A convenient method for the synthesis of 1,8-bis(pyridin-3-oxy)oct-4-ene-2,6-diyne

Article abstract of DOI:10.1081/SCC-120004137

A convenient and rapid synthesis of the title compound is described. The key step in the procedure is the Stephens Castro coupling of 3-prop-2-ynyloxy-pyridine with cis-1,2- dichloroethylene and subsequent column purification in the final stage.

Full text of DOI:10.1081/SCC-120004137

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SYNTHETIC COMMUNICATIONS, 32(10), 1489–1494 (2002)
A CONVENIENT METHOD FOR THE
SYNTHESIS OF 1,8-BIS(PYRIDIN-
3
-OXY)OCT-4-ENE-2,6-DIYNE
Diwan S.Rawat and Jeffrey M.Zaleski *
Department of Chemistry, Indiana University,
IN 47405, USA
ABSTRACT
A convenient and rapid synthesis of the title compound is
described. The key step in the procedure is the Stephens
Castro coupling of 3-prop-2-ynyloxy-pyridine with cis-1,2-
dichloroethylene and subsequent column purification in the
final stage.
Key Words: Enediyne; Metal binding enediyne; Pyridylene-
diyne; Metalloenediyne
Syntheses of enediynes have received much attention after the discov-
1
ery of the natural product anticancer molecules such as esperamicin, cali-
2
3
4
5
cheamicin, dynemicin, neocarzinostatin, and C 1027 chromophore. The
key feature of these natural products is the 1,5-diyne-3-ene unit that
undergoes Bergman cyclization in the presence of biological reducing
6
equivalents to generate benzene-1,4-diradicals that abstract the hydrogen
atom from the sugar phosphate backbone of DNA, leading to strand
7
cleavage and, finally, cell death.
The ability to control formation of the 1,4-benzenoid diradical inter-
mediate of the enediyne antitumor antibiotics leads to the potential for
*
Corresponding author. E-mail: zaleski@indiana.edu
489
1
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1
490
RAWAT AND ZALESKI
8
designing new chemical entities with pharmacological utility. A number of
9
10
11
unique synthetic, photochemical, and electrochemical approaches have
been explored to initiate Bergman cyclization of organic enediynes in a
controlled manner.
The recent discovery that enediyne cyclization can be promoted at
reduced temperatures by the addition of metal salts has inspired the use
1
2–17
of transition metals for influencing Bergman cyclization reactions.
Recently we have reported the synthesis and thermal properties of a novel
metal chelating enediyne ligand, namely, 1,8-bis(pyridin-3-oxy)oct-4-ene-
2,6-diyne (5), which upon complexation with copper, cyclizes at a very
moderate temperature. These copper complexes also cyclize photochemi-
1
6
1
cally and show DNA cleaving activity. We have synthesized this metal
8
1
9
chelating ligand (5) using 1,8-dibromooct-4-ene-2,6-diyne as a starting
material, which was prepared by the coupling of tetrahydro-2-(2-propyny-
loxy)-2H-pyran with cis-1,2-dichloroethylene, followed by bromination.
Unfortunately, this method is very tedious, requires toxic reagents, is une-
conomical, and takes three days to prepare the desired compound.
In light of our ongoing study on metalloenediynes, we have developed
a simple and more facile method for the synthesis of this novel compound.
This new approach involves the use of 3-hydroxypyridine (1) and propargyl
bromide (2) as starting materials to prepare 3-prop-2-ynyloxy-pyridine (3) in
2
0,21
21
62% yield. Only two references are found in the scientific and patent
literature which actually describe the preparation of (3) (41% yield). In our

