Decarboxylative cycloaromatization of enediyne model compounds-mechanism of the radical and ionic pathway

Article abstract of DOI:10.1016/S0040-4039(99)02009-2

Stable α-alkynylacetic acid derivatives related to cis-enediyne were synthesized and the rate of decarboxylative cycloaromatization of 3,5-difluoro derivative 7c was found to be much faster than that of the corresponding phenyl derivative 7a. The cycloaro

Full text of DOI:10.1016/S0040-4039(99)02009-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 95–98
Decarboxylative cycloaromatization of enediyne model
compounds— mechanism of the radical and ionic pathway
Masakazu Wakayama, Ichiro Suzuki, Tadaaki Kawakami, Hisao Nemoto and
Masayuki Shibuya ∗
Faculty of Pharmaceutical Sciences, University of Tokushima, Sho-machi 1, Tokushima 770-8505, Japan
Received 27 August 1999; revised 7 October 1999; accepted 12 October 1999
Abstract
Stable α-alkynylacetic acid derivatives related to cis-enediyne were synthesized and the rate of decarboxylative
cycloaromatization of 3,5-difluoro derivative 7c was found to be much faster than that of the corresponding phenyl
derivative 7a. The cycloaromatization reaction mechanisms of 7c under various conditions were investigated.
© 1999 Elsevier Science Ltd. All rights reserved.
Keywords: diynes; enynes; radicals; ionization; mechanisms.
Simple acyclic (Z)-1,2,4-heptatrien-6-ynes, which undergo cycloaromatization to produce reactive
dehydrotoluene biradicals (Myers–Saito-type cyclization),1 have been investigated as chemical models
for a class of potent antitumor antibiotics, neocarzinostatin,2 and related natural enediyne drugs.3
The preparation of enyne–allene models possessing characteristic triggering devices which initiate the
generation of dehydrotoluene biradicals is a challenge which is currently being met by many research
groups.4 Recently, we reported a development of the enediyne models 1 which produce the reactive
enyne–allenes 2 and ultimately result in a cycloaromatization via a reaction cascade triggered by
hydrolysis of the malonyl ester group (Scheme 1).5 From the reaction products we could not detect
the compounds 5 which would be formed directly from biradicals 3, and the products were the acetals
6. From the results of deuterium-labeling studies, we concluded that the reaction involves an ionization
process of toluene biradicals 3 producing zwitterionic species 4. For the elucidation of this cascade
reaction mechanism and development of biologically active substances, the preparation of thermally
stable carboxylic acid derivatives, which cycloaromatize under mild conditions, is essential. For this
purpose, we designed novel α-alkynylacetic acid derivatives. Reported in this communication is a
study on the preparation and the reactivities of α-alkynylphenylacetic acid 7a. In order to accelerate
the decarboxylation step, analogous compounds 7b,c having electron-withdrawing 3-fluoro- and 3,5-
difluorophenyl groups were prepared as well.
∗
Corresponding author. Tel: +81 88 633 7283; fax: +81 88 633 9505; e-mail: mshibuya@ph.tokushima-u.ac.jp
0040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02009-2

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Scheme 1.
The carboxylic acids 7a–c were synthesized as shown in Scheme 2. Propargyl bromide was allowed to
react with the alkynylketone 86 in the presence of zinc to provide the tert-alcohol, which was then treated
with MsCl and Et3N to furnish predominantly the enediyne 9 having the cis geometry.7 The lithium
salt of the enediyne 9 was treated with methyl benzoylformate followed by methylation of the resultant
alcohol to give the desired α-alkynylphenylacetate 10a. Mono- and difluoro derivatives 10b and 10c were
prepared in a similar manner, respectively. While the hydrolysis of 10a and 10b with KOH (2 equiv.) in
MeOH at room temperature afforded the thermally stable carboxylic acids 7a and 7b, respectively, the
hydrolysis of 10c under similar conditions gave the acetal 12c in a good yield. Therefore, the carboxylic
acid 7c was prepared by an alternative method via the phenylsulphonylethyl ester 11 (Scheme 2).8
Scheme 2. a: (i) Propargyl bromide, Zn, THF, 0°C, 5 min; (ii) MsCl, Et3N, CH2Cl2, 0°C, 10 min. b: (i) n-BuLi, THF, −78°C,
15 min; (ii) CH3I, Ag2O, CaSO4, rt, 12 h. c: KOH (2 equiv.), MeOH, rt. d: (i) n-BuLi, THF, −78°C, then 2-phenylthioethyl
3,5-difluorobenzoylformate, −78°C, 15 min; (ii) Ag2O, CaSO4, MeI, rt, 9 h; (iii) mCPBA, CH2Cl2, rt, 10 min. e: DBU, MeOH,
37°C, 0.5 min, then Amberlyst-15, 0°C, 10 min
For preliminary investigations on decarboxylative cycloaromatization of 7a–c, the reactions of 7a–c
with KOH (2 equiv.) in MeOH at 37°C affording the acetals 12 were carried out, and the results are
summarized in Table 1. As we expected, the reaction rate of 7c was much faster than that of 7a,b, and
therefore 7c was found to be suitable for further mechanisitic study.
A series of decarboxylative cycloaromatization reactions under various conditions were carried out and
the results are summarized in Table 2. The products 12–17 (Scheme 3) were isolated and characterized by
means of spectroscopic analysis. The intermediate corresponding to enyne–allene could not be detected
1
on TLC or by H NMR during each reaction. Compound 7c was essentially stable in the absence of a
base in MeOH or benzene, while it cycloaromatized in the presence of Et3N (entries 1–7). The reaction

