Concise synthesis of the angular dihydrofuroquinoline alkaloids via cyclopropane opening in the presence of polyphosphoric acid

Article abstract of DOI:10.1080/00397910500446530

We report a concise method for synthesis of dihydrofuroquinolinone alkaloids, in which the cyclopropane opening and closure was the key step. The only angluar type product was obtained in fairly high yields. IR, UV, ¹H NMR, ¹³C NMR,

Full text of DOI:10.1080/00397910500446530

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Concise Synthesis of the Angular
Dihydrofuroquinoline Alkaloids via
Cyclopropane Opening in the Presence of
Polyphosphoric Acid
Jiangtao Su a , Juan Xiong a , Shucai Liang a , Guofu Qiu a , Xichun Feng a
Hanbing Teng a , Lamei Wu a & Xianming Hu a
,
a State Key Laboratory of Virology, College of Pharmacy, Wuhan University,
Wuhan, China
Version of record first published: 16 Aug 2006.
To cite this article: Jiangtao Su , Juan Xiong , Shucai Liang , Guofu Qiu , Xichun Feng , Hanbing Teng , Lamei
Wu & Xianming Hu (2006): Concise Synthesis of the Angular Dihydrofuroquinoline Alkaloids via Cyclopropane
Opening in the Presence of Polyphosphoric Acid, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 36:6, 693-699
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Synthetic Communicationsw, 36: 693–699, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500446530
Concise Synthesis of the Angular
Dihydrofuroquinoline Alkaloids
via Cyclopropane Opening in the
Presence of Polyphosphoric Acid
Jiangtao Su, Juan Xiong, Shucai Liang, Guofu Qiu,
Xichun Feng, Hanbing Teng, Lamei Wu, and Xianming Hu
State Key Laboratory of Virology, College of Pharmacy,
Wuhan University, Wuhan, China
Abstract: We report a concise method for synthesis of dihydrofuroquinolinone
alkaloids, in which the cyclopropane opening and closure was the key step. The
only angluar type product was obtained in fairly high yields. IR, UV, 1H NMR,
13C NMR, and MS were used to confirm the structure. A possible mechanism in also
described.
Keywords: Angluar, cyclopropane, furoquinolinone, ring opening and closure
Dihydrofuroquinolinones are an extremely diverse set of natural products
which are the most widely distributed of quinoline alkaloids, as well as furo-
quinoline alkaloids[1] (Figure 1). They are primarily isolated from Rutaceae
and often incorporate a terpenoid fragment. Their wide range of biological
properties has stimulated interest in the synthesis of dihydrofuroquinolinone
derivatives.[2]
Although they are of relatively modest complexity by today’s standards
of organic synthesis, a few number of synthetic approaches to the dihydrofur-
oquinolinone alkaloids have been reported.[3] Most of the methods were
Received in Japan August 3, 2005
Address correspondence to Jiangtao Su, State Key Laboratory of Virology, College
of Pharmacy, Wuhan University, Wuhan 430072, China. E-mail: jiangtsu@yahoo.
com.cn
693

694
J. Su et al.
Figure 1. Furoquinoline alkaloids existed in nature and two types in the structure.
involved in the alkylation at the C-3 situation of quinolinone and then
formation of furan ring. A mixture of angular and linear regioisomers was
obtained. The procedure of these two steps was hitherto needed in the
synthesis of this kind of compound. Now we reported a new method that
forms the quinolinone ring and furan ring in one step. The only angular furo-
quinoline was obtained.
During our design and synthesis of the spiro-3,3-diallylquinoline system,
which was regarded as analogous quinoline alkaloids, we became interested in
the strained ring in C-3 situation in which cleavage or enlargement easily
happens. When the cyclopropane was considered, opening and then closing
were observed as expected.
The route started from the 2,2-dimethylcyclopropanedicarboxylate,
which was synthesized by a Michael initiated ring closure (MIRC)
reaction.[4] Then, a monoester was obtained after monosaponification in a
1 N NaOH/ethanol (1.1 eq) solution at room temperature for 12 h. Conversion
of monocarboxylic acid with thionyl chloride provided cyclopropanecarbonyl
chlorides, and subsequent treatment with substituted aniline gave amides 1 in
50–60% yield. After hydrolyzation of 1 in the 1 N NaOH/methanol (1.1 eq)
solution at refluxing for 4 h, 2 was obtained. Treatment of 2 in the polypho-
sphoric acid (PPA) at 100–1108C for 2 h afforded dihydrofuroquinolin-one
as a white solid in moderate yield (Scheme 1).
1
The assignment of 1 and 2 was confirmed by H NMR analysis of the
expected chemical shifts (see Table 1) and geminal coupling constants associ-
ated with the methylene group (JAB) in the cyclopropane ring, which disap-
peared when the ring opened in the molecule 3. Only a single product 3
was observed, and the assignment was confirmed by 1H and 13C NMR
analysis. The regiochemistry of the linear and angular adduct was

