Quantum Chemical and Experimental Studies on the Mechanism of Alkylation of β-Dicarbonyl Compounds. The Synthesis of Five and Six Membered Heterocyclic Spiro Derivatives
1
Baku St. University, Faculty of Chemistry, Department of Organic Chemistry, Baku, Azerbaijan
2
Osmangazi University, Faculty of Arts and Sciences, Chemistry Department, 26040 Eskişehir, Turkey
3
Anadolu University, Faculty of Sciences, Chemistry Department, 26470 Eskişehir, Turkey
4
Baku St. University, Faculty of Chemistry, Department of Analytical Chemistry, Baku, Azerbaijan
*
Author to whom correspondence should be addressed.
Molecules 2004, 9(11), 922-938; https://doi.org/10.3390/91100922
Submission received: 5 March 2004
/
Accepted: 24 June 2004
/
Published: 30 November 2004
Abstract
:The alkylation of β-dicarbonyl compounds in a K2CO3/DMSO system was found to afford O- and C-alkylated derivatives, depending on the type of the β-dicarbonyl compound involved. The alkyl derivatives obtained were used in the synthesis of some new spiro barbituric acid derivatives. Quantum chemical calculations were carried out to elucidate the reaction mechanisms for some typical synthesis.
Introduction
The alkylation reactions of β-dicarbonyl derivatives with dibromide and 1,2,3-trihalopropane derivatives have been studied in detail [1,2,3] and the products obtained have been used in the synthesis of various heterocyclic compounds. Although many researchers have been working on synthesis of novel spiro derivatives [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22], we did not come across any studies of the alkylation of β-dicarbonyl derivatives with 2-chloro-1-(2-chloroethoxy)ethane in the literature. We now report our studies on alkylation reactions of β-dicarbonyl derivatives with 2-chloro-1-(2-chloroethoxy)ethane in a K2CO3/DMSO system and the synthesis of new spiro derivatives of barbituric acid. Some additional theoretical work had been carried out to elucidate the reaction mechanisms of some typical and novel syntheses.
Results and Discussion
The reaction of acetylacetone (R1) with 2-chloro-1-(2-chloroethoxy)ethane (R2) at 70oC for 20 h afforded 4-[2-(2-chloroethoxy)ethoxy]pent-3-en-2-one (1) in 59% percent yield via O-alkylation. 4-{2-[2(1-methyl-3-oxobut-1-enyloxy)ethoxy]pent-3-en-2-en (2) was also obtained in low yield (i.e. 15 %) as a side product, along with compound 1 (Scheme 1). Similarly, the reaction of benzoylacetone (R3) with compound R2 under the same conditions afforded the O-alkylation product 3-[2-(2-chloro-ethoxy)ethoxy]-1-phenylbut-2-en-1-one (3) in 57% yield, along with 3-{2-[2(1-methyl-3-oxo-3-phenylprop-1-enyloxy)ethoxy]ethoxy}-1-phenylbut-2-en-1-one (4) formed as a side product in 16% yield (Scheme 1).
Scheme 1.
The presence of the olefinic protons (i.e. 5.31-5.36 ppm) in the 1H-NMR spectra indicates the formation of enol ethers. Formation of 2-[2-(2-chloroethoxy)ethyl]-1-phenylbutane-1,3-dione (3a) and 2-{2-[4-oxo-3-(phenylcarbonyl)pentyloxy]ethyl}-1-phenybutane-1,3-dione (4a) along with 3 and 4 are expected during the alkylation of benzoylacetone. It seems that enolization occurs at the acetyl carbonyl but not in the benzoyl fragment, due to the interrelation of the benzoyl fragment with the aromatic ring.
The alkylation of dimedone (R4) with R2 under similar conditions (Scheme 2) afforded both an O-alkyl derivative, 3-[2-(2-chloroethoxy)-ethoxy]-5,5-dimethylcyclohex-2-en-1-one (5), formed in 46% yield, and the C-cyclization products 3,3-dimethyl-9-oxaspiro[5.5]undacane-1,5-dione (6, 28 %) and 3-{2-[2-(5,5-dimethyl-3-oxocyclohex-1-enyloxy)ethoxy]ethyl}-5,5-dimethyl-cyclohex-2-en-1-one (7, 12%).
Scheme 2.
When acetyl acetate (R5) was used instead of dimedone the mechanism changed, C,C-cyclo-alkylation now became feasible and 1-(4-acetylperhydro-2H-pyran-4-yl)ethan-1-one (8) was produced in 55 % yield. Along with compound 8 the O-alkylation products ethyl 3-[2-(2-chloroethoxy)-ethoxy]but-2-enoate (9) and ethyl 3-(2-{2-[2-(ethoxycarbonyl)-1-methylvinyloxy]ethoxy}ethoxy)-but-2-enoate (10) were obtained in yields of 23 and 10 %, respectively (Scheme 3).
Under the proper conditions the reaction of malonic esters R6 with R2 efforts only the C-alkylation ester products ethyl 4-(ethoxycarbonyl)perhydro-2H-pyran-4-carboxylate (11), diethyl 2-[2-(2-chloro-ethoxy)ethyl]propane-1,3-dioate (12) and diethyl 2-{2-[3,3-bis(ethoxycarbonyl)-propoxy]ethyl} propane-1,3-dioate (13) in yields of 57, 10 and 14 %, respectively (Scheme 3).
Scheme 3.
In this way it was proven that the mechanisms of the alkylation reactions basically depend on the β-dicarbonyl compound used, as indicated above. It seems that when the keto-enol equilibrium shifts toward the keto side the formation of O-alkylated products decreases, whereas the formation of C-alkylated products increases.
It is well known that the classical technique for synthesis of 1,2-azolones and barbuturic acid is condensation of acetoacetic and malonic esters with NH2-X type compounds (X=-OH, -NH2, -CONH2, -CSNH2 ) [23]. To synthesize new spiro derivatives of 1,2-azolone and barbuturic acids the ketoester 8 and diester 11 were condensed with the above mentioned groups.
The reaction of ketoester 8 at 90-95oC with hydroxylamine hydrochloride (R8) in 10 % sodium acetate solution affords the oxime of 4-acetyl-4-tetrahydropyran carbamic acid ethyl ester (14) as a stable compound in a high yield. When this oxime was heated at 180-200oC to distill off the ethyl alcohol formed upon cyclization, then the compound 3-aza-4-methyl-2,8-dioxaspiro[4.5]dec-3-en-1-one (15) was isolated (Scheme 4). The ethoxy and hydroxyl peaks that were observed in the 1H-NMR of compound 14 were absent in the 1H-NMR of compound 15.
