A CAN-Induced Cyclodimerization - Ritter Trapping Strategy for the One-Pot Synthesis of 1-Amino-4-aryltetralins from Styrenes

Article abstract of DOI:10.1021/ol0257934

(matrix presented) A facile one-pot synthesis of 1-amino-4-aryl-tetralin derivatives by the CAN-induced cyclodimerization of various styrenes in acetonitrile and acrylonitrile is described.

Full text of DOI:10.1021/ol0257934

ORGANIC
LETTERS
2002
Vol. 4, No. 9
1575-1577
A CAN-Induced Cyclodimerization−Ritter
Trapping Strategy for the One-Pot
Synthesis of 1-Amino-4-aryltetralins
from Styrenes†
Vijay Nair,* Roshini Rajan,‡ and Nigam P. Rath§
,‡
Organic Chemistry DiVision, Regional Research Laboratory (CSIR), TriVandrum,
India, and Department of Chemistry, UniVersity of Missouri, St. Louis, Missouri 63121
gVn@csrrltrd.ren.nic.in
Received February 28, 2002
ABSTRACT
A facile one-pot synthesis of 1-amino-4-aryl-tetralin derivatives by the CAN-induced cyclodimerization of various styrenes in acetonitrile and
acrylonitrile is described.
Ever since the pioneering work of Heiba and Dessau on
cerium(IV) ammonium nitrate (CAN)-mediated carbon-
carbon bond forming reactions there has been a number of
studies in this area.1 Our own investigations have uncovered
some novel reactions including a dimerization of alkoxy-
styrenes mediated by CAN.2 Intrigued by the possibility that
an R-aminotetralin derivative may be formed by the cy-
clodimerization of styrenes if the reaction takes place in an
environment conducive for the termination of the reaction
by the Ritter trapping of the cationic intermediate, we
exposed an acetonitrile solution of 4-methylstyrene 1a to
CAN in an argon atmosphere. In the event, a facile reaction
occurred and the R-acetamido tetralins cis-2a and trans-2a
were obtained (Scheme 1).
Scheme 1
* Fax: +91-471-491712.
† This paper is dedicated with respect and affection to Professor Gilbert
Stork, a legend in his own time, for the gift of chemistry he has given to
hundreds of students during the past six decades.
‡ Regional Research Laboratory (CSIR).
§ University of Missouri.
(1) (a) Heiba, E. I.; Dessau, R. M. J. Am. Chem. Soc. 1971, 93, 524. (b)
Baciocchi, E.; Civataresse, G.; Ruzziconi, R. Tetrahedron Lett. 1987, 28,
5357. (c) Nair, V.; Mathew, J.; Prabhakaran, J. Chem. Soc. ReV. 1997, 127.
(2) (a) Nair, V.; Mathew, J.; Kanakamma, P. P.; Panicker, S. B.; Zeena,
S.; Sheeba, V.; Eigendorf, G. K. Tetrahedron Lett. 1997, 38, 2191. (b) Nair,
V.; Sheeba, V.; Panicker, S. B.; George, T. G.; Rajan, R.; Balagopal, L.;
Vairamani, M.; Prabhakar, S. Tetrahedron 2000, 56, 2461.
It is noteworthy that R-aminotetralin derivatives manifest
a number of important and therapeutically useful biological
10.1021/ol0257934 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/27/2002

