Domino reactions that combine an Azido-Schmidt ring expansion with the Diels-Alder reaction

Article abstract of DOI:10.1021/ol047809r

(Chemical Equation Presented) The combination of the intramolecular Schmidt reaction with the Diels-Alder reaction provides expedient access to a variety of heterocycles. Two different modes of reaction planning are presented. In one, the azide and ketone moieties necessary for the intramolecular Schmidt reaction originate on different molecules that are reacted and subsequently undergo a ring-adjustment step. Alternatively, an azido ketone can be used provided the ketone is deactivated by its presence in an enone.

Full text of DOI:10.1021/ol047809r

ORGANIC
LETTERS
2004
Vol. 6, No. 26
4993-4995
Domino Reactions That Combine an
Azido-Schmidt Ring Expansion with the
Diels−Alder Reaction
Yibin Zeng, D. Srinivasa Reddy, Erin Hirt, and Jeffrey Aube´*
Department of Medicinal Chemistry, 1251 Wescoe Hall DriVe, Room 4070,
Malott Hall, UniVersity of Kansas, Lawrence, Kansas 66045-7582
jaube@ku.edu
Received October 25, 2004
ABSTRACT
The combination of the intramolecular Schmidt reaction with the Diels−Alder reaction provides expedient access to a variety of heterocycles.
Two different modes of reaction planning are presented. In one, the azide and ketone moieties necessary for the intramolecular Schmidt
reaction originate on different molecules that are reacted and subsequently undergo a ring-adjustment step. Alternatively, an azido ketone can
be used provided the ketone is deactivated by its presence in an enone.
Domino reactions, which result from the combination of
multiple transformations in a single pot, are most valuable
when they efficiently afford complex products from simple,
readily available starting materials.1 The design of an
effective domino process involves control over the order of
the various steps that make up the overall transformation.
In seeking to develop streamlined heterocyclic syntheses
using the azido-Schmidt reaction, we have begun to explore
the combination of this useful ring expansion reaction with
“strategy-level” C-C bond-forming processes such as the
Diels-Alder reaction.
The azido-Schmidt reaction is the Lewis or protic acid-
promoted reaction of an alkyl azide with a ketone, affording
bicyclic lactam products.2,3 In this work, we concentrated
on rigging a domino sequence so that the azido-Schmidt
reaction would react with ketones revealed in situ by a Lewis
acid-promoted Diels-Alder reaction. Two conceptually
different ways of timing the individual reactions are shown
in Scheme 1. Since the intermolecular Schmidt reaction of
azides is substantially less facile than the intramolecular
version, one straightforward strategy is to segregate the
ketone and azide on the dienophile and diene, respectively,
and to use the Diels-Alder reaction bring the two pieces
together (Scheme 1a). Only then should a subsequent
intramolecular azido-Schmidt reaction take place.
Scheme 1
(1) For reviews of domino processes, see: (a) Ho, T.-L. Tandem
Reactions in Organic Synthesis; Wiley: New York, 1992. (b) Tietze, L.
F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131-163. (c)
Waldmann, H. Organic Synthesis Highlights II; Wiley-VCH: Weinheim,
1995; pp 193-202. (d) Tietze, L. F. Chem. ReV. 1996, 96, 115-136. (e)
Padwa, A. Chem. Commun. 1998, 1417-1424. (f) Tietze, L. F.; Modi, A.
Med. Res. ReV. 2000, 20, 304-322.
(2) (a) Aube´, J.; Milligan, G. L.; Mossman, C. J. J. Org. Chem. 1992,
57, 1635-1637. (b) Desai, P.; Schildknegt, K.; Agrios, K. A.; Mossman,
C.; Milligan, G. L.; Aube´, J. J. Am. Chem. Soc. 2000, 122, 7226-7232.
10.1021/ol047809r CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/19/2004

