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ABSTRACT
Reactions of α-stannyl bromides and xanthates with tributyltin hydride generate α-stannyl radicals. Intramolecular cyclizations of these radicals with a formyl group afford γ-stannyl alkoxy radicals that undergo a 1,3-stannyl shift from carbon to oxygen. The carbon radicals obtained can be trapped inter- or intramolecularly. Approximately, the rates of 5-exo cyclizations of α-stannyl radicals with a formyl group and terminal olefin are similar.
Intramolecular radical addition to a carbonyl to give cyclic alcohol is a potentially useful reaction.1 However, this type of cyclizations is reversible, and the reverse reaction is generally faster than the cyclization.2 In the cases of acylgermanes,3 acylsilanes,1 thioesters and selenoesters,4 intramolecular radical additions to the carbonyl moiety in these compounds are followed by irreversible processes. Therefore, these cyclizations can be stopped at the cyclization side.5 Herein, we wish to report the intramolecular cyclization of a formyl group with an
1 Chang, S.-Y.; Jiaang, W.-T.; Cherng, C.-D.; Tang, K.-H.; Huang, C.-H.; Tsai, Y.-M. J. Org. Chem. 1997, 62, 9089–9098 and references cited therein.
2 (a) Beckwith, A. L. J.; Hay, B. P. J. Am. Chem. Soc. 1989, 111, 230– 234. (b) Beckwith, A. L. J.; Hay, B. P. J. Am. Chem. Soc. 1989, 111, 2674–2681. (c) Beckwith, A. L. J.; Raner, K. D. J. Org. Chem. 1992, 57, 4954–4962.
3 (a) Curran, D. P.; Liu, H. J. Org. Chem. 1991, 56, 3463–3465. (b) Curran, D. P.; Palovich, M. Synlett 1992, 631–632. (c) Curran, D. P.; Diederichsen, U.; Palovich, M. J. Am. Chem. Soc. 1997, 119, 4797–4804. (d) Diederichsen, U.; Curran, D. P. J. Organomet. Chem. 1997, 531, 9–12.
4 Kim, S.; Jon, S. Y. J. Chem. Soc., Chem. Commun. 1996, 1335–1336. 5 For other strategies to drive the equilibrium, see: (a) Hays, D. S.; Fu, G. C. J. Org. Chem. 1998, 63, 6375–6381. (b) Kim, S.; Oh, D. H. Synlett 1998, 525–527. (c) Batey, R. A.; MacKay, D. B. Tetrahedron Lett. 1998,
39, 7267–7270.
α-stannyl radical6 (eq 1) In this cyclization, a novel homolytic 1,3-stannyl shift from carbon to oxygen7,8,9,10 serves as the driving force.
6 Tsai, Y.-M.; Chang, S.-Y. J. Chem. Soc., Chem. Commun. 1995, 981– 982.
7 For homolytic 1,5-stannyl shift from carbon to oxygen, see: (a) Kim, S.; Lee, S.; Koh, J. S. J. Am. Chem. Soc. 1991, 113, 5106–5107. (b) Kim, S.; Lim, K. M. Tetrahedron Lett. 1993, 34, 4851–4854.
8 For homolytic 1,6-stannyl shift from carbon to oxygen, see: (a) Kim, S.; Lim, K. M. J. Chem. Soc., Chem. Commun. 1993, 1152–1153. (b) Kim, S.; Do, J. Y.; Lim, K. M. Chem. Lett. 1996, 669–670.
9 For homolytic 1,4-stannyl shift from oxygen to oxygen, see: Alberti, A.; Hudson, A. Chem. Phy. Lett. 1977, 48, 331–333.
10 For homolytic 1,5-stannyl shift from oxygen to oxygen, see: Davies, A. G.; Tse, M.-W. J. Organomet. Chem. 1978, 155, 25–30.