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2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
1
,8-BIS(PYRIDIN-3-OXY)OCT-4-ENE-2,6-DIYNE
1491
2
2
scheme, Stephens Castro coupling of 3-prop-2-ynyloxy-pyridine (3) with
cis-1,2-dichloroethylene (4) in the presence of Pd(0) and CuI led to the
formation of the desired product (5) in 51% yield. The monochloro product
2
3
(
6) is also produced in the reaction and can be easily separated by flash
chromatography. It is important to note that at room temperature this
ꢀ
reaction was very slow, while at 45 C, the reaction proceeds to complete
ꢀ
in 4 h. However, at higher temperatures (60–65 C), the alkyne decomposes
within 2 h. Progress of the reaction was monitered by NMR and TLC.
We conclude that the above-described synthesis of (5) is convenient,
economical, and provides rapid access to (5) in two steps. This synthesis
does not mandate preparation of 1,8-dibromooct-4-ene-2,6-diyne, which is
lachrymatic and requires bromine as a key reagent.
EXPERIMENTAL
Synthesis of 3-Prop-2-ynyloxy-pyridine (3)
To a mixture of 3-hydroxypyridine (5.0 g, 50 mmol) and KOH (8.8 g,
58 mmol) in DMF (30 ml), a solution of propargyl bromide (7.5 g,
3 mmol) in 10 ml DMF was added at 5–10 C. The reaction mixture was
1
6
ꢀ
stirred for 15 min and the product extracted with dichloromethane. The
organic layer was washed with excess of water to remove the DMF and
stirred with activated charcoal (5%) for 30 min. The dichloromethane layer
was filtered through a celite bed and the solvent removed. The pale yellow
product thus obtained did not require purification by column chromatogra-
ꢀ
1
phy. Yield: 4.3 g (62%); b.p. 185–186 C; H NMR (400 MHz, CDCl ): 2.65
3
(
1
s, 1H, CH), 4.72 (s, 2H, OCH ), 7.22–7.27 (m, 2H), 8.25 (m, 1H), 8.37 (s,
2
1
H); C NMR (CDCl ): 56.32 (OCH ), 76.36 (CH), 78.0 (Cquart), 121.88
3
3 2
(
CH), 123.98 (CH), 138.67 (CH), 143.19 (CH), 156.0 (Cquart); Mass; m/z:
þ þ
33 (M ), 95; HR-MS (EI) m/z: 133.14269 [M calcd for C H NO:
8 7
1
1
1
À1
33.14942]; IR (neat, cm ): 3056, 2120, 1575, 1476, 1427, 1278, 1220,
050, 925, 797, 705.
Synthesis of 1,8-Bis(Pyridin-3-oxy)oct-4-ene-2,6-diyne (5)
3
-Prop-2-ynyloxy-pyridine (3.0 g, 22 mmol) in 20 ml benzene was
added dropwise to a suspension of cis-1,2-dichloroethylene (1.0 g,
0 mmol), Pd(PPh ) (0.69 g, 0.59 mmol), CuI (0.23 g, 1.2 mmol), n-butyl-
1
3
4
ꢀ
amine (3.76 g, 50 mmol) and benzene (50 ml) at 45 C and reaction mixture
was stirred for 4 h at that temperature. The solvent was removed and the

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492
RAWAT AND ZALESKI
residue chromatographed (flash chromatography) on silica gel (10%
ether/dichloromethane) to yield 51% of the desired product (5) along with
12% of the chloro compound (6). Spectral data for (5); Cyclization tem-
perature 136 C (DSC); H NMR (400 MHz, CDCl ): 4.89 (s, 4H, OCH ),
ꢀ
1
3
2
1
.90 (s, 2H, CH), 7.24–7.30 (m, 4H), 8.20 (d, 2H), 8.40 (d, 2H); C NMR
3
5
(
CDCl ): 56.7 (OCH ), 84.6 (Cquart), 90.9 (Cquart), 119.8 (CH), 121.9
3
2
(
CH), 123.8 (CH), 138.6 (CH), 142.8 (CH), 153.7 (Cquart); Mass; m/z:
þ þ
90 (M ); HR-MS (EI) m/z: 290.10427 [M calcd for C H N O :
18 14 2 2
2
2
1
À1
90.1411]; IR (neat, cm ): 3056, 2216, 1576, 1475, 1375, 1180, 1130,
001, 798, 706, 619.
Synthesis of 3-(5-Chloro-pent-4-en-2ynyloxy)-pyridine (6)
ꢀ
1
Yield: 12%; b.p. 211–212 C; H NMR (400 MHz, CDCl ): 4.95 (s, 2H,
3
OCH ), 5.90 (d, J ¼ 8 Hz, 1H, CH), 6.46 (d, J ¼ 8 Hz, 1H, CH), 7.25–7.33
2
1
3
(
m, 2H), 8.27 (m, 1H), 8.42 (s, 1H); C NMR (CDCl ): 56.95 (OCH ), 82.0
3 2
(
(
1
1
1
Cquart), 91.23 (Cquart), 111.28 (CH), 121.94 (CH), 123.98 (CH), 130.97
þ
CH), 138.70 (CH), 143.05 (CH), 153.94 (Cquart); Mass: m/z; 195 (M þ2),
þ þ
93 (M ), 158, 130; HR-MS (EI) m/z: 193.02900 [M calcd for C H ClNO:
10 8
À1
93.02944]; IR (neat, cm ): 3084, 2213, 1574, 1475, 1427, 1276, 1219, 1128,
048, 1001, 796, 705.
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Received in the USA May 14, 2001