9338 Chem. Commun., 2013, 49, 9338--9340 This journal is c The Royal Society of Chemistry 2013 Cite this: Chem. Commun., 2013, 49, 9338 Non-enzymatic acylative kinetic resolution of primary allylic amines† Amandine Kolleth, Martin Cattoen, Stellios Arseniyadis* and Janine Cossy* A non-enzymatic acetyl transfer-based kinetic resolution of primary allylic amines is reported. The process involves the use of (1S,2S)-1 in conjunction with a supported ammonium salt and affords the corresponding enantio-enriched N-acetylated allylic amines with unprecedented levels of selectivity (s-factors up to 34). Enantiomerically pure allylamines 1 represent a particularly impor- tant class of molecules due to their intriguing biological properties and ubiquitous nature. They are also valuable intermediates in the synthesis of various pharmaceuticals and other biologically active compounds including amino acids 2 and alkaloids. 3 Synthesis-wise, they are generally obtained through transition-metal-catalyzed allylic substitution, 4 vinylation of imines, 5 aza-Claisen rearrange- ment of allylic trichloroacetimidates 6 or through an aza-Morita– Baylis–Hillman reaction. 7 Alternatively, enantioenriched allyla- mines can also be accessed through the kinetic resolution of the corresponding racemic amines; 8 however, their strong nucleo- philicity has hampered the development of efficient processes. During the past two decades, several particularly selective reagents and catalysts have been reported for the stereoselective acylation of racemic amines, notably by Shibuya, 9 Atkinson, 10 Murakami, 11 Krasnov, 12 Fu, 13 Arseniyadis and Mioskowski, 14 Toniolo, 15 Karnik and Kamath, 16 and more recently by Birman, 17 Miller, 18 Bode 8,19 and Seidel. 20 For our part, we recently showed that (1S,2S)- N-acetyl-1,2-bis-trifluoromethanesulfonamidocyclohexane (1S,2S)-1 could be used as a highly selective acetylating agent for the KR of primary propargylic amines affording the corre- sponding acetamides with unprecedented levels of selectivity (s-factors up to 193) while displaying a unique solvent-induced reversal of stereoselectivity. 21 Interestingly, despite all the efforts, only one example of non- enzymatic kinetic resolution of allylamines has been reported so far. The strategy, which was developed by Seidel and co-workers, 8 is based on a particularly elegant dual-catalysis/anion-binding approach involving 4-(pyrrolidino)pyridine and a readily avail- able chiral hydrogen-bonding co-catalyst and affords s-factors 22 of up to 20 at 78 1C. Here, we wish to report a new benchmark reached in the kinetic resolution of primary allylic amines using (1S,2S)-1 in conjunction with a supported ammonium salt. The method is simple to execute, reliable and affords high levels of selectivity on a wide range of substrates. In order to develop an efficient kinetic resolution process, we decided to initiate our study by first screening various solvents at room temperature using ( )-3-phenylbut-3-en- 2-amine 2a as a model substrate. The results are depicted in Table 1. Table 1 Evaluation of the reaction parameters a Entry Solvent n ee b (%) 1 Toluene 0 42 (R c ) 2 Et 2 O 0 40 (R) 3 CH 2 Cl 2 0 30 (R) 4 THF 0 25 (R) 5 DMF 0 62 (S) 6 NMP 0 66 (S) 7 THF 0.5 51 (S) 8 1.0 66 (S) 9 2.0 73 (S) 10 5.0 73 (S) 11 10 75 (S) 12 d THF 2 83 (S) a All reactions were carried out on a 0.25 mmol scale using 0.5 equiv. of (1S,2S)-1 at rt with n equiv. of polymer-supported salt. b Enantiomeric excess of compound 3a determined by chiral supercritical fluid chroma- tography (SFC) analysis. c Absolute configuration of the major enantio- mer. d Reaction run at 20 1C. NMP = N-methyl-2-pyrrolidone. Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 rue Vauquelin, 75231 Paris Cedex 05, France. E-mail: [email protected], [email protected]; Fax: +33 (0)1 40 79 46 60; Tel: +33 (0)1 40 79 46 62 † Electronic supplementary information (ESI) available: Details of experimental procedures and 1 H NMR, 13 C NMR spectra of all new compounds. This material is available free of charge via the internet at http://pubs.rsc.org. See DOI: 10.1039/ c3cc45453c Received 18th July 2013, Accepted 13th August 2013 DOI: 10.1039/c3cc45453c www.rsc.org/chemcomm ChemComm COMMUNICATION Published on 14 August 2013. Downloaded by Princeton University on 19/09/2013 22:02:51. View Article Online View Journal | View Issue
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9338 Chem. Commun., 2013, 49, 9338--9340 This journal is c The Royal Society of Chemistry 2013
Cite this: Chem. Commun.,2013,49, 9338
Non-enzymatic acylative kinetic resolution of primaryallylic amines†
Amandine Kolleth, Martin Cattoen, Stellios Arseniyadis* and Janine Cossy*
A non-enzymatic acetyl transfer-based kinetic resolution of primary
allylic amines is reported. The process involves the use of (1S,2S)-1 in
conjunction with a supported ammonium salt and affords the
corresponding enantio-enriched N-acetylated allylic amines with
unprecedented levels of selectivity (s-factors up to 34).