Under similar conditions compound 8 gives condensation reactions with the hydrochloride salts of ketohydrazine and phenylhydrazine to afford 2,3-diaza-4-methyl-8-oxaspiro[4.5]dec-3-en-1-one (16) and 2,3-diaza-4-methyl-8-oxa-2-phenylspiro[4.5]dec-3-en-1-one (17), respectively, in yields of 71 and 90 %. Diester 11 easily condenses with carbamide or thiocarbamate in absolute ethanol and in the presence of sodium ethoxide to afford the sodium salts of 2,4-diaza-3-hydroxy-9-oxaspiro[4.5]undec-2-ene-1,5-dione (18) and 2,4-diaza-9-oxa-3-sulfanylspiro[4.5]undec-2-ene-1,5-dione (19), respectively (Scheme 5). When the salts thus obtained were dissolved in water and these solutions were made weakly acidic with HCl they were converted in high yield into 2,4-diaza-9-oxaspiro[4.5]undecane-1,3,5-trione (20) and 2,4-diaza-9-oxa-3-thioxospiro[4.5]undecane-1,5-dione (21). The above mentioned reactions can be viewed as a simple synthetic method for preparing 1,2-azolones and spiro derivatives of barbituric acids from easily obtainable ketoester (8) and diester (11) compounds.
Scheme 4.
Scheme 5.
Theoretical Approaches
There is no doubt that one of the most versatile methods for elucidating reaction mechanisms nowadays is the use of theoretical calculations. The superiority of computations comes from the fact that they let us to simultaneously calculate more than one parameter, such as dihedral angles, bond lengths, atomic charges, etc. that are related to structure and thermodynamic parameters, which in turn are related to thermodynamics and kinetics. In the present work we aimed to elucidate the reaction mechanism of some synthesis using semi-empirical calculation approach.
Discussion of Computational Work
The aqueous phase PM3 calculation data are given in Table 1. Using appropriate computed parameters and related equations the tautomeric equilibrium constants, KT, were calculated for the Keto ![Molecules 09 00922 i001]()
Enol tautomerism of the main molecules and the obtained data is collected in Table 2.
Enol tautomerism of the main molecules and the obtained data is collected in Table 2.For the formation of products 1 and 2 (Scheme 1), although the KT value of 0.06 for the R1K ![Molecules 09 00922 i001]()
R1E equilibrium suggests the predominance of the keto form (i.e. the R1K form) in aqueous media, it seems that this situation is reversed in basic media and the enolate form R1E1(a) predominates over the carbene form R1K(a) and the reaction proceeds by the nucleophilic attack of R1E1(a) on R2 to first form compound 1 and then it proceeds via a second attack of R1E1(a) on 1 to form compound 2. Further evidence to support this argument is the higher nucleophilicity, η; and the higher basicity (i.e. smaller pKa value for deprotonation) of R1E1(a) compared to the R1K1(a) form (Table 1 and Table 2) .
R1E equilibrium suggests the predominance of the keto form (i.e. the R1K form) in aqueous media, it seems that this situation is reversed in basic media and the enolate form R1E1(a) predominates over the carbene form R1K(a) and the reaction proceeds by the nucleophilic attack of R1E1(a) on R2 to first form compound 1 and then it proceeds via a second attack of R1E1(a) on 1 to form compound 2. Further evidence to support this argument is the higher nucleophilicity, η; and the higher basicity (i.e. smaller pKa value for deprotonation) of R1E1(a) compared to the R1K1(a) form (Table 1 and Table 2) .
| Compound | ΔH (cal mol-1) | ΔS (cal mol-1) | ΔG (kcal mol-1)a | ΔHf (kcalmol-1) | HOMO | LUMO | Nucleophilicity (η)b | Experimental Yield (% ) |
|---|---|---|---|---|---|---|---|---|
| T = 343 K (ε = 47.24) | ||||||||
| R1K | 6249.087 | 86.069 | -23.273 | -105.766 | -11.329 | 0.018 | -11.347 | |
| R2 | 5604.130 | 85.404 | -23.689 | -75.785 | -10.857 | 0.718 | -11.575 | |
| 1 | 9064.189 | 108.952 | -28.306 | -37.861 | -10.065 | -1.863 | -8.202 | 59 |
| 2 | 12782.249 | 131.221 | -32.227 | -103.808 | -9.921 | -1.859 | -8.062 | 15 |
| 3 | 11268.273 | 120.470 | -30.053 | -99.461 | -9.936 | -0.802 | -9.134 | 57 |
| 4 | 15983.897 | 146.434 | -34.243 | -132.297 | -9.834 | -0.753 | -9.081 | 16 |
| R1K(a) | 12604.066 | 98.677 | -21.239 | -185.011 | -8.685 | 0.625 | -9.310 | |
| R1E1 | 13327.849 | 101.118 | -21.356 | -87.118 | -9.904 | 0.017 | -9.921 | |
| R1E1(a) | 12604.066 | 97.186 | -20.731 | -185.181 | -8.804 | -0.406 | -8.398 | |
| R3K | 7242.087 | 93.873 | -24.956 | -69.146 | -10.145 | -0.739 | -9.406 | |
| R3K(a) | 18143.301 | 120.397 | -23.153 | -147.226 | -8.707 | -0.105 | -8.602 | |
| R3E1 | 18129.246 | 119.193 | -22.754 | -47.677 | -9.913 | -0.538 | -9.375 | |
| R3E1(a) | 18190.937 | 120.608 | -23.178 | -148.021 | -8.847 | 0.098 | -8.945 | |
| R3E2 | 18222.994 | 119.722 | -22.842 | -47.937 | -10.041 | -0.155 | -9.886 | |
| R3E2(a) | 18924.776 | 124.037 | -23.620 | -146.083 | -8.685 | -0.320 | -8.365 | |
| H3O+ | 2750.472 | 47.158 | -13.425 | 61.928 | -15.994 | 1.652 | -17.646 | |
| H20 | 2730.416 | 46.135 | -13.095 | -61.414 | -12.794 | 4.268 | -17.062 | |
| R4K | 8118.436 | 97.785 | -25.422 | -111.147 | -11.392 | 0.065 | -11.457 | |
| 5 | 10389.545 | 114.701 | -28.953 | -142.383 | -10.042 | -0.481 | -9.561 | 46 |
| 6 | 11016.198 | 115.088 | -28.459 | -148.209 | -10.938 | -0.143 | -10.795 | 24 |
