Thermolysis of 2-(3-phenylsulfonyiprop-l-ynyl)benzonitrile: An aza-Myers type cyclization to isoquinolines

Article abstract of DOI:10.1039/a905509f

Thermolysis of 2-(3-phenylsulfonylprop-l-ynyl)benzonitrile (3) in refluxing benzene containing cyclohexa-1,4diene and triethylamine gave isoquinolone 4 in 7% yield and compound 5 in 10% yield and 14% of the starting material was recovered. When this cyclizatioen reaction was carried out under oxygen atmosphere, compound 4 was isolated in 14% yield and 20% of the starting,benzonitrile 3 was recovered. Under refluxing carbon tetrachloride, cyclizatioen of 3 gave the chloroisoquinoline 6 in 18% yield and 5 in 22% yield. The isolation of compounds 4 and 6 strongly suggests the formation of biradical 8 through a (Z)hexa-2,4,5-trienenitriIe intermediate 7. The Royal Society of Chemistry 1999.

Full text of DOI:10.1039/a905509f

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Thermolysis of 2-(3-phenylsulfonylprop-1-ynyl)benzonitrile:
an aza-Myers type cyclization to isoquinolines
Ming-Jung Wu,* Chi-Fong Lin, Shang-Hung Chen and Fang-Chen Lee
School of Chemistry, Kaohsiung Medical College, Kaohsiung, Taiwan
Received (in Cambridge, UK) 8th July 1999, Accepted 6th September 1999
Thermolysis of 2-(3-phenylsulfonylprop-1-ynyl)benzo-
nitrile (3) in refluxing benzene containing cyclohexa-1,4-
diene and triethylamine gave isoquinolone 4 in 7% yield and
compound 5 in 10% yield and 14% of the starting material
was recovered. When this cyclization reaction was carried
out under oxygen atmosphere, compound 4 was isolated in
14% yield and 20% of the starting benzonitrile 3 was re-
covered. Under refluxing carbon tetrachloride, cyclization
of 3 gave the chloroisoquinoline 6 in 18% yield and 5 in
22% yield. The isolation of compounds 4 and 6 strongly
suggests the formation of biradical 8 through a (Z)-
hexa-2,4,5-trienenitrile intermediate 7.
When a benzene solution of 3 (0.01 M), containing cyclo-
hexa-1,4-diene (1.5 M) and Et3N (3 equiv.), was heated to reflux
for 2.5 days, isoquinolone 4 was obtained in 7% yield and com-
pound 5 was produced in 10% yield after preparative-scale thin
layer chromatography. 14% of the starting nitrile 3 is recovered
(Scheme 2).10 When compound 3 was stirred in refluxing carbon
The mechanism of the formation of biradicals derived from
enediyne antitumor antibiotics has attracted much attention
due to their DNA-cleaving properties.1 In 1972, Jones and
Bergman reported the thermal cyclization of (Z)-hex-3-ene-1,5-
diynes to 1,4-didehydrobenzene diradicals.2 This cyclization is
considered to be the major mode of formation of biradical inter-
mediates in enediyne antitumor antibiotics. In studies on the
mechanism of the DNA-cleaving activity of the neocarzinostatin
chromophore, Myers and co-workers reported the cyclization
of (Z)-hepta-1,2,4-trien-6-ynes to α,3-didehydrotoluene.3
Several potent DNA-cleaving agents have been developed based
on Myers cyclization.4,5 A similar cyclization occurs in the
thermolysis of alkynylcyclobuten-4-one in which a biradical
containing aryl and phenoxyl radical centers is produced via an
enyne-ketene, as described by Moore and Yerxa.6 An alternative
pathway to enyne-ketenes was reported by Saito and co-
workers, which involved the photochemical Wolff rearrange-
ment of enynyl α-diazo ketones.7 Recently, efforts have been
made to cycloaromatize a conjugated system involving hetero-
atoms.8 Among these studies, there are two reports that describe
the cyclization of (Z)-hexa-2,4,5-trienenitrile systems. One
failed to obtain the cyclization product and the other obtained
aniline adducts through an unusual stabilized allylic radical
addition to nitrile.9 In this communication, we report the
first successful example to isolate isoquinoline derivatives by
thermolysis of 2-(3-phenylsulfonylprop-1-ynyl)benzonitrile (3)
under alkaline conditions.