97
Table 1
Decarboxylative cycloaromatization of 7 to give 12 (2 equiv. KOH, MeOH, 37°C)
Table 2
Decarboxylative cycloaromatization of 7c to give 12ca
rates in MeOH were relatively slow and the reactions in the absence or presence of a radical scavenger
(O2 or 1,4-cyclohexadiene) produced the acetal 12c and the enediyne 17c in similar yields, respectively.
The reaction of enediyne 17c under similar conditions gave 12c in 69% yield. These results suggest
that the cycloaromatization proceeded via an ionic cyclization pathway (Scheme 3, route a) but not via
the biradical intermediate (route b). On the other hand, the reaction in benzene (entry 4) afforded the
isochromane 15c predominantly, which is assumed to be formed from the biradical via a 1,5-hydrogen
shift followed by recombination (Scheme 3). Formation of another product 13c might be ascribed to
ionization of the biradical to generate the zwitterionic intermediate followed by a reaction with water
adventitiously contained in the solvent. When the same reaction was carried out in an oxygen atmosphere
(entry 5), the yield of 13c was slightly increased, indicating the possibility that the participation of
oxygen can not be ruled out for the formation of 13c. The results of similar reactions in the presence
of cyclohexadiene (entries 6 and 7) substantiates the radical mechanism of these reactions. The product
14c must be formed by the hydrogen abstraction of the biradical intermediate before or after a 1,5-
hydrogen shift, and 16c is assumed to be formed by the incorporation of molecular oxygen. As compared
with the above reactions, the reaction in a polar solvent such as DMF (entry 8) was found to be relatively
fast without the addition of a base, and the major product was 15c. In contrast with this reaction, a
similar reaction in the presence of MeOH afforded the acetal 12c predominantly, which suggests that the
ionic pathway is accelerated by the proton source rather than the polar conditions. Thus, we propose the
mechanisms for these cycloaromatization reactions as represented in Scheme 3. Studies on the analogues
of this class of compounds, involving enzyme-induced biradical generation, are in progress.

98
Scheme 3.
Acknowledgements
This work was supported by a grant-in-aid for Scientific Research on Priority Areas No. 10132249
from the Ministry of Education, Science, Sports and Culture, Government of Japan.
References
1. (a) Myers, A. G.; Kuo, E. Y.; Finney, N. S. J. Am. Chem. Soc. 1989, 111, 8057–8059. (b) Myers, A. G.; Dragovich, P. S.;
Kuo, E. Y. J. Am. Chem. Soc. 1992, 114, 9369–9386. (c) Nagata, R.; Yamanaka, H.; Okazaki, E.; Saito, I. Tetrahedron
Lett. 1989, 30, 4995–4998.
2. (a) Ishida, N.; Miyazaki, K.; Kumagai, K.; Rikimaru, M. J. Antibiot., Ser. A 1965, 18, 68–76. (b) Edo, K.; Mizugaki, M.;
Koide, Y.; Seto, H.; Furihata, K.; Otake, N.; Ishida, N. Tetrahedron Lett. 1985, 26, 331–334. (c) Shibuya, M.; Toyooka,
K.; Kubota, S. Tetrahedron Lett. 1984, 25, 1171–1174.
3. Review: Nicolaou, K. C.; Smith, A. L.; Yue, E. W. Proc. Natl. Acad. Sci. USA 1993, 90, 5881–5888.
4. Review: Grissom, J. W.; Gunawardena, G. U.; Kingberg, D.; Huang, D. Tetrahedron 1996, 52, 6453–6518.
5. Shibuya, M.; Wakayama, M.; Naoe, Y.; Kawakami, T.; Ishigaki, K.; Nemoto, H.; Shimizu, H.; Nagao, Y. Tetrahedron Lett.
1996, 37, 865–868.
6. Ranu, B. C.; Bhar, S.; Chakraborti, R. J. Org. Chem. 1992, 57, 7349–7352.
7. Shibuya, M.; Sakai, Y.; Naoe, Y. Tetrahedron Lett. 1995, 36, 897–898.
8. Methyl 3-fluorobenzoylformate, methyl 3,5-difluorobenzoylformate, and 2-phenylthioethyl 3,5-difluorobenzoylformate
were prepared according to the following literature, respectively: Hallmann, G.; Hägele, K. Liebigs Ann. Chem. 1963, 662,
147–159.