Intramolecular electrophilic aromatic substitution reactions of 2-amidoacroleins: a new method for the preparation of tetrahydroisoquinolines, tetrahydro-3-benzazepines, and hexahydro-3-benzazocines.

Article abstract of DOI:10.1021/ol016592n

[reaction: see text]. A variety of heterocyclic ring systems can be prepared by subjecting N-aryl-substituted 5-amido-1,3-dioxins to Lewis acids. The reactions proceed via catalyzed retrocycloadditions to afford 2-amidoacroleins and concomitant regioselec

Full text of DOI:10.1021/ol016592n

ORGANIC
LETTERS
2001
Vol. 3, No. 21
3349-3351
Intramolecular Electrophilic Aromatic
Substitution Reactions of
2-Amidoacroleins: A New Method for
the Preparation of
Tetrahydroisoquinolines,
Tetrahydro-3-benzazepines, and
Hexahydro-3-benzazocines
James R. Fuchs and Raymond L. Funk*
Department of Chemistry, PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
rlf@chem.psu.edu
Received August 15, 2001
ABSTRACT
A variety of heterocyclic ring systems can be prepared by subjecting N-aryl-substituted 5-amido-1,3-dioxins to Lewis acids. The reactions
proceed via catalyzed retrocycloadditions to afford 2-amidoacroleins and concomitant regioselective electrophilic aromatic substitution reactions.
The transformation is also successful using dioxins with amides that are within the incipient ring to afford the analogous lactams.
The â-phenethylamine pharmacophore is present in numerous
biologically active compounds either in its acyclic form or
embodied in polycyclic frameworks.1 The diverse biological
properties of these compounds has stimulated the develop-
ment of extensive methodology for their preparation. We
envisaged a conceptually new approach to these compounds
based upon our recently reported synthesis of 2-amidoac-
roleins via retrocycloaddition reactions of 5-amido-1,3-
dioxins.2 We had previously employed these reactants as
dienophiles or heterodienes in natural product synthesis
endeavors and have continued to exploit their excellent
reactivity properties in reactions other than cycloadditions.
In the case at hand (Scheme 1), it was hoped that Lewis
acid activated amidoacroleins 2 and 5, generated from the
corresponding dioxins 1 and 4, respectively, might serve as
the electrophilic components in a variety of intramolecular
electrophilic aromatic substitution reactions.3,4 The products
that emerge from this transformation, amides 3 and lactams
6, both contain the desired â-phenethylamine substructure
but differ by the location of the amide carbonyl, versatility
that is of value for strategic bond construction(s) in projected
total synthesis applications. Herein we report on the scope
and limitations of this new methodology and document its
usefulness in the preparation of novel morphine analogues.
The various protocols that have been developed for the
preparation of the requisite 5-amido-1,3-dioxins are shown
in Scheme 2. Treatment of 1,3-dioxin-5-one5 (7) with primary
amines in the presence of 4 Å molecular sieves afforded the
corresponding imines 8. This condensation proceeds at a
faster rate in chloroform, although it is more convenient to
(1) (a) Bentley, K. W. Nat. Prod. Rep. 2001, 18, 148 and previous reviews
therein. (b) The Merck Index, 12th ed.; Budavari, S., Ed.; Merck & Co.,
Inc.: Whitehouse Station, NJ, 1996.
(2) (a) Maeng, J.-H.; Funk, R. L. Org. Lett. 2000, 3, 1125. (b) Funk, R.
L.; Greshock, T. J., submitted for publication.
10.1021/ol016592n CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/12/2001

Scheme 1
Table 1. Intramolecular Electrophilic Aromatic Substitution
Reactions of 2-Amidoacroleins Generated in Situ from
5-Amido-1,3-dioxins
use toluene since it is the preferred solvent for the subsequent
enamide formation. Thus, either anhydrides and diisopro-
pylethylamine (Table 1, entries 1, 2, and 3) or acid chlorides
and lutidine (entries 4, 8, and 9) are added to the toluene
solution of imines to afford the desired 5-amido-1,3-dioxins
in good yields. 5-Triflamido-1,3-dioxins 10 can also be
prepared by addition of triflic anhyride and diisopropylethy-
lamine to the corresponding imine (Table 1, entry 6). When
the N-(m-methoxyphenethyl)imine 8 was subjected to these
conditions, none of the desired dioxin (cf. entry 5) was
isolated. Instead, a product derived from a competitive
Pictet-Spengler cyclization of the presumed trifluorometh-
ylsulfonyl iminium ion intermediate was obtained. Accord-
ingly, the N-benzyl triflamide 10 (R1 ) Bn) was hydroge-
nated with Pearlman’s catalyst to afford triflamide 11, which
in turn could be smoothly alkylated6 with alkyl halides to
establish an alternative route to 5-triflamido-1,3-dioxins 10
(entries 5 and 7).
We were pleased to discover that the 5-amido-1,3-dioxins
shown in Table 1 underwent facile Lewis acid catalyzed
retrocycloadditions to 2-amidoacroleins and concomitant,
albeit slower, regioselective cyclization to a variety of
heterocyclic ring systems. These cyclizations are especially
Scheme 2
3350
Org. Lett., Vol. 3, No. 21, 2001