| 7 | 15999.285 | 145.441 | -33.887 | -220.448 | -10.033 | -0.509 | -9.524 | 12 |
| R4K(a) | 18370.540 | 119.539 | -22.631 | -193.605 | -8.797 | 0.436 | -9.233 | |
| R4E1 | 19259.580 | 122.297 | -22.688 | -92.314 | -9.970 | -0.437 | -9.533 | |
| R4E1(a) | 18483.670 | 120.297 | -22.823 | -193.418 | -8.779 | 0.444 | -9.223 | |
| R5K | 6741.119 | 90.785 | -24.398 | -149.949 | -11.482 | 0.049 | -11.531 | |
| 8 | 10185.203 | 111.495 | -28.058 | -185.961 | -11.056 | -0.037 | -11.019 | 55 |
| 9 | 10080.245 | 113.231 | -28.768 | -183.145 | -10.103 | -0.223 | -9.880 | 48 |
| 10 | 14245.501 | 137.720 | -32.992 | -292.902 | -9.958 | -0.297 | -9.661 | 10 |
| R5K(a) | 15761.846 | 122.368 | -26.210 | -229.112 | -8.791 | 0.665 | -9.456 | |
| R5E1 | 16477.994 | 114.511 | -22.799 | -129.609 | -10.005 | -0.251 | -9.754 | |
| R5E1(a) | 16726.542 | 117.887 | -23.709 | -228.808 | -8.826 | 0.634 | -9.460 | |
| R5E2 | 16610.422 | 115.076 | -22.861 | -123.669 | -9.608 | -0.196 | -9.412 | |
| R5E2(a) | 15770.958 | 112.325 | -26.187 | -229.079 | -8.789 | 0.666 | -9.455 | |
| R6K | 8091.277 | 100.368 | -26.335 | -195.638 | -11.606 | 0.308 | -11.914 | |
| 11 | 10618.015 | 114.735 | -28.736 | -230.841 | -11.146 | 0.184 | -11.330 | 57 |
| 12 | 10731.533 | 118.688 | -29.978 | -245.052 | -10.955 | 0.144 | -11.099 | 10 |
| 13 | 15969.012 | 148.524 | -34.974 | -423.969 | -11.063 | -0.061 | -11.002 | 14 |
| R6K(a) | 17368.114 | 117.216 | -22.837 | -273.403 | -8.799 | 0.867 | -9.666 | |
| R6E1 | 19569.412 | 126.417 | -23.792 | -168.694 | -10.095 | -0.201 | -9.894 | |
| R6E1(a) | 17334.207 | 117.216 | -22.871 | -273.373 | -8.792 | 0.870 | -9.662 | |
| T = 363 K (ε = 78.40) | ||||||||
| R7K | 11364.453 | 114.981 | -30.374 | -185.028 | -11.063 | -0.041 | -11.022 | |
| R8 | 3563.453 | 59.771 | -18.133 | -17.071 | -10.560 | 2.442 | -13.002 | |
| R9 | 3637.903 | 59.273 | -17.878 | 15.501 | -9.707 | 2.716 | -12.423 | |
| R10 | 6603.077 | 85.778 | -24.534 | 42.036 | -9.330 | -0.082 | -9.248 | |
| 14-OH | 12074.647 | 118.843 | -31.065 | -142.197 | -10.704 | 0.012 | -10.716 | 91 |
| 14-NH2 | 12606.540 | 121.978 | -31.671 | -115.892 | -9.717 | 0.198 | -9.915 | 91 |
| 14-NHPh | 14384.721 | 131.234 | -33.253 | -84.046 | -9.060 | -0.157 | -8.903 | 91 |
| R7K(a) | 24864.521 | 141.158 | -26.376 | -243.164 | -8.464 | 0.652 | -9.116 | |
| R7E1 | 25643.604 | 143.758 | -26.541 | -151.205 | -9.905 | 0.403 | -10.308 | |
| R7E1(a) | 11364.453 | 139.490 | -39.270 | -243.571 | -8.501 | 0.685 | -9.186 | |
| H3O+ | 2919.050 | 47.636 | -14.373 | 62.097 | -15.994 | 1.642 | -17.636 | |
| H2O | 2891.295 | 46.591 | -14.021 | -61.254 | -12.794 | 4.268 | -17.062 | |
| OH- | 2524.759 | 42.407 | -12.869 | -142.332 | -11.201 | 6.455 | -17.656 | |
| T = 473 K (ε = 78.40) | ||||||||
| 14-OH | 20047.920 | 137.927 | -45.192 | -134.917 | -10.704 | 0.012 | -10.716 | |
| 14-NH2 | 20884.456 | 141.853 | -46.212 | -107.621 | -9.717 | 0.200 | -9.917 | |
| 14-NHPh | 24748.689 | 156.029 | -24.120 | -73.683 | -9.060 | -0.157 | -8.903 | |
| 15 | 15544.809 | 116.427 | -39.525 | -81.917 | -11.084 | -0.640 | -10.444 | 95 |
| 16 | 15831.565 | 117.270 | -39.637 | -59.973 | -9.654 | -0.446 | -9.208 | 71 |
| 17 | 20574.229 | 136.912 | -44.185 | -25.753 | -9.800 | -0.461 | -9.339 | 90 |
| CH3CH2OH | 6808.702 | 74.566 | -28.461 | -59.262 | -11.102 | 3.295 | -14.397 | |
| T = 373 K (ε = 25.30) | ||||||||
| R11 | 13085.134 | 123.690 | -33.051 | -228.325 | -11.137 | 0.188 | -11.325 | |
| R12 | 5027.115 | 72.694 | -22.088 | -60.778 | -9.847 | 0.931 | -10.778 | |
| R13 | 5120.630 | 73.307 | -22.223 | -6.014 | -9.697 | -0.457 | -9.240 | |
| 18(a) | 11732.778 | 114.256 | -30.885 | -243.788 | -9.322 | 0.771 | -10.093 | 96 |
| 18E | 12135.123 | 116.007 | -31.136 | -137.535 | -9.974 | -0.335 | -9.639 | |
| 20K | 11753.872 | 113.663 | -30.642 | -147.469 | -10.046 | -0.109 | -9.937 | 92 |
| 19(a) | 11673.276 | 114.631 | -31.084 | -191.810 | -9.579 | -0.376 | -9.203 | 94 |
| 19E | 12750.364 | 120.777 | -32.274 | -79.395 | -9.802 | -0.788 | -9.014 | |
| 21K | 12047.588 | 116.145 | -31.274 | -86.109 | -10.326 | -1.368 | -8.958 | 90 |
| H3O+ | 3004.184 | 47.867 | -14.850 | 62.182 | -15.994 | 1.642 | -17.636 | |
| H2O | 2791.943 | 46.591 | -14.668 | -62.254 | -12.794 | 4.268 | -17.062 | |
aΔG = ΔH -TΔS, bη = EHOMO-ELUMO
| Reaction | δΔG(T)a | pKTb | KTc | δΔG(BH)d | pKae | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| T = 343 K, (ε = 47.24) | ||||||||||
| R1K R1E | 1.917 | 1.221 | 0.060 | - | - | |||||
| R1K R1K(a) | - | - | - | 1.703 | 1.085 | |||||
| R1E R1E(a) | - | - | - | 0.294 | 0.187 | |||||
| R3K R3E1 | 2.202 | 1.403 | 0.040 | - | - | |||||
| R3K R3E2 | 2.114 | 1.347 | 0.045 | - | - | |||||
| R3K R3K(a) | - | - | - | 1.472 | 0.938 | |||||
| R3E1 R3E1(a) | - | - | - | -0.755 | -0.481 | |||||
| R3E2 R3E2(a) | - | - | - | -1.109 | -0.706 | |||||
| R4K R4E | 2.734 | 1.742 | 0.018 | - | - | |||||
| R4K R4K(a) | - | - | - | 2.460 | 1.567 | |||||
| R4E R4E(a) | - | - | - | -0.466 | -0.297 | |||||
| R5K R5E1 | 1.599 | 1.019 | 0.096 | - | - | |||||
| R5K R5E2 | 1.537 | 0.979 | 0.105 | - | - | |||||
| R5K R5K(a) | - | - | - | -2.143 | -1.365 | |||||
| R5E1 R5E1(a) | - | - | - | -1.241 | -0.791 | |||||
| R5E2 R5E2(a) | - | - | - | -3.657 | -2.330 | |||||
| R6K R6E | 2.543 | 1.620 | 0.024 | - | - | |||||
