(Hive Bee)
04-12-03 06:51
No 425976
      Synthesis of a Tricyclic Mescaline Analogue
(Rated as: excellent)

Synthesis of a Tricyclic Mescaline Analogue by Catalytic C-H Bond Activation
Kateri A. Ahrendt, Robert G. Bergman, and Jonathan A. Ellman
Org. Lett.; 2003; 5(8) pp 1301 - 1303; (Letter) DOI:10.1021/ol034228d

Molecule: Tetrahydrobis(benzofuran) mescaline ("COC1=C(OCC3)C3=C(CCN)C2=C1OCC2")

A tetrahydrobis(benzofuran) mescaline analogue has been prepared in six steps and 38% overall yield from (4'-O-methyl)methyl gallate. The key step in this synthesis is a tandem cyclization reaction via directed C-H activation followed by olefin insertion.

Since its discovery in 1896,1 mescaline (1, Figure 1) has served as a prototypical compound for structure-activity relationship studies linking molecular structure to hallucinogenic activity.2 Mescaline exerts its behavioral effects primarily through interaction with the 5-hydroxytryptamine2 (5-HT2) receptors.3 The 5-HT2 family of receptors mediates a number of physiological processes including vascular and nonvascular smooth muscle contraction, platelet aggregation, and modulation of perception, mood, anxiety, and feeding behavior.4 Furthermore, these receptors are a therapeutic target for the treatment of central nervous system disorders such as schizophrenia and depression.5

 Figure 1 Mescaline (1) and dihydrobenzofuran and tetrahydrobis(benzofuran) analogues 2 and 3. 

The synthesis and biological activities of mescaline analogues 2 and 3 (Figure 1), in which one or two of the aromatic methoxy groups of mescaline are tethered into rotationally constrained dihydrobenzofuran rings, has recently been described.6 Compounds 2 and 3 exhibit increased affinities relative to mescaline for cloned human 5-HT2A, 5-HT2B, and 5-HT2C receptors as determined through competitive binding studies with radiolabeled agonist and antagonist ligands.7

Our interest in compound 3 was generated by the ability to rapidly assemble the tetrahydrobis(benzofuran) functionality utilizing catalytic C-H activation. To date, only a few examples of C-H activation in the synthesis of natural products or biologically active molecules have been reported.8,9 Recently, we have described the annulation of aromatic imines, in which an alkene is tethered meta to the imine. Rhodium-catalyzed, imine-directed ortho C-H activation followed by olefin insertion provides access to functionalized indanes, tetralanes, dihydroindoles, and dihydrobenzofurans.10 Herein we report the application of our annulation strategy to the concise synthesis of the conformationally restricted tetrahydrobis(benzofuran) mescaline analogue 3.

Our approach to 3 was based on the elaboration of intermediate 8 (Scheme 1), obtained from the rhodium-catalyzed tandem cyclization reaction of aromatic imine 7. Precursor 7 was prepared from (4'-O-methyl)methyl gallate 4.

 Scheme 1 

The synthesis began with the conversion of bis-phenol 411 to the bis-vinyl ether. The synthesis of phenyl vinyl ethers is generally accomplished by alkylation of phenol with 1,2-dibromoethane followed by elimination with KOtBu, or by subjection of phenol to high pressure of acetylene in the presence of a strong base. These procedures require forcing conditions, and the products are generally obtained in only low to modest yields.

Our initial efforts to form the bis-vinyl ether instead focused on a recently reported procedure for the iridium-catalyzed reaction of alcohols with vinyl pivalate.12 Unfortunately, subjection of 4 to the reported reaction conditions resulted in low yields of the desired bis-vinyl ether (Scheme 2, eq 1). Modification of reaction parameters, including reaction time and temperature, concentration, catalyst loading, and stoichiometry of vinyl acetate, did not improve the yield. Most conditions resulted in poor conversion, and under forcing conditions a significant amount of acetylated rather than vinylated material was observed.

 Scheme 2 

We then investigated an alternative procedure recently described by Blouin and Frenette.13 Treatment of bis-phenol 4 with tetravinyl tin and copper(II) acetate in the presence of oxygen led to the desired bis-vinyl ether 5 in reproducibly high yield (Scheme 2, eq 2).

With the bis-vinyl ether 5 in hand, conversion of the methyl ester to the aldehyde was examined. Preliminary reactions with DIBAl-H were unsuccessful, resulting in over-reduction of the ester to the benzylic alcohol. However, treatment of the ester with a pyrrolidine-modified aluminum hydride reagent according to the procedure of Abe and co-workers14 provided the desired benzaldehyde in high yield (Scheme 3). The aldehyde was then converted to the benzyl imine 7 by treatment with benzylamine in the presence of molecular sieves.