noteworthy considering that none of the previously reported
examples of intramolecular electrophilic aromatic substitution
reactions employ unsaturated aldehydes as the electrophile3
and only one cyclization of an unsaturated carbonyl com-
pound that lacked carbocation stabilizing groups on the
â-carbon (a 7-endo ketone) has been reported.3h Thus, as
we had planned, the amide moiety may be exo to the incipient
ring (entries 1-7) or endo to afford lactams (entries 8 and
9). To date, a tetrahydroisoquinoline (entry 1), as well as
3-benzazepines (entries 2-5 and 8) and 3-benzazocines
(entries 6 and 9) have been prepared using this method. The
reaction times indicate that a seven-membered ring closure
is preferred over the six- and eight-membered counterparts
(entry 2 vs. entry 1 and entry 8 vs. entry 9) in keeping with
molecular modeling that suggests a more accessible Wheland
intermediate for a seven-membered closure. Not surprisingly,
the cyclizations with the more electron-withdrawing trifla-
midoacroleins are more facile than the acetamido or benz-
amido variants and, consequently, can be catalyzed with a
milder Lewis acid (SnCl4) in substoichiometric quantities
(entry 5 vs. entries 2 and 4). Moreover, activated aromatic
rings are not essential for successful cyclization, although
more forcing conditions are required (entry 3 vs. entry 2).
Finally, the example shown in entry 7 demonstrates that
aromatic ring systems other than substituted benzenes
participate in this type of cyclization en route to uncommon
heterocyclic ring systems.
Scheme 3
moiety and removal of the triflamide group6 was ac-
complished by treatment of benzazocine 12 with lithium
aluminum hydride. The resulting secondary amine was
methylated using the standard reductive amination protocol,
and the methyl ether of the product 13 was cleaved with
boron tribromide to provide morphine analogue 14. Morphine
analogue 16 was obtained by initial decarbonylation of
benzazocine 12 using the Wilkinson reagent in refluxing
xylene to afford the triflamide 15, which was then subjected
to the same three-step sequence used to prepare analogue
14.8
In summary, we have shown that intramolecular aromatic
substitution reactions of amidoacroleins constitute a new
strategy for preparing heterocyclic compounds that embody
the biologically significant â-phenethylamine substructure.
The three-component aspect of this methodology, i.e., 1,3-
dioxin-5-one, primary amine, and acylating/sulfonylating
agent, makes it readily adaptable to natural product total
synthesis endeavors. Several possibilities are under consid-
eration and will be reported in due course.
To demonstrate that this methodology is indeed capable
of providing compounds possessing â-phenethylamine phar-
macophores, the product of entry 6, benzazocine 12 (Scheme
3), was converted to the new morphine analogues 14 and
16.7 To that end, simultaneous reduction of the aldehyde
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W. S.; Komaki, Y.; Sano, S.; Shiro, M. Chem. Lett. 1994, 597. (i) Ho,
T.-L.; Yang, P.-F. Tetrahedron 1995, 51, 181. exo carbonyl (j) Stork, G.;
Burgstahler, A. J. Am. Chem. Soc. 1951, 73, 3544. (k) Murphy, W. S.;
Watanasin, S. J. Chem. Soc., Perkin Trans. 1 1980, 1555. (l) Jung, M. E.;
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(4) For the photocyclization of a 2-(benzamido)acrylates, see: (a) Schultz,
A. G.; Sha, C.-K. Tetrahedron 1980, 36, 1757. (b) Naito, T.; Ninomiya, I.
Heterocycles 1988, 27, 1325. (c) Pyne, S. G.; Schafer, K. Tetrahedron 1998,
54, 5709. For the intramolecular Heck reactions of 2-{N-[(iodoaryl)alkyl]-
N-(tert-butoxycarbonyl)-amino}acrylates, see: (d) Gibson, S. E.; Guillo,
N.; Middleton, R. J.; Thuilliez, A.; Tozer, M. J. J. Chem. Soc., Perkin Trans.
1 1997, 447.
(5) Prepared in two steps from tris(hydroxymethyl)aminomethane hy-
drochloride. Hoppe, D.; Schmincke, H.; Kleemann, H.-W. Tetrahedron
1989, 45, 687.
Acknowledgment. We appreciate the financial support
provided by the National Institutes of Health (GM28553).
Supporting Information Available: Spectroscopic data
and experimental details for the preparation of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL016592N
(7) 3-Benzazocine analogues of morphine similar to 16 but lacking the
dihydrofuran ring have been previously reported; see: (a) Pecherer, B.;
Stumpf, J.; Brossi, A. HelV. Chim. Acta 1970, 53, 763. (b) Hori, M.;
Kataoka, T.; Shimizu, H.; Imai, E.; Koide, T.; Iwata, N.; Kurono, M. Chem.
Pharm. Bull. 1990, 38, 8. (c) Lai, B.; Bhedi, D. N.; Gidwani, R. M.; Sankar,
C. Tetrahedron 1994, 50, 9167 and ref 1 therein. Moreover, molecular
mechanics calculations suggest that the dihydrofuran ring as well as the
hydroxymethyl substituent of 14 contribute to the significant population of
the morphine-like conformer shown (0.75 kcal/mol above global minimum,
8% of a Boltzmann distribution of all conformers at 300 °K).
(6) Hendrickson, J. B.; Bergeron, R.; Sternbach, D. D. Tetrahedron 1975,
31, 2517. (b) Hendrickson, J. B.; Bair, K. W.; Bergeron, R.; Giga, A.;
Skipper, P. L.; Sternbach, D. D.; Wareing, J. A. Org. Prep. Proced. Int.
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(8) Benzazocines 14 and 16 have been submitted for biological evalu-
ation. These studies will be reported separately.
Org. Lett., Vol. 3, No. 21, 2001
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