Scheme 2 Reagents and conditions: i cyclohexa-1,4-diene, benzene,
Et3N, reflux, 2.5 days, 4 (7%) and 5 (10%). ii) CCl4, reflux, 2 days, 6
(18%) and 5 (20%).
tetrachloride in the presence of Et3N for two days, the 1-
chloroisoquinoline 6 was isolated in 18% yield along with
compound 5 in 22% yield. The structure of compound 5
was unambiguously determined by X-ray crystallography. The
isolation of compounds 4 and 6 strongly suggests the biradical
intermediate 8 is the intermediate of this cyclization reaction.
A rational explanation for the formation of compounds 4 and
6 is proposed (Scheme 3). Base-catalyzed isomerization of
The synthesis 2-(3-phenylsulfonylprop-1-ynyl)benzonitrile
(3) is outlined in Scheme 1. 2-Iodobenzonitrile (1) was directly
᎐
Scheme 1 Reagents and conditions: i) HC᎐CCH2SPh, Pd(PPh3)4, Et2O,
᎐
Scheme 3
CuI, BuNH2, 46%; ii) MCPBA, CH2Cl2, 76%.
coupled to propargyl phenyl sulfide using tetrakis(triphenyl-
phosphine)palladium(0) as the catalyst in the presence of
cuprous iodode and n-butylamine, to give 2-(3-phenylthioprop-
1-ynyl)benzonitrile (2) in 46% yield. Oxidation of sulfide 2 with
3 equivalents of MCPBA gave compound 3 in 76% yield.
propargyl sulfone 3 gives allenyl sulfone 7 which is not isolable
and subsequently undergoes a Myers-type cyclization to pro-
duce the biradical intermediate 8. Trapping the σ-radical of 8
with molecular oxygen and the α-radical with cyclohexadiene
gives compound 4. On the other hand, trapping the σ-radical
J. Chem. Soc., Perkin Trans. 1, 1999, 2875–2876
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(b) K. C. Nicolaou, P. Maligres, J. Shin, E. de Leon and D. Rideout,
of 8 with carbon tetrachloride and hydrogen abstraction by the
α-radical possibly from triethylamine leads to 6. In order to
examine our hypothesis for the formation of compound 4, a
control experiment was carried out; treatment of 3 with Et3N
under refluxing benzene and cyclohexa-1,4-diene under oxygen
atmosphere for 24 h. Compound 4 was isolated in 14% yield
and 20% of the starting nitrile 3 was recovered. The increased
amount of compound 4 isolated under these conditions
supports our hypothesis. The mechanism for the formation
of compound 5 is not clear at this stage. A possible pathway
is proposed. In the base-catalyzed isomerization of propargyl
sulfone to allenyl sulfone, a small amount of phenyl sulfonyl
anion was produced via an Ei mechanism. The phenyl sulfonyl
anion then added to the allenyl sulfone 7 via a 1,4-addition
to give compound 5.
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6 For a review of cyclization of enyne-ketenes, see: H. W. Moore and
B. R. Yerxa, Chemtracts, 1992, 273.
In conclusion, we have demonstrated the first successful
example of thermal cyclization of the (Z)-hexa-2,4,5-tri-
enenitrile system to form isoquinoline derivatives and proved
that this cyclization involved a diradical intermediate. The
discovery of this new method of biradical formation provides
a valuable source for theoretical study of enediyne related
systems and an opportunity to design new DNA-cleaving anti-
tumor agents.
7 K. Nakatani, S. Isoe, S. Maekawa and I. Saito, Tetrahedron Lett.,
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Q. Zhang and K. K. Wang, J. Org. Chem., 1999, 64, 925.
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61, 1516; (b) T. Gillmann, S. Heckhoff and T. Weeber, Tetrahedron
Lett., 1996, 37, 839.
