A Facile Route to the Synthesis of Novel 2-Amino-1,4,5,6-tetrahydropyrimidines from Baylis-Hillman Products of Acrylonitrile

Richa Pathak; Amrendra K. Roy; Sanjay Batra

doi:10.1055/s-2005-863728

LETTER

A Facile Route to the Synthesis of Novel 2-Amino-1,4,5,6-tetrahydropyrimidines from Baylis-Hillman Products of Acrylonitrile [1]

Richa Pathak, Amrendra K. Roy, Sanjay Batra*
Medicinal Chemistry Division, Central Drug Research Institute, Lucknow-226001, India
Fax: +91(522)2623405, +91(522)2623938; e-Mail: batra_san@yahoo.co.uk;

Abstract

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Abstract

A facile route for the synthesis of novel 5-substituted-2-amino-1,4,5,6-tetrahydro pyrimidines from the Baylis-Hillman adducts obtained from reaction of aldehydes and acrylonitrile is described.

Key words

Baylis-Hillman - 2-amino-1,4,5,6-tetrahydropyrimidines - 5,6,7,8-tetrahydro-2H-imidazo[1,2-a] pyrimidin-3-one

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References

CDRI Communication no. 6645, presented as poster at CBISNF-2004, 21^st-26^th Nov, N. Delhi.

<A NAME="RD35804ST-2">2</A> Basavaiah D. Jaganmohan Rao A. Satyanarayana T. Chem. Rev. 2003, 103: 811

<A NAME="RD35804ST-3">3</A> Kim JN. Lee KY. Curr. Org. Chem. 2002, 6: 627

<A NAME="RD35804ST-4">4</A> Weinhardt K. Wallach MB. Marx M. J. Med. Chem. 1985, 28: 694

<A NAME="RD35804ST-5A">5a</A> Cho HI. Lee SW. Lee K.-J. J. Heterocycl. Chem. 2004, 41: 799

<A NAME="RD35804ST-5B">5b</A> Basavaiah D. Rao JS. Reddy RJ. J. Org. Chem. 2004, 69: 7379

<A NAME="RD35804ST-5C">5c</A> Lee CG. Lee KY. GowriSankar S. Kim JN. Tetrahedron Lett. 2004, 45: 7409

<A NAME="RD35804ST-5D">5d</A> Singh V. Saxena R. Batra S. J. Org. Chem. 2005, 70: 353

<A NAME="RD35804ST-6">6</A> Dunbar PG. Durant GJ. Fang Z. Abuh YF. El-Assadi AA. Ngur DO. Periyasamy S. Hoss WP. Messer WS. J. Med. Chem. 1993, 36: 842

<A NAME="RD35804ST-7">7</A> Messer WS. Rajeswaran WG. Cao Y. Zhang H.-J. El-Assadi AA. Dockery C. Liske J. O’Brien J. Williams FE. Huang X.-P. Wroblewski ME. Nagy PI. Peseckis SM. Pharmaceut. Acta Helv. 2000, 74: 135

<A NAME="RD35804ST-8">8</A> Greenhill JV. Lue P. Prog. Med. Chem. 1993, 30: 203

<A NAME="RD35804ST-9A">9a</A> Sandin H. Swanstein M.-L. Wellner E. J. Org. Chem. 2004, 69: 1571

<A NAME="RD35804ST-9B">9b</A> Wellner E. Sandin H. Swanstein M.-L. Synlett 2004, 1817

<A NAME="RD35804ST-10A">10a</A> Patra A. Batra S. Kundu B. Joshi BS. Roy R. Bhaduri AP. Synthesis 2001, 276

<A NAME="RD35804ST-10B">10b</A> Cai J. Zhou Z. Zhao G. Tang C. Org. Lett. 2002, 4: 4723

