A combined pathway for the synthesis of nitidine family alkaloids

Article abstract of DOI:10.1007/s11164-019-03977-z

Three related alkaloids, oxynitidine, nitidine and 5,6-dihydronitidine, have been afforded by the new synthetic protocols. In this approach, the Ni-catalyzed annulation reaction is indicated as the key step to construct the isoquinolinone core structure. The subsequent transformations lead to the target alkaloids.

Full text of DOI:10.1007/s11164-019-03977-z

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-019-03977-z
A combined pathway for the synthesis of nitidine family
alkaloids
Gangaram Pallikonda1 · Chang‑Yu Hsieh1 · Haw‑Lih Su2 · Jen‑Chieh Hsieh1
Received: 26 April 2019 / Accepted: 28 June 2019
© Springer Nature B.V. 2019
Abstract
Three related alkaloids, oxynitidine, nitidine and 5,6-dihydronitidine, have been
aforded by the new synthetic protocols. In this approach, the Ni-catalyzed annula-
tion reaction is indicated as the key step to construct the isoquinolinone core struc-
ture. The subsequent transformations lead to the target alkaloids.
Keywords Alkaloids · Benzo[c]phenanthridine · Nitidine · Oxynitidine ·
5, 6-Dihydronitidine
Introduction
The benzo[c]phenanthridine alkaloids are important isoquinoline-type alkaloids. So
far, over than eighty alkaloids with this core structure have been identifed and iso-
lated from papaveraceous, Rutaceae and Fumariaceae plants [1]. Because of their
signifcant pharmacological properties, the benzo[c]phenanthridine alkaloids have
attracted considerable attention from the synthetic and the pharmaceutical chemists
[2, 3]. Among them, the nitidine salt and its structural analogs have been extremely
often reported and studied for a long time. In 1958, Arthur frst isolated the nitidine
hydroxide salt from the roots of Zanthoxylum nitidum, and it was later isolated from
a variety of Fagura species [4]. The nitidine salt with chloride as counter anion has
been found to possess several bioactivities, including inhibition of yeast respiration
[5], cardiovascular activity [6, 7], activity for the anti-infammatory [8] and anal-
gesic activities [9, 10]. In addition, because of the strong inhibition of DNA topoi-
somerase I, nitidine and its derivatives have been familiar as promising anti-tumor
drug candidates [11–13]; this inhibition also makes them exhibit strong anti-leuke-
mic activity in the leukemia L-1210 and P-388 systems [14].
* Jen-Chieh Hsieh
jchsieh@mail.tku.edu.tw
1
Department of Chemistry, Tamkang University, New Taipei City 25137, Taiwan, ROC
2
Central Laboratories Unit, Qatar University, Doha, Qatar
Vol.:(0123456789)
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G. Pallikonda et al.
The unique structural features of benzo[c]phenanthridine alkaloids with remark-
able biological properties and their limited availability from natural resources
made them as intriguing targets for total synthesis. Owing to the wide applications,
the design and development of simple and efcient strategies for their construc-
tion remains a challenge for the synthetic community. Thus, much efort has been
focused on the development of facile and straightforward route for the synthesis of
benzo[c]phenanthridines.
The reported literature for the synthesis of benzo[c]phenanthridine structures
includes (1) Pd-catalyzed coupling of azabicyclic alkene with o-iodobenzene fol-
lowed by tandem cyclization [15], (2) domino arylation of aryl trifates [16],
(3) imine–toluamide condensation [17], (4) cycloaddition of the lithiated tolu-
amide–benzonitrile [18, 19] and (5) condensation of homophthalic ester with imine
[20]. Although a lot of methods are known for the construction of benzo[c]phenan-
thridine alkaloids by either classical or modern pathways, most of them can only
proceed in harsh reaction conditions or use expensive catalysts with poor yields. In
this concern, Cheng has reported the synthesis of substituted isoquinolinone deriva-
tives through the Ni-catalyzed annulation reaction under mild condition with sat-
isfed yields, and applied this reaction to synthesize the oxyavicine as well [21].
