Synthesis of carbocycles by enone-selective reduction using organoiodotin hydride

Article abstract of DOI:10.1016/S0040-4039(00)00388-9

By using di-n-butyliodotin hydride (n-Bu₂SnIH), carbocycles were prepared from substrates bearing both enone and formyl moieties, where the enone-selective reduction was followed by a diastereoselective intramolecular aldol reaction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00388-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3403–3406
Synthesis of carbocycles by enone-selective reduction using
organoiodotin hydride
Toshihiro Suwa, Keita Nishino, Masato Miyatake, Ikuya Shibata and Akio Baba ∗
Department of Molecular Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita,
Osaka 565-0871, Japan
Received 31 January 2000; revised 2 March 2000; accepted 3 March 2000
Abstract
By using di-n-butyliodotin hydride (n-Bu2SnIH), carbocycles were prepared from substrates bearing both enone
and formyl moieties, where the enone-selective reduction was followed by a diastereoselective intramolecular aldol
reaction. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: organoiodotin hydride; enone-selective reduction; 1,4-reduction; intramolecular aldol reaction.
Chemoselective reduction of bifunctional substrates provides cyclic compounds when the initially
reduced functionality affords a nucleophilic intermediate to react with the remaining electrophile. The
preparation of carbocycles is important to enable access to naturally occurring compounds. Intramolecu-
lar aldol reactions which are useful and various methods for generating carbanions have been developed.1
On the other hand, the direct formation of an enolate nucleophile by the reduction of enone in the presence
of a formyl group has not been focused on so far (Scheme 1).2 This is because of the easy access to the
reduction of aldehydes other than enones when conventionally used reducing agents are employed.3
Scheme 1.
Recently, we have found that an iodo-substituted tin hydride such as n-Bu2SnIH4 causes selective
reduction of enones even in the presence of aldehydes.5 We thus focused our work on a novel type of
cyclization starting from substrates bearing enone and formyl groups.
We initially tried the reaction of aromatic bifunctional substrate 1 by an equimolar amount of
n-Bu2SnIH at room temperature for 5 h. After protonolysis of the reaction mixture, β-hydroxy cyclic
ketone 2 was obtained selectively (Scheme 2). Use of chlorotin hydride (n-Bu2SnClH) resulted in a
∗
Corresponding author. Tel: +81 6 6879 7384; fax +81 6 6879 7387; e-mail: shibata@ap.chem.eng.osaka-u.ac.jp (A. Baba)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00388-9
tetl 16668

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lower yield than when using n-Bu2SnIH. Tri-n-butyltin hydride did not give the product and the reaction
resulted in a complex mixture.
Scheme 2.
The result promoted by n-Bu2SnIH indicates that a 1,4-reduction of an enone group predominates
over the reduction of a formyl group. The resulting tin enolate(I) immediately attacks the remained
formyl group.6,7 No product derived from the reduction of the formyl groups or the non-cyclized one
was detected. Namely, the formyl group does not have to be protected at all. Moreover, the latter aldol
reaction proceeds with cis-selectivity. It seems that the high stereoselectivity arises from the selective
formation of (Z)-enolates(I) by the 1,4-reduction of the enone moieties of 1.8 The subsequent aldol
reaction proceeds through a six-membered cyclic transition state A to form an erythro aldol intermediate.9
The tin center of I bears adequate ligand accessibility because of the electron-withdrawing halogen
substituent. Unfortunately, a further increase of the yield of 2 was not successful. This would be because
of the ring strain of the intermediate A. So we next used a linear type substrate 3 (Scheme 3). As expected,
cis-substituted cyclohexane derivative 4 was obtained in a higher yield than in the case of 2. The enone-
selective reduction generated (Z)-tin enolate(II) which subsequently afforded 4 through the transition
state B with less ring strain than the transition state A.
Scheme 3.
We have already reported that n-Bu3SnH, when an equimolar n-Bu4NBr is added, forms itself into a
pentacoordinate tin, and acts as an effective reducing agent for aldehydes and ketones.10 In contrast to
the reaction when using n-Bu2SnIH, a non-halogen-substituted tin, n-Bu3SnH-Bu4NBr, gave cyclic ether
5 selectively (Scheme 4).
Selective reduction of the formyl group of 1 takes place, and the resulting Sn–O bond in III acts as a
nucleophile to attack the remaining enone in a fashion of 1,4-addition.11 The difference in chemoselectiv-
ity of n-Bu2SnIH from that of n-Bu3SnH-n-Bu4NCl arises from the halogen substituent on the tin center.
In the pentacoordinate tin complex, n-Bu3SnH-n-Bu4NBr, the Sn–H bond which occupies the apical
position acts as a hydride donor to cause the direct attack toward the formyl group. In contrast, the ability
of hydride donation in n-Bu2SnIH would be low; in addition, it seems that the tin–iodine bond has high
nucleophilicity.12 Hence, we consider that 1,4-addition of the enone by the Sn–I bond takes place prior
to addition by the Sn–H bond, which is a key reaction to determine the enone-selectivity (Scheme 5).13

