New synthesis of linear furoquinoline alkaloids

Article abstract of DOI:10.1016/j.tetlet.2004.09.041

A new synthetic method for the synthesis of the linear furoquinoline alkaloids, dictamnine, γ-fagarine, evolitrine and pteliene from 3-oxiranylquinoline using dimethylsulfonium methylide is described.

Full text of DOI:10.1016/j.tetlet.2004.09.041

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9483–9485
New synthesis of linear furoquinoline alkaloids
Umadevi Bhoga,* R. S. Mali and Srinivas R. Adapa*
Inorganic Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 24 June 2004; revised 25 August 2004; accepted 3 September 2004
Available online 5 November 2004
Abstract—A new synthetic method for the synthesis of the linear furoquinoline alkaloids, dictamnine, c-fagarine, evolitrine and
pteliene from 3-oxiranylquinoline using dimethylsulfonium methylide is described.
ꢀ 2004 Elsevier Ltd. All rights reserved.
OMe
N
1. Introduction
OMe
N
MeO
The furoquinoline alkaloids of dictamnine type (1–4) are
derivatives of the furo[2,3-b] quinoline system, which
occurs widely in Rutaceae plant species.1 These com-
pounds have several pharmacological properties such
as antimicrobial,2 antiviral,3 mutagenic4 and cytotoxic5
activities. Several methods have been reported for the
synthesis of furoquinoline alkaloids (Fig. 1).6–16
O
O
2
1
Pteleine
OMe
Dictamnine
OMe
A common feature of the reported syntheses of the furo-
quinoline alkaloids is that the quinoline ring is built
along with an appropriate carbon chain at the 3-posi-
tion, which is then modified into the furan ring. This
is necessary because incorporation of a carbon chain
later at the 3-position of the quinoline ring through an
electrophilic aromatic substitution is difficult. For exam-
ple, it has been reported that introduction of a formyl
group at the 3-position of 2,4-dimethoxyquinolines by
a Vilsmeier–Haack reaction gave a complex reaction
mixture. Narasimhan and co-workers14b,17,18 overcame
this problem by introducing a formyl group at the 3-
position using an aromatic lithiation reaction. 3-Form-
ylquinolines can be converted into 3-quinolinylacetalde-
hydes by reaction with Wittig ylides. These 3-
quinolinylacetaldehydes were then cyclized if an oxygen
substituent was present at the C-2 position of the quin-
oline ring, to furoquinoline alkaloids by reaction with
polyphosphoric acid. Herein we reportan improved syn-
thetic methodology for the construction of furoquino-
N
O
MeO
N
3
O
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4
γ
-fagarine
Evolitrine
Figure 1. Structures of furoquinoline alkaloids.
line alkaloids from 3-formylquinolines in good yields
requiring fewer steps than those reported earlier.
In our strategy, 3-formylquinolines were synthesized
from 2,4-dimethoxy quinolines (5a–d). The second step
was conversion of the 3-formylquinolines into the corre-
sponding 3-oxiranylquinolines, and finally inducing acid
catalyzed intramolecular cyclization to yield the desired
furoquinoline alkaloids. We synthesized the 3-formyl-
quinolines by reaction between 2,4-dimethoxyquinolines
and n-butyllithium and then dimethylformamide. This
gave the corresponding 3-formylquinolines (6a–d) in
good yields (48–60%). The 3-formylquinolines were treat-
ed with dimethylsulfonium methylide19 to afford the
corresponding 3-oxiranylquinolines. This reaction gave
various products depending on the substituents on the
aromatic ring. For example, 6a gave both 3-oxiranyl-
quinoline 7a and dictamnine 1, which were separ-
ated, in 34% and 10% yields, respectively, by column
*
Corresponding author: S. R. Adapa. E-mail addresses: rsmali@
rediffmail.com; asrinivas_raa@iict.res.in
Present address: University of North Maharashtra, 80, Umavinagar,
Jalgaon 425001, North Maharashtra, India. Tel.: +91 257 2258404;
fax: +91 257 2258403.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.041

