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Parallel Synthesis - Reductive Amination of Aldehyde Group
Parallel optimisation of reductive amination of substitutedfurane-2-aldehydes to 2-dialkylaminofuranes (4 x 24 sam-ples) by using the BÜCHI Syncore Reactor with its Filtra-tion Unit. The reaction itself, drying and evaporation of or- http://synthesis.buchi.com
ganic extracts are accelerated by using Syncore.
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SYNTHESIS 34 / 2004
Parallel Synthesis - Reductive Amination
of Aldehyde Group
Eugene Babaev, Eugene Belykh, Ilya Dlinnykh, Natalia Tkach, Combinatorial Chemistry Center, ChemistryDepartment, Moscow State University, Moscow, Russia and Wolfgang Bender, Bayer HealthCare, Wuppertal,Germany and Gerhard Schönenberger, Büchi Labortechnik AG, Flawil, Switzerland.
Introduction
The reagents of choice are Na[BH(OAc) ] or Na[BH CN] [3].
N-substituted aminomethyl groups (NHRCH - or NR CH -) are The usual impurities are the traces of alcohol (from concurrent famous pharmacophore groups presented in many drugs and aldehyde reduction) and starting materials. The reaction pro- natural products. Among the strategies used in the modern ceeds heterogeneously (at room temperature in DCM or DCE), organic synthesis to incorporate this group into a desired and good shaking of the reaction mixture is absolutely crucial molecule (see scheme 1) the well-known reactions are 1 Mannich aminomethylation,2 alkylation of amines by suitable electrophilic reagents of the Reductive amination of aldehydes with Syncore.
type R-CH -X (containing chlorometyl and analogous groups) In our experiments we have tested the reactivity of several 5- arylfurane-2-aldehydes (from Bayer Healthcare proprietary Synthone collection) in the reductive amination reaction. Intotal we have tested 9 aldehydes and 18 secondary aliphaticamines. The solutions of the aldehydes (15 mmol in 5 ml) andamines (15 mmol in 2 ml) in CH Cl were mixed in 24 Syncore flasks and were shaken for 30 minutes. In order to establishcomplete equilibrium for this first step it is advisable to allowreaction mixtures to stay overnight.The portions of 3 ml ofsuspension of Na[BH(OAc) ] in CH Cl were added into each of the 24 tubes. It is strongly recommended to place eachtube into the ultrasonic bath for a short period (2-3 minutes) tohomogenise the mixture.
The flasks were shaken on the Syncore for 2-3 days at 20 oC.
In some cases the heterogeneous process have required up Scheme 1: Reactions to trimethylamino derivatives to 5 days for completing. The content of the flasks became The first two strategies have evident restrictions and requires specific substrates, whereas the conversion of carbonyl groupseems almost universal, since aldehydes are very popular buil- Working-up steps
ding blocks that can be obtained by different ways and be- 20 ml of 20 % K CO solution were added to each tubes, and sides from quite different precursors.
the device was shaken until the end of hydrogen evolution.
The lower, organic layers were placed with the help of pi- The key feature of the reaction (3) mechanism is reversible pettes or syringes into another set of 24 flasks. This set was formation of the Schiff base. The imine can be selectively re- placed on the Syncore and Na SO was added to each flask.
duced (even in the presence of aldehyde) under the action of After shaking during 30 minutes the set was kept overnight.
specific reducing agents [2] (scheme 2).
The organic solutions underwent parallel filtering using theBÜCHI Filtration Unit (see pict. 1) under the dry nitrogen at-mosphere.
The parallel cleaning of tubes and filters from drying agent wasperformed by passing 2 times 30 ml of water, 2 times 30 ml ofacetone and finally the flow of nitrogen to dry the device. Theresulting solutions of amines underwent parallel evaporation ofDCM using the BÜCHI Vacuum Pump V-501 with BÜCHIVacuum Controller V-805 at 30-35 oC first at 670 mbar and Scheme 2: Mechanism of reaction (3) best@buchi
SYNTHESIS 34/ 2004
Purification
The compounds containing no impurities of starting amines Further purification of samples was performed after TLC analysis (and those obtained after chromatography) were precipitated of the evaporated samples (Silufol, CHCl :MeOH 10:1).
as oxalates. For this the solution of oxalic acid (15 mmol) in i-PrOH was added to the solution of the samples in CCl and the obtained precipitate was filtrated off.
Picture 2: Syncore Reactor in laboratory Picture 1: Syncore with Filtration Unit Results
The examples of structures of the starting aldehydes and
In cases of finding starting amine impurities (low R spots) the amines are shown in table 1. The overall yields are usually compound was passed via a short silicagel column (d 25 mm, high. The TLC datas for selected series prove the sufficient h 30 mm; CHCl then CHCl : MeOH = 20:1).
purity of obtained compounds (table 2).
Table 1: Examples of structures of the starting aldehydes and amines with overall yields. best@buchi
SYNTHESIS 34 / 2004
Table 2: Short overview of some synthesized products Conclusion
References
The acidophobic furan ring is usually considered sensitive [1] For reviews on reductive amination see: towards oxidation and other processes, and a lot of side (a) Emerson, W. S. Org. Reactions, Wiley; 1948, 4, reactions occur in the reactions involving furans. Therefore, the success achieved with furyl aldehydes is a good proof of (b) Lane, C. F. Synthesis, 1975, pp. 135-146.
the applicability of the protocol for other - more stable - alde- (c) Hutchins, R. O.; Hutchins, M. K. In Comprehensive hydes. Although there are random examples of reductive Organic Synthesis, Trost, B. M.; Fleming, I.; Eds.; amination of different furfurals (including 5-arylfurane-2-alde- Pergamon Press: Oxford, 1991, Vol. 8, pp. 25-78.
hydes [4]), the obtained protocol is first proof of safe parallel (d) Baxter, E. W.; Reitz, A. B. Org. Reactions, Wiley, 2002, synthesis of this process when using the BÜCHI Syncore.
[2] Henkel, T.; Brunne, R. M.; Mueller, H.; Reichel, F. Angew.
Common drugs - furosemide and ranitidine - are in fact, just Chem. Int. Ed. Engl. 1999, 38, pp. 643-647.
furans with alkylaminomethyl group, hence our result is a good [3] Abdel-Majid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, illustration of safe preparation of a library of ‘drug-like’ com- C. A.; Shah, R. D. J. Org. Chem. 1996, 61, pounds at the scale of hundreds of milligrams. Furthermore, the simplicity of the procedures when using the Syncore has [4] (a) Denis, A.; Renou C. Tetrahedron Lett., 2002, 43(23), allowed us to use this reaction in the education of students (see pict. 2) at Moscow State University during the practical (b) Alhambra, C.; Castro, J.; Chiara, J. L.; Fernandez, E.; Fernandez-Mayoralas, A.; Fiandor, J. M.;Garcia-Ochoa, S.; Martin-Ortega, M. D. TetrahedronLett., 2001, 42 (38), pp. 6675 - 6678.
(c) Bats, J. W.; Frost, T. M.; Hashmi, A.; Stephen, K. Acta Crystallogr. Sect. C: Cryst. Struct. Commun., 2001; 57(9); pp. 1081 - 1083.
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