| R6K R6K(a) | - | - | - | 3.167 | 2.017 | |||||
| R6E R6E(a) | - | - | - | 0.590 | 0.376 | |||||
| T = 363 K, (ε = 78.40) | ||||||||||
| R7K R7E | 3.833 | 2.307 | 4.932E-3 | - | - | |||||
| R7K R7K(a) | - | - | - | 3.646 | 2.194 | |||||
| R7E R7E(a) | - | - | - | -13.081 | -7.875 | |||||
| T = 373 K, (ε = 25.30) | ||||||||||
| 20K 18E | -0.494 | -0.298 | 1.986 | - | - | |||||
| 21K 19E | -0.955 | -0.560 | 3.631 | - | - | |||||
a δΔG(T) = ΔG(Enol) - ΔG(Keto); b pKT = δΔG(T) / 2.303RT; c pKT = −log KT; d δΔG(BH) = [ΔG(B-) + ΔG(H3O+)] - [ΔG(BH) + ΔG(H2O)]; epKa = δΔG(BH) / 2.303RT
For the formation of products 3 and 4 (Scheme 1), although KT values of 0.04 and 0.05 for the R3K ![Molecules 09 00922 i001]()
R3E1 and R3K ![Molecules 09 00922 i001]()
R3E2 equilibria, respectively, suggest the predominance of the keto form (i.e. R3K) in aqueous media, it appears that in basic media a competition among two enolate ions and one carbene ion becomes inevitable. Although the respective nucleophilicity values are ranked in the increasing order R3E1(a) < R3K(a) < R3E2(a), the magnitudes of the differences are not too large (Table 1). The same analogy exists within the pKa values: the basicity increases (or acidity decreases) in the order R3K(a) < R3E1(a) < R3E2(a) and again the magnitudes of the differences might allow for competition. It seems that in this case the competition was won by the R3E1(a) enolate ion which attacks R2 to form compound 3 in 57 % yield. An attack of the second R3E1(a) enolate ion on compound 3 then afforded compound 4 in 16 % yield.
R3E1 and R3K R3E2 equilibria, respectively, suggest the predominance of the keto form (i.e. R3K) in aqueous media, it appears that in basic media a competition among two enolate ions and one carbene ion becomes inevitable. Although the respective nucleophilicity values are ranked in the increasing order R3E1(a) < R3K(a) < R3E2(a), the magnitudes of the differences are not too large (Table 1). The same analogy exists within the pKa values: the basicity increases (or acidity decreases) in the order R3K(a) < R3E1(a) < R3E2(a) and again the magnitudes of the differences might allow for competition. It seems that in this case the competition was won by the R3E1(a) enolate ion which attacks R2 to form compound 3 in 57 % yield. An attack of the second R3E1(a) enolate ion on compound 3 then afforded compound 4 in 16 % yield.For the formation of products 5-7 (Scheme 2) a KT value of 0.02 for the R4K ![Molecules 09 00922 i001]()
R4E equilibrium suggests the predominance of the keto form (i.e. R4K) in aqueous media, but again in basic media it would seem that a competition exists between the enolate ion R4E(a), formed by deprotonation of the enol form R4E, and the carbene ion R4K(a), which forms by deprotonation of the keto form R4K. Since the yield of compound 5 (46%) is the highest, that implies that the R4E(a) enolate ion attacks R2 to form compound this compound. A further attack of enolate R4E(a) ion on compound 5 affords compound 7 in 12 % yield. Alternatively, when carbene ion R4K(a) attacks R2 then compound 6 is formed (in 24 % yield) by an intramolecular ring closure reaction as follows:
![Molecules 09 00922 i002]()
R4E equilibrium suggests the predominance of the keto form (i.e. R4K) in aqueous media, but again in basic media it would seem that a competition exists between the enolate ion R4E(a), formed by deprotonation of the enol form R4E, and the carbene ion R4K(a), which forms by deprotonation of the keto form R4K. Since the yield of compound 5 (46%) is the highest, that implies that the R4E(a) enolate ion attacks R2 to form compound this compound. A further attack of enolate R4E(a) ion on compound 5 affords compound 7 in 12 % yield. Alternatively, when carbene ion R4K(a) attacks R2 then compound 6 is formed (in 24 % yield) by an intramolecular ring closure reaction as follows:
The slightly higher nucleophilicity and stronger basic strength of R4E(a) compared to R4K(a) are indicative of a high yield for compound 5 than that of compound 6 (Table 1 and Table 2). For the formation of compounds 8-10 (Scheme 3) KT values of 0.10 and 0.11 for the R5K ![Molecules 09 00922 i001]()
R5E1 and R5K ![Molecules 09 00922 i001]()
R5E2 equilibria indicate the favorability of the keto form R5K over the enol forms R5E1 and R5E2 (Table 2). However, in basic media there seems to be a competition among the enolate ions and carbene ion. When we consider the higher yield of compound 8 it seems that this time the enolate ion R5K(a) is favored and this ion attacked R2 to afford compound 8 in 55 % yield. A competitive reaction is the attack of enolate ion R5E1(a) on R2 to afford compound 9 in a yield of 49 %. Attack of the same enolate ion R5E1(a) on compound 9 affords the molecule 10 in 10 % yield. The nucleophilicity of those three species were found to be in the increasing order: R5E1(a) < R5K(a) < R5E2(a), which accounts for the higher yield of the R5E2(a) enolate initiated reaction giving compounds 9 and 10 (total yield is 59 %) (Table 1). The basicity order is found be be in the increasing order R5E1(a) < R5K < R5E2(a) (Table 2). The higher basicity (or lower acidity) of R5E2(a) is further evidence for the higher yield of compounds 9 and 10.