Inspired by Cheng’s work, and also due to our continuous interest in the synthesis of
heterocyclic compounds and natural alkaloids [22–33], we tried to follow their strat-
egy to approach oxynitidine and extended the synthetic steps to synthesize two other
related Rutaceae alkaloids, nitidine chloride and 5,6-dihydronitidine.
Herein, we reported the combined steps for the synthesis of three nitidine family
alkaloids by using the Ni-mediated annulation as the key step to construct the iso-
quinolinone core structure.
Result and discussion
Our study started from the retro-synthetic analysis, which mainly relies on two
transformations. The frst one is the reduction of oxynitidine to generate either
the 5,6-dihydronitidine or the nitidine chloride; the second one is the formation of
oxynitidine through the Friedel–Crafts reaction followed by the dehydration, which
can fully refer to Cheng’s work for the synthesis of oxyavicine (Scheme 1). Accord-
ing to their report, formation of the precursor of oxyavicine can be accomplished
through the Ni-catalyzed cyclization of o-bromobenzamide with alkyne. Thus, we
tried to synthesize the required substrates for the construction of our isoquinolinone
core structure.
The preparation of starting substrates depends on the amidation and the Sonoga-
shira coupling reaction (Scheme 2). As indicated, 2-bromo-4,5-dimethoxy-N-meth-
ylbenzamide (1a) could be obtained simply by the treatment of 2-bromo-4,5-dimeth-
oxybenzoic acid with SOCl2 followed by methyl amine in 86% yield. And the
4-(benzo[d][1,3]dioxol-5-yl)but-3-yn-1-ol (1b) could be generated through the typi-
cal Sonogashira coupling reaction of 5-bromobenzo[d][1,3]dioxole with 3-butyne-
1-ol in 78% yield. After we got the required substrates 1a and 1b, we explored the
1 3

A combined pathway for the synthesis of nitidine family…
Scheme 1 Retrosynthetic pathway of oxynitidine, nitidine chloride and 5,6-dihydronitidine
Scheme 2 Synthesis of substrates
cyclization for the construction of our desired isoquinolinone core structure (2,
Table 1).
To optimize the reaction condition, we tried to use the Ni(dppe)Br2/Zn as the
catalytic system in the beginning. However, this catalytic system is only able to ef-
ciently construct our desired structure in small scale (0.2 mmol). Larger reaction
scale (over than 0.4 mmol) would cause a signifcantly lower yield. In addition, the
unstable reaction yields in the big reaction scale also made us explore other suitable
reaction protocol. Thus, we selected the easily handled Ni(COD)2 as our requisite
catalyst for further study.
We proceeded our further survey by using the stoichiometric amount of Ni(COD)2
to investigate the efect of every factor. As revealed in Table 1, when we used 1a and
1b as the substrates in the presence of 1.0 equivalent of Ni(COD)2 with 2.0 equiva-
lent of Et3N under CH3CN at 80 °C, the reaction was able to be completed within
2 h, and the desired product 2 was provided in 82% yield (entry 1). Changing the
base or the solvent did not improve the reaction yields (entries 2–9), while chang-
ing the reaction temperature and the amount of base also did not signifcantly afect
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G. Pallikonda et al.