As shown in eq 2, the aldehydes 111 were coupled with
tributyltin lithium,12 and the resulting α-stannyl alcohols
were converted to α-stannyl bromides using carbon tetrabromide and triphenylphosphine.13 The dithiane
moiety was then deprotected14 to give the aldehydes 2 in
mild yields over three steps. Treatment of the aldehyde 2a with tributyltin hydride15 (Scheme 1) followed by
quenching the reaction with benzoyl chloride gave cyclopentyl benzoate (3) in 57% yield. The uncyclized reduction product aldehyde 4 was also isolated in 12% yield along with trace amount of the benzoate 5. The benzoate 5 was presumably derived from over-reduction of the aldehyde 4 by the excess tributyltin hydride followed by benzoate formation.
Mechanistically, this cyclization reaction occurs through the formation of the α-stannyl radical 6 first. This radical then cyclizes with the formyl group to generate the γ -stannyl alkoxy radical 7. Because the radical cyclizations of carbonyl compounds are generally reversible,2 it is likely that the oxygen radical and stannyl group may have a chance to adopt a syn-relationship as shown in 7. The alkoxy radical 7 presumably undergoes a 1,3-stannyl shift from carbon to oxygen to generate the carbon radical 8. It is known that the O-Sn bond is stronger than the C-Sn bond by about 25 kcal/mol.16 This big difference provides
a strong thermodynamic driving force to trap the alkoxy radical 7. Abstraction of hydrogen from tributyltin hydride by the radical 8 gives the stannyl ether 9. The oxygen atom in stannyl ethers is known to be quite
Scheme 1
11 Konosu, T.; Oida, S. Chem. Pharm. Bull. 1993, 41, 1012–1018. 12 Still, W. C. J. Am. Chem. Soc. 1978, 100, 1481–1487.
13 Torisawa, Y.; Shibasaki, M.; Ikegami, S. Tetrahedron Lett. 1981, 22, 2397–2400.
14 (a) Ho, T.-L.; Ho, H. C.; Wong, C. M. J. Chem. Soc., Chem.
Commun. 1972, 791–791. (b) Ho, H. C.; Ho, T.-L.; Wong, C. M. Can. J. Chem. 1972, 50, 2718–2721.
15 The cyclization reaction was performed by slow addition (4 h) via syringe pump of a benzene solution of tributyltin hydride (1.3 equiv, 0.13 M in benzene) and AIBN (0.05 equiv) to a solution of the bromide (0.1 M) in refluxing benzene.
16 Jackson, R. A. J. Organomet. Chem. 1979, 166, 17–19.
nucleophilic.17 Therefore, for the convenience of isolation and identification, the stannyl ether 9 was converted directly to the corresponding benzoate 3.
Scheme 2
When the aldehyde 2a (Scheme 2) was treated with allyltributyltin (4 equiv) in the presence of hexabutylditin (0.2 equiv) and initiated by the photolysis of long wavelength UV light18 (12 h), we were able to isolate the alcohol 1019 in 35% yield. This reaction provided evidence that indeed the radical 8 was formed. In the case of 6-exo cyclization (eq 3), the aldehyde 2b reacted with tributyltin hydride15 and gave 27% of cyclohexanol (11), 29% of the uncyclized reduction product aldehyde 12, and 9% of the over-reduction product alcohol 13. The problem of this reaction was revealed by the reaction of the aldehyde 2b with allyltributyltin (eq 4). Along with the alcohol 1420 (10%), we obtained 50% yield of the aldehyde 15 that contains an allyl group at the α-position
17 Pereyre, M.; Quintard, J.-P.; Rahm, A. Tin in Organic Synthesis; Butterworths: London, 1997; Chap 11, p 261.
19 Curran, D. P.; Liu, H. J. Chem. Soc. Perkin Trans. 1 1994, 1377– 1393.
20 Hegedus, L. S.; McKearin, J. M. J. Am. Chem. Soc. 1982, 104, 2444– 2451.
of the carbonyl group. This result indicates that a 1,5-hydrogen transfer21 occurs after the generation of the α
-stannyl radical from the aldehyde 2b. This process leads to the formation of an α-carbonyl radical . The α-carbonyl radical is then trapped by allyltributyltin to give the aldehyde 15.