 Scheme 3 

To effect the tandem cyclization reaction, we first examined conditions that we had previously used for the annulation of alkene-substituted aromatic imines. Unfortunately, Wilkinson's catalyst provided only low yields of the desired tetrahydrobis(benzofuran) product after extended heating, as determined by 1H NMR experiments (Table 1, entry 1).

Consequently, a number of phosphines were screened in the presence of [RhCl(coe)2]2 in an effort to improve the reaction efficiency (Table 1).15 Higher yields were obtained with the use of more electron-rich phosphines, with the exception of the bulky P(t-Bu)3 ligand (entries 2-7). In the cases of the electron-rich phosphines, the optimal ratio of ligand to rhodium(I) for generating the bis-cyclization product was 1:1 (entry 6 versus entry 7). We were pleased to find that employing catalytic [RhCl(coe)2]2 with the electron-rich dicyclohexyl ferrocenyl phosphine ligand led to the desired bis-cyclization product in good yield (entry 6).16

Having identified an efficient catalyst system for the annulation reaction, the tetrahydrobis(benzofuran) 8 was isolated in 65% yield after acidic workup (Scheme 4).17 Aldehyde 8 was then converted to the target mescaline analogue 3 via a Henry reaction followed by reduction of the intermediate nitroalkene.

 Scheme 4 

In summary, tetrahydrobis(benzofuran) mescaline analogue 3 has been prepared in six steps and 38% overall yield from (4'-O-methyl)methyl gallate 4. The key step in this synthesis is a rhodium-catalyzed tandem C-H activation/C-C bond forming reaction. The bis-vinylation of 4 is also noteworthy. Importantly, this efficient annulation sequence can potentially be applied to the synthesis of other biologically relevant dihydrobenzofurans.

Table 1. Optimization of the Tandem C-H Activation/Olefin Insertion Reaction


 entry Rh catalyst a time (h) NMR yield (%)b
 1   (PPh3)3RhClc   20   10   
 2   P(t-Bu)3, [RhCl(coe)2]2  3  0
 3   P(n-Pr)3, [RhCl(coe)2]2  17  18
 4   PCy3, [RhCl(coe)2]2   8   48
 5   FcPPh2, [RhCl(coe)2]2   4   34
 6   FcPCy2,[RhCl(coe)2]2   2   75
 7   FcPCy2, [RhCl(coe)2]2d   5   52


a Reactions were performed with 20 mol % of Rh(I) and 20 mol % of phosphine.b Yields were determined by 1H NMR relative to an internal standard.c 20 mol % of Wilkinson's catalyst was used.d Reaction was performed with 20 mol % of Rh(I) and 40 mol % of phosphine. Abbreviations: coe = cyclooctene; Fc = ferrocenyl.

Kind of interesting. If anybody wants the article in PDF feel free to PM me with an email address to send it to.


(Hive Bee)
04-13-03 14:19
No 426272
      Nice! This compound seems to have some ...  Bookmark   


This compound seems to have some resemblence to Post 185131 (hest: "New Amph.  more potent than LSD", Serious Chemistry)
(Hive Bee)
04-13-03 20:17
No 426368
      Re: This compound seems to have some ...  Bookmark   

This compound seems to have some resemblence to hest: "New Amph.  more potent than LSD" (Serious Chemistry)

Yes, that is the first thing that came into my mind when I came across the article. smile


(Hive Bee)
04-13-03 20:59
No 426381
      Inactive  Bookmark   

The Nichols group has researched this compound previously. Haven't got the ref handy but it is mentioned in chapter 5 of The Heffter Review of Psychedelic Research, volume 1, 1998 by David Nichols, http://www.heffter.org/review/chapter5.pdf where they state that the compound is inactive. This is of course valuable information for scientists stuidying the 5-HT receptors but bad news for those who would wish to stimulate the receptors instead. Otherwise the link above makes a good read. I wholeheartedly recommend it to all the newbees dreaming about novel compounds because it explains what kind of interactions lie behind the activity of phenethylamine psychedelics.

EDIT: The original reference is J. Med. Chem., 40, 2997-3008 (1997)
(Chief Bee)
04-14-03 23:59
No 426697
      J. Med. Chem., 40, 2997-3008 (1997)  Bookmark   

J. Med. Chem., 40, 2997-3008 (1997) (../rhodium/pdf /nichols/nichols-dihydrobenzofuran-4-mescaline.pdf)