Convenient Access to 2-Arylpyrroles from 2-Lithio-N,N-dibenzylcyclopropylamine and Nitriles [1]

Abstract

N,N-Dibenzylaminocyclopropyl ketimines formed as ­intermediates upon treatment of 2-lithiated N,N-dibenzylcyclo­propylamines with nitriles, being donor-acceptor-substituted cyclopropanes, immediately underwent ring-enlarging rearrangement and 1,2-elimination of dibenzylamine to produce 2-substituted ­pyrroles in good yields (14 examples, 55-80%).

tin-lithium exchange - nitriles - 2-arylpyrroles - cyclopropylamines - donor-acceptor-substituted cyclopropanes

References and Notes

For one of us (A.d.M.) this is to be counted as Part 133 in the series, ‘Cyclopropyl Building Blocks for Organic Synthesis’:

1a For Part 132, see: Marradi M. Brandi A. Magull J. Schill H. de Meijere A. Eur. J. Org. Chem.  2006,  in press 

1b Part 131: Bagutski V. Moszner N. Zeuner F. Fischer UK. Adv. Synth. Catal.  2006,  in press 

2 Tanguy C. Bertus P. Szymoniak J. Larionov OV. de Meijere A. Synlett  2006,  in press  (e-First, DOI: 10.1055/s-2006-941600)

The well-known vinylcyclopropane-to-cyclopentene rearrangement is significantly accelerated by donor substit-uents like alkoxy and dialkylamino groups in the 2-position; compare with:

3a McGaffin G. Grimm B. Heinecke U. Michaelsen H. de Meijere A. Walsh R. Eur. J. Org. Chem.  2001,  3559 ; and references cited therein

3b Voigt T. Winsel H. de Meijere A. Synlett  2002,  1362 

The rearrangement of cyclopropylketimines, which is catalyzed by acids and known as the Cloke rearrangement, should also be accelerated by donor substituents:

4a Cloke JB. J. Am. Chem. Soc.  1929,  51:  1174 

4b Review: Hudliky T. Becker DA. Fan RL. Kozhushkov SI. In Methods of Organic Chemistry, Houben-Weyl   Vol. E17c:  de Meijere A. Thieme; Stuttgart: 1997.  p.2538 

4c See also: Funke C. Es-Sayed M. de Meijere A. Org. Lett.  2000,  2:  4249 ; and references cited therein

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11

Typical Procedure. To a solution of trans-2-(tributylstan-nyl)-N,N-dibenzylcyclopropylamine (3, 526 mg, 1 mmol) in THF (3 mL) was added n-BuLi (1.2 mmol, 2 M in hexane) at -30 °C. After stirring for 30 min at -30 °C, the respective nitrile (1.2 mmol) was added. The mixture was warmed to 0 °C within 2 h. At this stage, the reaction was quenched with AcOH (2 M in THF, 0.5 mL), the mixture extracted with EtOAc, the extracts dried over MgSO₄, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (PE-EtOAc, 9:1).

12

2-Phenyl-1 H -pyrrole ( 10a). ¹H NMR (250 MHz, CDCl₃): d = 6.24 (br s, 1 H), 6.46 (br s, 1 H), 6.79 (br s, 1 H), 7.13 (br s, 1H), 7.21-7.32 (m, 2 H), 7.35-7.41 (m, 2 H), 8.36 (br s, 1 H, NH). ¹³C NMR (63 MHz, CDCl₃): d = 105.9, 110.1, 118.8, 123.8, 126.2, 128.9, 132.6, 132.8. HRMS (ESI): m/z calcd for C₁₀H₁₀N: 144.0813 (M + H)⁺; found: 144.0811.
2- m -Tolyl-1 H -pyrrole ( 10b). ¹H NMR (250 MHz, CDCl₃): d = 6.26 (br s, 1 H), 6.44 (br s, 1 H), 6.78 (br s, 1 H), 6.96 (br s, 1 H), 7.17-7.23 (m, 3 H), 8.35 (br s, 1 H, NH). ¹³C NMR (63 MHz, CDCl₃): d = 21.5, 105.8, 110.0, 118.6, 120.9, 124.6, 127.0, 128.7, 132.2, 132.6, 138.4. HRMS (ESI): m/z calcd for C₁₁H₁₂N: 158.0970 (M + H)⁺; found: 158.0972.
2-(3-Methoxyphenyl)-1 H -pyrrole ( 10d). ¹H NMR (250 MHz, CDCl₃): d = 3.82 (s, 3 H), 6.28 (br s, 1 H), 6.51 (br s, 1 H), 6.73-6.77 (m, 1 H), 6.83 (br s, 1 H), 6.99-7.06 (m, 2 H), 7.22-7.29 (m, 1 H), 8.42 (br s, 1 H, NH). ¹³C NMR (63 MHz, CDCl₃): d = 55.2, 106.1, 109.7, 110.0, 111.5, 116.4, 118.8, 129.9, 131.9, 134.1, 160.0. HRMS (ESI): m/z calcd for C₁₁H₁₂NO: 174.0919 (M + H)⁺; found: 174.0918.

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