Reaction of Grignard reagents with carbonyl compounds under continuous flow conditions

This contribution details how a continuous flow reactor was used to react carbonyl compounds with Grignard reagents at room temperature in an efficient and safe manner. Flow rate, residence time and temperature were optimized for the preparation of a small collection of secondary and tertiary alcohols. Excellent yields and general applicability were observed using the set-up protocol. The procedure was also applied for the preparation of Tramadol, an analgesic drug belonging to the opioid group. The developed conditions allowed the selective addition of Grignard reagents to aldehydes and ketones in the presence of a nitrile function.

[1]  K. B. Sharpless,et al.  Titanium isopropoxide-mediated nucleophilic openings of 2,3-epoxy alcohols. A mild procedure for regioselective ring-opening , 1985 .

[2]  B. Feringa,et al.  Catalytic asymmetric conjugate addition and allylic alkylation with Grignard reagents. , 2008, Chemical reviews.

[3]  Rieke,et al.  Low-temperature formation of functionalized Grignard reagents from direct oxidative addition of active magnesium to aryl bromides , 2000, The Journal of organic chemistry.

[4]  H. Löwe,et al.  Chemistry in microstructured reactors. , 2004, Angewandte Chemie.

[5]  H. G. Richey.  Grignard reagents : new developments , 2000 .

[6]  D. Arnold,et al.  The effect of meta- or para-cyano substitution on the reactivity of the radical cations of arylalkenes and alkanes. Radical ions in photochemistry, Part 34' , 1991 .

[7]  Ryan L Hartman,et al.  Microchemical systems for continuous-flow synthesis. , 2009, Lab on a chip.

[8]  M. Yus,et al.  First enantioselective addition of diethylzinc and dimethylzinc to prostereogenic ketones catalysed by camphorsulfonamide-titanium alkoxide derivatives , 1998 .

[9]  Andreas Kirschning,et al.  Combining enabling techniques in organic synthesis: continuous flow processes with heterogenized catalysts. , 2006, Chemistry.

[10]  W. Kroutil,et al.  Tandem concurrent processes: one-pot single-catalyst biohydrogen transfer for the simultaneous preparation of enantiopure secondary alcohols. , 2009, The Journal of organic chemistry.

[11]  Dominique M. Roberge,et al.  Development of an Industrial Multi‐Injection Microreactor for Fast and Exothermic Reactions – Part II , 2008 .

[12]  P. Knochel,et al.  A LiCl-mediated Br/Mg exchange reaction for the preparation of functionalized aryl- and heteroarylmagnesium compounds from organic bromides. , 2004, Angewandte Chemie.

[13]  J. Deschamps,et al.  Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter. , 2007, Journal of medicinal chemistry.

[14]  K. Mae,et al.  Room-temperature Swern oxidations by using a microscale flow system. , 2005, Angewandte Chemie.

[15]  N. Miyaura,et al.  Rhodium-Catalyzed Addition of Organoboronic Acids to Aldehydes. , 1998, Angewandte Chemie.

[16]  D. Seyferth.  The Grignard Reagents , 2009 .

[17]  Kuo-Hui Wu,et al.  Chiral tertiary 2-furyl alcohols: diversified key intermediates to bioactive compounds. Their enantioselective synthesis via (2-furyl)aluminium addition to ketones catalyzed by a titanium catalyst of (S)-BINOL. , 2008, Chemical communications.

[18]  Frank J. Villani,et al.  Application of Microreactor Technology in Process Development , 2004 .

[19]  Shahriyar Taghavi-Moghadam,et al.  Microreaction Technology as a Novel Approach to Drug Design, Process Development and Reliability , 2001 .

[20]  M. Okabe,et al.  Aryl rearrangement on the photolysis of 2-aryl-2-ethoxy-2-phenylethyl cobaloxime. , 1983 .

[21]  C. Oliver Kappe,et al.  Microwave‐Assisted Synthesis under Continuous‐Flow Conditions , 2007 .

[22]  T. Miyamoto,et al.  Highly active chiral phosphoramide-Zn(II) complexes as conjugate acid-base catalysts for enantioselective organozinc addition to ketones. , 2007, Organic letters.

[23]  Laurent Ducry,et al.  Controlled autocatalytic nitration of phenol in a microreactor. , 2005, Angewandte Chemie.

[24]  G. Cahiez,et al.  Preparation of Highly Functionalized Grignard Reagents by an Iodine-Magnesium Exchange Reaction and its Application in Solid-Phase Synthesis. , 1998, Angewandte Chemie.

[25]  Junyong Zhang,et al.  An efficient and chemoselective synthesis of N-substituted 2-aminopyridines via a microwave-assisted multicomponent reaction. , 2007, Organic & biomolecular chemistry.

[26]  S. Ley,et al.  Pharmaceutical Strategy and Innovation: An Academics Perspective , 2007, ChemMedChem.

[27]  Andreas Kirschning,et al.  Continuous flow techniques in organic synthesis. , 2003, Chemistry.

