Asymmetric Michael Addition of Nitrobenzyl Pyridines to Enals via Iminium Catalysis

Abstract

The asymmetric Michael addition of nitrobenzyl pyri­dines to α,β-unsaturated aldehydes is described. This unprecedented transformation highlights the possibility of extending the nucleophile scope of iminium catalysis to include diaryl compounds in which the reactive methylene centre is not activated by classical electron-withdrawing groups. Indeed, combining the electronic effects of a p-nitro- or o-nitro-substituted aromatic and of a pyridine system fulfils the requirements for nucleophile activation. The synthetic utility of the method has been demonstrated via rapid access to enantioenriched tetrahydro-1-benzazepines.

asymmetric catalysis - secondary amine - Michael addition - organocatalysis - pyridine

References and Notes

1a List B. Angew. Chem. Int. Ed.  2010,  49:  1730 

1b MacMillan DWC. Nature (London)  2008,  455:  304 

1c Barbas CF. Angew. Chem. Int. Ed.  2008,  47:  42 

1d Melchiorre P. Marigo M. Carlone A. Bartoli G. Angew. Chem. Int. Ed.  2008,  47:  6138 

1e Bertelsen S. Jørgensen KA. Chem. Soc. Rev.  2009,  38:  2178 

2a Lelais G. MacMillan DWC. Aldrichimica Acta  2006,  39:  79 

2b Brazier JB. Tomkinson NCO. Top. Curr. Chem.  2010,  291:  281 

3a Paras NA. MacMillan DWC. J. Am. Chem. Soc.  2001,  123:  4370 

3b Austin JF. MacMillan DWC.
J. Am. Chem. Soc.  2002,  124:  1172 

3c Lee S. MacMillan DWC. J. Am. Chem. Soc.  2007,  129:  15438 

4 Malonates, having a pK _aof 16, have been used in iminium catalysis: Brandau S. Landa A. Franzen J. Marigo M. Jørgensen KA. Angew. Chem. Int. Ed.  2006,  45:  4305 

For few selected examples, see:

5a Gotoh H. Ishikawa H. Hayashi Y. Org. Lett.  2007,  9:  5307 

5b Palomo C. Landa A. Mielgo A. Oiarbide M. Puente A. Vera S. Angew. Chem. Int. Ed.  2007,  46:  8431 

6 Alonso DA. Kitagaki S. Utsumi N. Barbas CF. Angew. Chem. Int. Ed.  2008,  47:  4588 

7 Cassani C. Tian X. Escudero-Adán EC. Melchiorre P. Chem. Commun.  2011,  47:  233 

8 Cid MB. Duce S. Morales S. Rodrigo E. Ruano JLG. Org. Lett.  2010,  12:  3586 

9

The pK _a values are referred to DMSO and are taken from the Bordwell Tables, see: http://www.chem.wisc.edu/areas/reich/pkatable/index.htm.

10 ‘Enolate-like stabilisation of the anion may be achieved for any organic compound with an electron-withdrawing functional group, with at least one π-bond attached to a saturated carbon atom having at least one hydrogen atom’: Clayden J. Greeves N. Warren S. Wothers P. Organic Chemistry   Oxford University Press; Oxford: 2001.  p.529 

11 Anions on an alkyl side chain that are immediately adjacent to an aromatic ring are subject to varying degrees of stabilisation; this effect is stronger in the 2- or 4-position of a pyridine. Such anions are stabilised in much the same way as an enolate. The word ‘enaminate’ indicates this type of nitrogen-containing enolate-like anion: Joule JA. Mills K. Heterocyclic Chemistry   5th Ed.:  John Wiley & Sons; Hoboken: 2010.  p.54-55  

12a Marigo M. Wabnitz TC. Fielenbach D. Jørgensen KA. Angew. Chem. Int. Ed.  2005,  44:  794 

12b Hayashi Y. Gotoh H. Hayashi T. Shoji M. Angew. Chem. Int. Ed.  2005,  44:  4212 

12c For a recent review on the efficiency of TMS-diaryl prolinol catalysts, see: Mielgo A. Palomo C. Chem. Asian J.  2008,  3:  922 

13 For the industrial scale asymmetric synthesis of Telcagepant, see: Xu F. Zacuto M. Yoshikawa N. Desmond R. Hoerrner S. Itoh T. Journet M. Humphrey GR. Cowden C. Strotman N. Devine P. J. Org. Chem.  2010,  75:  7829 

14

The lack of consistency in the conversion when using THF-H₂O as the solvent system is probably a consequence of the poor solubility of some among the unsaturated aldehydes 2 in this reaction media.

15

The presence of an alkyl substituent at the β-position of the enal is not tolerated under the reaction condition: i.e., crotonaldehyde remained unreactive.

16

The observed modest diastereocontrol is not surprising: the privileged secondary amine catalysts, such as B, generally infer high enantioselectivity but with poor diastereocontrol when promoting the conjugate addition of prochiral carbon nucleophiles to α,β-unsaturated aldehydes; see, for example, ref. 6.

17

Both the diastereomerically pure aldehydes and the corresponding alcohols are stable, with no epimerisation events observed after storing in the fridge for several weeks. The NaBH₄ reduction is requested since the alcohols 3 allow for a far easier HPLC analysis than the aldehyde precursors.

18

Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre, accession number CCDC 802673(5), and are available free of charge via www.ccdc.cam.ac.uk/data_request/cif.

19a Cooper TWJ. Campbell IB. Macdonald SJF. Angew. Chem. Int. Ed.  2010,  49:  8082 ; and references therein

19b Pitt WR. Parry DM. Perry BG. Groom CR. J. Med. Chem.  2009,  52:  2952 

20

Benzazepines are the core structure of numerous biologically active compounds. More specifically, the tetrahydro-1-benzazepine scaffold can be found in a series of approved drugs such as Tolvaptan, Benazepril, Mozavaptan and Zilpaterol among others.

21

Experimental Procedure of the 2.0-mmol Scale Reaction (Table 2, entry 2): In an ordinary vial equipped with a magnetic stir bar, catalyst B (0.3 mmol, 97.5 mg, 15 mol%) and cinnamaldehyde (2a; 4 mmol, 503 µL) were dissolved in THF (1 mL). After 10 min stirring at r.t., 4-(4-nitrobenzyl)-pyridine (1a; 2.0 mmol, 427 mg) and DABCO (1 mmol, 112.2 mg, 0.5 equiv) were added. The vial was capped and the resulting mixture was stirred at r.t. After 48 h, the reaction mixture was cooled to 0 ˚C, diluted with MeOH (10 mL) and then a suspension of NaBH₄ (132.3 mg, 3.5 mmol) in MeOH (10 mL) was added dropwise. The resulting mixture was stirred for 30 min at 0 ˚C and then was quenched with H₂O (30 mL). The product was extracted with CH₂Cl₂ (3 × 30 mL) and the organics were dried over anhyd Na₂SO₄. The solvent was removed under reduced pressure and the crude products were purified by flash chromatography on silica gel (CH₂Cl₂ → CH₂Cl₂-MeOH, 95:5). Both of the diastereoisomers of compound 3a were easily isolated due to the appreciable difference in the R _f . First diastereoisomer: 187 mg (27% yield); 95% ee; R _f 0.28 (CH₂Cl₂-MeOH, 95:5); second diastereoisomer: 206 mg (31% yield); 96% ee; R _f 0.15 (CH₂Cl₂-MeOH, 95:5). See Supporting Information for full experimental details and product characterisation.