THE SYNTHESIS OF NEW SPIROLACTONES FROM SUBSTITUTED ISATINS

Abstract. Interaction of N-ethyl isatin 3 with dimethyl acetylenedicarboxylate in the presence triphenylphosphine has led to good selectivity of methyl 1'-ethyl-4-methoxy-2',5-dioxo-5H-spiro[furan-2,3'-indoline]-3-carboxylate 4 formation. Similar yields of spirolactones 6,8 were obtained by addition of dimethyl acetylenedicarboxylate to 5bromo functionalized isatins 5,7. However, reaction of N-butyl isatin 9 resulted in formation of an inseparable mixture of compounds. Treatment of N-benzyl isatin 10 and dimethyl acetylenedicarboxylate with triphenylphosphine proceeded with reduced selectivity of the spirooxindole 11 formation.

Herein, we focused on developing of a cycloaddition method of dimethyl acetylenedicarboxylate to 5-bromo functionalized isatins for a selective construction of spiro-butenolide oxindoles 1 featuring several functionalized centres.

Results and discussion
It has been reported [4] that mixture of equal amount of N-ethyl isatin 3, dimethyl acetylenedicarboxylate and triphenylphosphine is a satisfactory system for the high yield (up to 90%) construction of spirane 4 (Scheme 2).For this reason, our research was initiated toward the investigation of structure-reactivity relationships of N-alkyl isatins, acetylenedicarboxylate and triphenylphosphine to cope with such classical problem of heterocyclic chemistry.However, this approach for the synthesis of substance 4 provided а complex of products and main of them was isolated only with yield 60% by preparative TLC on silica gel.
The 1 H NMR spectrum of the white solid compound with m.p. 122-124 0 C, has two doublets and two triplets at δ Н 6.79-7.40ppm.Moreover, product has signal of two methylene protons (δ Н 3.67-3.90ppm) and one secondary methyl group at δ Н 1.26-1.30ppm and singlet attributable to MeO group at δ Н 3.55 ppm, the chemical shift of the last refl ecting its attachment to a carbonyl atom.It was observed a chemical shift difference for protons position of =C-O-Me between reported [4] and our spectrum data at δ Н 3.38 ppm and δ Н 4.34 ppm, respectively.Moreover, m.p. of our sample also is different with published in [4].
Chemistry Journal of Moldova. General, Industrial and Ecological Chemistry. 2015, 10(1), 64-70 We confi rmed the structure of 4 by single-crystal X-ray analysis (see Figure 1).Monocrystals of composition C 16 H 15 NO 6 belong to centrosymmetric space group P2 1 /n, thus represent racemate.The indole moiety is orthogonal to the furan ring as indicated by the dihedral angle of 88.85(5)° between them.The methyl ester group is about coplanar with furan ring and the dihedral angle between these fragments equals 10.6(1)°.The methoxy fragment of ester and attached to C10 methoxy group are in a proximate positions.Torsion angle O6-C13-C12-C10 equals -12.8(3)°.The C10-C12 bond distance equals 1.343(2)Å and unambiguously indicates the double character of this bond.The O2-C9 =1.353(2)Å and O2-C2=1.453(2)Å distances differ due to different hybridization of bonded carbon atoms.The compound exhibits structural similarities with an already reported related structure [33][34][35][36].Thus the major component in reaction of N-ethyl isatin 3, dimethyl acetylenedicarboxylate and triphenylphosphine could be formulated as 4.
There has been no study of the stereochemistry of the atom C(2) of the spiro compound 8 by X-ray crystallography.The structure of 8 was also unambiguously confi rmed by single crystal X-ray analysis.Monoclinic crystals of 8 have composition  Taking into account the previous experimental data (formation of the compounds 4,6,8) we introduced one more CH 2 group in substrate (compound 9) for obtaining the similar spirocyclic oxindole-butenolide derivative.But the reaction in the same conditions gave a complex of products without target butenolide, even standing at room temperature for a week.
Based on these results it is concluded that reaction of isatin 9 with reagents occurs slowly and is not selective.The opposite situation is observed in the case of spirolactone formation 11 from isatin 10 during one hour, which was indeed a major product (67% yield).
If the structure of product is 11, CH 2 group of the derived oxindole-butenolide with m.p. 188-190 0 C should give rise to an two doublets in the 1 H NMR spectrum while in low fi eld shown two protons.In fact the product shows a clear doublet (δ Н 3.75 ppm) with a spin-spin coupling (J AB = 16 Hz) of the magnitude predicted for a methylene group between the phenyl and amide fragments.
The synthesis of the polyfunctionalized spirolactones from the C4, C6, C7 as well as N-substituted isatines is in progress and the results will be presented later along with a detailed discussion of the pathways to the various products.However, a provisional scheme which satisfactorily explains the production of discussed spirocyclic oxindolebutenolides is outlined (Scheme 3).

Conclusions
In conclusion, we contend that the above-described synthesis of 5-bromo substituted oxindoles linkages in spirocyclic butenolides exhibit relatively dependence of the structure-reactivity relationships of N-substituted isatines, dimethyl acetylenedicarboxylate.In the future it is planned to use chiral phosphine to provide the corresponding optically active spirolactones.

Crystal structure determination
The X-ray data for 4 and 8 were collected at room temperature on an Oxford Diffraction Xcalibur-E diffractometer equipped with CCD area detector and a graphite monochromator utilizing MoKα radiation.The fi nal unit cell dimensions were obtained and refi ned on an entire data set.The structures were solved by direct methods using SHELX-97 program package [41] and refi ned with full-matrix least squares method with anisotropic thermal parameters for the non-hydrogen atoms.
In both structures the C(sp 2 )-bound H atoms and methylene groups H atoms were placed in calculated positions and were treated using AFIX 43 and AFIX 23 instructions, respectively, and a model approximation with Uiso(H) = 1.2Ueq(C), the H atoms of methyl groups were found and refi ned using AFIX 137 instruction and Uiso(H) = 1.5Ueq(C).The fi gures were produced using MERCURY [38].
The X-ray data and the details of the refi nement for 4 and 8 are summarized in Table 1.Crystallographic data for new structures reported herein were deposited with the Cambridge Crystallographic Data Centre and allocated the deposition numbers CCDC 1053146 and CCDC 1053147.These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.