Formal [3+2]-Cycloaddition-Based Approach Using Ethoxymethylene Malonate Derivatives: Novel and Expedient Access to Functionalized N-Acyliminium Precursors

Abstract

Combination of a base, ethoxymethylene malonates, and α-bromoacetamides was used to reach structurally diverse α-alkoxy-γ-lactams via a direct aza-MIRC sequence in excellent yields. Subsequent acidic treatment allowed the formed pyrrolo [2,1-a]isoquinoline alkaloid core to be isolated in high yield.

[3+2] annulation - aza-heterocycle - tandem reaction - α-alkoxy-γ-lactams - N-acyliminium - α-amidoalkylation

References and Notes

<A NAME="RG16710ST-1">1</A> For a review concerning the use of alkoxymethylene-malonates in organic synthesis, see: Milata V. Aldrichimica Acta  2001,  34:  20 ; and the references cited therein

<A NAME="RG16710ST-2">2</A> For a recent example in the synthesis of bioactive compounds, see: Hua B. Bernotas R. Unwalla R. Collini M. Quinet E. Feingold I. Goos-Nilsson A. Wilhelmsson A. Nambi P. Evans M. Wrobel J. Bioorg. Med. Chem. Lett.  2010,  20:  689 

<A NAME="RG16710ST-3">3</A> Moffett RB. J. Heterocycl. Chem.  1980,  17:  341 

<A NAME="RG16710ST-4">4</A> Gómez C. Manzano T. Navarro P. Heterocycles  1980,  14:  769 

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For authoritative reviews in this field, see:

<A NAME="RG16710ST-11A">11a</A> Maryanoff BE. Zhang HC. Cohen JH. Turchi IJ. Maryanoff CA. Chem. Rev.  2004,  104:  1431 

<A NAME="RG16710ST-11B">11b</A> Speckamp WN. Moolenaar MJ. Tetrahedron  2000,  56:  3817 

<A NAME="RG16710ST-12">12</A> Leonard NM. Woerpel KA. J. Org. Chem.  2009,  74:  6915 ; and references cited therein

For representative and recent papers on heterocyclization, see:

<A NAME="RG16710ST-13A">13a</A> Pesquet A. Daïch A. Decroix B. Van Hijfte L. Org. Biomol. Chem.  2005,  3:  3937 

<A NAME="RG16710ST-13B">13b</A> Hamid A. Oulyadi H. Daïch A. Tetrahedron  2006,  62:  6398 

<A NAME="RG16710ST-13C">13c</A> Oukli N. Comesse S. Chafi N. Oulyadi H. Daïch A. Tetrahedron Lett.  2009,  50:  1459 

For catalytic α-amidoalkylation process, see:

<A NAME="RG16710ST-13D">13d</A> Ben Othman R. Bousquet T. Othman M. Dalla V. Org. Lett.  2005,  7:  3535 

<A NAME="RG16710ST-13E">13e</A> Pin F. Comesse S. Garrigues B. Marchalín Š. Daïch A. J. Org. Chem.  2007,  72:  1181 

<A NAME="RG16710ST-13F">13f</A> Ben Othman R. Affani R. Tranchant MJ. Antoniotti S. Duñach E. Dalla V. Angew. Chem. Int. Ed.  2010,  49:  776 

<A NAME="RG16710ST-14A">14a</A> Allous I. Comesse S. Daïch A. Lett. Org. Chem.  2008,  3:  73 

<A NAME="RG16710ST-14B">14b</A> Comesse S. Sanselme M. Daïch A. J. Org. Chem.  2008,  73:  5566 

<A NAME="RG16710ST-14C">14c</A> Pin F. Comesse S. Sanselme M. Daïch A. J. Org. Chem.  2008,  73:  1975 