Enantiomerically pure allylamines1 represent a particularly impor-tant class of molecules due to their intriguing biological propertiesand ubiquitous nature. They are also valuable intermediates in thesynthesis of various pharmaceuticals and other biologically activecompounds including amino acids2 and alkaloids.3 Synthesis-wise,they are generally obtained through transition-metal-catalyzedallylic substitution,4 vinylation of imines,5 aza-Claisen rearrange-ment of allylic trichloroacetimidates6 or through an aza-Morita–Baylis–Hillman reaction.7 Alternatively, enantioenriched allyla-mines can also be accessed through the kinetic resolution of thecorresponding racemic amines;8 however, their strong nucleo-philicity has hampered the development of efficient processes.
During the past two decades, several particularly selectivereagents and catalysts have been reported for the stereoselectiveacylation of racemic amines, notably by Shibuya,9 Atkinson,10
Murakami,11 Krasnov,12 Fu,13 Arseniyadis and Mioskowski,14
Toniolo,15Karnik and Kamath,16 and more recently by Birman,17
Miller,18 Bode8,19 and Seidel.20 For our part, we recently showedthat (1S,2S)-N-acetyl-1,2-bis-trifluoromethanesulfonamidocyclohexane(1S,2S)-1 could be used as a highly selective acetylating agentfor the KR of primary propargylic amines affording the corre-sponding acetamides with unprecedented levels of selectivity(s-factors up to 193) while displaying a unique solvent-inducedreversal of stereoselectivity.21
Interestingly, despite all the efforts, only one example of non-enzymatic kinetic resolution of allylamines has been reported so far.
The strategy, which was developed by Seidel and co-workers,8 isbased on a particularly elegant dual-catalysis/anion-bindingapproach involving 4-(pyrrolidino)pyridine and a readily avail-able chiral hydrogen-bonding co-catalyst and affords s-factors22
of up to 20 at �78 1C.Here, we wish to report a new benchmark reached in the
kinetic resolution of primary allylic amines using (1S,2S)-1 inconjunction with a supported ammonium salt. The method issimple to execute, reliable and affords high levels of selectivityon a wide range of substrates.
In order to develop an efficient kinetic resolution process,we decided to initiate our study by first screening varioussolvents at room temperature using (�)-3-phenylbut-3-en-2-amine 2a as a model substrate. The results are depicted inTable 1.
a All reactions were carried out on a 0.25 mmol scale using 0.5 equiv. of(1S,2S)-1 at rt with n equiv. of polymer-supported salt. b Enantiomericexcess of compound 3a determined by chiral supercritical fluid chroma-tography (SFC) analysis. c Absolute configuration of the major enantio-mer. d Reaction run at �20 1C. NMP = N-methyl-2-pyrrolidone.
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 rue Vauquelin,
† Electronic supplementary information (ESI) available: Details of experimentalprocedures and 1H NMR, 13C NMR spectra of all new compounds. This material isavailable free of charge via the internet at http://pubs.rsc.org. See DOI: 10.1039/c3cc45453c
This journal is c The Royal Society of Chemistry 2013 Chem. Commun., 2013, 49, 9338--9340 9339
As expected, considering the results previously obtainedwith benzylic14 and propargylic amines,21 solvents having a lowrelative permittivity such as toluene (et = 2.38), Et2O (et = 4.33),CH2Cl2 (et = 8.93), and THF (et = 7.58) led to preferential acetylationof the (R)-enantiomer23 with ee values ranging from 25% to42% (Table 1, entries 1–4), while dipolar-aprotic solvents such asDMF (et = 36.71) and NMP (et = 32.2) (Table 1, entries 5 and 6)induced both an increase in selectivity and a complete reversalof stereoselectivity resulting in the preferential acetylation of the(S)-enantiomer with ees of up to 66% (s = 9.5).