10 Some physical properties of 2, 3, 5, 6 and 7. 2: 1H NMR (CDCl3, 200
MHz) δ 7.19–7.64 (m, 9H), 3.91 (s, 3H); 13C NMR (CDCl3, 49.9
MHz) δ 134.8, 132.7, 132.6, 132.2, 130.5, 129.1, 128.3, 127.1, 126.8,
125.3, 117.4, 115.3, 92.4, 79.7, 60.4; MS (EI) m/z 249 (Mϩ, 100%),
140 (85%) (HRMS (EI) calcd. for C16H11NS 249.0613. Found
Acknowledgements
1
249.0609). 3: H NMR (CDCl3, 200 MHz) δ 8.07 (dd, 2H, J = 8.4,
We thank the National Science Council of the Republic of
China for financial support of this work.
1.4 Hz), 7.44–7.72 (m, 7H), 4.29 (s, 2H); 13C NMR (CDCl3, 49.9
MHz) δ 137.8, 134.4, 133.0, 132.8, 132.4, 129.3, 129.2, 128.8, 125.4,
117.0, 115.3, 83.5, 83.4, 49.3; MS (EI) m/z 281 (Mϩ, 5%), 233 (7%),
140 (100%) (HRMS (EI) calcd. for C16H11NO2S 281.0511. Found
281.0516). 4: 1H NMR (CDCl3, 400 MHz) δ 7.96 (d, 2H, J = 8.1 Hz),
7.51–7.69 (m, 6H), 7.35 (t, 1H, J = 7.6 Hz), 6.21 (s, 1H), 4.27 (s, 2H);
MS (EI) m/z 299 (Mϩ, 23%), 267 (36%), 158 (100%) (HRMS calcd.
Notes and references
1 For selected reviews of enediyne chemistry, see: (a) J. W. Grissom,
G. U. Gunawardena, D. Klingberg and D. Huang, Tetrahedron,
1996, 52, 6453; (b) K. K. Wang, Chem. Rev., 1996, 96, 207;
(c) K. C. Nicolaou, W.-M. Dai, S.-C. Tsai, V. Z. Estevez and
W. Wrasidlo, Science, 1992, 256, 1172; (d) K. C. Nicolaou and
A. L. Smith, Acc. Chem. Res., 1992, 25, 497; (e) K. C. Nicolaou and
W.-M. Dai, Angew. Chem., Int. Ed. Engl., 1991, 30, 1387.
1
for C16H13NO3S 299.0617. Found 299.0608). 5: H NMR (CDCl3,
400 MHz) δ 8.21 (s, 1H), 7.93 (dd, 2H, J = 8.6, 1.1 Hz), 7.46–7.76
(m, 14H), 4.42 (s, 2H); MS (EI) m/z, 282 (Mϩ Ϫ C6H5SO2), 218 (17),
141 (38), 77 (100) (HRMS calcd. for C16H12NOS (Mϩ Ϫ C6H5SO2)
1
282.0590. Found 282.0590). 6: H NMR (CDCl3, 400 MHz) δ 8.20
(dt, 1H, J = 7.9, 0.7 Hz), 7.86 (dt, 2H, J = 7.9, 0.7 Hz), 7.42–7.73 (m,
6H), 6.64 (s, 1H), 4.26 (d, 2H, J = 3.1 Hz); 13C NMR (CDCl3, 100
MHz) δ 144.9, 138.3, 136.1, 135.1, 134.5, 129.7, 129.4, 129.2, 128.5,
128.4, 126.0, 120.7, 109.5, 29.7 (HRMS calcd. for C16H12O2N35ClS
317.0279. Found 317.0266).
2 R. R. Jones and R. G. Bergman, J. Am. Chem. Soc., 1972, 94, 660.
3 (a) A. G. Myers, P. S. Dragovich and E. Y. Kuo, J. Am. Chem. Soc.,
1992, 114, 9369; (b) A. G. Myers, E. Y. Kuo and N. S. Finney, J. Am.
Chem. Soc., 1989, 111, 8057; (c) A. G. Myers and P. S. Dragovich,
J. Am. Chem. Soc., 1989, 111, 9130.
4 (a) K. Toshima, O. Kazumi, A. Ohashi, T. Nakamura, M. Nakata,
K. Tatsuta and S. Matsumura, J. Am. Chem. Soc., 1995, 117, 4822;
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