Angular Dihydrofuroquinoline Alkaloids
695
Scheme 1. Synthesis of the angular dihydrofuroquinoline alkaloids via cyclopropane
opening in the presence of polyphosphoric acid.
characterized in IR spectrum 1620–1660 cm21 (amide in the angular type)
and intense ultraviolet absorption at 270–290 nm. As a result of regioselective
ring opening, the angular regioisomer 3 was the single product (see Table 2).
The mechanism investigated by Pirrung and Blume[3b] resembled this
procedure, which involves initial cyclopropanation in the C-3 situation of
quinoline ring, cyclopropane ring opening to a zwitterion, and then cyclopro-
pane ring closure, but no selectivity for cyclopropane ring closure. The expla-
nation mentioned by the authors was that the reaction was under kinetic
control and balanced electron density at C-2 and C-4 oxygen in the putative
zwitterions affected the production of similar amounts of the angular and
linear regioisomers.[3b] In our procedure, formation of the quinolinone ring
and cyclopropane ring opening occurred at the same time. The intermediate
in Friedel–Crafts reaction changed the electron density at C-4 oxygen that
affected the formation of furan ring. The angular regioisomer was the
exclusive product (Figure 2).

Table 1.
Compound
1a
Mp (8C)
1H NMR (CDCl3, 300 MHz, ppm)
Yield (%)
62.26
53–55
1.23 (s, 3H, –CH3), 1.24 (s, 3H, –CH3), 1.64 (d, JAB ¼ 5.1, 1H, –CH2–), 1.90 (d, JAB ¼ 5.1, 1H,
–CH2–), 1.32 (t, J ¼ 6.9, 3H, –CH2CH3), 4.23 (q, J ¼ 7.5, 2H, –CH2CH3), 7.06–7.11 (m, 1H,
ArH), 7.29–7.34 (m, 2H, ArH), 7.56–7.58 (m, 2H, ArH), 9.86 (s, 1H, –NH–).
1.23 (s, 3H, –CH3), 1.22 (s, 3H, –CH3), 1.62 (d, JAB ¼ 4.8, 1H, –CH2–), 1.88 (d, JAB ¼ 4.8, 1H,
–CH2–), 1.31 (t, J ¼ 7.2, 3H, –CH2CH3), 2.31 (s, 3H, ArCH3), 4.22 (q, J ¼ 7.2, 2H, –CH2CH3),
7.12 (d, J ¼ 8.1, 2H, ArH), 7.45 (d, J ¼ 8.1, 2H), 9.77 (s, 1H, –NH–).
1b
1c
1d
1e
59–60
46
68.9
43.5
63.7
65
1.24 (s, 3H, –CH3), 1.23 (s, 3H, –CH3), 1.65 (d, JAB ¼ 5.1, 1H, –CH2–), 1.89 (d, JAB ¼ 5.1, 1H,
–CH2–), 1.32 (t, J ¼ 6.9, 3H, –CH2CH3), 4.23 (q, J ¼ 6.9, 2H, –CH2CH3), 7.01–7.04 (m, 2H,
ArH), 7.50–7.55 (m, 2H, ArH), 9.89 (s, 1H, –NH–).
77–78
49–50
1.31 (s, 3H, –CH3), 1.25 (s, 3H, –CH3), 1.65 (d, JAB ¼ 5.1, 1H, –CH2–), 1.90 (d, JAB ¼ 5.1, 1H,
–CH2–), 1.33 (t, J ¼ 7.2, 3H, –CH2CH3), 4.26 (q, J ¼ 6.9, 2H, –CH2CH3), 7.04–7.14 (m, 3H,
ArH), 8.32 (t, 1H, ArH), 10.14 (s, 1H, –NH–).
1.24 (s, 3H, –CH3), 1.25 (s, 3H, –CH3), 1.69 (d, JAB ¼ 5.4, 1H, –CH2–), 1.92 (d, JAB ¼ 5.4, 1H,
–CH2–), 1.32 (t, J ¼ 7.2, 3H, –CH2CH3), 4.24 (q, J ¼ 7.2, 2H, –CH2CH3), 7.57 (m, 2H, ArH),
7.71 (m, 2H, ArH), 10.20 (s, 1H, –NH–).