[28]  B. Wakefield.  Organomagnesium Methods in Organic Synthesis , 1995 .

[29]  F. Carreaux,et al.  Metal-catalyzed release of supported boronic acids for C-C bond formation. , 2001, Organic letters.

[30]  G. Silverman,et al.  Handbook of Grignard Reagents , 1996 .

[31]  Peter H Seeberger,et al.  Microreactors as tools for synthetic chemists-the chemists' round-bottomed flask of the 21st century? , 2006, Chemistry.

[32]  Jun-ichi Yoshida,et al.  Integrated micro flow synthesis based on sequential Br-Li exchange reactions of p-, m-, and o-dibromobenzenes. , 2007, Chemistry, an Asian journal.

[33]  P. Knochel,et al.  Soluble lanthanide salts (LnCl3.2LiCl) for the improved addition of organomagnesium reagents to carbonyl compounds. , 2006, Angewandte Chemie.

[34]  Jeremy L. Steinbacher,et al.  Greener approaches to organic synthesis using microreactor technology. , 2007, Chemical reviews.

[35]  Aiichiro Nagaki,et al.  Aryllithium compounds bearing alkoxycarbonyl groups: generation and reactions using a microflow system. , 2008, Angewandte Chemie.

[36]  Peter Styring,et al.  A facile method for catalyst immobilisation on silica: nickel-catalysed Kumada reactions in mini-continuous flow and batch reactors , 2004 .

[37]  S. Haswell,et al.  Kumada-Corriu reactions in a pressure-driven microflow reactor. , 2001, Lab on a chip.

[38]  L. Pu,et al.  THE FIRST HIGHLY ENANTIOSELECTIVE CATALYTIC DIPHENYLZINC ADDITIONS TO ALDEHYDES : SYNTHESIS OF CHIRAL DIARYLCARBINOLS BY ASYMMETRIC CATALYSIS , 1999 .

[39]  L. Ackermann,et al.  Moderne Magnesiumorganische Chemie. Neues von der Grignard‐Reaktion , 2009 .

[40]  K. Sharpless,et al.  Ti(O-i-Pr)4-mediated nucleophilic openings of 2,3-epoxy alcohols. A mild procedure for regioselective ring-opening , 1985 .

[41]  S. Matsukawa,et al.  Catalytic cyanomethylation of carbonyl compounds and imines with highly basic phosphine , 2008 .

[42]  T. Wirth,et al.  Microreactors in organic synthesis and catalysis , 2008 .

[43]  N. Mills,et al.  Reactions of 2-methyleneallyl dianion with aldehydes, ketones, epoxides, and allyl halides , 1979 .

[44]  Á. Guzmán,et al.  Synthesis of Tramadol and Analogous , 2005 .

[45]  N. Anderson.  Practical Use of Continuous Processing in Developing and Scaling Up Laboratory Processes , 2001 .

[46]  W. Maio,et al.  Synthesis of β-hydroxy nitriles and 1,3-amino alcohols from epoxides using acetone cyanohydrin as a LiCN precursor , 2004 .

[47]  Peter Styring,et al.  From discovery to production: Scale-out of continuous flow meso reactors , 2009, Beilstein journal of organic chemistry.

[48]  J. Deschamps,et al.  Vinylogous amide analogs of methylphenidate. , 2005, Bioorganic & medicinal chemistry letters.

[49]  W. Bailey,et al.  Asymmetric addition of achiral organomagnesium reagents or organolithiums to achiral aldehydes or ketones: a review , 2009 .

[50]  F. Fleming,et al.  Metalated Nitriles: Organolithium, -magnesium, and -copper Exchange of α-Halonitriles , 2005 .

[51]  Qiang Feng,et al.  Novel hexadentate imidazolium salts in the rhodium-catalyzed addition of arylboronic acids to aldehydes , 2006 .

[52]  A. Fürstner,et al.  Preparation of allyl-, alkenyl- and of functionalized arylmanganese reagents by oxidative insertion of manganese-graphite into organic halides , 1996 .

[53]  T. Wirth,et al.  Advanced organic synthesis using microreactor technology. , 2007, Organic & biomolecular chemistry.

[54]  J. Yoshida,et al.  Grignard Exchange Reaction Using a Microflow System: From Bench to Pilot Plant , 2005 .

[55]  Simon J. F. Macdonald,et al.  Mesoscale Flow Chemistry: A Plug-Flow Approach to Reaction Optimisation , 2007 .

[56]  Fernando Benito-Lopez,et al.  High pressure in organic chemistry on the way to miniaturization , 2008 .

[57]  Philip Hodge,et al.  Organic synthesis using polymer-supported reagents, catalysts and scavengers in simple laboratory flow systems. , 2003, Current opinion in chemical biology.

[58]  P. Knochel,et al.  Highly functionalized organomagnesium reagents prepared through halogen-metal exchange. , 2003, Angewandte Chemie.