Table 1 Optimization of the reaction conditions for the cyclization
Entry
x
Base (y equiv)
Solvent
z (h)
t (°C)
Yield (%)a
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.4
0.2
0.1
0.05
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
K2CO3 (2)
Na2CO3 (2)
NaOMe (2)
DIPEA (2)
Et3N (2)
Et3N (2)
Et3N (1)
Et3N (3)
Et3N (4)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
CH3CN
MeOH
THF
Toluene
DMF
2
2
2
2
2
2
2
2
2
2
2
2
2
2
8
13
24
> 30
80
80
80
80
80
80
80
80
80
60
90
80
80
80
80
80
80
80
82
54
68
77
74
40
35
51
73
78
82
80
75
73
84
83
86
6
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
9
10
11
12
13
14
15
16
17
18
Reaction condition: 1a (0.4 mmol, 1.0 equiv), 1b (0.44 mmol, 1.1 equiv), Ni(COD)2 (x equiv), base (y
equiv), solvent (2.0 mL), indicated temperature, under N2, z h
aIsolated yields
the yields (entries 10–14). We then reduced the amount of Ni(COD)2 and carefully
monitored the reaction. It was found that while the amount of Ni(COD)2 decreas-
ing, the reaction time increased, but the yields did not have obvious change except
5 mol% Ni(COD)2 (entries 15–18). Therefore, we selected the 10 mol% Ni(COD)2
with 2.0 equivalent of Et3N under CH3CN at 80 °C for 24 h as our condition for the
synthesis of the isoquinolinone core structure 2.
After getting the optimized condition for the Ni-catalyzed cyclization to form the
isoquinolinone core structure 2, we then proceeded the further transformations to
furnish our desired alkaloids, and thus, the subsequent four steps have been con-
ducted (Schemes 3, 4). Compound 3 could be obtained from compound 2 through
the Dess–Martin periodinane (DMP) oxidation by using CH2Cl2 as solvent at 0 °C
to ambient temperature in 82% yield. Our frst targeted alkaloid oxynitidine (4)
1 3

A combined pathway for the synthesis of nitidine family…
Scheme 3 Procedure for the synthesis of oxynitidine
Scheme 4 Synthesis of nitidine chloride and 5,6-dihydronitidine
Scheme 5 Synthesis of 5,6-dihydro-6-methoxynitidine
could be generated through the acid-catalyzed ring-closure/dehydration reaction of
compound 3 in 88% yield. Reduction of the oxynitidine (4) by LiAlH4 followed by
the treatment with diluted HCl leads to the second alkaloid nitidine chloride (5) in
91% yield (Scheme 4). When the reduction was conducted with excess LiAlH4, the
third targeted alkaloid 5,6-dihydronitidine (6) could be also provided smoothly in
72% yield.
An additional related alkaloids 5,6-dihydro-6-methoxynitidine (7) could be
also furnished via the reported procedure by treating nitidine chloride with ammo-
nium hydroxide at room temperature and then the methoxylation by hot methanol
(Scheme 5) [34].
1 3

G. Pallikonda et al.
The overall yields from the substrates 1a and 1b to oxynitidine, nitidine and
5,6-dihydronitidine are 60%, 55% and 40%, respectively. Including the preparation
of 1a and 1b from the commercial sources, the overall yields would be calibrated to
around 80% of the above numbers.
Conclusion
In conclusion, we have provided a simple and concise strategy for the synthesis of
Rutaceae alkaloids oxynitidine, nitidine and 5,6-dihydronitidine from the easily syn-
thesized starting substrates employing the Ni-assisted annulation reaction as the key
step. This strategy contained a combined pathway of the previous reports but with
diferent reaction protocols, which provided the targeted three alkaloids in satisfed
overall yields from the commercial sources. Further studies to explore the possibil-
ity to synthesize the alkaloids with structural similarity by using the present pathway
are currently underway.