1f
47–49
134–136
149–150
1.24 (s, 3H, –CH3), 1.22 (s, 3H, –CH3), 1.62 (d, JAB ¼ 5.4, 1H, –CH2–), 1.88 (d, JAB ¼ 5.4, 1H,
–CH2–), 1.31 (t, J ¼ 7.2, 3H, –CH2CH3), 4.22 (q, J ¼ 7.2, 2H, –CH2CH3), 3.79 (s, 3H,
–ArOCH3), 7.47 (m, 2H, ArH), 6.86 (m, 2H, ArH), 9.72 (s, 1H, –NH–).
1.29 (s, 3H, –CH3), 1.35 (s, 3H, –CH3), 1.76 (d, JAB ¼ 4.8, 1H, –CH2–), 1.88 (d, JAB ¼ 4.8, 1H,
–CH2–), 7.10–7.15 (m, 1H, ArH), 7.31–7.36 (m, 2H, ArH), 7.52–7.55 (m, 2H, ArH), 9.17
(s, 1H, –NH–).
79.4
66.9
99.3
2a
2b
1.28 (s, 3H, –CH3), 1.34 (s, 3H, –CH3), 1.75 (d, JAB ¼ 5.1, 1H, –CH2–), 1.84 (d, JAB ¼ 5.1, 1H,
–CH2–), 2.32 (s, 3H, ArCH3), 7.13 (d, J ¼ 8.1, 2H, ArH), 7.40 (d, J ¼ 8.1, 2H, ArH), 9.06(s, 1H,
–NH–).
2c
2d
2e
2f
142–144
106–109
138–141
117–118
1.28 (s, 3H, –CH3), 1.35 (s, 3H, –CH3), 1.76 (d, JAB ¼ 5.1, 1H, –CH2–), 1.90 (d, JAB ¼ 5.1, 1H,
–CH2–), 6.99–7.05 (m, 2H, ArH), 7.47–7.52 (m, 2H, ArH), 9.26 (s, 1H, –NH–).
1.29 (s, 3H, –CH3), 1.37 (s, 3H, –CH3), 1.77 (d, JAB ¼ 5.1, 1H, –CH2–), 1.96 (d, JAB ¼ 5.1, 1H,
–CH2–), 7.02–7.14 (m, 4H, ArH), 8.23–8.28 (m, 1H, ArH), 9.70 (s, 1H, –NH–).
1.29 (s, 3H, –CH3), 1.38 (s, 3H, –CH3), 1.79 (d, JAB ¼ 5.1, 1H, –CH2–), 1.99 (d, JAB ¼ 5.1, 1H,
–CH2–), 7.58 (m, 2H, ArH), 7.69 (m, 2H, ArH), 9.66 (s, 1H, –NH–).
80.5
79.7
94.1
85.4
1.28 (s, 3H, –CH3), 1.34 (s, 3H, –CH3), 1.76 (d, JAB ¼ 5.1, 1H, –CH2–), 1.82 (d, JAB ¼ 5.1, 1H,
–CH2–), 3.79 (s, 3H, –ArOCH3), 6.86 (m, 2H, ArH), 7.42 (m, 2H, ArH), 8.95 (s, 1H, –NH–).

