai Institute of Materia Medica, SIBS, Chinese Academy of Sciences, Shanghai 201203, China
Received 18 May 2006; revised 13 July 2006; accepted 14 July 2006
Available online 4 August 2006
Abstract—A concise method to synthesize benzo[c]phenanthridine alkaloid, nornitidine, was developed utilizing nickel- or palladium-
catalyzed iminoannulation of an internal alkyne. The advantages of this strategy included readily available starting materials, inexpensive
reagents, short reaction steps, and good yields.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
have devoted enormous efforts to establish concise and ver-
satile methods for the preparation of benzo[c]phenanthridine
alkaloids and their analogues.4 Many of the previously re-
ported benzophenanthridine synthetic processes have shown
some disadvantages such as numerous steps, low yields or
poor generality. Thus, a convenient synthesis is needed for
the synthesis of these compounds as well as their analogues.
In this paper we report a concise synthesis of nornitidine,
which is a synthetic precursor to nitidine.5
The fully aromatized benzo[c]phenanthridine alkaloids, such
as nitidine and fagaronine (Fig. 1), are an important group of
naturally occurring alkaloids with a broad range of pharma-
cological activities, including anti-tumor and anti-viral activ-
ities.1 Nitidine and other benzo[c]phenanthridine alkaloid
analogues exhibit potent anti-tumor activity by the inhibition
of DNA topoisomerase I,2 and are considered as potential
anti-tumor drugs. However, these compounds can only be
isolated in very small amounts. For example, nitidine could
be isolated in a yield of 0.003–0.07% from Zanthoxylum
and Fagara varieties.3 For these reasons, synthetic chemists
Retrosynthetic analysis indicated that the application of
Larock’s6 or Cheng’s7 methodology could afford isoquino-
lines, which could be further transformed to benzo[c]phe-
nanthridine alkaloids (Scheme 1). In this paper we report
a new synthetic approach to nornitidine by nickel- and
palladium-catalyzed annulation reactions. The advantages
of our method include easy access to starting materials, short
reaction steps, good yields and one-step reaction to construct
all carbon atoms of the alkaloid.
R1
R2
R1
R2
R5
R4
R5
R4
N+
N
R3
R3
nitidine
O
R1+R2=OCH2O,
nornitidine
R3=H, R4=R5=OMe
R1
R1
R2
R5
R2
R5
R4
R1=OH, R2=R4=R5=OMe,
R3=H
norfagaronine
fagaronine
N
N
N
R4
R3
R1+R2=OCH2O,
sanguinarine
R3
norsanguinarine
R3+R4=OCH2O, R5=H
OH
Figure 1. Structures of some benzo[c]phenanthridine alkaloids.
R1
R2
OH
R5
R4
R5
R4
R2
R1
N
+
X
Keywords: Benzo[c]phenanthridine; Isoquinolines; Nitidine; Palladium;
Nickel; Catalysis.
R3
R3
* Corresponding author. Fax: +86 21 62602475; e-mail: wlu@chem.ecnu.
edu.cn
Scheme 1. Retrosynthesis of benzo[c]phenanthridine alkaloids.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.048

9132
Y. Luo et al. / Tetrahedron 62 (2006) 9131–9134
OH
2. Results and discussion
O
O
H3
First, 2-bromobenzaldimine 3, 2-iodobenzaldimine 4, and
alkyne 6 were prepared as outlined in Scheme 2. 2-Bromo-
benzaldimine 3 was prepared in a 96% yield, by treatment
of the aldehyde 1 with tert-butylamine.6 2-Iodobenzaldi-
mine 4 was synthesized from the aldehyde 2,6 which was
prepared from 1 in three steps.8 The internal alkyne 6 was
prepared via Sonogashira reaction9 from the commercially
available bromide 5 in 80% yield.
O
O
N
H2 H1
7
Figure 2. NOESY spectrum of isoquinoline 7.
showed the correlation with the methylene. As expected, the
regioselectivity of the annulation reaction was correct.
O
O
O
O
N
(a)
O
Br
Br
Subsequently, oxidation of 7 was investigated. While oxida-
tion of compound 7 with PCC or Dess–Martin reagent gave
a low yield, Swern oxidation10 of isoquinoline 7 proceeded
smoothly to afford aldehyde 8, which was then cyclized
under acidic conditions11 to afford nornitidine 9 in a good
yield, as illustrated in Scheme 3.
1
3
ref 8, three steps
O
O
O
O
ref 6
N
I
O
I
2
4
OH
O
Br
O
O
O
O
O
(b)
O
O
O
O
O
O
O
(a)
(b)
6
5
7
N
N
Scheme 2. Reagents and conditions: (a) tert-butylamine, 96%; (b)
Pd(PPh3)2Cl2, CuI, 3-butyn-1-ol, DIPA, 80%.
nornitidine
8
9
Scheme 3. Reagents and conditions: (a) (COCl)2, DMSO, DIPEA, CH2Cl2,
77%; (b) AcOH, 40% HBr, 78%.
