Penol Catalyzed Claisen ortho Ester Rearrangment of Allylic Alcohols with Trimethyl-β-hoxy) ortho Propionate

Abstract

E -A lkylidene Cycloalkanes, Claisen orthoEster Rearrangement, Trimethyl-/?-(methoxy) ortho Propionate Phenol catalyzed Claisen ortho ester rearrang ment of allylic alcohols with trimethyl-/?-(methoxy) ortho propionate can be affected in rela tively quick time and lower temperature with only I.5 equivalents o f ortho ester. The rearrrangement does not experience undesirable side reac tions reported earlier in literature [3].The Claisen ortho ester rearrangm ent [1] pro vides a versatile m ethod for construction of new carbon to carbon bonds with high regio and stereospecificity [2]. It proceeds under the influence of an acid catalyst [1,3]. During the syntheses of alkylidene cycloalkane esters 5a-d (Scheme 1), we found that phenol is a catalyst superior to pro pionic acid earlier employed by Johnson [1] and both pivalic acid and 2,4,6-trimethoxy-benzoic acid respectively employed by Raucher [3]. Pivalic acid undergoes undesirable esterification with al lylic alcohols, requires longer reaction time (72 h at 154 °C) and 5 fold excess of ortho ester. 2,4,6-Trimethoxdy benzoic acid, on the other hand, re quires a tem perature of 190 °C.The synthesis of alkylidene cycloalkane esters 5a-d is achieved by heating allylic alcohols 4a-d (obtained in 3 steps from cycloalkanones la -d [4 -6 ]) with 1.5 eq of trimethyl-/?-(methoxy) ortho propionate in the presence of 0.06 eq of phenol at 145 °C for 1 h. The excess of ortho ester was recovered by vaccum distillation (50-52 °C, 9 mm) to give in each case a mixture of diastereoisomers which were purified by flash chromatogra-* Reprint requests to Prof. Dr. A. Malik. la-d 2a-d 3a-d 4a-d a n = 1 b n = 2 c n = 3 d n = 4 Scheme 1. Reagents and conditions: i, liq. N H 3. Na metal, C H = C H , -7 8 °C, 42-97% ; ii, A c 0 H /H 20 , Dowex-50 resin, reflux, 8 5 -9 5 % ; iii, N aB H 4, Ce3+, M eOH, 2h, 6 5 -90%; iv, C H ,O C H 2CH2C (O C H 1)3, phenol, 145 °C, lh, 8 1 -9 8 % .phy over silicagel using hexan-EtOAc (98:2) as eluent to obtain pure 5a-d as colourless liquids in high yield (Scheme 1). The diastereomeric ratios were determ ined by and 13C NM R spectra of the crude reaction mixtures (cf. Table I). Table I. Physical data of 5a-d. Compound Yield [%1 HRMS/ Mol.Formula Diastereomeric ratio 5a 81 212.13084 c 12h 2 0 o 3 3:2 5b 92 226.1568 c 13h 2 2 o 3 3:2 5c 98 240.175 C 14H 24O 3 2.4:2 5d 89 254.19165 C15H260 3 2.3:2We have noted that phenol is a superior catalyst for Claisen ortho ester rearrangm ent as it proceeds without any undesirable esterification and the re action is com pleted in 1 h at 145 °C, requiring only 1.5 eq. of the ortho ester.

Facile Approach to Versatile Chiral Intermediates for Fused Cyclopentanoid Natural Products

“…These were reduced with N aBH4 in the presence of cerium chloride in m ethanol to afford the epimeric alcohols 4a-d [5], Claisen rearrange ment with triethyl orthoacetate provided com pounds 5a-d. In the reaction sequence phenol was used as the acid catalyst and its superiority over the traditional pivalic acid has already been re ported by us in a previous short communication [6],…”

“…O ur interest was not only to develop a high yielding facile route to these intermediates but also to extend the strategy to their ring ana logues (n = 0,2,3). In our methodology we have used a com bination of Rupe and Claisen orthoes ter rearrangem ents [4,6 ] to arrive at the target molecules.…”