An Efficient and Straightforward Method to New Organic Compounds: 
Homodrimane Sesquiterpenoids with Diazine Units

Kaleria Kuchkova; Aculina Aricu; Alic Barba; Pavel Vlad; Sergiu Shova; Elena Secara; Nicon Ungur; Gheorghită Zbancioc; Ionel I. Mangalagiu

doi:10.1055/s-0032-1318253

Synlett, Table of Contents

Synlett 2013; 24(6): 697-700
DOI: 10.1055/s-0032-1318253

letter

An Efficient and Straightforward Method to New Organic Compounds: Homodrimane Sesquiterpenoids with Diazine Units

Kaleria Kuchkova

^aInstitute of Chemistry of the Academy of Sciences of Moldova, Academy 3, Chisinau, 2028, Republic of Moldova

,

Aculina Aricu

^aInstitute of Chemistry of the Academy of Sciences of Moldova, Academy 3, Chisinau, 2028, Republic of Moldova

,

Alic Barba

^aInstitute of Chemistry of the Academy of Sciences of Moldova, Academy 3, Chisinau, 2028, Republic of Moldova

,

Pavel Vlad

^aInstitute of Chemistry of the Academy of Sciences of Moldova, Academy 3, Chisinau, 2028, Republic of Moldova

,

Sergiu Shova

^b‘P. Poni’ Institute of Macromolecular Chemistry, Aleea Grigore Ghica Voda 41-A, Iasi 700487, Romania

,

Elena Secara

^aInstitute of Chemistry of the Academy of Sciences of Moldova, Academy 3, Chisinau, 2028, Republic of Moldova

,

Nicon Ungur

^aInstitute of Chemistry of the Academy of Sciences of Moldova, Academy 3, Chisinau, 2028, Republic of Moldova

,

Gheorghită Zbancioc

^c‘Al. I. Cuza’ University of Iasi, Organic and Biochemistry Department, Bd. Carol 11, Iasi 700506, Romania Fax: +40(232)201313 Email: ionelm@uaic.ro

,

Ionel I. Mangalagiu*

^c‘Al. I. Cuza’ University of Iasi, Organic and Biochemistry Department, Bd. Carol 11, Iasi 700506, Romania Fax: +40(232)201313 Email: ionelm@uaic.ro

› Author Affiliations

Abstract

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Abstract

A comprehensive study of the synthesis and structure of new homodrimane sesquiterpenoids with diazine skeleton is presented. This is the first synthesis of homodrimane sesquiterpenoids with diazine skeleton. In the same time, an efficient way for the one-pot bisacylation of 2-aminopyrimidine is reported. The structure of the bisacylamide was proven unambiguously, including the single-crystal X-ray structure determination. A reliable explication and feasible reaction mechanisms for the obtained compounds are presented.