R5E1 and R5K R5E2 equilibria indicate the favorability of the keto form R5K over the enol forms R5E1 and R5E2 (Table 2). However, in basic media there seems to be a competition among the enolate ions and carbene ion. When we consider the higher yield of compound 8 it seems that this time the enolate ion R5K(a) is favored and this ion attacked R2 to afford compound 8 in 55 % yield. A competitive reaction is the attack of enolate ion R5E1(a) on R2 to afford compound 9 in a yield of 49 %. Attack of the same enolate ion R5E1(a) on compound 9 affords the molecule 10 in 10 % yield. The nucleophilicity of those three species were found to be in the increasing order: R5E1(a) < R5K(a) < R5E2(a), which accounts for the higher yield of the R5E2(a) enolate initiated reaction giving compounds 9 and 10 (total yield is 59 %) (Table 1). The basicity order is found be be in the increasing order R5E1(a) < R5K < R5E2(a) (Table 2). The higher basicity (or lower acidity) of R5E2(a) is further evidence for the higher yield of compounds 9 and 10.For the formation of compounds 11-13 (Scheme 3) a KT value of 0.02 for the R6K ![Molecules 09 00922 i001]()
R6E equilibrium suggests the ketone form R6K is favored (Table 2). When we take into account the percent yield and the structures of the products 11-13 it seems that only the carbene ion R6K(a), formed by deprotonation of R6K in basic media, acts as nucleophile to attack R2 and give compound 12 in 10 % yield and a subsequent intramolecular rearrangement of compound 12 in basic media produces compound 11 in a 57 % yield. Alternatively, attack of the carbene ion on 12 produces compound 13 in 14 % yield. The nucleophilicities of enolate and carbene ions are almost the same (Table 1) but the basicity of the carbene ion is greater than that of the enolate ions (Table 2) which explains why the enolate ion is inactive in this reaction. For the formation of compounds 14-OH, 14-NH2 and 14-NHPh (Scheme 4) the KT value of 0.01 for the R7K ![Molecules 09 00922 i001]()
R7E equilibrium suggests the keto form R7K is favored (Table 2). It seems that the formation of compounds 14-OH, 14-NH2 and 14-NHPh occurs by nucleophilic attack of R8, R9 and R10 on R7K, which is more electropositive compared to R7E. These products were found to produced in about 91 % yield. These products rearrange into compounds 15, 16 and 17 respectively. The overall mechanism can be summarized as follows:
![Molecules 09 00922 i003]()
R6E equilibrium suggests the ketone form R6K is favored (Table 2). When we take into account the percent yield and the structures of the products 11-13 it seems that only the carbene ion R6K(a), formed by deprotonation of R6K in basic media, acts as nucleophile to attack R2 and give compound 12 in 10 % yield and a subsequent intramolecular rearrangement of compound 12 in basic media produces compound 11 in a 57 % yield. Alternatively, attack of the carbene ion on 12 produces compound 13 in 14 % yield. The nucleophilicities of enolate and carbene ions are almost the same (Table 1) but the basicity of the carbene ion is greater than that of the enolate ions (Table 2) which explains why the enolate ion is inactive in this reaction. For the formation of compounds 14-OH, 14-NH2 and 14-NHPh (Scheme 4) the KT value of 0.01 for the R7K R7E equilibrium suggests the keto form R7K is favored (Table 2). It seems that the formation of compounds 14-OH, 14-NH2 and 14-NHPh occurs by nucleophilic attack of R8, R9 and R10 on R7K, which is more electropositive compared to R7E. These products were found to produced in about 91 % yield. These products rearrange into compounds 15, 16 and 17 respectively. The overall mechanism can be summarized as follows:
Conclusions
It seems that theoretical calculations can give some clues about the mechanism and the possible yields of some synthetic reactions. However, to be more conclusive further work should be done using other calculation methods and different basis sets which might give better correlation experimental values.
Experimental
General
The 1H-NMR spectra were recorded using a JEOL C-90 MHz spectrometer at room temperature. Elemental analysis were done using a Carlo Erba EA 1108 type instrument.
Syntheses; general method for the alkylation reactions of β-carbonyl derivatives with 2-chloro-1-(2-chloroethoxy)ethane
The appropriate β-dicarbonyl compound (1 mole) was added to a mixture of 2-chloro-1-(2-chloroethoxy)ethane (1.2 mole) and K2CO3 (2.5 mole) in DMSO (400 mL) and stirred vigorously at 70oC for 20h. The reaction mixture was then cooled down and water was added until all the K2CO3 was dissolved. The solution was then extracted with ether a few times. The combined ether extracts were washed with water till neutral and dried over anhydrous Na2SO4. After filtration and evaporation of the ether the residue was distilled under vacuum to separate the products.
