Synthesis of a tricyclic mescaline analogue by catalytic C-H bond activation

Article abstract of DOI:10.1021/ol034228d

(Matrix presented) 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 b

Full text of DOI:10.1021/ol034228d

ORGANIC
LETTERS
2003
Vol. 5, No. 8
1301-1303
Synthesis of a Tricyclic Mescaline
Analogue by Catalytic C−H Bond
Activation
Kateri A. Ahrendt, Robert G. Bergman,* and Jonathan A. Ellman*
Center for New Directions in Organic Synthesis, Department of Chemistry and
DiVision of Chemical Sciences, Lawrence Berkeley National Laboratory,
UniVersity of California, Berkeley, California 94720
bergman@cchem.berkeley.edu; jellman@uclink.berkeley.edu
Received February 7, 2003
ABSTRACT
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 hal-
lucinogenic 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
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 com-
petitive 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) functional-
ity 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 re-
The synthesis and biological activities of mescaline
analogues 2 and 3 (Figure 1), in which one or two of the
(1) Heffter, A. Chem. Ber. 1896, 29, 216.
(2) (a) Nichols, D. E. In Amphetamine and Its Analogues; Cho, A. K.,
Segal, D. S., Eds.; Academic Press: San Diego, CA, 1994; pp 3-41. (b)
Nichols, D. E.; Glennon, R. A. In Hallucinogens: Neurochemical,
BehaVioral, and Clinical PerspectiVes; Jacobs, B. L., Ed.; Raven Press:
New York, 1984; pp 95-142.
(3) (a) Aghajanian, G. K.; Marek, G. J. Neuropsychopharmacology 1999,
21, 16S. (b) Appel, J. B.; Callahan, P. M. Eur. J. Pharmacol. 1989, 159,
41. (c) Titeler, M.; Lyon, R. A.; Glennon, R. A. Psychopharmacology 1988,
94, 213. (d) Rasmussen, K.; Aghajanian, G. K. Brain Res. 1986, 385, 395.
(4) Roth, B. L.; Willins, D. L.; Kristiansen, K.; Kroeze, W. K. Pharmacol.
Ther. 1998, 79, 231 and references therein.
Figure 1. Mescaline (1) and dihydrobenzofuran and tetrahydrobis-
(benzofuran) analogues 2 and 3.
(5) (a) Roth, B. L.; Shapiro, D. A. Expert Opin. Ther. Targets 2001, 5,
685. (b) Stefanski, R.; Goldberg, S. R. CNS Drugs 1997, 7, 388.
10.1021/ol034228d CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/22/2003