Experimental section
Procedure for the synthesis of 2‑bromo‑4,5‑dimethoxy‑N‑methylbenzamide
(1a) 2-Bromo-4,5-dimethoxybenzoic acid (520 mg, 2 mmol, 1.0 equiv) stirring in
SOCl2 (1.25 mL) was added DMF (0.01 mL, 0.1 mmol, 10 mol%) and kept stir-
ring at 50 °C for 2 h. The resulted mixture was concentrated in vacuo and then
dissolved in CH2Cl2 (10 mL). A methylamine solution (40% in H2O, 20 mL) was
then added to the residue/CH2Cl2 solution and kept stirring at room temperature
for 18 h. Upon completion of the reaction as observed by TLC, the mixture was
diluted with water (15 mL) and extracted with EtOAc (4×15 mL), dried over anhy-
drous Na2SO4 and concentrated in vacuo. The residue was purifed by fash column
chromatography [Rf =0.5 (20% ethyl acetate in hexanes)] to give compound 1a as
white solid (464 mg, 85%); mp: 146 °C; IR (KBr): 1502, 1647, 2939 cm−1; 1H NMR
(600 MHz, CDCl3) δ 3.01 (d, J=4.8 Hz, 3H), 3.88 (s, 3H), 3.89 (s, 3H), 6.28 (s,
br, 1H), 6.98 (s, 1H), 7.21 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 26.8, 56.1, 56.3,
109.7, 113.0, 115.7, 129.1, 148.4, 150.8, 167.5; HRMS [(EI), (M+)]:273.0004 (cal.
for C10H12BrNO3 273.0001).
Procedure for the synthesis of 4‑(benzo[d][1,3]dioxol‑5‑yl)but‑3‑yn‑1‑ol (1b) To a
solution of 1-bromo-3,4-(methylenedioxy)benzene (2.05 mL, 17 mmol, 1.0 equiv)
in ultra pure water (35 mL) was added but-3-yn-1-ol (1.54 mL, 20.4 mmol, 1.2
equiv), pyrrolidine (1.40 mL, 17 mmol, 1.0 equiv), Pd(PPh3)4 (982 mg, 0.85 mmol,
5 mol%) and CuI (324 mg, 1.7 mmol, 10 mol%) under nitrogen atmosphere. The
reaction mixture was kept stirring at 60 °C for 4 h and cooled to the room tem-
perature. The aqueous layer was extracted with EtOAc (100 mL×2), and the
organic layer was washed with H2O and brine, dried over MgSO4 and concentrated
in vacuo. The residue was purifed by fash column chromatography [Rf =0.4 (25%
ethyl acetate in hexanes)] to give compound 1b as brownish oil (2.59 g, 80%); IR
1 3

A combined pathway for the synthesis of nitidine family…
(KBr): 1038, 1260, 1275, 1643, 3005 cm−1; 1H NMR (600 MHz, CDCl3) δ 2.64 (t,
J=6.0 Hz, 2H), 3.78 (t, J=6.0 Hz, 2H), 5.94 (s, 2H), 6.71 (d, J=7.8 Hz, 1H), 6.85
(d, J=1.2 Hz, 1H), 6.92 (dd, J=8.4, 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
23.7, 61.1, 82.1, 84.6, 101.2, 108.3, 111.6, 116.5, 126.0, 147.3, 147.5; HRMS [(EI),
(M+)]: 190.0627 (cal. for C11H10O3 190.0630).
Procedure for the synthesis of 3‑(Benzo[d][1,3]dioxol‑5‑yl)‑4‑(2‑hydroxyethyl)‑6,7‑di
methoxy‑2‑methylisoquinolin‑1(2H)‑one (2) In an nitrogen-flled glove box, a 4-mL
vial equipped with a magnetic stirrer bar was charged sequentially with compound
1a (109 mg, 0.4 mmol, 1.0 equiv), compound 1b (84 mg, 0.44 mmol, 1.1 equiv),
Ni(COD)2 (11 mg, 0.04 mmol, 10 mol%) and Et3N (0.11 mL, 0.8 mmol, 2.0 equiv),
followed by the addition of CH3CN (2.0 mL). The vial was closed and removed
from the glove box, and the reaction mixture was kept stirring at 80 °C for 24 h.
