Double anionic cycloaromatization of 2-(6-substituted-3-hexene-1,5-diynyl)-benzonitriles initiated by methoxide addition

Article abstract of DOI:10.1021/ol990137y

Formula presented Treatment of 2-((3Z)-undecene-1,5-diynyl)benzonitrile with 5 equiv of sodium methoxide in refluxing methanol for 16 h gave 1-pentyl-6-methoxyphenanthridine in 12% yield, 1-pentyl-6-phenanthridone in 6% yield, and 2-(2-pentyl-6-methoxyphe

Full text of DOI:10.1021/ol990137y

ORGANIC
LETTERS
1999
Vol. 1, No. 5
767-768
Double Anionic Cycloaromatization of
2-(6-Substituted-3-hexene-1,5-diynyl)-
benzonitriles Initiated by Methoxide
Addition
Ming-Jung Wu,* Chi-Fong Lin, and Shang-Hung Chen
School of Chemistry, Kaohsiung Medical College, Kaohsiung, Taiwan
mijuwu@cc.kmc.edu.tw
Received June 21, 1999
ABSTRACT
Treatment of 2-((3Z)-undecene-1,5-diynyl)benzonitrile with 5 equiv of sodium methoxide in refluxing methanol for 16 h gave 1-pentyl-6-
methoxyphenanthridine in 12% yield, 1-pentyl-6-phenanthridone in 6% yield, and 2-(2-pentyl-6-methoxyphenyl)benzonitrile in 4% yield. Under
the same reaction conditions, methanolysis of several other benzonitriles gave similar results. Phenanthridine and biphenyl derivatives were
obtained as the major products. A mechanism for this novel cycloaromatization reaction of enediynes is proposed.
The cycloaromatization of enediynes and structurally related
molecules has attracted much attention due to their ability
to cleave DNA, their value for theoretical investigation, and
their utility in synthetic chemistry.1 Most of the investigations
of the cycloaromatization mechanisms of enediynes and
related compounds have concentrated on the formation of
diradical intermediates because it has been generally assumed
that the formation of a diradical intermediate is a prerequisite
for biological activity.2 Only a few workers have described
the nonradical cycloaromatization of enediynes. Recently
Magnus3 reported a nonradical cycloaromatization of the
azabicyclo[7.3.1]enediyne core which was initiated by thi-
olate addition and concluded that diradical formation is not
a prerequisite for biological activity in that system. Another
nonradical type cycloaromatization of enediynes has been
reported by Saito’s group4 which demonstrates that neo-
carzinostatin cycloaromatizes with incorporation of one
deuterium atom (80%) in the aromatic ring under physico-
logical conditions (D2O/buffered 2-mercaptoethanol). To
better understand the duality of the mechanisms of the
cycloaromatization of enediynes and the relationship of these
mechanisms to their biological activity, we have investigated
a direct nonradical cycloaromatization of (3Z)-3-hexene-1,5-
diyne.
In this paper we report that 2-(6-substituted-3-hexene-1,5-
diynyl)benzonitriles (1) undergo anionic cycloaromatization
upon treatment with sodium methoxide in refluxing methanol
to form phenanthridines5 and biphenyls.6 Both of these
classes of molecules have biological and structural signifi-
cance.
(1) (a) Nicolaou, K. C.; Dai, W. M. Angew. Chem., Int. Ed. Engl. 1991,
30, 1387. (b) Grissom, J. W.; Gunawardena, G. U.; Klingberg, D.; Huang,
D. Tetrahedron 1996, 52, 6453. (c) Wang, K. K. Chem. ReV. 1996, 96,
207.
(4) Sugiyama, H.; Yamashita, K.; Nishi, M.; Saito, I. Tetrahedron Lett.
1992, 33, 515.
(2) Nicolaou, K. C.; Smith, A. L. Acc. Chem. Res. 1992, 25, 497.
(3) Magnus, P.; Eisenbeis, S. A.; Rose, W. C.; Zein, N.; Solomon, W.
J. Am. Chem. Soc. 1993, 115, 12627.
(5) Lews, J. R. Nat. Prod. Rep. 1997, 14, 303.
(6) (a) Mislow, K. Introduction of Stereochemistry, Benjamin: Reading,
MA, 1965; pp 78-82. (b) Oki, M. Top. Stereochem. 1983, 14, 1.
10.1021/ol990137y CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/03/1999

