2. CAPÍTULO 2:ANÁLISIS DEL PROYECTO COCA CODO SINCLAIR 29
2.4.3. Desarrollo Sostenible del País 40
We applied the principle of intramolecular oxymercuriation to the synthesis of 1,2,4-trioxanes (Scheme 61)^^.
OH HO I V .
111.
BrHg
113 114 115 116
i. cat CF3COOH, CH2CI2
ii. Hg(0Ac)2 , 6 mol% HCIO4
iii. KBr
iv. NaBH4,NaOH
Scheme 61
The starting 2,3-dimethylbut- l-en-3-yl hydroperoxide (113), was obtained in up to 90% yield by tetraphenylporphine-sensitised photooxygenation of 2,3-dimethylbut-2- ene^^. Hemiperoxyacetal (114), was generated by the trifluoroacetic acid-catalysed addition reaction of crude 113 with aldehyde in dichloromethane solvent.
The formation of 114 was confirmed by nmr spectroscopy from the HOCHR proton signal of appropriate muliplicity at 6 4.8-5.2 where R was aliphatic and at Ô 6.2-6.3 where R was aromatic. The extent of formation of 114 as determined
by nmr spectroscopy was 90-95% where aliphatic aldehydes were used and as little as 5% where the starting aldehydes were aromatic. Generally the intermediate hemiperoxyacetals were not isolated and were treated in situ with mercury acetate and perchloric acid catalyst. The oxymercumtions (5-20 mmol scale) were completed in 1-3 hrs as judged by the time taken for the solid mercury acetate to dissolve, although there were no deleterious effects if the reactions were allowed to run overnight. In the examples where aliphatic aldehydes were used, the organomercury(II) bromides (115), were obtained as a pair of diastereoisomers after anion exchange with potassium bromide. Isolation by simple column chromatography (Si0 2, CH2CI2) gave
the pure componds in yields ranging from 56-86% (Table 2). Table 2 C om p o u n d R 115% yield 116% yield a Nfe 60 62% b Et 62 54% c Pr 80 85* d ipr 56 55+ e tBu 59 58+
f CCI3 8 6 not isolated
g 2-NO2C6H4 2 0 27*
h 4-CIC6H4 2 1 23*
i C6H5 not isolated 38*
(Where x is the overall yield calculated from 113 by ’one-pot' method and + is the overall yield calculated from 113 by the reduction of 115)
The sodium borohydride reductions^® proceeded in over 90% yield with little or no side products and the 3-alkyl-1,2,4-trioxanes (116, R=alkyl) were purified by simple column chromatography (Si0 2 , CH2CI2) followed by bulb-to-bulb distillation
under reduced pressure if necessary. In the examples where aromatic aldehydes were used, the crude organomercury(II) bromides (115, R=aryl) contained appreciable amounts of starting aldehyde, which could not be removed by simple column chromatography. However separation of the 5-(bromomercuriomethyl)-3-(aryl)-1,2,4- trioxanes 115, from unreacted aromatic aldehydes was achieved by treating the mixture with a sodium chlorite-hydrogen peroxide system buffered with sodium phosphate
(Scheme 62)^^ The net result of this reaction was oxidation of the aromatic aldehyde impurity to the corresponding carboxylic acid which was subsequently converted to the sodium salt and washed out in the aqueous layer, leaving 115 (R=aryl) dissolved in the organic layer.
NaClOo HoO HCIO2 + NaOH
RCHO + HCIO2 RCOOH + HOCl
The purpose of the hydrogen peroxide was to scavenge the HOCl
HOCl + H2O2 HCl + HoO + Go
Scheme 62
The aromatic organomercury(II) bromides 115, were then purified by column chromatography (Si02, CH2CI2) and obtained in yields ranging from 2o-21 % (Table
2).
The low yields for aromatic 1,2,4-trioxanes 115 and 116 may be due to a very low extent of hemiperoxyacetal 114 formation (about 5% as judged from nmr spectroscopy). Low formation of 114 was attributed to the low reactivity of aromatic aldehydes with compounds like 113, because of resonance stabilisation (Fig 1).
Figure 1
t o
o-
In addition the electron-withdrawing effect of substituents like -Cl on the aryl group would tend to reduce the nucleophilicity of the internal nucleophile ( OH) in 114 (Fig 2) making trioxane formation by intramolecular oxymercuriation less likely.
Figure 2
n u cleop h ilicity o f -O H is decreased by the electron-w ithdraw ing effect o f aryl group
The three steps of the syntheses (Scheme 59) could also be carried out consecutively in the same reaction vessel. In this one-pot' procedure, the anion exchange was omitted and the solution was washed with 5% aqueous sodium bicarbonate before commencing the sodium borohyride reduction. The 'one-pot' procedure for the aromatic compounds involved using ethanolic rather than aqueous sodium borohydride for the reductions. In this way the unreacted aldehydes present were converted into their corresponding alcohols, which were readily separated from 116 (R=aryl) by chromatography (Si02, CH2CI2). The 'one-pot' method is fast and
convenient as it avoids handling the intermediate mercurials 115. The overall yields of the mercury-free 1,2,4-trioxanes were improved by the one-pot' method by up to 10%. For example compound 116a was isolated in 55% yield after reduction of 115a, but by using the one-pot' procedure the yield was improved to 62%. Similarly compound 116c, obtained by reduction of compound 115c was isolated in 80% yield, but this overall yield was improved to 85% by omitting the anion exchange step and following the 'one-pot' route.