Given the improved results previously obtained when perform-ing the kinetic resolution in the presence of ammonium, pyridi-nium or phosphonium salts,14b,21 we next decided to explore thepossibility of using a recyclable polymer-supported salt whichwould have the advantage of being easily removable at the end ofthe reaction by simple filtration and thus ease the purificationprocedure. We naturally chose to evaluate a supported analogue ofAliquatt 336, which gave the best results to date; the latter wasprepared in one step by mixing Merrifield resin with an excess oftrioctylamine in hot DMF overnight. To our delight, by performingthe reaction in THF at room temperature in the presence of0.5 equiv. of the polymer-supported ammonium salt, we were ableto observe a complete reversal of the selectivity and isolate thecorresponding acetamide 3a in quantitative yield and 51% ee(Table 1, entry 7). Increasing the amount of the supported saltfrom 0.5 to 2.0 equiv. further improved the selectivity, as the sameacetamide was isolated with up to 73% ee (Table 1, entries 8 and 9).Interestingly, the use of more than 2.0 equiv. of supported ammo-nium salt gave virtually identical results (Table 1, entries 10 and 11)prompting us to discard these last conditions. Finally, reducing thereaction temperature to �20 1C afforded an additional increase inselectivity allowing to isolate the corresponding acetamide inquantitative yield and with up to 83% ee (s = 28, Table 1, entry 12).
With these optimized conditions in hand (0.5 equiv. of(1S,2S)-1, 2.0 equiv. of the supported salt in THF at �20 1C),we next decided to evaluate the influence of the substituent onthe olefin at the C2 position. As shown in Scheme 1, increasingthe bulk of the substituent and running the reaction underotherwise identical conditions had a striking effect on theselectivity. Indeed, by replacing the hydrogen (R = H, 2b) by amethyl (R = Me, 2c), a phenyl (R = Ph, 2d) or a trimethylsilylgroup (R = TMS, 2e), we were able to drastically improve theselectivity from s = 6.8 (R = H) to s = 28 (R = TMS) withoutobserving any noticeable change in reactivity.
A broader range of allylic amines were therefore prepared andsubjected to our optimized conditions. The results are depicted inTable 2. In every single case, the corresponding acetamides wereobtained in excellent yields and moderate to good selectivitiesdepending on the substitution pattern on both the olefin and thealiphatic side chain. Hence, while the a-styryl-substituted ethyl-amine 2a was successfully resolved with a high level of selec-tivity (s = 28), the corresponding (Z) and (E)-b-styryl regio-isomers (2f and 2g) afforded much lower selectivities; (1S,2S)-1being more efficient toward the Z-stereoisomer (s = 7.7). Exchan-ging the methyl (2a) for an ethyl (2i) or a butenyl (2m) group inthe parent substrate led to a small increase in selectivity froms = 28 to s = 31, whereas substrates bearing a bulkier substituentsuch as an isopropyl (2j, s = 14) or a benzyl (2k, s = 8) group wereisolated with slightly lower ees. Unfortunately, (1S,2S)-1 was notable to distinguish between two different p-systems, as exem-plified by the resolution of substrate 2p, which afforded thecorresponding acetamide 3p with only 25% ee (s = 2) albeit in aquantitative yield. Compound 2q also gave a modest level ofselectivity, suggesting the importance of a conjugated p-system.Remarkably, gem-disubstituted a-styryl amines bearing substi-tuents on different positions of the aromatic ring (2r–s) werealso effectively resolved regardless of the electronic nature ofthe substituents (with s-factors ranging from s = 20 to s = 34)(Table 2).
Having evaluated the scope and limitation of the method,we next compared the selectivity of (1S,2S)-1 toward other typesof primary amines under our optimized conditions. As shown
Scheme 1 Influence of the substituent on the olefin a to the carbon bearingthe amine moiety.
Table 2 Scope and limitations of the methoda
a All reactions were carried out on a 0.25 mmol scale using 0.5 equiv. of(1S,2S)-1 at –20 1C with 2 equiv. of polymer-supported salt. b Enantio-meric excess of compounds 3a–s determined by chiral SFC analysis.c Calculated selectivity and conversion.
9340 Chem. Commun., 2013, 49, 9338--9340 This journal is c The Royal Society of Chemistry 2013
in Scheme 2, the method is superior in the case of benzylic14
(2t, s = 79) and propargylic21 (2u, s = 67) amines, reflecting thehigher reactivity of allylic amines towards acylating agents.
In summary, we have elaborated a particularly selectiveprocess for the kinetic resolution of racemic primary allylicamines affording unprecedented levels of selectivity in a widerange of substrates. The use of a recyclable24 polymer-supportedsalt allowed us to not only modify the polarity of the solvent andthus trigger a reversal of selectivity, but also improve the ees andsimplify the protocol. Further applications of this method arecurrently under investigation and will be reported in due course.
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24 The polymer-supported salt was used up to six times without anynoticeable loss of selectivity.
Scheme 2 Comparison of benzylic, propargylic and allylic amines.