activities; some of them are potent CNS stimulants and others
are antibiotics, immunomodulators, and antitumor agents.3
Special mention may be made of the top selling antide-
pressant sertraline 3 (Figure 1).4
Table 1. Dimerization of Various Styrenes To Afford
R-Acetamido Tetralin Derivatives
Figure 1. Sertraline.
In view of the potent biological activities of such R-ami-
notetralin derivatives by virtue of their structural similarity
to sertraline, the mechanistic implication of the reaction, and
the facility with which cis-2a and trans-2a are formed, it
was obligatory for us to investigate the reaction in some
detail.5 Our preliminary results are presented here.
As already mentioned, in a pilot experiment, 4-methyl-
styrene on treatment with CAN in acetonitrile in a totally
oxygen-free atmosphere afforded the R-acetamido tetralins
cis-2a and trans-2a in 62% yield as diastereomers in the
ratio 1.3:1 (Scheme 1). The R-acetamido tetralin cis-2a was
1
characterized on the basis of spectroscopic data. In the H
NMR spectrum, the methyl group of the amide moiety
resonated as a singlet at δ 2.02 while the two methyl groups
on the aromatic rings resonated as two singlets at δ 2.19
and 2.34. The doubly benzylic proton was seen as a multiplet
at δ 3.97-3.99 (for trans-2a this proton was seen in the range
δ 4.03-4.06). The benzylic proton attached to nitrogen
resonated as a multiplet at δ 5.13-5.15 (for trans-2a this
proton resonated at δ 5.25-5.27). The NH proton resonated
at δ 5.84, supporting the IR absorption at 3301 cm-1. The
13C signal for the amide carbonyl was seen at δ 168.99.
Finally, the configuration of the major diastereomer was
ascertained to be cis by single-crystal X-ray analysis (see
Supporting Information).
a Structure of the major isomer is shown. b Determined by HPLC analysis
c Combined isolated yield of both isomers.
Analogous results were obtained with a number of other
styrenes, and the results are summarized in Table 1.
A mechanistic rationale for the formation of the R-aceta-
mido tetralins is presented in Scheme 2. The styrene 1 in
the presence of Ce(IV) undergoes oxidative electron transfer
to afford the radical cation I, which in turn would add to
another styrene molecule to generate a distonic radical cation
II. This 1,4 radical cation undergoes 1,6 cyclization to give
a substituted hexatriene radical cation III, which on losing
a proton yields the radical intermediate IV.6,7 The radical
intermediate IV undergoes oxidation to a cation V, which
(3) Lautens, M.; Rovis, T. Tetrahedron 1999, 55, 8967 and references
therein.
(4) (a) Welch, W. M.; Kraska, A. R.; Sarges, R.; Koe, B. K. J. Med.
Chem. 1984, 27, 1508. (b) U.S. Patent 5,442,116, 1995. (c) Koe, B. K.;
Weisman, A.; Welch, W. M.; Broune, R. G. J. Pharmacol. Exp. Ther. 1983,
226, 686. (d) William, M.; Quallich, G. Chem. Ind. (London) 1990, 10,
315. (e) Corey, E. J.; Gant, T. G. Tetrahedron Lett. 1994, 35, 5373. (f)
Chen, C.; Reamer, R. A. Org. Lett. 1999, 1, 293. (g) Davies, H. M. L.;
Stafford, D. G.; Hansen, T. Org. Lett. 1999, 1, 233.
(5) It may be mentioned that Baciocchi et al. have reported the formation
of dinitrates from styrenes when the latter were treated with CAN in
acetonitrile under photochemical or thermal conditions, the yields being
quantitative in the latter case (Baciocchi, E.; Rol, C.; Giacco, D.; Murgia,
S. M.; Sebastiani, G. V. Tetrahedron 1988, 44, 6651. Baciocchi, E.; Rol,
C.; Sebastiani, G. V.; Zampini, A. J. Chem. Soc., Chem. Commun. 1982,
1045).
(6) Bauld, N. L. Tetrahedron 1989, 45, 5307.
(7) Schepp, N. P.; Johnston, L. J. J. Am. Chem. Soc. 1996, 118, 2872.
1576
Org. Lett., Vol. 4, No. 9, 2002

Scheme 2
Scheme 4
subsequently gets trapped by the solvent acetonitrile in a
manner analogous to the Ritter reaction.8,9
Interestingly, when styrenes 1a-d were treated with CAN
employing acrylonitrile as the reaction medium, the corre-
sponding R-acrylamido tetralin derivatives cis-4a-d and
trans-4a-d were obtained (Scheme 3).
Vinyl naphthalenes 1g and 1h also afforded the corre-
sponding R-acrylamido tetralin derivatives under the above
conditions (Scheme 4).
In conclusion, we have devised a novel and expeditious
one-pot synthesis of R-aminotetralin derivatives that bear
close resemblance to potent therapeutic agents. Further work
to unravel the reaction mechanism, to expand the scope of
the reaction, and to devise asymmetric synthesis are in
progress; the results will be reported in due course.
Acknowledgment. R.R. thanks Council of Scientific and
Industrial Research, New Delhi, for a research fellowship.
Scheme 3
Supporting Information Available: General experimen-
1
tal procedures, IR, H NMR, and 13C NMR data for all
compounds and single-crystal X-ray structure for cis-2a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0257934
(8) (a) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045. (b)
Krimen, L. I.; Cota, D. J. Org. React. 1969, 17, 213. (c) ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 6, 1.9, p 261.
(9) The oxidative ligand transfer leading to the formation of a benzylic
nitrate and its intermediacy may also be considered as a possibility; this
insight was provided by a referee.
Org. Lett., Vol. 4, No. 9, 2002
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