Key words

homodrimane - sesquiterpenoids - diazine - one-pot bisacylation - bisacylamide

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References

References and Notes
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28 The crystal structure for compound 8 has been deposited at the Cambridge Crystallographic Data Centre and allocated the deposition number CCDC 893824. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44(1223)336033 or email: deposit@ccdc.cam.ac.uk].
29 Typical Procedure for the Synthesis of Bicyclohomofarnezenic Acid Derivatives with Diazine Skeleton – Method I To a solution of the acid 4 (200 mg, 0.80 mmol) in anhydrous benzene (4 mL) a solution of (COCl)₂ (0.8 mL, 1.16 g, 9.17 mmol) in anhydrous benzene (2 mL) was added. Then the reaction mixture was stirred at r.t. for 1 h and then refluxed (1 h). Benzene and excess (COCl)₂ were evaporated under reduced pressure. To the residue CH₂Cl₂ (8 mL) and aminodiazine 6a–c (1.26 mmol) were added, and the resulting mixture was heated (40 °C) under stirring for an appropriate period of time [2 h for 4-aminopyrimidine (6a), 5 h for aminopyrazine (6b), 15 h for 2-aminopyrimidine (6c)]. A precipitate was filtered off, washed with CH₂Cl₂, and the filtrate was concentrated to dryness. The residue was dissolved in CHCl₃ (3 mL) and was purified by flash chromatography on silica (CHCl₃). The following supplementary operations and remarks were to be pointed out in the case of reaction products derived from amine 6c: elution with CHCl₃ afforded gradually the bisacylamide 8, the monoacyl amide 7c, and a two-component mixture. This mixture was subject to a second flash over silica (PE–Et₂O, 8:2) when monoacyl amide 7c and some unreacted acid 4 were separated.
30 Typical Procedure for the Synthesis of Bicyclohomofarnezenic Acid Derivatives with Diazine Skeleton – Method II A solution of DCC (215 mg, 1.04 mmol), DMAP (100 mg, 0.82 mmol), aminodiazine 6a–c (0.84 mmol), and the acid 4 (100 mg, 0.40 mmol) in CH₂Cl₂ (4 mL) was stirred at r.t. for an appropriate period of time [10 h for 4-aminopyrimidine (6a), 28 h for aminopyrazine (6b), 5 h for 2-aminopyrimidine (6c)]. A precipitate was filtered off, washed with CH₂Cl₂, and the filtrate was evaporated under reduced pressure. The residue was dissolved in CHCl₃ (5 mL) and was purified by flash chromatography on silica (CHCl₃). The following supplementary operations and remarks were to be pointed out in the case of reaction products derived from amine 6c: elution with CHCl₃ gave a mixture of the bisacylamide 8 and the urea 9. For the separation of these compounds, the mixture was extracted first with PE. The undissolved precipitate was filtered off and washed thoroughly with PE when the bisacylamide 8 was obtained. The filtrate solution was evaporated to dryness and the residue crystallized from MeCN giving urea 9. The remaining silica from the first flash chromatography was washed with CHCl₃ affording a mixture of the monoacyl amide 7c and dicyclohexylurea 10. This mixture was extracted with Et₂O. The undissolved precipitate of dicyclohexylurea 10 was filtered off, and the ether filtrate was concentrated to dryness. The obtained residue was crystallized from MeCN to give the monoacyl amide 7c.