<A NAME="RG16710ST-15">15</A>

Typical Procedure for the Preparation of 9a-j
The required alkoxymethylene derivative 1a-d (1.0 mmol) and N-alkyl-α-bromoacetamide (8a-e, 1.1 mmol) were dissolved in freshly distilled THF (10 mL) at 0 ˚C. NaH (48 mg, 60% suspension in mineral oil, 1.2 mmol) was then added in small portions, and the mixture was stirred for 3 h. The reaction was carefully quenched by addition of a sat. aq NH₄Cl solution (10 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL), the organic layers were combined, dried over MgSO₄, and evaporated. The residue was then chromatographed on silica gel and provided the desired
α-alkoxy-γ-lactams 9a-j.
Physical Data for 9j
This product was isolated as colorless oil; yield 96% (EtOAc-cyclohexane, 30:70). IR (KBr): 3419, 1965 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 1.15 (t, J = 7.0 Hz, 3 H), 1.22-1.23 (m, 6 H), 2.61 (d, J = 17.7 Hz, 1 H), 2.82 (m, 2 H), 3.19-3.29 (m, 1 H), 3.42 (d, J = 17.7 Hz, 1 H), 3.64 (q, J = 7.0 Hz, 2 H), 3.75-3.81 (m, 1 H), 3.84 (s, 3 H), 3.86 (s, 3 H), 4.10-4.32 (m, 4 H), 5.42 (s, 1 H), 6.73-6.81 (m, 3 H) ppm. ^¹³C NMR (75 MHz, CDCl₃): δ = 14.1, 14.2, 15.5, 33.8, 36.5, 42.8, 56.0, 56.1, 59.9, 62.4, 62.5, 67.3, 91.7, 111.5, 112.2, 120.7, 131.5, 147.9, 149.2, 166.7, 169.3, 171.4 ppm.

<A NAME="RG16710ST-16">16</A>

Full crystallographic data have been deposited at the Cambridge Crystallographic Data Centre; CCDC reference number 777319 for product 9h. Copies of the data can be obtained free of charge at the following address:
http://www.ccdc.cam.ac.uk.

<A NAME="RG16710ST-17">17</A>

Optimized Procedure for the Preparation of Compounds 9a-i
Starting from ethoxymethylene malononitrile (1d, 270 mg, 2.2 mmol) and N-alkyl-α-bromoacetamide (8c, 1 mmol) were dissolved in freshly distilled MeCN (10 mL). K₂CO₃ (166 mg, 1.2 mmol) was then added, and the mixture was stirred for 2 h under reflux. The reaction was filtered through a small pad of Celite 545 using CH₂Cl₂, and the organic layer was evaporated. The residue was then purified by chroma-
tography on silica gel column and provided the desired α-alkoxy-γ-lactam.
Physical Data for Compound 9i
This product was isolated as colorless oil; yield 89% (EtOAc-cyclohexane, 20:80). IR (KBr): 2982, 2257, 1723 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 1.14 (t, J = 6.9 Hz, 3 H), 3.02 (d, J = 16.8 Hz, 1 H), 3.17 (d, J = 16.8 Hz, 1 H), 3.49 (dq, J = 15.2, 7.0 Hz, 1 H), 3.74 (dq, J = 15.2, 7.0 Hz, 1 H), 3.94 (d, J = 14.9 Hz, 1 H), 4.82 (s, 1 H), 4.94 (d, J = 14.9 Hz, 1 H), 7.12-7.15 (m, 2 H), 7.21-7.29 (m, 3 H) ppm.
^¹³C NMR (75 MHz, CDCl₃): δ = 14.8, 35.0, 38.7, 44.8, 67.8, 90.4, 111.7, 113.4, 128.2, 128.6, 129.2, 134.0, 167.0 ppm.

<A NAME="RG16710ST-18">18</A> Zhang Q. Tu G. Zhao Y. Cheng T. Tetrahedron  2002,  58:  6795 

For recent examples, see:

<A NAME="RG16710ST-19A">19a</A> Chiou W.-H. Lin G.-H. Hsu C.-C. Chaterpaul SJ. Ojima I. Org. Lett.  2009,  11:  2659 

<A NAME="RG16710ST-19B">19b</A> Evanno L. Ormala J. Pihko PM. Chem. Eur. J.  2009,  15:  12963 

<A NAME="RG16710ST-19C">19c</A> Coldham I. Jana S. Watson L. Martin NG. Org. Biomol. Chem.  2009,  7:  1674 ; and the references cited therein

<A NAME="RG16710ST-20">20</A>

Synthesis of Diethyl 8,9-Dimethoxy-3-oxo-2,3,5,6-tetrahydropyrrolo[2,1- a ]isoquinoline-1,1 (10 bH )-dicarboxylate (10)
TFA (0.23 mL, 3 mmol) was added dropwise at r.t. to a solution of α-alkoxy-γ-lactam 9j (438 mg, 1 mmol) in freshly distilled MeCN (10 mL). The mixture was refluxing overnight, cooled to 0 ˚C and then carefully hydrolyzed with a sat. solution of NaHCO₃ (10 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL), the organic layers were combined, dried over MgSO₄, and evaporated. The residue was purified by chromatography on silica gel column to provide 10.
Physical Data for Compound 10
This product was isolated as colorless crystals; mp 157-159 ˚C (recrystallized from Et₂O); yield 87% (EtOAc-cyclohexane, 30:70). 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) ppm. ^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 ppm.