9484
U. Bhoga et al. / Tetrahedron Letters 45 (2004) 9483–9485
R1
R1
OMe
OMe
N
R2
R2
R3
CHO
n-BuLi/ether
DMF/0 0C/rt
Me
O
N
Me
O
R3
1 h/48-60%
R4
R4
5a-d
6a-d
5a : R1=R2=R3=R4=H
5b : R1=R3=R4=H;R2=OMe
5c : R1=R2=R4=H;R3=OMe
5d : R1=R2=R3=H;R4=OMe
R1
R1
OMe
OMe
N
OMe
O
R2
R3
R2
(CH3)3S+I-
CHO
+
DMSO/NaH
THF/0 0C/30 min
50%
Me
O
N
O
Me
O
N
R3
R4
7a
R4
1
6a
R1
R1
R1
OMe
N
OMe
OMe
R2
R3
O
R2
R2
(CH3)3S+I-
CHO
Me
CHO
+
DMSO/NaH
Me
O
Me
O
THF/0 0C/30 min
50%
N
N
O
R3
R3
R4
R4
R4
6b-d
7b-d
8b-d
R1
R1
OMe
N
OMe
N
O
R2
R2
R3
PPA
105 0C/2 h
40-70%
Me
O
R3
O
R4
7a-d
R4
1,2,3,4
R1
R1
OMe
OMe
R2
R2
R3
CHO
Me
1 : R1=R2=R3=R4=H
PPA
2 : R1=R3=R4=H;R2=OMe
3 : R1=R2=R4=H;R3=OMe
4 : R1=R2=R3=H;R4=OMe
105 0C/2 h
40-70%
N
O
N
O
R3
R4
8b-d
R4
2,3,4
Scheme 1. Synthesis of furoquinoline alkaloids.
chromatography. Complete conversion of the oxiranyl-
quinoline to dictamnine did not occur (Scheme 1).
(15mL) in dry THF (15mL) was added 6a (3.1g,
15mmol) at0 ꢁC and the reaction mixture was allowed
to stir for 25min at rt with monitoring by TLC. After
the reaction was complete the reaction mixture was
poured in ice-cold water (250mL) and extracted with
chloroform (5 · 10mL). The combined extracts were
washed with water and sodium thiosulfate solution and
dried over Na2SO4. Evaporation of the solvent gave a
residue which was purified by chromatography over sil-
ica gel using benzene as eluent to afford firstly the 3-
oxiranylderivative 7a as solid (1g, 34%), mp 95ꢁC,
1H NMR (300MHz, CDCl3): d 2.60 (m, 1H), 2.90 (m,
1H), 3.95 (s, 3H, OCH3), 4.08 (s, 3H, OCH3), 5.05
(m, 1H), 7.32 (m, 1H), 7.38 (m, 1H), 7.56 (m, 1H), 7.74
(m, 1H).
The reaction of 3-formylquinolines (6b–d) with the sul-
fonium ylide gave 3-oxiranylquinolines (7b–d) and
quinolinylacetaldehydes (8b–d) in 43–55% and 42–
57% yields, respectively. This suggests that the 3-oxiran-
ylquinoline undergoes a 1,2-hydride shiftto give 3-quin-
olinylacetaldehydes. However, the mechanism is not
well understood. Finally, the 3-oxiranylquinolines and
the 3-quinolinylacetaldehydes were separately cyclized
in polyphosphoric acid (PPA) to obtain the correspond-
ing furoquinolines in 30–80% yields.
The synthesis of 3-formylquinolines is well known.14b
Further elution with benzene gave dictamnine 1 (310mg,
10%), which was identical with an authentic sample.
Mp130ꢁC (lit. mp 131ꢁC),20 1H NMR (300MHz,
CDCl3): d 4.28 (s, 3H), 6.95 (d, J = 2.7Hz, 1H), 7.39
(ddd, J = 8.3, 6.8, 1.5Hz, 1H), 7.53 (d, J = 2.7Hz,
2. Typical reaction: 2,4-dimethoxy-3-oxiranylquinoline 7a
To a well-stirred solution of trimethylsulfonium iodide
(4.5g, 22mmol), NaH (528mg, 22mmol) and DMSO

U. Bhoga et al. / Tetrahedron Letters 45 (2004) 9483–9485
9485
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1H), 7.64 (ddd, J = 8.3, 6.8, 1.7Hz, 1H), 8.00 (dd,
J = 8.6, 1.5Hz, 1H), 8.19 (dd, J = 8.3, 1.7Hz, 1H).
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3. 2,4,6-Trimethoxyquinolinyl-3-acetaldehyde 8b
1
Yield 42%, mp 111ꢁC, H NMR (300MHz, CDCl3): d
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J = 1.5Hz, 1H), 7.18 (dd, J = 8, 1.5Hz, 1H), 7.48 (d,
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4. Furoquinoline alkaloids
3-Oxiranylquinolines (7a–d) and quinolinylacetalde-
hydes (8b–d) (1.3mmol) were separately heated with
polyphosphoric acid at125–130 ꢁC for 2h. The reaction
mixture was poured onto crushed ice (10g), neutralized
with aqueous sodium bicarbonate and extracted with
ether (5 · 10mL). The combined organic layer was
washed with water and dried (Na2SO4). Evaporation
of the solvent furnished a residue, which was purified
14. (a) Narasimhan, N. S.; Paradkar, M. V.; Alurkar, R. H.
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ugakuzasshi 1968, 88, 1050–1053.
by chromatography over silica gel using benzene as elu-
21,22
entot afford furoquinoline alkaloids. Dictamnine 1
was obtained in 70% yield using the above procedure.
16. Rajamanickam, P.; Shanmugam, P. Indian J. Chem. 1987,
26B, 910–913.
17. Narasimhan, N. S.; Paradkar, M. V. Chem. Ind. 1967,
831–832.
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Tetrahedron 1970, 27, 1347–1355.
Acknowledgements
19. (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965,
87, 1353–1355; (b) Treatment of trimethylsulfonium
iodide with a strong base (60% NaH in DMSO–THF)
gave a solution of dimethylsulfonium methylide. This heat
labile reagent liberated in situ is an exceedingly selective
methylene transfer reagent, which is of great use for
converting carbonyl compounds into epoxides. In this
reaction, THF is used to prevent freezing of the reaction
The authors thank the Head, Department of Chemistry,
Garware Research Centre, University of Pune and the
Director, IICT for their constant encouragement and
providing ample facilities.
References and notes
mixture.
Reactions
involving
dimethylsulfonium
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