Alkylation of acetylacetone: Acetylacetone (0.5 mole), 2-chloro-1-(2-chloroethoxy)ethane (0.6 mole), K2CO3 (1.25 mole) and DMSO (200 mL) afforded the following compounds:
4-[2-(2-chloroethoxy)ethoxy]pent-3-en-2-one (1): c.a. 60.9 g (59 % yield); b.p. 104-105oC (1 mm Hg); ![Molecules 09 00922 i004]()
:1.1258; ![Molecules 09 00922 i005]()
: 1.4964; 1H-NMR (CCl4): δ(ppm) = 1.94 (s, 3H), 2.12 (s, 3H), 3.37-3.87 (m, 8H), 5.36 (s, 1H); Anal. Calc. for C9H15ClO3: C, 52.30; H, 7.26; Cl, 17.19 %, found: C, 52.33; H, 7.28; Cl, 17.17 %.
:1.1258; 
: 1.4964; 1H-NMR (CCl4): δ(ppm) = 1.94 (s, 3H), 2.12 (s, 3H), 3.37-3.87 (m, 8H), 5.36 (s, 1H); Anal. Calc. for C9H15ClO3: C, 52.30; H, 7.26; Cl, 17.19 %, found: C, 52.33; H, 7.28; Cl, 17.17 %.4-{2-[2(1-methyl-3-oxobut-1-enyloxy)ethoxy}pent-3-en-2-one (2): c.a. 20.8 g (45 % yield); b.p. 160-161 oC (1 mm Hg); ![Molecules 09 00922 i004]()
:1.4997; ![Molecules 09 00922 i005]()
:1.0935; 1H-NMR (CCl4): δ (ppm) = 1.96 (s, 6H), 2.11 (s, 6H), 3.73 (m, 8H), 5.36 (s, 2H); Anal. Calc. for C14H22O5: C, 62.61; H, 8.17 %, found: C, 62.22; H, 8.15 %.
:1.4997; :1.0935; 1H-NMR (CCl4): δ (ppm) = 1.96 (s, 6H), 2.11 (s, 6H), 3.73 (m, 8H), 5.36 (s, 2H); Anal. Calc. for C14H22O5: C, 62.61; H, 8.17 %, found: C, 62.22; H, 8.15 %.Alkylation of benzoylacetone: Benzoylacetone (0.2 mole), 2-chloro-1-(2-chloroethoxy)ethane (0.24 mole), K2CO3 (0.5 mole) and DMSO (100 mL) afforded the following compounds:
3-[2-(2-chloroethoxy)ethoxy]-1-phenylbut-2-en-1-one (3): c.a. 30.7 g (57.2 % yield); b.p. 111-113 oC (1 mm Hg); ![Molecules 09 00922 i004]()
:1.5305; ![Molecules 09 00922 i005]()
:1.1722; 1H-NMR (CCl4): δ (ppm) = 1.92 (s, 3H), 3.39-3.88 (m, 8H), 7.36-7.96 (m, 5H); Anal. Calc. for C14H17ClO3: C, 62.57; H, 6.33; Cl, 13.22 %, found: C, 62.55; H, 6.32; Cl, 13.24 %.
:1.5305; :1.1722; 1H-NMR (CCl4): δ (ppm) = 1.92 (s, 3H), 3.39-3.88 (m, 8H), 7.36-7.96 (m, 5H); Anal. Calc. for C14H17ClO3: C, 62.57; H, 6.33; Cl, 13.22 %, found: C, 62.55; H, 6.32; Cl, 13.24 %.3-{2-[2(1-methyl-3-oxo-3-phenylprop-1-enyloxy)ethoxy]ethoxy}1-phenylbut-2-en-1-one (4): c.a. 12.6 g (16 % yield); b.p. 154-157oC (1 mm Hg); ![Molecules 09 00922 i004]()
:1.5305; ![Molecules 09 00922 i005]()
:1.1580; 1H-NMR (CCl4): δ (ppm) = 1.95 (s, 6H), 7.34-7.97 (m, 10H); Anal. Calc. for C24H26O5: C, 73.10; H, 6.60 %, found: C, 73.12; H, 6.58 %.
:1.5305; :1.1580; 1H-NMR (CCl4): δ (ppm) = 1.95 (s, 6H), 7.34-7.97 (m, 10H); Anal. Calc. for C24H26O5: C, 73.10; H, 6.60 %, found: C, 73.12; H, 6.58 %.Alkylation of dimedone: Dimedone (0.43 mole), 2-chloro-1-(2-chloroethoxy)ethane (0.6 mole), K2CO3 (1.25 mole) and DMSO (400 mL) afforded the following compounds:
3-[2-(2-Chloroethoxy)ethoxy]-5,5-dimethylcyclohex-2-en-1-one (5): c.a. 32 g, (46.3 % yield); b.p. 165-166 oC (1 mm Hg); ![Molecules 09 00922 i004]()
:1.5130; ![Molecules 09 00922 i005]()
:1.2554; 1H-NMR (CCl4): δ (ppm) = 0.98 (s, 6H), 2.00 (s, 2H), 3.85 (t, 2H), 5.15 (s, 1H); Anal. Calc. for C12H19ClO3: C, 58.42; H, 7.71; Cl, 14.40 %. Found: C, 58.41; H, 7.33; Cl, 14.38 %.
:1.5130; :1.2554; 1H-NMR (CCl4): δ (ppm) = 0.98 (s, 6H), 2.00 (s, 2H), 3.85 (t, 2H), 5.15 (s, 1H); Anal. Calc. for C12H19ClO3: C, 58.42; H, 7.71; Cl, 14.40 %. Found: C, 58.41; H, 7.33; Cl, 14.38 %.3,3-Dimethyl-9-oxaspiro[5.5]undacane-1,5-dione (6) : c.a. 25 g (28.3 % yield); b.p. 157-158oC (1 mm Hg); 1H-NMR (CCl4): δ (ppm) = 0.60 (s, 6H), 1.81 (t, 4H), 2.48 (s, 4H), 3.55 (m, 8H), 5.14 (s, 2H); Anal. Calc. for C12H18O3: C, 68.57; H, 8.57 %, found: C, 68.56; H, 8.58 %.
3-{2-[2-(5,5-Dimethyl-3-oxocyclohex-1-enyloxy)ethoxy]ethyl}-5,5-dimethlycyclohex-2-en-1-one (7): c.a. 21.6 g (12.3 % yield); b.p. 222-230oC (1 mm Hg); 1H-NMR (CCl4): δ (ppm) = 0.95 (s, 12H), 2.05 (s, 4H), 2.27 (s, 4H), 3.69 (m, 8H), 5.14 (s, 2H); Anal. Calc. for C20H30O5: C, 68.52; H, 8.57 %, found: C, 68.80; H, 8.62 %.
