Diastereoselective Benzylic Arylation of Tetralins
COMMUNICATION
atic under the previous protocol, such as a dimethoxy deriv-
ative 5k (Table 4, entry 12) were reactive giving the desired
trans-product in excellent yield. In addition, this protocol
allows reactions involving more sensitive nucleophiles, such
as furan (Table 4, entry 7) and greater regioselectivity was
observed. It is worth noting that while two equivalents of
AlCl3 were used in this study, it was subsequently shown
that the reaction to produce tetralin 7ek was also successful
in the presence of one equivalent of AlCl3 (Table 4, entry 3).
This result supports the notion that two equivalents of the
Lewis acid are generally required to counteract coordination
of the acid to amino groups present at the 2-position of the
tetralin substrates.
Following the development of successful protocols for the
trans-selective benzylic arylation of racemic tetralin systems,
the Friedel–Crafts reaction conditions were applied to the
phthalimide-tetralin substrate 5e, which was prepared in an
enantioselective fashion (ee of the rhodium(I)-catalysed
ring-opening product determined to be 98%). Thus, follow-
ing hydrogenation of the alkene functionality, and reaction
with veratrole under the optimised Friedel–Crafts condi-
tions, the enantiomeric excess of the product tetralin 7ek
was determined to be 97% (Scheme 4). Therefore, the two-
step reaction sequence does not result in a loss in the enan-
tiomeric purity of the sample.
such instances, we propose that the nitrogen atom on the ad-
jacent carbon atom to the in situ generated carbocation spe-
cies may coordinate to this site, shielding this face from nu-
cleophilic attack, and therefore resulting in the formation of
the trans-product. Further investigations into the mechanism
of this reaction are underway.
To further demonstrate the utility of these trans-selective
Friedel–Crafts procedures, compound 7ek was treated with
hydrazine to afford the primary amine, which upon treat-
ment with paraformaldehyde in formic acid, underwent a
one-pot Pictet–Spengler/Eschweiler–Clarke methylation re-
action to give the tetracyclic tertiary amine compound 9
(Scheme 6). The core of this compound bears similarity to
the pharmaceutically relevant compounds shown in
Scheme 2.
Scheme 6. Synthesis of tetracyclic amine 9.
In summary, we have developed Friedel–Crafts protocols
for the intermolecular, trans-selective benzylic arylation of
tetralin systems. Attractive features of these protocols are
the broad substrate scope, ease, and scalability of the reac-
tions. Furthermore, the use of enantiopure substrates allows
the preparation of the trans-aryl-substituted tetralins in high
ee. Further investigations into the mechanism of this reac-
tion and expansion on the scope of the reaction are under-
way.
Scheme 4. Preparation of tetralin 7ek in high enantiopurity.
To probe the mechanism of this trans-selective Friedel–
Crafts reaction, the cis-tetralin substrate 8 was prepared and
subjected to the reaction conditions with toluene as nucleo-
phile (Scheme 5). As expected, the trans-product 7aa was
isolated, thus supporting the idea of an intermediate benzyl-
ic carbocation species. While there is no doubt that steric
factors would favour the formation of the trans-product, the
exclusive formation of the trans-compounds, especially in
the case of the non-congested free amine substrate suggests
that additional factors may be involved (Table 2, entry 6). In
Acknowledgements
This work is supported by the Natural Sciences and Engineering Re-
search Council of Canada (NSERC), the Merck Frosst Centre for Thera-
peutic Research and the University of Toronto. We thank Solvias AG for
the supply of a rhodium catalyst and chiral ligands and for initial support
of this study. M.D. thanks the French ꢁMinistꢂre des Affaires Etrangꢂresꢃ
(Bourse Lavoisier). All studies were conducted at the University of Tor-
onto.
Keywords: alkylation · benzylic alcohols · carbocations ·
diastereoselectivity · electrophilic aromatic substitution
[1] a) K. Mertins, I. Iovel, J. Kischel, A. Zapf, M. Beller, Angew. Chem.
Scheme 5. Reaction of cis-tetralin 8 with toluene.
Chem. Eur. J. 2010, 16, 50 – 54
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