The Synthesis of Functionalized Tetrahydrofurans via Vanadium(V

Chapter 3

The Synthesis of Functionalized Tetrahydrofurans via Vanadium(V)-Catalyzed Oxidation of Alkenols Jens Hartung, Arne Ludwig, Mario Demary, and Georg Stapf Downloaded by UNIV OF OTTAWA on May 30, 2013 | http://pubs.acs.org Publication Date: August 30, 2007 | doi: 10.1021/bk-2007-0974.ch003

Department of Chemistry, Technische Universität Kaiserslautern, Erwin-Schrödinger Straße, D-67663 Kaiserslautern, Germany

Vanadium(V) complexes formed from tridentate Schiff-bases or 2,6-dihydroxymethyl-substituted piperidines are able to catalyze the synthesis of β-hydroxyl-substituted tetrahydrofurans from alkenols and tert-butyl hydroperoxide (TBHP). (Schiff-base)vanadium(V) complexes showed their highest catalytic activity in anhydrous chlorinated methanes. Selective alkenol, aniline, bromide, and thianthrene S-oxide oxidation in protic solvents (e.g. EtOH, H O ) , however, was feasible using piperidine-derived vanadium(V) complexes for T B H P activation. Data from ligand substitutions indicate that auxiliaries, in which the Ο,Ν,Ο-donor atom sites are part of a conjugated π-electron system, bind stronger to vanadium(V) than those which lack this structural motif. 2

38

© 2007 American Chemical Society

In Vanadium: The Versatile Metal; Kustin, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.

Downloaded by UNIV OF OTTAWA on May 30, 2013 | http://pubs.acs.org Publication Date: August 30, 2007 | doi: 10.1021/bk-2007-0974.ch003

39 A considerable number of naturally occurring tetrahydrofurans has been selected in recent years for pursuing more detailed pharmacological studies (/). This assay-guided lead selection, however, faces at some stage of the investigation the challenge, how to cover the supply of the active compound in adequate amounts. Extraction from natural sources may be feasible, if crops or other renewable herbal sources serve as raw material. Partial or total synthesis have to be considered, if the active compound originates from a rare or even protected organism (2). In view of this background, the synthesis of tetrahydrofuran-derived building blocks has received considerable attention within the last decade. Major advances originated in particular from the field of transition metal-catalyzed oxidation (3,4,5). This concept is based on an in situ adduct formation between the central ion, an 0-atom donor ligand, and the substrate. Differences in steric congestion associated with competing reaction channels frequently serve as means for controlling regio- and/or stereoselectivity of the oxygenation step. This strategy has been applied, for instance, in order to develop an efficient synthesis of p-hydroxyl-substituted mid-sized ethers from alkenols and /erf-butyl hydroperoxide (TBHP). Activation of the primary oxidant in this case occurs via peroxide binding to a (Schiff-base)vanadium(V) complex. This step provides a novel peroxy reagent that may bind, e.g., substrate (R)-l, to afford "loaded" complex I. Intramolecular O-atom transfer in intermediate I thus affords tetrahydrofuran (25,5/?)-2 (Figure 1) with an excellent regio- and stereoselectivity (6).

HO H

H

ROOH RO[V]

H

Ph

-ROH

H I

Ph

RO[V]

H

O HO Ph (2S,5R)-2

Figure 1. Stereoselective tetrahydrofuran formation via vanadium-catalyzed alkenol oxidation. ROfVJ = (alkoxo)(Schiff-base)vanadium(V) complex (6, 7).

Other alkenols than (R)-l are oxidized in a similar predictable way to afford functionalized tetrahydrofurans in synthetically useful diastereoselectivities and yields (Figure 2) (7,10). In spite of the recognition this method has received in organic synthesis (7,8), its incompatibility with aqueous solvents is a severe restriction these days (6,9). Another drawback originates from the activity of


40

61 :39 OH

H

H =

H

P

H

H

H

P

H


Ph >98:2

\

98:2

70:30

Figure 2. Natural products and synthetic analogues (7,10). Arrows denote cis/trans-ratios associated with oxidative, vanadium(V)-catalyzed alkenol cyclizations.

the catalyst, which fades after approximately 50 cycles (6). Both issues thus have to be addressed in order to broaden the scope of the method. Following guidelines from a computational analysis (//), Schiff-bases II formed from substituted salicylic aldehydes (S = e.g. NEt , N 0 ) and/or substituted P-aminophenols (S = e.g. OMe, N 0 ; Figure 3) were considered to bind stronger to vanadium(V) than the unsubstituted derivative 3a (Figure 4). Also, a formal hydrogenation of 7i-bonds between the 0 , N , 0 donor atom entity in auxiliary II was predicted (11) to furnish ligands that show a stronger affinity toward vanadium(V) than the dianion of 3a. In the first part of this chapter, results from the synthesis of (Schiff-base)vanadium(V) complexes, their properties, and their performance in a benchmark oxidation for stereoselective tetrahydrofuran formation (7) are summarized. The second part of the chapter deals with the synthesis of vanadium(V) complexes starting from 2,6dihydroxymethyl-substituted piperidines III and their use in oxidation catalysis. An emphasis has been laid on reactions in protic media. 1

2

2

2

2

(Schiff-base)vanadium(V) Complexes Preparation and Ligand Substitutions Imines 3a-f and 3h-i (Figure 4) were prepared upon treatment of an appropriate or/Ao-(hydroxy)arylcarbaldehyde with a P-aminoalcohol in hot EtOH (3a: quant; 3b: 78 %; 3c: 94 %; 3d: 84 %; 3e: 74 %; 3f: 26 %; 3h: 94 %;



41

Figure 4. Structure formulae of tridentate Schijf-base-derived ligands 3a-f 3h-i, and secondary amine 3g.


42 3i: quant) (6J0J2) NaBH -reduction of 7V-salicylidene-2-aminophenol (3a) furnished amine 3g (Figure 4) in 51 % yield. The reaction of triethyl vanadate (4) with N0 -donor ligands 3a-i in hot EtOH provided complexes 5a-i (5a: quant; 5b: 92 %; 5c: 19 %; 5d: 99 %; 5e: 95 %; 5f: 93 %; 5g: 60 %; 5h: 33 %; 5i: quant) as dark brown to red brown cristalline solids (Figure 5) , / i ) . Compound identification was achieved via UV/Vis-spectroscopy, IR-analysis [v =o /cm" (KBr) = 5a: 990, 5b: 994, 5c: 983; 5d: 962; 5e: 959, 5f: 988, 5g: 988, 5h: 976, 5i: 997], combustion analysis, V - N M R [in CDC1 , referenced versus V O C l in CDC1 : 5a: 8 = -529, 5b: 531, 5c: -524; 5d: -535; 5e: -519, 5g: -535, 5h: -510/-531 = 1/1.7 (CD OD); 5i: -5347-538 = 1/1.2 (CD OD)] and X-ray diffraction analysis (5a, 5d, 5i). 4

2

1

v

5 ,

3

3

3

3


3

EtOH H L 2

n

+VO(OEt)

-

3

n

VOL (OEt)(EtOH) + (2-q)EtOH q

78 °C 3a-i

4

5a-i

Figure 5. Synthesis of vanadium(V) complexes Sa-i from auxiliaries 3a-i (see also Figure 4; q = 0 or 1) (6).

0,N

=N 9/0 x

3a/EtOH [5b]: [5a] = 2 9 : 71

\

//— O

OEt

Et N

78°C/5h

5b

9

=N 9^0 X

3b/EtOH [5b]: [5a] = 23 : 77

The Synthesis of Functionalized Tetrahydrofurans via Vanadium(V

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