A simple synthesis of the debrominated analogue of veranamine

Article abstract of DOI:10.3184/174751915X14225441524178

A facile synthesis of 4,5,5-trimethyl-5,6-dihydrobenzo[c][2,7]naphthyridine, the debrominated analogue of the marine alkaloid veranamine, has been achieved in three steps with a 38% overall yield. from the commercially available 2-bromoaniline. The key be

Full text of DOI:10.3184/174751915X14225441524178

JOURNAL OF CHEMICAL RESEARCH 2015
VOL. 39 FEBRUARY, 105–107
RESEARCH PAPER 105
A simple synthesis of the debrominated analogue of veranamine
Dawei Lianga*, Yueqiu Wanga, Yanyan Wangb and Donghua Dic
aDepartment of Pharmacy & Laboratory, Ya’an Vocational College, Ya’an 625000, Sichuan, P.R. China
bDepartment of Traditional Chinese Medicine (TCM), Lianyungang TCM Branch of Jiangsu Union Technical Institute, Lianyungang 222007,
Jiangsu, P.R. China
cSchool of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, P.R. China
A facile synthesis of 4,5,5-trimethyl-5,6-dihydrobenzo[c][2,7]naphthyridine, the debrominated analogue of the marine
alkaloid veranamine, has been achieved in three steps with a 38% overall yield. from the commercially available
2-bromoaniline. The key benzo[c][2,7]naphthyridine moiety was constructed using a Sonogashira coupling, a tandem Rupe
rearrangement–Donnelly–Farrell cyclisation and a Diels–Alder reaction as the key steps. The synthetic strategy allows rapid
access to various analogues of veranamine.
Keywords: facile synthesis, veranamine, benzo[c][2,7]naphthyridine, 2‑bromoaniline, Sonogashira coupling
Natural products have played a substantial role in drug
discovery in recent decades,1 and some have shown striking
biological activities2–4 and have served as lead compounds
for pharmaceutical development.5 Veranamine (2, Fig. 1)
was isolated by Hamann and co‑workers from the marine
sponge Verongula rigida harvested in the Florida Keys.6 The
evaluation of the compound by means of an in vivo assay known
as a forced swim test, showed that veranamine had potent
antidepressant and antianxiety activity when compared with
the commercially available antidepressant drug, desipramine.
Consequently, veranamine, including the aromatised benzo[c]
[2,7]naphthyridine ring system, represented a promising
heterocyclic lead in antidepressant drug discovery.7
commercially available 3‑bromoaniline. Veranamine (2) was
subjected to a reductive dehalogenation using PdCl2(dppf) to
afford its debrominated analogue (1) in 70% yield. The key step
in the synthesis is a novel vinylogous Pictet–Gams reaction
to assemble the dihydronaphthyridine scaffold of the natural
product.8 As part of our approach towards the total synthesis
of veranamine analogues, we were interested in developing an
alternative synthetic route to construct the key benzo[c][2,7]
naphthyridine core skeleton.
Results and discussion
The retrosynthetic analysis is outlined in Scheme 1. It was
envisioned that the target compound 1 could be obtained
from compound 5 by establishing the 5,6‑dihydrobenzo[c]
In spite of the particularly important pharmacological
properties, only a few synthetic routes of veranamine and
their analogues have been reported. Most recently, Araujo
completed the first total synthesis of veranamine (2) in a seven‑
step process and an overall yield of 20% starting from the
[2,7]naphthyridine core skeleton through
reaction. In turn, the quinolin‑4‑one 5 could be synthesised
from the intermediate utilising tandem Rupe
rearrangement–Donnelly–Farrell cyclisation. Compound
could be obtained from the commercially available
a Diels–Alder
4
a
4
2‑bromoaniline (3).
N
We began the study with the preparation of the key
intermediate 5. The commercially available starting material,
2‑bromoaniline (3) was coupled with 2‑methyl‑3‑butyn‑2‑ol
via the Sonogashira coupling in the presence of Pd(PPh3)2Cl2
(0.05 equiv.) and CuI (0.05 equiv.), to afford the intermediate
4 in 95% yield. Cyclisation of the resulting 4 in concentrated
R = H (1)
Br (veranamine, 2)
R
N
H
Fig. 1 Structure of veranamine (2) and its debrominated analogue (1).
Tandem Rupe
rearrangement–
Donnelly–Farrell
cyclization
O
N
Diels-Alder
reaction
N
H
N
H
1
5
Sonogashira
coupling
OH
Br
NH2
NH2
4
3
Scheme 1 Retrosynthetic analysis of 4,5,5-trimethyl-5,6-dihydrobenzo[c][2,7]naphthyridine (1).
* Correspondent. E‑mail: ldawei@yahoo.com

