Proximal Ester Assistance vs. Stereoelectronic Prohibition in Catalytic N-Acyliminium Ion Reactions: Stereoselective Formation of Aza-Heterocycles with Two Contiguous Quaternary-Tertiary Stereocenters

Abstract

The catalytic intramolecular and intermolecular α-amidoalkylation of deactivated N,O-acetals equipped with either two ester groups or both an ester and a cyano groups α to the reactive center has been developed. Reactions in the cyano ester series proceeded under harsher reaction conditions than those in the diester series, but furnished products with two contiguous quaternary and tertiary stereocenters with high to complete diastereocontrol. The reactivity trends and stereoselectivity profiles exhibited by these reactions may be consistent with a relay mode exerted by the ester arm(s), which might possibly direct the catalyst delivery and/or stabilize the raising carbenium ion through anchimeric bridging.

Key words

catalysis - bistrifluoromethanesulfonimide - N-acyl­iminium - directing effect and relay mode - diastereocontrol

References and Notes

• 1a For authoritative reviews on N-acyliminium ion chemistry, see: Speckamp WN. Moolenaar MJ. Tetrahedron  2000,  56:  3817 
• 1b Maryanoff BE. Zhang H.-C. Cohen JH. Turchi IJ. Maryanoff CA. Chem. Rev.  2004,  104:  1431 
• For two recent exhaustive reviews on the intermolecular amidoalkylation of N,O-acetals, see:
• 2a Yazici A. Pyne SG. Synthesis  2009,  339 
• 2b Yazici A. Pyne SG. Synthesis  2009,  513 
• 3 Pin F. Comesse S. Garrigues B. Marchalin Š. Daich A. J. Org. Chem.  2007,  72:  1181 
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• 5 Ben Othman R. Affani R. Tranchant MJ. Antoniotti S. Duñach E. Dalla V. Angew. Chem. Int. Ed.  2010,  49:  776 
• For some other recent reports on catalytic amidoalkylation of N,O-acetals:
• 6a Okitsu O. Suzuki R. Kobayashi S.
  J. Org. Chem.  2001,  66:  809 
• 6b Camilo NS. Pilli RA. Tetrahedron Lett.  2004,  45:  2821 
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• 6d Ben Othman R. Bousquet T. Fousse A. Othman M. Dalla V. Org. Lett.  2005,  7:  2825 ; and references therein
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• For a recent series of papers reporting diastereoselective alkylation of chiral alcohol derivatives bearing an adjacent ester group, see:
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12

Typical Procedure for the Preparation of 4a-d
To a solution of an N,O-acetal 3a-d (0.4 mmol) in a freshly distilled solvent as indicated in Table  [¹] (1.5 mL) was added dropwise a 0.5 M CH₂Cl₂ solution of HNTf₂ (40 µL, 0.02 mmol, 0.05 equiv). The reaction was stirred at the temper-ature indicated in Table  [¹] and followed by TLC. At the end of the reaction, the solution was quenched at r.t. by a 5% aq solution of NaHCO₃, and the aqueous phase was extracted two times with EtOAc (3 mL). The combined organic layers were dried over MgSO₄, the solvent was removed under vacuum, and the residue was then purified by silica gel chromatography to provide the desired tricycles 4a-d.
Physical Data for 4b
Isolated as white solid (recrystallized from Et₂O); mp 157-159 ˚C; yield 95% (EtOAc-cyclohexane, 40:60). IR (KBr): 1728, 1691 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 0.84 (t, J = 7.0 Hz, 3 H), 1.36 (t, J = 7.0 Hz, 3 H), 2.60 (d, J = 16.4 Hz, 1 H), 2.79-3.03 (m, 3 H), 3.05 (d, J = 16.4 Hz, 1 H), 3.62-3.84 (m, 2 H), 3.84 (s, 6 H), 4.29-4.50 (m, 3 H), 5.54 (s, 1 H), 6.57 (s, 1 H), 7.30 (s, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 13.7, 14.3, 28.6, 37.8, 40.1, 60.9, 62.0, 26.6, 110.8, 110.5, 123.6, 127.9, 147.7, 148.4, 168.9, 169.8, 170.7.

13

A simple steric bias (ester > cyano) could also be considered as an alternative or competitive mechanism, in line with ref. 10.

14

Analytical data and copy of the ^¹H NMR spectrum for compound 4d are provided in the Supporting Information.

15

Full crystallographic data have been deposited at the Cambridge Crystallographic Data Centre; CCDC reference number 833548 for the major diastereoisomer of product 4d. Copies of the data can be obtained free of charge at the following address: http://www.ccdc.cam.ac.uk.

16

For typical procedure for the preparation of 6-10, see the Supporting Information.

17

When these allylations were performed at 60 ˚C overnight, around 25% conversion into the desired product was observed, thus confirming the importance of the two ester functions for an efficient process under mild conditions in the intermolecular reactions too.

18

For typical procedure for the preparation of 12-15, see the Supporting Information.