General Procedure for the Synthesis of 1,4,5,6-Tetrahydropyrimidines (11, 12a-e, 13, 14).
A solution of appropriate diamines from 7, 8a-e, 9, 10a (2.3 mmol) and cyanogen bromide (2.3 mmol, 0.243 g) in absolute EtOH (5 mL) was allowed to stir at 80 °C for 4-6 h. Thereafter the excess solvent was evaporated and the reaction mixture was washed with 10% aq NaHCO₃ and extracted with EtOAc. The organic layers were combined, dried over Na₂SO₄ and evaporated to furnish a residue. The residue upon triturating with hexane or through column chromatography (CHCl₃-MeOH, 9.5:0.5, v/v) yielded the pyrimidines.
Representative Data (as Diastereoisomeric Mixture) of 2-Amino-1,4,5,6-Tetrahydropyrimidines.
Compound 11e: ¹H NMR (300 MHz, CDCl₃ + TFA_d): δ = 2.66-2.71 (m, 2 H, 2 × CH), 3.28-3.63 (m, 8 H, 2 × CH₂-NH and 2 × CH₂-N), 4.49, 4.53 (2 s, 4 H, 2 × CH₂-Ph), 4.95, 5.01 (2 d, 2 H, 2 × CH-OH), 6.67, 6.73 (2 s, 2 H, 2 × =CH), 7.19-7.64 (m, 18 H, ArH). ¹³C NMR (75.4 MHz, CDCl₃ + TFA_d): δ = 35.9, 36.1, 39.4, 40.4, 47.5, 48.0, 53.9, 54.2, 65.3, 66.1, 105.3, 109.0, 112.8, 116.5, 120.3, 124.7, 126.2, 126.9, 127.1, 127.7, 129.3, 129.4, 129.8, 130.1, 130.3, 130.9, 131.0, 132.4, 132.7, 132.8, 133.2, 134.7, 148.7, 154.0, 171.0, 171.1. Anal. Calcd for C₂₁H₂₁ClN₄O₂: C, 63.55; H, 5.33; N, 14.12. Found: C, 63.19; H, 5.58; N, 13.88.
Compoumd 12d: ¹H NMR (300 MHz, CDCl₃ + TFA_d): δ = 2.42 (s, 6 H, 2 × CH₃), 2.69 (br s, 2 H, 2 × CH), 3.31-3.35 (m, 2 H, 2 × 1 H of CH₂-NH), 3.48-3.59 (m, 6 H, 2 × CH₂-N and 2 × 1 H of CH₂-NH), 4.49, 4.52 (2 s, 4 H, 2 × CH₂-Ph), 4.95, 5.01 (2 d, 2 H, 2 × CH-OH), 6.58, 6.67 (2 s, 2 H, 2 × =CH), 7.05-7.33 (m, 12 H, ArH), 7.55 (d, 4 H, J = 8.0 Hz, ArH). ¹³C NMR (75.4 MHz, CDCl₃ + TFA_d): δ = 20.8, 21.6, 36.0, 36.4, 39.5, 40.3, 47.2, 47.8, 53.1, 53.2, 65.4, 66.2, 101.4, 109.2, 113.0, 116.7, 116.8, 116.9, 120.6, 124.3, 127.0, 128.8, 128.9, 129.0, 129.1, 129.6, 130.2, 130.7, 141.9, 154.1, 163, 164.8, 171.8, 171.9, 178.4. Anal. Calcd for C₂₂H₂₃FN₄O₂: C, 64.06; H, 6.11; N, 13.58. Found: C, 63.91; H, 6.18; N, 13.72.

General Procedure for the Synthesis of 5,6,7,8-Tetrahydro-2 H -imidazo[1,2- a ]pyrimidin-3-ones (15, 16).
To the solution of compound 11e or 12c (0.63 mmol) in dry DMF was added K₂CO₃ (0.63 mmol, 0.104 g) and bromoethyl acetate (0.63 mmol, 0.28 mL) and the mixture was heated at 80 °C under stirring for 6 h. Then the reaction mixture was extracted with EtOAc and H₂O. The usual work up of the organic layer afforded a residue that upon column chromatography over silica gel using hexane-EtOAc (70:30, v: v) yielded the pure compounds as oils.
Representative Data (as Diastereoisomeric Mixture) of 5,6,7,8-Tetrahydro-2 H -imidazo[1,2- a ]pyrimidin-3-ones. Compound 15: ¹H NMR (300 MHz, CDCl₃): δ = 2.62-3.44 (m, 10 H, 2 × CH₂-NH, 2 × CH₂-N and 2 × CH), 3.86-3.93 (m, 8 H, 2 × CH₂CO and 2 × CH₂-Ph), 4.52, 4.57 (2 d, 2 H, J = 3.8 Hz, 2 × CH-OH), 6.47, 6.67 (2 s, 2 H, 2 × =CH), 7.22-7.64 (m, 18 H, ArH). ¹³C NMR (75.4 MHz, CDCl₃ + TFA_d): δ = 36.7, 36.9, 42.3, 43.5, 45.0, 45.7, 54.1, 54.3, 56.2, 65.1, 65.7, 103.8, 127.4, 128.4, 128.6, 129.1, 130.7, 131.1, 131.3, 133.1, 135.8, 161.2, 167.8, 172.5, 172.8, 185.1, 185.4. Anal. Calcd for C₂₃H₂₁ClN₄O₃: C, 63.23; H, 4.84; N, 12.82. Found: C, 63.10; H, 5.01; N, 13.07.