106 JOURNAL OF CHEMICAL RESEARCH 2015
HCl–H2O (1:1, v/v) at 120 °C for 1.5 h, followed by a basic
naphthyridine ring. In contrast, the irradiation of the methyl
group (C‑1) in the isomer 6 at δ 2.28 ppm enhanced the signal
intensity (12.7%) of the aromatic proton (C‑10), and thus
confirmed their regio‑relationship. This synthetic method is
regarded as an efficient procedure from the viewpoint of the
number of steps and the overall yields, and has a great potential
to be utilised extensively in the synthesis of the veranamine
derivatives.
workup to give the key intermediate 5 in 75% yield. Compound
1
5 was characterised by its H NMR spectrum which revealed
the appearance of methylene protons (2H) at δ 2.60 ppm as a
single peak (s, 2H). It was also characterised by the 13C NMR
spectrum with the appearance of the carbonyl carbon at δ
193.9 ppm. The mass spectrum exhibited the mass value of m/z
176.1071 (M+H)+ was in agreement with the structure. The
possible mechanism may be considered for the tandem Rupe
rearrangement–Donnelly–Farrell cyclisation reaction which
was outlined by Pisaneschi et al.9–13 With the key intermediate
5 in hand, we then turned our attention to construction of
the benzo[c][2,7]naphthyridine ring. A catalytic Diels–Alder
reaction of 1,2,4‑triazine with in situ generated pyrrolidine
enamines under mild conditions was recently used in the
development of new procedures for the synthesis of biologically
active heterocyclic isoquinoline derivatives.14 Following this
precedent, we undertook the simple catalytic Diels–Alder
reaction of quinolin‑4‑one 5 with corresponding 3‑methyl‑
1,2,4‑triazine15 in refluxing dichloromethane under N2(g) for
2 days to afford the potentially bioactive 4,5,5‑trimethyl‑5,6‑
dihydrobenzo[c][2,7]naphthyridine (1) and its regional isomer
6 (Scheme 2). These two isomers 1 and 6 were separated by
column chromatography in 53% and 14% yields, respectively.
Conclusion
In conclusion, a facile synthesis of 4,5,5‑trimethyl‑5,6‑
dihydrobenzo[c][2,7]naphthyridine (1) via a 3‑step process
was achieved with 38% overall yield starting from the
commercially available 2‑bromoaniline (3). The Rupe
rearrangement–Donnelly–Farrell cyclisation led to the
quinolin‑4‑one moiety, and the catalytic Diels–Alder reaction
afforded the benzo[c][2,7]naphthyridine ring were the key
steps. The newly synthetic strategy allows rapid access to
various analogues of veranamine.
Experimental
Melting points were determined on an X–5 digital microscope
melting point apparatus (Yuhua, China) and are uncorrected. Some
commercially available solvents were dried by standard procedures
before use: DMF (CaH2), Et3N (KOH). Other commercial materials
were analytical grade and used without further purification. IR spectra
were run as KBr discs (and neat for liquid samples) on a PerkinElmer
1
The H NMR results, showed that the isomer 1 was the target
product due to the appearance of a signal characteristic for
the methyl group (C‑4) at δ 2.69 ppm while in the isomer 6
1
120–000A apparatus (υmax in cm–1). H NMR and 13C NMR spectra
1
the methyl proton appeared at δ 2.28 ppm. The H NMR, 13C
1
were recorded with Bruker ARX–400 (400 MHz for H NMR and
NMR and HRMS results of compound 1 were in agreement
with those reported in the literature.8 Moreover, in the NOE
difference experiments for the isomer 1 and 6 (Fig. 2). Selective
irradiation of the methyl protons (C‑4) in compound 1 at δ
2.69 ppm produced an enhancement of 4.3% in the signal of
the dimethyl protons (C‑5), which revealed that the methyl
group was close to the dimethyl group on one side of the
100 MHz for 13C NMR) spectrometer using TMS as an internal
standard (chemical shifts in δ values, J in Hz). 1D selective NOESY
measurements were performed at 25.0 °C using the standard Bruker
pulse program (selnogp). High–resolution MS data were obtained on
Agilent–6520 QTOF LC/MSD spectrometer, using ESI ionisation.
Column chromatography was performed on silica gel (200–300 mesh,
Qingdao Haiyang Chemical Co., Ltd, Qingdao, China). Analytical
TLC was performed on plates precoated with silica gel (GF254,
0.25 mm, Qingdao Haiyang Chemical Co., Ltd, Qingdao, China) and
iodine vapour was used to develop colour on the plates.
2
H3C
N
5
1
1
3
4
N
H
7
4-(2-Aminophenyl)-2-methyl-but-3-yn-2-ol (4): 2‑Methyl‑but‑3‑yn‑2‑ol
(1.01 g, 12 mmol) was added at room temperature to a stirred solution
of 2‑bromoaniline (3) (1.72 g, 10 mmol) in DMF (15 mL) and Et3N
(5 mL). Then Pd(PPh3)2Cl2 (0.35 g, 0.5 mmol) and CuI (0.10 g,
0.05 mmol) were added to the reaction mixture under a nitrogen
atmosphere and the mixture was stirred at 70 °C for 5 h. After
completion of the reaction (monitored by TLC) the reaction mixture
was cooled and quenched with H2O (50 mL). The resulting mixture
10
7
4
10
9
8
9
8
CH3
CH3
N
5
N
H
CH3
H
6
1
Fig. 2 Observed NOE differences for the isomer 1 and 6.
OH
1) HCl (con.), H2O
120 °C
Br
OH
2) K2CO3
75%
Pd(PPh3)2Cl2, CuI,
NEt3, DMF, 70 °C
95%
NH2
NH2
3
4
N
N
N
O
N
N
+
pyrrolidine, CH2Cl2, reflux
53%
N
N
N
H
H
H
5
1
6
Scheme 2 Synthesis of 4,5,5-trimethyl-5,6-dihydrobenzo[c][2,7]naphthyridine (1).

