Implementation on pilot-plant scale of the titanocene-catalyzed reduction of a lactone with poly(methylhydrosiloxane)

Organic Process Research and Development

Volumn 12, Issue 1, 2008, Pages 96-100

  Depré, Dominique ^a,b   Horváth, András ^a,b   Snissaert, Walter ^a,c   Van Den Bergh, Leo ^a,c   Dermaut, Wim ^a,d  

^a JANSSEN RESEARCH AND DEVELOPMENT   (Belgium)

^b Process Research

^c Pilot Plant ^*

^d Safety Testing Laboratory

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[No Author keywords available]

Indexed keywords

EID: 38949192133     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op700207m     Document Type: Article

References (16)

1. (a) Kanojia, R. M.; Jain, N. F.; NG, R.; Sui, Z.; Xu, J. Patent WO 03/053977 A1.
2. (b) Jain, N.; Kanojia, R. M.; Xu, J.; Jian-Zhong, G.; Pacia, E.; Lai, M.-T.; Du, F.; Musto, A.; Allan, G.; Hahn, D. W.; Lundeen, S.; Sui, Z. J. Med. Chem. 2006, 49, 3056.
3. Kanazawa, R.; Tokoyorama, T. Synthesis 1976, 526.
4. Igarashi, M.; Mizuno, R.; Fuchikami, T. Tetrahedron Lett. 2001, 42, 2149.
5. (a) Mimoun, H. J. Org. Chem. 1999, 64, 2582.
6. (b) Mimoun, H. Patent WO 96/12694, 1995.
7. (a) Verdaguer, X.; Berk, S. C.; Buchwald, S. L. J. Am. Chem. Soc. 1995, 117, 12641.
8. (b) Verdaguer, X.; Hansen, M. C.; Berk, S. C.; Buchwald, S. L. J. Org. Chem. 1997, 62, 8522.
9. In fact, an excess of PMHS was necessary to perform the complete conversion of 1 into 2. Using less silane led to incomplete conversion. This was already observed by the group of Buchwald and attributed to some steric hindrance by the reduction product fixed on the polysiloxane chain.
10. For comparison, the prices for phenylsilane and PMHS were about 166 ε/25 g and 35 ε/250 g (2007 Aldrich catalogue) whilst the flash points were 7°C and 121°C respectively (Aldrich MSDS).
11. A few experiments conducted in collaboration with Markó's group at the Université catholique de Louvain for the reduction of other substrates showed that the stability of the activated catalyst was in fact improved in the presence of hydrogen and that flushing continuously the reactor with nitrogen or argon after the catalyst got activated was detrimental for its stability. We assume that the described stability of the catalyst came from the fact that residual hydrogen gas was left in the flask during the experiments performed S. Buchwald et al.
12. Other high-boiling solvents like 1,2-dimethoxyethane or dioxane should be also suitable solvents for the activation step.
13. Due to the foaming, we recommend not to fill the reactor more than 50% capacity during the activation step.
14. Though the catalyst was described as water- and air-stable (see ref 5), a partial deactivation was sometimes observed on standing when the experiment was performed on small scale, resulting in a colour change from dark blue to greenish. The use of this deactivated catalyst in the reduction step led to serious foaming, probably due to reactivation of the catalyst and concomitant hydrogen evolution. The deactivation was found to be due to accidental exposure with air, and the stability of the catalyst was strongly improved when kept under hydrogen (see note 8). This deactivation of the catalyst was nevertheless not observed on scale.
15. Druce, P. M.; Kingston, B. M.; Lappert, M. F.; Spalding, T. R.; Srivastava, R. C. J. Chem. Soc. A 1969, 2106.
16. Though we did not confirm the activation of the catalyst other than by the colour change, the activation point can be also detected by measuring the gas evolution and, due to the high exothermicity of the activation, by measuring the heat flows between the reaction mixture and the reactor mantle.