This stannyl shift that promotes the radical cyclization reaction can be employed in a tandem cyclization mode. Instead of using α-stannyl bromides, we synthesized the xanthates 16 and 17 for our studies.6 The reaction of the xanthate 16 with tributyltin hydride15 (eq 5) gave the monocyclic aldehyde 18 in 33% yield. This aldehyde was derived from the addition of an α-stannyl radical to the olefin first. An alcohol 19 (5%) was also obtained. This material was presumably derived from the reduction of the aldehyde 18 by the excess tributyltin hydride. The bicyclic alcohol 20 was isolated in 29% yield. Small amounts of the benzoate derived from the bicyclic alcohol 21 were
detected in 4% yield through benzoylation of the crude cyclization mixture. The benzoates derived from the alcohols 20 and 21 thus obtained are identical to that reported by Wilcox et al.22 The stereochemistry of the alcohols 20 and 21 can therefore be determined. There appeared to be other stereoisomers of the alcohols 20 and
21; however, the amount was very small and we were not
able to identify these minor isomers. The bicyclic alcohols
20 and 21 are tandem cyclization products derived from
the addition of the α-stannyl radical 22 (Scheme 3) to the formyl group first. The cyclization presumably prefers to adopt a chair transition state23 with the large groups located at the equatorial position as shown in 22. This leads to the formation of the alkoxy radical 23 with a predominant trans-1,3-relationship. The stannyl shift of the alkoxy radical 23 gives the radical 24. This radical
21 Beckwith, A. L. J.; Ingold, K. U. Rearrangements in ground and
excited states; de Mayo, P., Ed.; Academic Press: New York, 1980; Vol 1,
pp161–310.
22 Nagai, M.; Lazor, J.; Wilcox, C. S. J. Org. Chem. 1990, 55, 3440– 3442.
23 (a) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron Lett. 1985, 26, 373–376. (b) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925–3941. (c) Spellmeyer, D. C.; Houk, K. N. J. Org. Chem. 1987, 52, 959–974.
cyclizes with the olefin to give the bicyclic alcohol 20 as the major isomer with the known endo-selectivity.24
Scheme 3
The rates for the addition of an α-stannyl radical to an olefin and a formyl group appear to be similar because the total yield of the monocyclic products 18 and 19 is close to that of the bicyclic alcohols 20 and 21. With this information available, it is possible to attenuate the tandem system to favor the bicyclic product. For example, it is known that the 5-exo cyclization of 5-hexynyl radical is slower than the corresponding 5-hexenyl radical cyclization by nearly ten folds.25 Therefore, for the xanthate 17, one would expect the carbonyl cyclization to be faster than the alkyne cyclization. As shown in eq 6, the cyclization of the xanthate 17 gave the four isomeric bicyclic alcohols 25 and 26 in a combined yield of 68%.26 The monocyclic alcohol 27 was isolated in 10% yield. The ratio of carbonyl addition products versus alkyne addition products was about 7:1.
24 (a) RajanBabu, T. V. Acc. Chem. Res. 1991, 24, 139-145. (b) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical Reactions; VCH: New York, 1996; p 57.
25 Beckwith, A. L. J. Tetrahedron 1981, 37, 3073–3100.
26 The stereochemistry of these compounds were determined by NOE experiments.
In conclusion, a 1,3-stannyl shift promoted cyclization of an α-stannyl radical with a formyl group was developed. This process is successful for the 5-exo cyclization. In comparison, the corresponding 6-exo cyclization seriously competes with a 1,5-hydrogen transfer reaction. Approximately, the 5-exo cyclization of an α-stannyl radical with a formyl group or with a terminal olefin have similar rates. This information will be useful in the design of tandem cyclizations. However, the reversibility of the formyl group cyclization requires further investigation. In the tandem cyclizations, the α-stannyl xanthate moiety serves as a novel gem-diyl equivalent.27
