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OK Extraction done .

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moo:
Thanks for asking, an interesting example which I had overlooked, even though I've seen it several times before. That preparation is obviously tried and true. I'm convinced that steric factors play a major role here as phenylacetonitrile is more acidic than acetonitrile, and methylmagnesium iodide more basic than benzylmagnesium chloride. Also note the inverted addition. So, I must take my word back about the reactivity of the nitrile group not being the issue. Here is another example of a Grignard addition to nitrile, propionitrile in this case: Post 475862 (moo: "one pot 1-phenyl-2-butanamine etc", Novel Discourse).

Here is the reaction scheme from the original article JACS 109 3378-3387:

Rhodium:
Novel diacid accelerated borane reducing agent for imines
Zhi-Hui Lu, Nandkumar Bhongle, Xiping Su, Seth Ribe and Chris H. Senanayake
Tetrahedron Letters 43, 8617–8620 (2002) (https://www.thevespiary.org/rhodium/Rhodium/pdf/grignardimine.amph-2002.pdf)



Abstract
A remarkable effect of diacids in modulating the reactivity of borane has been discovered. This novel process provides a rapid and excellent access for reduction of a variety of imines with different functionalities.
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New resolution approach for large-scale preparation of enantiopure didesmethylsibutramine (DDMS)
Zhengxu Han, Dhileepkumar Krishnamurthy, Q. Kevin Fang, Stephen A. Wald and Chris H. Senanayake
Tetrahedron: Asymmetry 14, 3553–3556 (2003) (https://www.thevespiary.org/rhodium/Rhodium/pdf/grignardimine.amph-2003.pdf)



Abstract
An improved synthesis and efficient resolution method to prepare both enantiopures of DDMS using crystallization of enantiomerically pure tartaric acid salts of racemic DDMS are disclosed.

Experimental
A 1 L three-necked round-bottomed flask was charged with 1-(4-chlorophenyl)-1-cyclobutylcarbonitrile (CCBC, 50.0 g, 261 mmol) and toluene (150 mL), followed by iso-butyl magnesium chloride (395 mL, 1.0 M in MTBE), and the resulting mixture was distilled until the internal temperature reached 105°C. After stirring at that temperature for 2 h, the mixture was cooled to 0°C and methanol was added slowly (295 mL), followed by sodium borohydride (10.4 g, 1.06 equiv.) portion-wise. The resulting mixture was stirred at rt for 15 min and was added to a 2N HCl solution (330 mL) slowly, stirred for 15 min and the phases were separated. The aqueous phase was extracted with toluene (300 mL), the combined organic phases were distilled to remove methanol, and then washed with aqueous NaOH solution (1.5 M, 100 mL) and water (100 mL) twice. The resulting organic phase was heated to 50–60°C, followed by an addition of D-tartaric acid (40.0 g) in water (80 mL) and acetone (40 mL) slowly. The reaction mixture was azeotrope distilled until the internal temperature reached 92°C and then cooled to ambient temperature in 1–2 h. The slurry was filtered, and the wet cake was washed with MTBE (100 mL) and dried at 40–45°C under reduced pressure to afford (RS)-DDMS·D-TA (100.5 g) in 95.8% yield.
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A Study and Identification of Potential By-Products of Sibutramine
G. Om Reddy, M. R. Sarma, B. Chandrasekhar, J. Moses Babu, A. S. R. Prasad, and C. M. Haricharan Raju
Organic Process Research & Development 3, 488-492 (1999) (https://www.thevespiary.org/rhodium/Rhodium/pdf/grignardimine.byproducts.pdf)

Abstract
In the synthesis and process development of sibutramine (9), the isolation and characterization of two potential by-products namely heptane dinitriles (4a-b) and bis-cyclobutyl alkylamine (10) have been studied. The key steps in the synthesis of sibutramine which have contributed to the formation of above by-products are cycloalkylation of 4-chlorophenyl acetonitrile (1) and tandem Grignard reduction on 1-(4-chlorophenyl)-cyclobutyl carbonitrile (3).
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Synthesis of sibutramine, a novel cyclobutylalkylamine useful in the treatment of obesity, and its major human metabolites
J.E. Jeffery, F.Kerrigan, T.K. Miller, G.J. Smith and G.B. Tometzki, J. Chem. Soc. Perkin Trans. 1, 2583-2589 (1996)
DOI:10.1039/P19960002583

Abstract
Synthetic routes to N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamine (sibutramine) 1 and its demethylated and hydroxylated human metabolites N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-methylamine 2, 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine 3, 4-amino-4-[1-(4-chlorophenyl)cyclobutyl]-2-methylbutan-1-ol 4 and c-3-(1-amino-3-methylbutyl)-3-(4-chlorophenyl)cyclobutan-r-1-ol 5a are described. Key steps are tandem Grignard–reduction reactions on 1-(4-chlorophenyl)cyclobutanecarbonitrile 7 and its 3-(tetrahydropyran-2-yloxy)-substituted analogue 14 and a convenient one-pot conversion of 4-chlorophenylacetonitrile 6 into the 3-hydroxycyclobutanecarbonitrile 13.

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