1-Oxa-3-azapentalen-2-ones as precursors of cis -2-amino alcohols: synthesis from acetylenic alcohols, carbon dioxide and amines via intramolecular amidoalkylation of oxazolidinones

The reaction of 4-methyl-4-(4-methyl-3-pentenyl)-5-methylen-1,3-dioxolan-2-one 1a with primary amines 2 leads to the corresponding 4-hydroxy-4-methyloxazolidin-2-ones 3 which are transformed by intramolecular amidoalkylation into 1-oxa-3-azapentalen-2-ones 4 and 5 , potential precursors of cyclopentane cis -2-amino alcohols.


Introduction
Some chiral 2-amino alcohols are of considerable interest as catalysts for asymmetric Diels-Alder reactions, 1a Michael 1b synthesis and enantioselective catalytic reductions.1c These alcohols exhibit a wide range of biological activities.We have developed a simple approach to precursors of related cyclopentane cis-2-amino alcohols on the basis of the reaction of dioxolanone 1a with primary amines 2, which results in the formation of intermediate oxazolidinones 3. Intramolecular amidoalkylation of 3 in formic acid gives azapentalenones 4 and 5 with cisoriented substituents at the annulation centers.Compounds 4 and 5 are considered to be potential precursors of the alcohols.Oxazolidinones (3) are often prepared by the addition of organometallic compounds to oxazolidin-2,4-diones. 4,5However, this method has disadvantages such as by-product formation, moderate yields and a complicated procedure.There is also a technique to afford 4methoxyoxazolidin-2-ones, compounds related to ours, via Sn-and Se-organics which provide good yields and stereo-control. 6This is a valuable method although it still suffers from some of the problems noted above.The readily available dioxolanones 1 3 appear to be useful precursors to the oxazolidinones

Results and Discussion
Preparation of 4-hydroxyoxazolidinones.The highly basicity amines 2 react with dioxolanones 1 to afford yields in the 38-100 % range during 12-144 h at rt (3a-g, i) and at 110 o C (3h) (Scheme 1).Catalysis by Lewis bases, in our case triethylamine, is a good choice for the less active N,N-dimethylhydrazine (2f) and amines 2c and 2g.The structure of oxazolidinones 3 is supported by 1 H NMR: there are signals for both the OHgroup and the methyl group at the NMR spectra. 3The methylene protons in 3a, 3b and 3i are two doublets with a small coupling constant due to the asymmetric center at the 4-position of the ring.If there are two asymmetric centers in the oxazolidinone cycle (mixture of two diastereomeric pairs), the NMR spectra interpretation is much more difficult because signal duplication takes place.The mixtures of such diastereomeric pairs display two spots on TLC.These diastereomeric pairs have no sharp melting points (besides some of compounds 3 dehydrate when heated or even at rt).Compound 3a was chromatographically separated to give two pairs 3a' and 3a''; they melt at different temperatures and their 1 H NMR spectra are not identical.In CDCl3 both pairs are transformed into 3-benzyl-5-methyl-5-(4-methyl-3-pentenyl)-4-methylenoxazolidin-2-on by traces of DCl in a week (characterized with 1 H NMR) (Figure 1).Amidoalkylations of oxazolidinones 3 result in azapentalenones 4a-e with yields in 26-96% over 48-168 h at ambient temperature (Scheme 2).Allyl groups in compounds 3e and 3d do not participate in amidoalkylation as it would require a geometrically disadvantageous 5-endo-trig transition state.In the case of 4d, acylation of the β -hydroxyethyl group proceeds in addition to intramolecular amidoalkylation.We did not attempt to identify the absolute configuration of compounds 4a-e.From the theoretical 5,8 and x-ray analysis data on compound 5' (see below), we suggest that these compounds should have the stereochemical structure presented in Scheme 2. The reaction proceeds through a standard mechanism, i.e. the acyliminium ion reacts with the double bond in A in such a manner that maximum overlapping of molecular orbitals in transition state B would be achieved, and strain energy in the newly generated cycle would be minimized.The formation of transition state B is followed by the tertiary carbocation C generation and five-membered cycle closure.Although this cycle is less beneficial from an energy standpoint than the sixmembered one, the reaction passes in this very direction as the six-membered cycle involves the generation of less stable secondary carbocation D. The stabilization of tertiary ion C may be achieved in two ways: both by proton loss and anion addition (HCOO -).The predominating generation of unsaturated compounds 4a-e makes it possible to assume that the rate of proton elimination is much higher than that of formate-anion addition.
Both processes take place when a nitrogen heterocyclic substituent capable of protonation is available at position 3 of the ring (Scheme 3).In the instance of amidoalkylation of 3b, we identified the generation of four potential products 4f'/4f'', 5' and 5''.We managed to separate compounds 5' and 5'' by chromatography but failed with compounds 4' and 4''.The 1 H NMR spectroscopy data on hetero-substituted 3h and 3i supports the formation of similar products.A protonated heterocyclic compound capable of coordinating the formate-ion responsible for the generation of formyl derivatives 5 is likely to be available.Carbocations E and F (analogs of C, Scheme 2) can be stabilized either by proton loss or by the addition of this heterocyclecoordinated formyl anion.The rates of both processes are evidently proportional, and therefore the yields of 4f and 5 are also comparable.The formation of stereoisomeric products 4f'/5' and 4f/5 is regulated by two counteracting factors in E and F, i.e. by overlapping of orbitals and repulsion of positively charged centers.Since the yields of the stereoisomeric pairs 4f'/5' and 4f''/5'' are almost equal the counteracting factors are likely to be comparable.
ISSN 1551-7004 Page 502  ARKAT USA, Inc Scheme 3 The configuration of ester 5' in the solid state was proven by x-ray analysis (Figure 2).As expected, the methyl groups at the vicinal atoms of the bicyclic fragment are cis-oriented.According to the literature data, dilution of the reaction mixture leads to an increase in the yields of azapentalenones.The yield of 4a increases from 54 to 65% with a decrease of the initial concentration of starting 3a from 0.111 to 0.055 mmol/mL.The mass spectrometry data evidence that the available by-products (viscous oils) have doubled molecular mass versus 3a, minus mass of two water molecules.The products are probably dimeric, whose formation have been discussed in the literature. 7

Conclusions
The preparation of compounds 4 and 5 with the specified stereochemistry has been accomplished.All steps of the synthesis (dioxolanone 1 to oxazolidinone 3 to azapentalenone 5 or/and 4) proceed with good yields and under mild conditions, with easy separation of products i (intermediates 3 may be used without isolation).

ISSN 1551-7004
Page 507  ARKAT USA, Inc After 72 h at rt the reaction mixture was diluted with 10 mL of dichloromethane.The solution was washed with water and filtered through cotton wool.After solvent evaporation, a substance formed which was crystallized from 9.5 mL of benzene-hexane 4:1 to yield a light yellow powder (6.76