Scheme 2
Scheme 3
the cis-fused perhydroindole (6, 7) with good yields and high
diastereoselectivity. The relative stereochemistry of each
isolated heterocycle was confirmed by NOESY studies,
which show that the domino reaction proceeds through an
endo-selective Diels-Alder reaction followed by stereose-
lective Schmidt ring expansion. It is interesting to note that
reaction of 3 with acrolein gave both decahydroisoquinoline
(8) and perhydroindole (9) products, which result from
hydride migration or ring expansion, respectively (Scheme
3).
The enone deactivation method shown in Scheme 1b was
first examined using acylic azido enones 10 or 11,7 which
readily undergo tandem Diels-Alder/Schmidt reactions when
reacted with variously substituted dienes using MeAlCl2 as
a Lewis acid in DCM from 0 °C f room temperature
(Scheme 4). The products 12-16 are trans-hexahydroindoles
that would otherwise require a trans-enamide dienophile (and
subsequent ring closure) for their direct synthesis. It should
be noted that these hexahydroindoles are stereochemically
and constitutionally complementary to those obtained using
the first strategy (cf. 6 and 7 in Scheme 2 with 12-16).
Although 10 and 11 worked nicely in the above examples,
reaction of these enones with 1,3-cyclohexadiene afforded
only Diels-Alder adduct (17 and 18), presumably due to
the rigid trans disposition of the azide and ketone function-
alities in this product.
A less obvious method works by “deactivating” the ketone
functionality prior to Diels-Alder cycloaddition (Scheme
1b). We have shown that enones rarely undergo even
intramolecular azido-Schmidt reactions.4 Thus, an azide
attached to an R,â-unsaturated ketone will be reluctant to
attack the carbonyl group until conjugation has been
eliminated by the Diels-Alder reaction. In the example
shown, premature azido-Schmidt reaction is also less likely
due to the presence of an E double bond between the ketone
and azide. In this letter, we describe how both approaches
allow for efficient, single-step syntheses of a variety of
complex heterocycles.5
Some representative examples of the domino intermo-
lecular Diels-Alder/intramolecular Schmidt reactions as
exemplified in Scheme 1a are shown in Scheme 2.6 Initial
investigations using the unactivated azido diene 1 afforded
modest yields of cyclic lactams such as 2, but as expected,
better results were obtained using the more electron-rich
silyloxydiene 3. Of a limited set of Lewis acids examined,
the best results so far were obtained using the aluminum- or
tin-based reagents in DCM from -78 °C f room temper-
ature. It is worth noting that these reactions provide a highly
efficient synthesis of natural productlike skeleta such as
pyrroloisoquinolone (2, 4), azepinoindolone (5a, 5b), and
(6) There are many examples of domino reactions involving the Diels-
Alder reaction (see reviews listed in ref 1). Some recent examples include:
(a) Akai, S.; Tanimoto, K.; Kita, Y. Angew. Chem., Int. Ed. 2004, 43, 1407-
1410. (b) Sabitha, G.; Reddy, E. V.; Fatima, N.; Yadav, J. S.; Krishna, K.
V. S. R.; Kunwar, A. C. Synthesis 2004, 1150-1154. (c) Tietze, L. F.;
Rackelmann, N.; Mueller, I. Chem. Eur. J. 2004, 10, 2722-2731. (d) Tietze,
L. F.; Rackelmann, N. Z. Naturforsch. B: Chem. Sci. 2004, 59, 468-477.
(e) Yadav, J. S.; Reddy, B. V. S.; Narsimhaswamy, D.; Lakshmi, P. N.;
Narsimulu, K.; Srinivasulu, G.; Kunwar, A. C. Tetrahedron Lett. 2004, 45,
3493-3497. (f) Raw, S. A.; Taylor, R. J. K. J. Am. Chem. Soc. 2004, 126,
12260-12261.
(3) (a) Aube´, J.; Milligan, G. L. J. Am. Chem. Soc. 1991, 113, 8965-
8966. (b) Milligan, G. L.; Mossman, C. J.; Aube´, J. J. Am. Chem. Soc.
1995, 117, 10449-10459.
(4) Reddy, D. S.; Judd, W. R.; Aube´, J. Org. Lett. 2003, 5, 3899-3902.
(5) A single example of an intramolecular variant of an analogous reaction
to that shown in Scheme 1b was published in the context of a total synthesis
of stenine: Golden, J. E.; Aube´, J. Angew. Chem., Int. Ed. 2002, 41, 4316-
4318. To our knowledge, this is the only example of a tandem process
involving any variation of the Schmidt reaction prior to the present work.
(7) All azides and other starting materials were prepared using standard
methods; see Supporting Information for details. All azides should be used
with caution!
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Org. Lett., Vol. 6, No. 26, 2004

Scheme 4
Scheme 5
cesses. In particular, we note the diversity of ring systems
and substitution types obtained using these one-pot methods.
Importantly, this concept can be extended to encompass other
Lewis acid-promoted reactions such as the Mukaiyama aldol
and Sakurai reactions; our preliminary work in these areas
will be submitted for publication in due course. Future work
will apply these reactions to both target- and diversity-
oriented synthesis projects.
Acknowledgment. We thank the National Institutes of
Health (GM-49093) for support of this work. The authors
also thank Douglas Powell for X-ray crystallographic
analyses (the X-ray apparatus was acquired through NSF
CHE-0079282) and David Vander Velde and Sarah Neuen-
swander for assistance with the NMR spectroscopy
Finally, the cyclic azido enone 197 readily underwent
domino Diels-Alder/Schmidt reactions to give homopyrrolo-
[2,1-j]quinolin-5-ones (20-22) in excellent yields as outlined
in Scheme 5. The structure of 22 was confirmed by X-ray
crystallographic analysis.
In summary, we have investigated two conceptually
different ways to combine the azido-Schmidt ring expansion
with the Diels-Alder reaction. These experiments highlight
the potential of the azido-Schmidt reaction when enhanced
by its combination with other Lewis acid-promoted pro-
Supporting Information Available: Experimental pro-
cedures and characterization of compounds (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL047809R
Org. Lett., Vol. 6, No. 26, 2004
4995