ported.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 acti-
vation followed by olefin insertion provides access to func-
tionalized indanes, tetralanes, dihydroindoles, and dihydro-
benzofurans.10 Herein we report the application of our annula-
tion strategy to the concise synthesis of the conformationally
restricted tetrahydrobis(benzofuran) mescaline analogue 3.
Our approach to 3 was based on the elaboration of inter-
mediate 8 (Scheme 1), obtained from the rhodium-catalyzed
Scheme 2
Scheme 1
reaction time and temperature, concentration, catalyst load-
ing, 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.
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
tandem cyclization reaction of aromatic imine 7. Precursor
7 was prepared from (4′-O-methyl)methyl gallate 4.
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.
Scheme 3
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 Unfor-
tunately, 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
(6) Monte, A. P.; Waldman, S. R.; Marona-Lewicka, D.; Wainscott, D.
B.; Nelson, D. L.; Sanders-Bush, E.; Nichols, D. E. J. Med. Chem. 1997,
40, 2997.
(7) Competition studies employed the agonist ligands [125I]DOI and [3H]-
seratonin, and antagonist ligands [3H]ketanserin, [3H]rauwolscine, and [3H]-
mesulergine.
(8) For examples of the application of C-H bond activation in target-
oriented synthesis, see: (a) Harris, P. W. R.; Woodgate. P. D. J. Organomet.
Chem. 1997, 530, 211. (b) Johnson, J. A.; Sames, D. J. Am. Chem. Soc.
2000, 122, 6321. (c) Dangel, B. D.; Godula, K.; Youn, S. W.; Sezen, B.;
Sames, D. J. Am. Chem. Soc. 2002, 124, 11856. (d) Wehn, P. M.; Du Bois,
J. J. Am. Chem. Soc. 2002, 124, 12950.
imine 7 by treatment with benzylamine in the presence of
molecular sieves.
(9) For examples of the application of rhodium-carbenoid insertions
into C-H bonds in target-oriented synthesis, see: (a) Taber, D.; Song, Y.
J. Org. Chem. 1997, 62, 6603. (b) Davies, H. M. L.; Stafford, D. G.; Hansen,
T. Org. Lett. 1999, 1, 233. (c) Davies, H. M. L.; Gregg, T. M. Tetrahedron
Lett. 2002, 43, 4951 and references therein.
(10) Thalji, R. K.; Ahrendt, K. A.; Bergman, R. G.; Ellman, J. A. J.
Am. Chem. Soc. 2001, 123, 9692.
(11) 4-Methoxy-3,5-bis-hydroxy-benzoic acid methyl ester is prepared
by alkylation of commercially available methyl benzoate. Cardona, M. L.;
Fernandez, M. I.; Garcia, M. B.; Pedro, J. R. Tetrahedron 1986, 42, 2725.
(12) Okimoto, Y.; Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc. 2002, 124,
1590.
(13) Blouin, M.; Frenette, R. J. Org. Chem. 2001, 66, 9043.
1302
Org. Lett., Vol. 5, No. 8, 2003

To effect the tandem cyclization reaction, we first exam-
ined conditions that we had previously used for the annu-
lation of alkene-substituted aromatic imines. Unfortunately,
Wilkinson’s catalyst provided only low yields of the desired
tetrahydrobis(benzofuran) product after extended heating, as
Scheme 4
1
determined by H NMR experiments (Table 1, entry 1).
Table 1. Optimization of the Tandem C-H Activation/Olefin
Insertion Reaction
NMR
yield (%)b
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.
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.
entry
Rh catalysta
(PPh3)3RhClc
P(t-Bu)3, [RhCl(coe)2]2
P(n-Pr)3, [RhCl(coe)2]2
PCy3, [RhCl(coe)2]2
FcPPh2, [RhCl(coe)2]2
F cP Cy2,[Rh Cl(coe)2]2
FcPCy2, [RhCl(coe)2]2
time (h)
1
2
3
4
5
6
7
20
3
17
8
4
2
10
0
18
48
34
75
52
d
5
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.
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
Acknowledgment. This work was supported by the
National Institutes of Health Grant GM50353 (to J.A.E.),
and by the Director, Office of Energy Research, Office of
Basic Energy Sciences, Chemical Sciences Division, U.S.
Department of Energy, under Contract No. DE-AC03-
76SF00098 (to R.G.B). K.A.A. thanks Pharmacia for a
graduate fellowship. The Center for New Directions in
Organic Synthesis is supported by Bristol-Myers Squibb as
a sponsoring member and Novartis as a supporting member.
Supporting Information Available: Experimental pro-
cedures and characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Abe, T.; Haga, T.; Negi, S.; Morita, Y.; Takayanagi, K.; Hamamura,
K. Tetrahedron 2001, 57, 2701.
(15) [RhCl(coe)2]2 is commercially available from Aldrich Chemical Co.,
though for these studies it was prepared in one step from RhCl3‚(H2O)3
and cyclooctene: van der Ent, A.; Onderdelinden, A. L. Inorg. Synth. 1973,
14, 92.
OL034228D
(17) No starting material or side products were isolated after silica gel
chromatography. The remaining material is attributed to intractable mixtures
of oligomers or polymers. Lowering the concentration of the reaction
improved the product yield.
(16) Lowering the catalyst loading to 5 mol % of [RhCl(coe)2]2 resulted
in reduced product yield (60% NMR yield).
Org. Lett., Vol. 5, No. 8, 2003
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