2-(6-Substituted-3-hexene-1,5-diynyl)benzonitriles (1a-
d) were obtained in 17-52% yields by the reaction of vinyl
chlorides 2a-d with 2-ethynylbenzonitrile (3)7 in ethyl ether
containing 5 mol % tetrakis(triphenylphosphine)palladium
(0), 15 mol % cuprous iodide, and 5 equiv of n-butylamine
(eq 1). The results of the cycloaromatization reactions of
anionic cycloaromatization to form anion 9a. Anion 9a then
undergoes a second anionic cycloaromatization to give anion
9b. Protonation of 9b affords phenanthridine 4 which is
hydrolyzed during acid workup to give phenanthridinone 5.
If protonation of 9a takes place faster than the second anionic
cycloaromatization, isoquinoline 7 is obtained. The formation
of 6 involves the addition of methoxide to C2 of the enediyne
unit and anionic cycloaromatization by the initially formed
vinyl anion to give 10. Finally, protonation of 10 leads to
biphenyl 6 (Scheme 2).
Scheme 2
1a-d are summarized in Scheme 1. Treatment of 1a with 5
equiv of sodium methoxide in refluxing methanol for 16 h
gave, after the isolation of the products and column chro-
matography, phenanthridine 4a in 4% yield along with
phenanthridinone 5a in 7% yield. Methanolysis of 1b under
the same reaction conditions gave 4b in 12% yield, 5b in
6% yield, and 6b in 4% yield. Similarly, cycloaromatization
of 1c gave biphenyl 6c in 9% yield along with 4c (1%) and
5c (17%). Under the same reaction conditions, compound
1d cyclized in the same manner as 1a-c to give 4d in 26%
yield and isoquinoline 7d in 12% yield (Scheme 1).
Scheme 1
In conclusion, we have demonstrated that treatment of
(3Z)-2-(6-substituted-3-hexene-1,5-diynyl)benzonitriles with
sodium methoxide in refluxing methanol gave phenan-
thridines and biphenyls. A reaction mechanism is proposed
which is the anionic cycloaromatization of the enediyne, and
product formation is dependent upon the regiochemistry of
the nucleophilic addition. This novel cascade cyclization
provides another aspect of enediyne chemistry which is not
only of pharmaceutical and theoretical value but also has
potential synthetic applications.
Acknowledgment. We thank the National Science Coun-
cil of the Republic of China for financial support of this
work.
A plausible mechanistic explanation for the formation of
4, 5, and 7 involves methoxide addition to the cyano group
of 1. The initially formed iminium anion undergoes an
Supporting Information Available: Listing of selected
spectroscopic data for compounds 1a-d, 4a-d, 5a-c, 6b-
c, and 7d. This material is available free of charge via the
Internet at http://pubs.acs.org.
(7) 2-Ethynylbenzonitrile (3) was prepared from 1,2-diiodobenzene in
three steps: palladium-catalyzed coupling reaction of trimethylsilylacetylene
with 1,2- diiodobenzene to give 2-(2-trimethylsilylethynyl)iodobenzene (11)
in 58% yield; iodobenzene 11 was then coupled with Zn(CN)2 using
palladium(0) as a catalyst to give 2-(2-trimethylsilylethynyl)benzonitrile (12)
in 45% yield; and finally the trimethylsilyl group of 12 was removed by
treatment of 12 with tetrabutylammonium fluoride to give 3 in 97% yield.
OL990137Y
768
Org. Lett., Vol. 1, No. 5, 1999