JOURNAL OF CHEMICAL RESEARCH 2015 107
was extracted with dichloromethane (3×20 mL). The combined
organic phase was washed with brine (3×10 mL) and dried over
anhydrous MgSO4, and then concentrated in vacuo. The residue
was chromatographed on silica gel using 20% EtOAc/petroleum
ether, affording 4 1.66 g (95%) as a brown solid. m.p. 40–42 °C
(lit.16 39–41 °C); IR (KBr): 3357, 2979, 2925, 2213, 1614, 1490, 1156,
746 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.22 (d, J=8.0 Hz, 1H),
7.12–7.09 (m, 1H), 6.69 (t, J=7.2 Hz, 2H), 4.20 (s, 2H), 1.64 (s, 6H);
13C NMR (100 MHz, CDCl3): δ 146.7, 132.1, 129.1, 118.0, 115.7, 113.5,
97.9, 80.2, 66.0, 31.5; HRMS (ESI) calcd for C11H13NO (M+H)+:
176.1075, found: 176.1081.
225.1391, found: 225.1387. Compound 6 was isolated as a brown solid;
m.p. 145–147 °C; IR (KBr): 3250, 2961, 1610, 1597, 775 cm–1; 1H NMR
(400 MHz, CDCl3): δ 8.33 (d, J=5.0 Hz, 1H), 7.80 (d, J=5.0 Hz, 1H),
7.51 (dd, J=7.8, 1.1 Hz, 1H), 7.25–7.19 (m, 1H), 7.07–7.01 (m, 1H), 6.65
(dd, J=7.2, 1.0 Hz, 1H), 2.87 (s, 1H), 2.28 (s, 3H), 1.58 (d, J=1.0 Hz,
6H); 13C NMR (100 MHz, CDCl3): δ 153.2, 153.9, 152.5, 151.7, 139.1,
127.9, 121.8, 121.0, 116.3, 107.8, 107.3, 57.2, 29.1, 25.9; HRMS (ESI)
calcd for C15H16N2 (M+H)+: 225.1391, found: 225.1387.
This work was funded by Dalian DTRX Chemical Co., Ltd and
the authors thank Mr Zhaoyang Wang for his constant support
and encouragement. We would also like to thank Dr Dongpo
Li (Jiangsu Kanion Pharmaceutical Co., Ltd) for the NMR
analysis.
2,2-Dimethyl-2,3-dihydro-1H-quinolin-4-one (5):
A solution of
4‑(2‑aminophenyl)‑2‑methyl‑but‑3‑yn‑2‑ol (4) (1.75 g, 10 mmol)
in concentrated HCl–H2O (30 mL) (1:1, v/v) was heated at 120 °C
for 1.5 h. When the reaction was complete, the reaction mixture was
then concentrated in vacuo. H2O (30 mL) was added and followed by
K2CO3 to pH=11. The mixture was extracted twice with CH2Cl2 and
the combined organic phases were washed water, saturated brine,
dried over anhydrous MgSO4 and evaporated under reduced pressure.
The residue was purified by using 40% EtOAc/petroleum ether,
affording 1.31 g (75%) of 5 as a light yellow oil. IR (KBr): 3330, 2923,
Received 18 December 2014; accepted 20 January 2015
Paper 1403085 doi: 10.3184/174751915X14225441524178
Published online: 13 February 2015
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2849, 1657, 1610, 1480 cm–1; H NMR (400 MHz, CDCl3): δ 7.82 (dd,
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4,5,5-Trimethyl-5,6-dihydrobenzo[c][2,7]naphthyridine (1) and its
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115.2, 115.0, 54.0, 29.5, 26.7; HRMS (ESI) calcd for C15H16N2 (M+H)+:
5
6
7
8
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