Alkylation of acetyl acetate: Acetyl acetate (1 mole), 2-chloro-1-(2-chloroethoxy)ethane (1.2 mole), K2CO3 (2.5 mole) and DMSO (400 mL) afforded the following compounds:
1-(4-Acetylperhydro-2H-pyran-4-yl)ethan-1-one (8): c.a. 110 g (55 % yield); b.p. 78-79oC (1 mm Hg); ![Molecules 09 00922 i004]()
:1.4648; ![Molecules 09 00922 i005]()
:1.1065; 1H-NMR (CCl4): δ (ppm) = 1.25 (s, 3H), 2.06 (m, 4H), 4.12 (q, 2H); Anal. Calc. for C10H16O4: C, 60.00; H, 8.00 %, found: C, 60.07; H, 8.05 %.
:1.4648; :1.1065; 1H-NMR (CCl4): δ (ppm) = 1.25 (s, 3H), 2.06 (m, 4H), 4.12 (q, 2H); Anal. Calc. for C10H16O4: C, 60.00; H, 8.00 %, found: C, 60.07; H, 8.05 %.Ethyl 3-[2-(2-chloroethoxy)ethoxy]but-2-enoate (9): c.a. 48 g (48 % yield); b.p. 114-116oC (1mm Hg); ![Molecules 09 00922 i004]()
:1.4755; ![Molecules 09 00922 i005]()
:1.1342; 1H-NMR (CCl4): δ (ppm) = 1.25 (s, 3H), 2.55 (s, 3H), 3.37-4.85 (m, 10H), 4.88 (s, 1H); Anal. Calc. for C10H14ClO4: C, 50.84; H, 7.19; Cl, 15.01, found: C, 50.72; H, 7.21; Cl, 14.99 %.
:1.4755; :1.1342; 1H-NMR (CCl4): δ (ppm) = 1.25 (s, 3H), 2.55 (s, 3H), 3.37-4.85 (m, 10H), 4.88 (s, 1H); Anal. Calc. for C10H14ClO4: C, 50.84; H, 7.19; Cl, 15.01, found: C, 50.72; H, 7.21; Cl, 14.99 %.Ethyl 3-(2-{2-[(2-(ethoxycarbonyl)-1-methylvinyloxy]ethoxy}ethoxy)but-2-enoate (10): c.a. 33 g (10 % yield); b.p. 179-181oC (1 mm Hg); 1H-NMR (CCl4): δ (ppm) = 1.14 (t, 6H), 2.19 (s, 6H), 3.71 (m, 8H), 3.95 (q, 4H);4.81 (s, 2H); Anal. Calc. for C16H26O7: C, 58.18; H, 7.88, found: C, 56.16; H, 7.89 %.
Alkylation of malonic ester: Malonic ester (1 mole), 2-chloro-1-(2-chloroethoxy)ethane (1.2 mole), K2CO3 (2.5 mole) and DMSO (400 mL) afforded the following compounds:
Ethyl 4-(ethoxycarbonyl)perhydro-2H-pyran-4-carboxylate (11): c.a. 130 g (56.5 % yield); b.p. 179-181oC (1 mm Hg); ![Molecules 09 00922 i004]()
:1.4554; ![Molecules 09 00922 i005]()
:1.1081; 1H-NMR (CCl4): δ (ppm) = 1.12 (t, 6H), 1.84 (m, 4H), 4.12 (q, 4H); Anal. Calc. for C11H18O5: C, 57.39; H, 7.83, found: C, 57.37; H, 7.81 %.
:1.4554; :1.1081; 1H-NMR (CCl4): δ (ppm) = 1.12 (t, 6H), 1.84 (m, 4H), 4.12 (q, 4H); Anal. Calc. for C11H18O5: C, 57.39; H, 7.83, found: C, 57.37; H, 7.81 %.Diethyl 2-[2-(2-chloroethoxy)ethyl]propane-1,3-dioate (12): c.a. 27 g (10.1 % yield); b.p. 116-118oC (1 mm Hg); ![Molecules 09 00922 i004]()
:1.4542; ![Molecules 09 00922 i005]()
:1.1346; 1H-NMR (CCl4): δ (ppm) = 1.30 (t, 6H), 2.00 (m, 2H), 3.50 (m, 7H), 4.12 (q, 4H); Anal. Calc. for C11H19ClO5: C, 49.53; H, 7.13; Cl, 13.32, found: C, 49.51; H, 7.11; Cl, 13.30 %.
:1.4542; :1.1346; 1H-NMR (CCl4): δ (ppm) = 1.30 (t, 6H), 2.00 (m, 2H), 3.50 (m, 7H), 4.12 (q, 4H); Anal. Calc. for C11H19ClO5: C, 49.53; H, 7.13; Cl, 13.32, found: C, 49.51; H, 7.11; Cl, 13.30 %.Diethyl 2-{2-[3,3-bis(ethoxycarbonyl)propoxy]ethyl}propane-1,3-dioate (13): c.a. 54 g (13.8 % yield); b.p. 186-188oC (1 mm Hg); ![Molecules 09 00922 i004]()
:1.4552; ![Molecules 09 00922 i005]()
:1.1175; 1H-NMR (CCl4): δ (ppm) = 1.12 (t, 12H), 1.87 (m, 4H), 3.36 (m, 6H) 4.00 (q, 8H); Anal. Calc. for C18H30O9: C, 55.39; H, 7.69, found: C, 57.37; H, 7.70 %.
:1.4552; :1.1175; 1H-NMR (CCl4): δ (ppm) = 1.12 (t, 12H), 1.87 (m, 4H), 3.36 (m, 6H) 4.00 (q, 8H); Anal. Calc. for C18H30O9: C, 55.39; H, 7.69, found: C, 57.37; H, 7.70 %.Synthesis of 1,2-azolones
Ketoester 8 (0.10 mol), the hydrochloride salts of hydroxylamine, hydrazine or phenyl hydrazine (0.11 mol) and sodium acetate (10 %, 0.12 mol) solutions were mixed and stirred at 90oC for 6 h. The precipitate was filtered off, washed with water, dried and recrystallized. If a liquid product was obtained the reaction mixture was extracted with ether two or three times. The ether extracts were mixed and washed with water, then dried over Na2SO4. After evaporating the ether the residue was distilled under vacuum to separate the product.
