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Synlett 2003(9): 1275-1278
DOI: 10.1055/s-2003-40331
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A New Approach to Substituted Cyclobutanes: Direct β-Deprotonation/ Magnesiation of Cyclobutane Carboxamides

Philip E. Eaton*a, Mao-Xi Zhanga, Naruyoshi Komiyaa, Cai-Guang Yanga, Ian Steelea, Richard Gilardib
a Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA
Fax: +1(773)7022053; e-Mail: eaton@uchicago.edu;
b Laboratory for the Structure of Matter, The Naval Research Laboratory, Washington, D.C. 20375, USA
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Publication History

Received 17 March 2003
Publication Date:
30 June 2003 (online)

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Abstract

BuMgN(i-Pr)2 is shown to be kinetically and thermodynamically efficient for deprotonation/magnesiation cis and β to an activating carboxamido group on a cyclobutane ring. The resulting carboxamido-stabilized amido-Grignards are useful reagents. The method provides an entirely new approach to controlled substitution on cyclobutanes. BuMgN(i-Pr)2 will also metalate pivaloyl amides.

Key words

metalation - diastereoselective - amido-Grignards - cyclobutanes - substituent effects

    References

  • 1a Eaton PE. Zhang MX. Angew. Chem. Int. Ed.   2002.  41:  p.2169 
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  • 1b See also: Eaton PE. Lee CH. Xiong Y. J. Am. Chem. Soc.  1989,  111:  8016 
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  • 1c Eaton PE. Xiong Y. Lee CH. J. Chin. Chem. Soc.  1991,  38:  303 
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  • 2 The activating/stabilizing carboxamido group need not be on the β-carbon, see: Eaton PE. Lukin K. J. Am. Chem. Soc.  1993,  115:  11370 
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  • 3 Streitwieser A. Caldwell RA. Young WR. J. Am. Chem. Soc.  1969,  91:  529 
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  • Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre, e-mail: deposit@ccde.cam.ac.uk, as supplementary publications numbered:
  • 6a

    206444;

  • 6b

    173571;

  • 6c

    209582 (racemate);

  • 6d

    205769.

  • 7 Remarkably little is known about what happens at the magnesiated carbon during Grignard reactions with {E+}. See: Gawley RE. In Grignard Reagents. New Developments   Richey HG. Wiley; Chichester: 2000.  p.139 
  • 10 Zhang MX. Komiya N. Eaton PE. 224th ACS National Meeting, Boston   2002.  p.341-ORGN 
4

We assign the liganding interaction shown by analogy to that seen in a cyclopropyl example for which we have a single crystal X-ray structure: Eaton, P. E.; Zhang, M. X.; Steele, I., unpublished results

5

Typical Procedure. Dry diisopropylamine (202 mg, 2.0 mmol) was added dropwise to a stirred 1 M solution of Bu2Mg in heptanes (Aldrich, 2.0 mL, 2.0 mmol) at 0 °C. The mixture was stirred at r.t. for 1.5 h to give a pale yellow BuMgN(i-Pr)2 solution. Amide 3 (99 mg, 0.5 mmol) in THF (1.5 mL) was added at r.t. to the base solution so made. The resulting pale yellow solution was taken to reflux (73 °C, bath at 85 °C) for 4 h. Afterwards, the solution was cooled to r.t. and added to I2 (1 g, 4 mmol) in THF (5 mL) at 0 °C. The mixture was stirred at r.t. for 1.5 h then quenched with aq 10% HCl (5 mL), extracted with CHCl3 (3 × 10 mL) and washed with aq sat. (NH4)2SO4 (10 mL). The extract was washed with an aq 10% Na2S2O3 (10 mL), then again with aq sat. (NH4)2SO4 (2 × 10 mL), dried over Na2SO4 and concentrated at r.t. in vacuo. The residual brown liquid was chromatographed (silica gel, CH2Cl2) to give 7 (124 mg, 77%) as a colorless solid: mp 119-120 °C. 1H NMR (400 MHz, CDCl3): δ = 4.96 (dd, J = 10 and 9 Hz, 1 H), 3.73 (sept, J = 7 Hz, 1 H), 3.27 (sept, J = 7 Hz, 1 H), 2.48 (m, 1 H), 2.31-2.42 (m, 2 H), 2.02 (m, 1 H), 1.47 (s, 3 H), 1.39 (d, J = 7 Hz, 3 H), 1.38 (d, J = 7 Hz, 3 H), 1.17 (d, J = 7 Hz, 3 H), 1.15 (d, J = 7 Hz, 3 H). 13C NMR (100 MHz): δ = 174.1, 49.7, 47.9, 46.0, 32.6, 28.8, 28.1, 25.7, 20.7, 20.4., Anal. Calcd for C12H22INO: C, 44.59; H, 6.86; N, 4.33. Found: C, 44.97; H, 6.79; N, 4.36. The epimer of 7 was eluted somewhat later from the column: mp 109-110 °C. 1H NMR (400 MHz, CDCl3): δ = 4.21 (dd, J = 6.0 and 5.6 Hz, 1 H), 3.45 (sept, J = 6.4 Hz, 1 H), 3.29 (sept, J = 6.8 Hz, 1 H), 3.17 (dd, J = 20.0 and 11.2 Hz, 1 H), 2.85-2.75 (m, 1 H), 2.09 (m, 1 H), 1.64-1.57 (m, 1 H), 1.53 (s, 3 H), 1.40 (d, J = 6.8 Hz, 3 H), 1.38 (d, J = 6.8 Hz, 3 H), 1.35 (d, J = 6.4 Hz, 3 H), 1.18 (d, J = 6.4 Hz, 3 H). 13C NMR (100 MHz): δ = 173.2, 52.0, 48.3, 46.1, 30.8, 30.2, 29.2, 22.2, 21.6, 21.1, 20.5, 20.2. MS (ES): 324.0 [M + 1].

8

We estimate that we would have seen in the NMR spectra of the crudes any other isomer present in >10% yield.

9

Bu2Mg as supplied commercially (Aldrich) has a mix of
n-butyl and sec-butyl groups. Thus, two bases result from reaction with HN(i-Pr)2: n-BuMgN(i-Pr)2 and sec-BuMgN(i-Pr). We have made each separately and have found only small differences in their ability to deprotonate/magnesiate 3.

11

Best value at present for neopentane:cyclohexane relative kinetic acidity is 8.2:1 (per hydrogen) obtained using CsCHA at 50 °C. Private Communication, Prof. A. Streitwieser, March 4, 2003.