Table 2.
IR(KBr)
cm21
MS
(IE)m/z
Yield
(%)
Compound
Mp (8C)
1H and 13C NMR (CDCl3, 300 MHz, ppm)
3a
228–229
3114, 2990,
1659, 1620
1H NMR: 1.60 (s, 6H, 2 Â –CH3), 3.08 (s, 2H, –CH2–), 7.18–7.72
(m, 4H, Ar-H), 11.86 (s, 1H, –NH–). 13C NMR: 28.9, 40.4, 91.4,
107.6, 112.2, 116.6, 122.1, 122.6, 130.9, 139.7, 163.7, 163.8.
214.2
230.2
53.5
3b
241–242
3114, 2990,
1659, 1620
1H NMR: 1.60 (s, 6H, 2 Â –CH3), 2.41 (s, 3H, –CH3), 3.08 (s, 2H,
–CH2–), 7.30–7.49 (m, 4H, Ar-H), 12.10 (s, 1H, –NH–). 13C NMR:
21.2, 28.8, 40.4, 91.2, 107.6, 112.1, 116.5, 122.0, 131.7, 132.3, 137.8,
163.5, 163.7.
12
3c
253–254
249–251
3394, 2999,
1659, 1626
1H NMR: 1.60 (s, 6H, 2 Â –CH3), 3.08 (s, 2H, –CH2–), 7.22–7.48
232.1
232.2
69
21
(m, 4H, Ar-H), 12.35 (s, 1H, –NH–). 13C NMR: 28.74, 40.41, 91.71
3d
3154, 2978,
1661, 1626
1H NMR: 1.60 (s, 6H, 2 Â –CH3), 3.04 (s, 2H, –CH2–), 7.13–7.18
(m, 1H, Ar-H), 7.26–7.32 (m, 1H, Ar-H), 7.49–7.52 (m, 1H, Ar-H),
12.35 (s, 1H, –NH–).
3e
3f
267–269
234
3154, 2978,
1662, 1627
1H NMR: 1.63 (s, 6H, 2 Â –CH3), 3.09 (s, 2H, –CH2–), 7.28–7.44
282.2
246.1
5
(m, 1H, Ar-H), 7.70–7.76 (m, 1H, Ar-H), 10.75 (s, 1H, –NH–).
3154, 2978,
1662, 1626
1H NMR: 1.60 (s, 6H, 2 Â –CH3), 3.09 (s, 2H, –CH2–), 3.86 (s, 3H,
–CH3), 7.08–7.26 (m, 1H, Ar-H), 7.40–7.43 (m, 1H, Ar-H), 12.34
(s, 1H, –NH–). 13C NMR: 28.9, 40.8, 56.0, 91.3, 102.9, 108.0, 112.5,
118.1, 121.1, 134.5, 154.9, 163.2, 163.3.
35.8

Angular Dihydrofuroquinoline Alkaloids
699
Figure 2. Mechanism of formation of quinolinone ring and furan ring in one step.
TYPICAL PROCEDURE
SOCl2 was added to the solution of monoester in petroleum ester and then
refluxed for 1–2 h. The mixture was concentrated in vacuo, and the solvent
was removed. The solution of substituted anline and Et3 N in THF was
added dropwise at 08C and stirred at room temperature for 1.5 h after the
dropping finished. The THF was removed, water was added, and then the
mixture was extracted by EtOAc. The organic layer was dried and concen-
trated. The product 1 was obtained after purification by column chromatogram
(PE/EtOAc).
A suspension of 1 in MeOH and 1 N NaOH was stirred under refluxing for
2 h. The resulting clear solution was condensed in vacuo. The residue was
acidified by addition of an excess of 0.5 M HCl and extracted with ethyl
acetate. The organic layer was washed by water, dried by MgSO4, filtered,
and evaporated in vacuo to give pure 2 as a solid.
The mixture of 2 in PPA was heated at 100–1108C for 1 h. The mixture
was poured into cold water and extracted with ethyl acetate. After drying, the
organic layer was concentrated in vacuo, and the crude product 3 was
obtained. Purification could be done by ethanol.
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