Upon cooling to room temperature, the mixture was diluted with CH2Cl2 (10 mL)
and fltered through a Celite pad with additional CH2Cl2 (10 mL) as an eluent. The
organic solution was concentrated under reduced pressure, and the residue was puri-
fed through fash column chromatography [Rf =0.2 (75% ethyl acetate in hexanes)]
to give the compound 2 as white solid (127 mg, 83%); mp: 237 °C; IR (KBr): 1034,
1
1240, 1636, 2875 cm−1; H NMR (600 MHz, CDCl3) δ 2.73–2.82 (m, 2H), 3.26
(s, 3H), 3.72 (t, J=7.2 Hz, 2H), 4.01 (s, 3H), 4.03 (s, 3H), 6.07 (s, 2H), 6.73–6.74
(m, 2H), 6.93 (d, J=8.4 Hz, 1H), 7.11 (s, 1H), 7.90 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 31.9, 34.0, 56.1, 56.2, 62.5, 101.5, 103.7, 108.2, 108.8, 109.7, 110.9,
119.6, 123.1, 128.9, 131.7, 140.2, 148.0, 148.2, 149.1, 153.4, 161.7; HRMS [(EI),
(M+)]: 383.1363 (cal. for C21H21NO6 383.1369).
Procedure for the synthesis of 2‑(2‑(Benzo[d][1,3]dioxol‑5‑yl)‑6,7‑dimethoxy‑4‑oxo‑3,4‑
dihydronaphthalen‑1‑yl)acetaldehyde (3) Compound 2 (115 mg, 0.3 mmol, 1.0
equiv) was dissolved in dry CH2Cl2 (10 mL) and stirred at 0 °C in an ice bath. The
solution was added Dess–Martin periodinane (191 mg, 0.45 mmol, 1.5 equiv) in one
portion, and the reaction was kept stirring at room temperature for 4 h. The reaction
was quenched at 0 °C by stirring with a solution of Na2S2O3 (0.2 g in 5 mL water)
and NaHCO3(aq) (saturated, 5 mL) for 10 min to quench the unreacted Dess–Mar-
tin reagent. The reaction mixture was diluted with CH2Cl2 and extracted by aque-
ous NaHCO3. The combined organic layer was collected, dried over the MgSO4
and concentrated in vacuo. The residue was purifed through fash column chroma-
tography [Rf =0.5 (40% ethyl acetate in hexanes)] to give the compound 3 as pale
yellow solid (94 mg, 82%); mp: 223 °C; IR (KBr): 1035, 1274, 1514, 1638, 1716,
3005 cm−1; 1H NMR (600 MHz, CDCl3) δ 3.30 (s, 3 H), 3.50–3.51 (m, 2H), 3.93 (s,
3H), 3.99 (s, 3 H), 6.05 (s, 2H), 6.70–6.72 (m, 2H), 6.75 (s, 1H), 6.91 (d, J=8.4 Hz,
1H), 7.87 (s, 1H), 9.56 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 34.2, 44.4, 56.0,
56.2, 101.6, 103.3, 106.0, 108.3, 109.0, 109.3, 119.4, 122.9, 128.4, 131.4, 141.6,
148.3, 148.4, 149.2, 153.5, 161.8, 199.6; HRMS [(EI), (M+)]: 381.1216 (cal. for
C21H19NO6 381.1212).
1 3

G. Pallikonda et al.
Procedure for the synthesis of oxynitidine (4) To a solution of compound 3 (114 mg,
0.3 mmol, 1.0 equiv) in acetic acid (4 mL) was added 10% hydrochloric acid
(0.2 mL) at room temperature. After stirring the reaction for 8 h, acetic acid was
removed in vacuo. The resulted solid was then dissolved in CH2Cl2 and extracted
by aqueous NaHCO3. The combined organic layer was collected, dried over the
MgSO4 and concentrated in vacuo. The residue was purifed through fash column
chromatography [Rf =0.59 (70% ethyl acetate in hexanes)] to give oxynitidine as
white solid (96 mg, 88%); mp: 279 °C; IR (KBr): 1041, 1274, 1637, 3005 cm−1;
1H NMR (600 MHz, CDCl3) δ 3.98 (s, 3H), 4.06 (s, 3H), 4.10 (s, 3H), 6.10 (s, 2H),
7.18 (s, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.59 (s, 1H), 7.64 (s, 1H), 7.93 (s, 1H), 7.99
(d, J=9.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 41.2, 56.1, 56.3, 101.5, 102.6,
102.8, 104.8, 108.6, 116.7, 118.3, 119.1, 121.0, 123.2, 128.9, 131.8, 135.9, 147.0,
147.5, 149.7, 153.5, 164.3; HRMS [(EI), (M+)]: 363.1110 (cal. for C21H17NO5
363.1107).