Then, the annulation of 2-bromobenzaldimine 3 and 2-iodo-
benzaldimine 4 with the alkyne 6 was investigated (Table 1).
We first chose Pd(OAc)2 as the catalyst6 and bromide 3 and
iodide 4 as the substrates to synthesize iosquinoline 7. Bro-
mide 3 did not react with alkyne 6 (entry 1), while iodide 4
reacted with alkyne 6 to give compound 7 in a poor yield
(entry 2). Optimization of this reaction, using a variety of li-
gands such as PPh3, tri-o-tolylphosphin, rac-BINAP, did not
improve the yield. Cyclization of bromide 3 and alkyne 6 by
NiBr2(dppe)/Zn7 afforded isoquinoline 7 in a good yield,
while annulation of iodide 4 and alkyne 6 gave a moderate
yield. Since bromide 1 was more conveniently available
than iodide 2 (Scheme 2), synthesis of isoquinoline 7 from
2-bromobenzaldimine 3 appeared to be more appealing
both synthetically and economically. The NOESY spectrum
of compound 7, shown in Figure 2, indicated the correlation
between H1 and H2. Therefore, H3 could be assigned, which
3. Conclusion
We have developed a concise synthetic method to prepare
nornitidine via nickel- or palladium-catalyzed annulation
in three linear steps in a good yield, using readily available
starting materials and inexpensive reagents. This efficient
process should allow for easy synthesis of a variety of
benzo[c]phenanthridine alkaloids and their analogues.
4. Experimental
4.1. General
1H, 13C NMR, and NOESY spectra were recorded on Bruker
DRX-500. Chemical shifts (d, ppm) were reported for signal
center, and coupling constant J was reported in units of hertz.
High-resolution mass spectra were recorded on Finnigan
MAT-95 mass spectrometer. Elemental analyses were per-
formed on Elementar Vario EL III. Column chromatography
was performed on 200–300 mesh silica gel. All reagents were
used directly as obtained commercially, unless otherwise
noted.
Table 1. Catalytic annulation of bromide 3 and iodide 4 with alkyne 6
OH
O
O
N
O
O
6
+
O
X
N
O
X=Br
X=I
3
7
4
Entry
Imine
Methoda
Yieldb (%)
4.1.1. N-(2-Bromo-4,5-dimethoxybenzylidene)-tert-butyl-
amine (3). A mixture of 2-bromo-4,5-dimethoxybenzalde-
hyde 1 (4.00 g, 16.3 mmol) and tert-butylamine (25 mL)
was stirred under a nitrogen atmosphere at room temperature
for 20 h. The excessive tert-butylamine was removed under
reduced pressure, and the resulting mixture was dissolved in
dichloromethane, dried (Na2SO4), and filtered. Removal of
1b
2
3
4
3
4
3
4
Pd(OAc)2
Pd(OAc)2
NiBr2(dppe)/Zn
NiBr2(dppe)/Zn
—
38
73
58
a
Isolated yields.
No reaction occurred.
b

Y. Luo et al. / Tetrahedron 62 (2006) 9131–9134
9133
the solvent afforded 4.7 g of imine 3 as a pale yellow solid
(96% yield). 1H NMR (500 MHz, CDCl3): d¼1.33 (s, 9H),
3.92 (s, 3H), 3.97 (s, 3H), 7.02 (s, 1H), 7.60 (s, 1H), 8.54
(s, 1H). 13C NMR (125 MHz, CDCl3): d¼29.5, 55.6, 55.8,
57.2, 109.6, 114.5, 116.2, 127.6, 148.3, 150.9, 153.7. MS
(EI): m/z¼299, 301.
solution of oxalyl chloride (0.21 mL, 2.2 mmol) in 7.0 mL
of CH2Cl2 was added dropwise a solution of DMSO
(0.32 mL, 4.4 mmol) in 3 mL of CH2Cl2, and the mixture
was stirred for 15 min. Then a solution of compound 7
(0.40 g, 1.1 mmol) in 30 mL of CH2Cl2 was added dropwise,
and the stirring was continued for 30 min. Then DIPEA
(2.8 mL, 17 mmol) was added slowly. After stirring for
15 min, the mixture was allowed to reach room temperature,
and quenched with water (25 mL). The organic phase was
separated, dried (Na2SO4), and evaporated to afford a
residue, which was purified by silica gel chromatography
(acetone/chloroform ¼ 1:15) to give 0.31 g of pure 8 (77%
4.1.2. 4-(3,4-Methylenedioxyphenyl)-3-butyn-1-ol (6). A
mixture of Pd(PPh3)2Cl2 (0.71 g, 1.00 mmol), CuI (0.19 g,
1.00 mmol), bromide 5 (6.8 g, 33.8 mmol), and 3-butyn-1-
ol (2.6 g, 37.2 mmol) in degassed DIPA (20 mL) was refluxed
for 4 h under nitrogen atmosphere. After cooling, the reaction
mixture was filtered, and the filtrate was concentrated to give
a residue, which was purified by silica gel chromatography
(ethyl acetate/petroleum ether ¼ 3:1) to afford 5.1 g of com-
pound6 (80%yield). 1H NMR(500 MHz, CDCl3):d¼2.66(t,
J¼6.3 Hz, 2H), 3.79 (t, J¼6.3 Hz, 2H), 5.96 (s, 2H), 6.73 (d,
J¼7.8 Hz, 1H), 6.86 (d, J¼1.5 Hz, 1H), 6.93 (dd, J¼1.5 Hz,
J¼7.8 Hz, 1H). 13C NMR (125 MHz, CDCl3): d¼23.3, 60.6,
81.5, 84.7, 100.9, 107.9, 111.3, 116.4, 125.7, 146.9, 147.1.