3405
Scheme 4.
The reaction does not proceed in a radical manner — no decrease of the yield of 2 under the conditions
in Scheme 2 was observed in the presence of a radical inhibitor such as p-dinitorobenzene.
Scheme 5.
Synthesis of carbocycle was also possible when dienone 6 was used as the starting substrate. Treatment
with 1 equiv. of n-Bu2SnIH gave cyclic diketone 7 as a major product with high trans-selectivity (Scheme
6). 1,4-Reduction of one of the enones takes place and the generated tin enolate(IV) induces a Michael
addition toward the other unreacted enone. In this case, the reaction was accompanied with saturated
ketone 8 derived from the 1,4-reduction of both enones.
Scheme 6.
ortho-Substituted aromatic dienone 9 also afforded cyclic products 10 in moderate yields under the
same conditions (Scheme 7).14 The reaction proceeded with high diastereoselectivities, and no product
formed by the reduction of both enones was detected.
Scheme 7.
In this way, iodo-substituted tin hydride (n-Bu2SnIH) afforded a novel type of cyclization by enone-
selective reduction in the reduction of a bifunctional substrate. Various carbocycles could be prepared in
a one-pot procedure.

3406
Acknowledgements
This work was financially supported by a Grant-in-Aid for Scientific Research from the Ministry of
Education, Science and Culture, and JSPS Research Fellowships for Young Scientists.
References
1. Heathcock, C. H. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2,
pp. 133.
2. There is a example of cyclization by PtO2-catalyzed hydrogenation of enone in the presence of ketone: Paquette, L. A.;
Kang, H. J. J. Am. Chem. Soc., 1991, 113, 2610.
3. Hutchins, R. O.; Hutchins, M. K. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford,
1991; Vol. 8, pp. 25.
4. n-Bu2SnIH was prepared in situ by mixing n-Bu2SnH2 and n-Bu2SnI2. (a) Sawer, A. K.; Brown, J. E.; Hanson, E. L. J.
Organomet. Chem. 1965, 3, 464. (b) Sawer, A. K.; Brown, J. E. J. Organomet. Chem. 1996, 5, 438.
5. Kawakami, T.; Miyatake, M.; Shibata, I.; Baba, A.; Matsuda, H. J. Org. Chem. 1996, 61, 376.
6. Representative procedure: To a solution of n-Bu2SnH2 (0.5 mmol) in 1 mL of THF was added n-Bu2SnI2 (0.5 mmol). The
mixture was stirred at room temperature for 10 min. IR spectra showed the change from 1800 cm−1 to 1857 cm−1, which
indicates the formation of n-Bu2SnIH. To the solution was added 1 (1 mmol) and the mixture was stirred at rt until the Sn–H
absorption disappeared (5 h). After quenching with MeOH (5 mL), volatiles were removed under reduced pressure. The
residue was subjected to column chromatography (Fuji-gel FL100DX) eluting with hexane:EtOAc (9:1) to give product 2.
Further purification was performed by kugelrohr distillation or preparative TLC eluting with hexane:Et2O (9:1). 1H NMR
(CDCl3) δ 3.04 (br, 1H, OH), 3.15 (dd, 1H, J=8.3 and 16.1 Hz, CH), 3.60 (dd, 1H, J=7.8 and 16.1 Hz, CH), 4.31–4.39 (m,
1H, CHCOPh), 5.51 (d, 1H, J=5.8 Hz, CHOH), 7.24–8.05 (m, 9H, Ph).
7. Substrates 1 or 3 were prepared by the reaction of the corresponding dialdehyde with 1 equiv. of a Wittig reagent.
8. The formation of (Z)-enolate by the reaction of a simple enone with Bu2SnIH has been confirmed.5
9. Moon Kim, B.; Williams, S. F.; Masamune, S. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 2, pp. 239.
10. (a) Shibata, I.; Yoshida, T.; Baba, A.; Matsuda, H. Chem. Lett. 1991, 307. (b) Kawakami, T.; Shibata, I.; Baba, A. J. Org.
Chem. 1996, 61, 82.
1
11. H NMR data for 5 was as follows: (CDCl3) δ 3.34 (dd, 1H, J=4.9 and 16.6 Hz, CHCOPh), 3.54 (dd, 1H, J=7.3 and
16.6 Hz, CHCOPh), 5.08 (dd, 1H, J=1.0 and 12.2 Hz, OCH), 5.15 (dd, 1H, J=2.4 and 12.2 Hz, OCH), 5.87–5.93 (m, 1H,
OCHCH2), 7.19–8.02 (m, 9H, Ph).
12. Shibata, I.; Baba, A.; Iwasaki, H.; Matsuda, H. J. Org. Chem. 1986, 51, 2177.
13. The 1,4-reduction of enal was performed in a similar manner by an iodotin hydride complex. Suwa, T.; Shibata, I.; Baba,
A. Organometallics 1999, 18, 3965.
1
14. H NMR for 10a: (CDCl3) δ 3.09 (dd, 1H, J=7.3 and 16.1 Hz), 3.25 (dd, 1H, J=7.8 and 16.6 Hz), 3.43 (dd, 1H, J=9.3 and
16.1 Hz), 3.50 (dd, 1H, J=5.9 and 16.6 Hz), 4.09–4.17 (m, 1H), 4.40–4.47 (m, 1H), 7.16–7.98 (m, 14H).