Ethyl 4-((hydroxyamino)ethyl)perhydro-2H-pyran-4-carboxylate (14): Ketoester 8 (0.05 mole) and hydroxylamine hydrochloride (0.05 mole) mixture afforded 9.8 g of the product (90.8 % yield), b.p. 116-117oC (1 mm Hg); 1H-NMR (CCl4): δ (ppm) = 1.25 (t, 3H), 1.76 (m, 4H), 2.00 (s, 3H), 3.25-3.87 (m, 4H), 4.12 (q, 2H), 9.25 (s, 1H); Anal. Calc. for C10H17NO4: C, 55.81; H, 7.91; N, 6.51, found: C, 55.78; H, 7.82; N, 6.49 %.
3-Aza-4-methyl-2,8-dioxaspiro[4.5]dec-3-en-1-one (15): Heating of oxime 14 (0.045 mole) at 180-200oC afforded product 15, c.a. 8 g (95 % yield), b.p. 98-99 oC (1 mm Hg); 1H-NMR (CCl4): δ (ppm ) = 1.75 (m, 4H), 2.00 (s, 3H), 3.75 (m, 4H); Anal. Calc. for C8H1NO3: C, 56.81; H, 6.51; N, 8.28, found: C, 56.78; H, 6.50; N, 8.29 %.
2,3-Diaza-4-methyl-8-oxaspiro[4.5]dec-3-en-1-one (16): Reaction of ketoester 8 (0.1 mole), hydrazine hydrochloride (0.1 mole) and sodium acetate (1.2 mole) in water (90 mL) afforded the product 16, c.a. 12 g (71.14 % yield), m.p. 169-171oC (from ethyl alcohol); 1H-NMR (DMSO-d6): δ (ppm) = 1.72-2.19 (m, 4H), 2.28 (s, 3H), 3.84-4.46 (m, 4H), 11.20 (s, 1H broad); Anal. Calc. for C8H12N2O2: C, 57.14; H, 7.14; N, 16.67, found: C, 57.12; H, 7.13; N, 66.69 %.
2,3-Diaza-4-methyl-8-oxa-2-phenylspiro[4.5]dec-3-en-1-one (17): A mixture of ketoester 8 (0.1 mole) phenylhydrazine hydrochloride (0.11 mole) and sodium acetate (0.27 mole) in water (90 mL) afforded the product 17, c.a. 22 g (90 % yield), m.p. 94-96oC (from ethyl alcohol); 1H-NMR (DMSO-d6): δ (ppm) = 1.84-2.26 (m, 4H), 2.39 (s, 3H), 3.81-4.46 (m, 4H); Anal. Calc. for C14H16N2O2: C, 68.85; H, 6.56; N, 11.44; found: C, 68.78; H, 7.88; N, 11.40 %.
General method for the preparation of barbituric acids.
A mixture of diester 11 (0.05 mol), metallic sodium (0.05 mol) and carbamide or thiocarbamide in absolute ethanol (50 mL) was mixed for 7 h at 100oC. The precipitated sodium salt was filtered, washed with absolute ethanol and dissolved in water. The solution was acidified with HCl. The precipitate was filtered and recrystallized from water.
2,4-Diaza-3-hydroxy-9-oxaspiro[4.5]undec-2-ene-1,5-dione sodium salt (18): A mixture of diester 11 (0.05 mole), sodium metal (0.05 mole) and carbamide (0.05 mole) afforded the product 18, c.a. 10.6 g (96 % yield).
2,4-Diaza-9-oxaspiro[4.5]undecane-1,3,5-trione (20): The salt 18 (0.048 mole) afforded the acid 20, c.a. 9.1 g (92 % yield) m.p. 166-167oC;. 1H-NMR (DMSO-d6): δ (ppm) = 2.25 (m, 4H), 3.83 (m, 4H), 13.08 (s, 2H broad); Anal. Calc. for C8H10N2O4: C, 48.49; H, 5.05; N, 14.14, found: C, 48.49; H, 5.04; N, 14.10 %.
2,4-Diaza-9-oxa-3-sulfanylspiro[4.5]undec-2-ene-1,5-dione sodium salt (19): A mixture of diester 11 (0.05 mole), sodium metal (0.05 mole) and thiocarbamide (0.05 mole) afforded the product 19, c.a. 11.0 g, (94 % yield).
2,4-Diaza-9-oxa-3-thioxospiro[4.5]undecane-1,5-dione (21): The salt 19 (0.046 mole) afforded the acid 21, c.a. 9.6 g (90 % yield), m.p. 191-193oC; 1H-NMR (DMSO-d6): δ (ppm)=2.48 (m, 4H), 3.92 (m, 4H), 7.37; 9.80 and 10.72 (s, 2H broad); Anal. Calc. for C8H10N2O3S: C, 44.87; H, 4.67; N, 13.08; S, 14.95, found: C, 44.87; H, 4.19; N, 13.02; S, 15.99 %.
Computational Details
Theoretical calculations were carried out at the restricted Hartree-Fock level (RHF) using PM3 semi empirical SCF-MO method in the MOPAC 7.0 program [24], implemented on an Intel Pentium4 400 MHz computer. All the structures were optimized to a gradient norm of <0.1 in the liquid phase. The initial estimates of the geometry of all structures were obtained by a molecular mechanics program of CS ChemOffice Pro for Windows [25], followed by full optimized of all geometrical variables (bond lengths, band angles and dihedral angles), without any symmetry constraint, using semi empirical PM3 quantum chemical methods in the MOPAC 7.0 program.
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Sadikov, N.; Nasibov, S.; Ogretir, C.; Berber, H.; Hüseyinli, A. Quantum Chemical and Experimental Studies on the Mechanism of Alkylation of β-Dicarbonyl Compounds. The Synthesis of Five and Six Membered Heterocyclic Spiro Derivatives. Molecules 2004, 9, 922-938. https://doi.org/10.3390/91100922
AMA Style
Sadikov N, Nasibov S, Ogretir C, Berber H, Hüseyinli A. Quantum Chemical and Experimental Studies on the Mechanism of Alkylation of β-Dicarbonyl Compounds. The Synthesis of Five and Six Membered Heterocyclic Spiro Derivatives. Molecules. 2004; 9(11):922-938. https://doi.org/10.3390/91100922
Chicago/Turabian StyleSadikov, Nurettin, Sahin Nasibov, Cemil Ogretir, Halil Berber, and Ali Hüseyinli. 2004. "Quantum Chemical and Experimental Studies on the Mechanism of Alkylation of β-Dicarbonyl Compounds. The Synthesis of Five and Six Membered Heterocyclic Spiro Derivatives" Molecules 9, no. 11: 922-938. https://doi.org/10.3390/91100922