Procedure for the synthesis of nitidine chloride (5) LiAlH4 (11 mg, 0.3 mmol, 1.0
equiv) was added to a solution of oxynitidine (109 mg, 0.3 mmol, 1.0 equiv) in
dry THF (5 mL) and kept stirring at room temperature for 60 min. EtOAc was then
added to quench the excess hydride. Filter and concentrated, the reaction residue
was then treated with 10% HCl (5 mL) at room temperature. The resulting precipi-
tates were collected by fltration to aford nitidine chloride as yellow solid (95 mg,
91%); mp: 280 °C; IR (KBr): 1260, 1275, 1636 cm−1; 1H NMR (600 MHz, DMSO-
d6) δ 4.03 (s, 3H), 4.22 (s, 3H), 4.89 (s, 3H), 6.33 (s, 2H), 7.76 (s, 1H), 7.91 (s, 1H),
8.27 (d, J=9.0 Hz, 1H), 8.30 (s, 1H), 8.35 (s, 1H), 8.89 (d, J=9.0 Hz, 1H), 9.87 (s,
1H); 13C NMR (125 MHz, CDCl3) δ 41.2, 56.1, 56.3, 101.5, 102.7, 102.8, 104.8,
108.7, 116.7, 118.4, 119.2, 121.0, 123.2, 128.9, 131.9, 135.9, 147.0, 147.5, 149.7,
153.5, 164.3; HRMS [(FAB), (M+)]: 348.1236 (cal. for C21H18NO4+ 348.1230).
Procedure for the synthesis of 5,6‑dihydronitidine (6) LiAlH4 (22 mg, 0.6 mmol, 2.0
equiv) was added to a solution of oxynitidine (109 mg, 0.3 mmol, 1.0 equiv) in dry
THF (5 mL) and kept stirring at room temperature for 12 h. The reaction mixture
was diluted by CH2Cl2 and extracted by water. The organic layer was collected,
dried over the MgSO4 and concentrated in vacuo. The residue was purifed through
fash column chromatography [Rf =0.5 (100% CH2Cl2)] to give 5,6-dihydronitidine
1
as yellow solid (75 mg, 72%); mp: 213 °C; IR (KBr): 1032, 1463, 1641 cm−1; H
NMR (600 MHz, CDCl3) δ 2.60 (s, 3H), 3.95 (s, 3H), 4.00 (s, 3H), 4.14(s, 2H),
6.05 (s, 2H), 6.80 (s, 1H), 7.12 (s, 1H), 7.31 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.66
(s, 1H), 7.69 (d, J=8.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 41.0, 54.8, 56.0,
56.2, 100.6, 101.0, 104.3, 106.4, 110.1, 119.9, 123.8, 124.4, 124.5, 124.9, 126.4,
130.7, 142.8, 147.4, 148.1, 148.6, 148.8; HRMS [(EI), (M+)]: 349.1319 (cal. for
C21H19NO4 349.1314).
Acknowledgements We thank the Ministry of Science and Technology of Taiwan (ROC) for the fnan-
cial support of this research (MOST 107-2113-M-032-006) and the fellowship for Gangaram Pallikonda
(MOST 107-2811-M-032-002).
1 3

A combined pathway for the synthesis of nitidine family…
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