All new 1,2,4-trioxanes gave satisfactory C and H analyses and positive peroxide tests with acidic iron(II) thiocyanate. The high field proton and carbon-13 nmr spectra were consistent with their structures. The organomercurials 115 were each obtained as a pair of diastereoisomers and isomerism was removed by reduction to compounds 116.
2.2.2 H alo g en o d em ercu râtio n s o f o rg a n o m e rc u ria l 1,2,4-trioxanes
Halogenodemercuiàtions were carried out in subdued lighting by the dropwise addition of a solution of bromine or iodine to 115. The halogen-substituted 1,2,4- trioxanes (117) thus formed were isolated by column chromatography (Si02, CH2CI2)
in high yields (Scheme 63).
R R O O
i
BrHg* 11 5 X 117 a. R=Me, X=Br, 90% f. R=Et, X=I, 98% Scheme 632.2.3 NM R Studies an d D eterm ination of S tereochem istry
The presence of the 1,2,4-trioxane ring in compounds 115,116 and 117 was confirmed by the nmr signals observed for the ring-carbon atoms at 5 94-99 (C-3), 5 80-84 (C-6) and Ô 75-79 (C-5) and by the iR nmr signals of appropriate multiplicity observed for the CH R proton at 5 5.0-5.5 (R=alkyl), or Ô 6.3-6.8 (R=aryl) (see spectra at the end of this chapter).
The spectra of the organomercurials 115, additionally showed characteristic signals for the CH2HgBr group at 8c 45-46 [U(^^C-^^^Hg) ca. 1550 Hz] and 8h 2.0-
2.3 (AB pattern with the downfield doublet showing long range coupling to the gem methyl group). This suggested restricted rotation about the BrHgCH2-ring bond, as a
result of steric effects or due to attractive interactions between the mercurial group and the atom of the trioxane ring.
The halogeno compounds, 117 were formed as a pair of diastereoisomers as expected from the presence of chiral centres at C-3 and C-5. The key nmr features were very similar to the starting organomercurials. The nmr spectra of the major isomer showed the characteristic signals of appropriate multiplicity. The spectra differed from those of the precursor 115, in the chemical shifts of the H^H® doublets which appeared between 8 3.1-3.4. Here again as for compounds 115, the downfield doublet of the AB pattern showed long range coupling to the gem methyl group. This implied that restriction about the CH2-ring bond could not be due to attractive interactions and
was therefore probably steric in origin. Another distinctive feature in the carbon spectra of 117, was the signal due to CH2X (X=Br or I) which was observed at Ô 14.38 for
117f (X=I) and at Ô 38.6 for 117a (X=Br).
Nuclear Overhauser effect (NOE) experiments were carried out to determine the stereochemistries of the major and minor diastereoisomers of organomercurial compounds 115. NOE works by the principle that two protons close in space will interact. Saturation of the signal due to one proton will therefore cause rapid relaxation of the second proton's signal resulting in an enhancement of that signal. Compound l l S d (R=iPr) was used for the NOE measurements. The R group attached to C-3 was reasonably assumed to lie in the equatorial position so had to be axial, therefore any proton exhibiting an NOE to must also be axial or in an axial group.
Table 3 NOE measurements
Iso m e rs H» HO % enhancem ent
of Ro
M ajor Me on C-6 R7 4.3
H7 Me on C-6 4.0
Me on C-5 R3 7.2
M inor H7 R3 4.2
Rl-proton irradiated, H°-proton observed
HgBr
MAJOR
HgBr
MINOR
Figure 3 Figure 4
The results (Table 3) show that in the major isomer (Figure 3), the CH2HgBr group
must lie in the equatorial position as there is a key NOE measurement of 7.2% between and the protons of the axial methyl group on C-5. In the minor isomer (Figure 4), the CH2FlgBr group must therefore lie in the axial position. This was confirmed by
irradiation of the downfield signal which resulted in a 4.2% enhancement at (the upfield signal overlaps with the major isomer). All the methyl group signals were
irradiated but table 3 shows only those cases where an NOE was observed. 2.2.4 O th e r hydroperoxides
The trifluoroacetic acid catalysed reaction of cyclohexenyl hydroperoxide (118) with aldehydes gave hemiperoxyacetals (119). However subsequent reaction of 119 with mercury(II) acetate did not give 1,2,4-trioxanes, even after 12 hrs reaction time (Scheme 64). The iR and nmr spectra of the end products were very complicated and but clearly showed that unsaturation was still present. We were unable to identify the products. HO 1. RCHO OOH O— O 119 118 11, ■R yellow, sticky mess! i. cat. CF3CO2H, CH2CI2 ii. Hg(0Ac)2 Scheme 64
Overman et formed hemiacetal (121) by reacting 2-cyclohexen-l-ol (120) with chloral. Treatment of 121 with mercury(II) trifluoroacetate for a critical 48 hrs followed by demercuration with alkaline sodium borohydride afforded the cyclic chloral adduct (123) in 62% yield (Scheme 65).
H C C I3