MS (EI): m/z¼190. HRMS (EI): m/z calcd for C11H10O3
[M+]: 190.0630; found: 190.0632.
1
yield). H NMR (500 MHz, CDCl3): d¼4.02 (s, 3H), 4.05
(s, 3H), 4.12 (s, 2H), 6.02 (s, 2H), 6.82–6.87 (m, 2H),
6.92–6.93 (m, 2H), 7.28 (s, 1H), 9.07 (s, 1H), 9.78 (s, 1H).
13C NMR (125 MHz, CDCl3): d¼45.0, 56.0, 101.1, 101.8,
106.0, 108.1, 110.0, 117.9, 123.1, 123.7, 132.5, 134.7,
147.4, 147.7, 149.0, 150.2, 152.4, 153.7, 199.0. MS (EI):
m/z¼351. HRMS (EI): m/z calcd for C20H17O5 [M+]:
351.1107; found: 351.1201.
4.1.5. Nornitidine (9). To a mixture of aldehyde 8 (0.13 g,
0.37 mmol) and acetic acid (3.0 mL), was added 40% hydro-
bromic acid (1.0 mL), and stirred at room temperature for
30 min. To the mixture was added 10% NaOH solution
(30 mL), and it was extracted with CH2Cl2 (80 mL). The
organic phase was dried and evaporated to give a residue,
which was purified by silica gel chromatography (acetone/
chloroform ¼ 1:100) to give 96 mg of nornitidine (78%
4.1.3. 6,7-Dimethoxy-4-(2-hydroxy-ethyl)-3-(3,4-methyl-
enedioxyphenyl)-isoquinoline (7).
4.1.3.1. Palladium-catalyzed annulation. To a mixture
of dry DMF (34 mL), Pd(OAc)2 (100 mg, 0.44 mmol),
Na2CO3 (980 mg, 9.2 mmol), and alkyne
6 (2.6 g,
13.6 mmol) under nitrogen atmosphere was added imine 4
(3.2 g, 9.2 mmol). The contents were heated in an oil bath
at 100 ꢀC for 8 h. The reaction mixture was cooled, diluted
with chloroform (90 mL), which was washed with water
(400 mL). The organic layer was concentrated and the resi-
due was purified by silica gel chromatography (acetone/
dichloromethane ¼ 1:4) to afford 1.2 g of pure compound
1
yield). H NMR (500 MHz, CDCl3): d¼4.10 (s, 3H), 4.17
(s, 3H), 6.13 (s, 2H), 7.28 (s, 1H), 7.41 (s, 1H), 7.84 (d,
J¼9 Hz, 1H), 7.91 (s, 1H), 8.30 (d, J¼9 Hz, 1H), 8.73 (s,
1H), 9.26 (s, 1H). MS (EI): m/z¼333. HRMS (EI): m/z calcd
for C20H15NO4 [M+]: 333.1001; found: 333.1010.
1
7 (38% yield). H NMR (500 MHz, CDCl3): d¼3.32 (t,
J¼7 Hz, 2H), 3.86 (t, J¼7 Hz, 2H), 4.05 (s, 3H), 4.07 (s,
3H), 6.01 (s, 2H), 6.89 (d, J¼8 Hz, 1H), 6.96 (dd, J¼8 Hz,
J¼1.2 Hz, 1H), 6.99 (d, J¼1.2 Hz, 1H), 7.23 (s, 1H), 7.37
(s, 1H), 8.97 (s, 1H). 13C NMR (125 MHz, CDCl3):
d¼32.1, 56.0, 56.1, 62.4, 101.0, 102.3, 105.8, 108.0,
110.0, 122.9, 123.8, 123.9, 132.4, 135.2, 147.0, 147.4,
147.7, 149.9, 151.4, 153.3. MS (EI): m/z¼353. HRMS
(EI): m/z calcd for C20H19NO5 [M+]: 353.1263; found:
353.1276. Anal. Calcd for C20H19NO5: C, 67.98; H, 5.42;
N, 3.96. Found: C, 67.51; H, 5.72; N, 4.04.
Acknowledgements
Financial supports from Shanghai Science and Technology
Mission (0543199021) and the National Natural Science
Foundation of China (305722321) are gratefully acknowl-
edged.
References and notes
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4.1.4. 6,7-Dimethoxy-4-(2-oxo-ethyl)-3-(3,4-methylene-
dioxyphenyl)-isoquinoline (8). To a cooled (ꢁ60 ꢀC)

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