31 Δ^8,13-Bicyclohomofarnezenic Acid Amide (7c) White crystals; mp 149–150 °C. [α]_D ²⁶ –14.8 (c 0.6, CHCl₃). IR: 3262, 3189, 3111 (NH amide), 3078, 892 (semicyclic methylene), 1725 (C=O, amide), 1649, 1574, 1435, 1155 (pyrimidine cycle) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.60 (2 H, d, J = 8.0 Hz, H-18, H-20), 8.51 (1 H, br s, NH), 6.99 (1 H, t, J = 4.9 Hz, H-19), 4.79 (1 H, s, Ha-13), 4.54 (1 H, s, Hb-13), 2.95 (1 H, dd, J = 16.6, 10.1 Hz, Ha-11), 2.79 (1 H, dd, J = 16.6, 3.7 Hz, Hb-11), 2.56 (1 H, dd, J = 10.1, 3.7 Hz, H-9), 2.41 (1 H, ddd, J = 13.0, 4.0, 2.4 Hz, Ha-7), 2.15 (1 H, td, J = 13.0, 4.0 Hz, Hb-7), 1.26 (1 H, dd, J = 12.6, 2.1 Hz, H-5), 1.80–1.10 (8 H, m), 0.90 (3 H, s, H-14), 0.83 (3 H, s, H-15), 0.76 (3 H, s, H-16). ¹³C NMR (100 MHz, CDCl₃): δ = 172.64 (s, C-12), 158.32 (d, C-20), 158.32 (d, C-18), 157.70 (s, C-17), 149.27 (s, C-8), 116.14 (d, C-19), 106.51 (t, C-13), 55.21 (d, C-5), 52.27 (d, C-9), 42.12 (t, C-3), 39.24 (s, C-10), 39.09 (t, C-1), 37.67 (t, C-7), 33.57 (q, C-14), 33.56 (t, C-11), 33.53 (s, C-4), 24.13 (t, C-6), 21.77 (q, C-15), 19.35 (t, C-2), 14.75 (q, C-16).
32 2-Bis-Δ^8,13-bicyclohomofarnezenoylaminopyrimidine (8) White crystals; mp 205–206 °C. [α]_D ²⁶ 27.78 (c 0.33, CHCl₃). IR: 3088, 897 (semicyclic methylene), 1704 (C=O, amide), 1644, 1567, 1460, 1410, 1162 (pyrimidine cycle) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.87 (2 H, d, J = 4.9 Hz, H-18, H-20), 7.34 (1 H, t, J = 4.9 Hz, H-19), 4.80 (2 H, s, Ha-13, Ha-13′), 4.52 (2 H, s, Hb-13, Hb-13′), 2.72 (2 H, dd, J = 16.9, 2.6 Hz, Ha-11, Ha-11′), 2.56 (2 H, dd, 16.9, 10.2 Hz, Hb-11, Hb-11′), 2.49 (2 H, dd, J = 10.0, 2.0 Hz, H-9, H-9′), 2.39 (2 H, ddd, J = 13.0, 4.0, 2.3 Hz, Ha-7, Ha-7′), 2.10 (2 H, td, J = 13.0, 5.0, Hz, Hb-7, Hb-7′), 1.18 (2 H, dd, J = 12.5, 2.5 Hz, H-5, H-5′), 1.80–1.03 (16 H, m), 0.87 (6 H, s, H-14, H-14′), 0.79 (6 H, s, H-15, H-15′), 0.59 (6 H, s, H-16, H-16′). ¹³C NMR (100 MHz,CDCl₃): δ = 175.22 (s, C-12), 159.95 (s, C-17), 159.34 (d, C-18), 159.34 (d, C-20), 148.92 (s, C-8), 120.20 (d, C-19), 106.41 (t, C-13), 55.12 (d, C-5), 51.90 (d, C-9), 42.05 (t, C-3), 39.03 (t, C-1), 38.90 (s, C-10), 37.54 (t, C-7), 34.38 (t, C-11), 33.56 (q, C-14), 33.49 (s, C-4), 23.97 (t, C-6), 21.73 (q, C-15), 19.25 (t, C-2), 14.63 (q, C-16).
33 N-Δ^8,13-Bicyclohomofarnezenoyl-N,N′-Dicyclohexylurea (10) White crystals; mp 166–167 °C. [α]_D ²⁶ 11.9 (c 1.34, CHCl₃). IR: 3266 (NH amide), 3074, 879 (semicyclic methylene), 1698 (C=O amide), 1658 (C=O amide) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 6.47 (1 H, br s, NH), 4.75 (1 H, s, Ha-13), 4.43 (1 H, s, Hb-13), 4.02 (1 H, m, H-17), 3.72 (1 H, m, H-24), 2.49 (3 H, m, Ha-11, Hb-11, H-9), 2.38 (1 H, ddd, J = 12.9, 3.8, 2.2 Hz, Ha-7), 2.13 (1 H, td, J = 12.9, 4.9 Hz, Hb-7), 2.05–1.05 (28 H, m), 1.22 (1 H, dd, J = 12.7, 2.1 Hz, H-5), 0.90 (3 H, s, H-14), 0.82 (3 H, s, H-15), 0.71 (3 H, s, H-16). ¹³C NMR (100 MHz, CDCl₃): δ = 172.51 (s, C-12), 154.32 (s, C-23), 149.45 (s, C-8), 105.97 (t, C-13), 55.15 (d, C-5), 52.09 (d, C-9), 49.86 (d, C-17), 49.13(d, C-24), 42.04 (t, C-3), 39.09 (t, C-1), 39.02 (s, C-10), 37.68 (t, C-7), 33.56 (q, C-14), 33.50 (s, C-4), 32.80 (t, C-25 and C-29), 31.55 (t, C-11), 31.22 (t, C-22), 30.69 (t, C-18), 26.25 (t, C-19 and C-21), 25.48 (t, C-27), 25.40 (t, C-20), 24.73 (t, C-26 and C-28), 24.05 (t, C-6), 21.73 (q, C-15), 19.29 (t, C-2), 14.81 (q, C-16).