Tandem double intramolecular [4 + 2]/[3 + 2] cycloadditions of nitroalkenes

Article abstract of DOI:10.1021/ol016385n

(equation presented) A new class of tandem [4 + 2]/[3 + 2] cycloadditions of nitroalkenes is described in which both pericyclic processes are intramolecular. Two subclasses of intra [4 + 2]/intra [3 + 2] cycloadditions have been explored in which the dipo

Full text of DOI:10.1021/ol016385n

ORGANIC
LETTERS
2001
Vol. 3, No. 18
2907-2910
Tandem Double Intramolecular
[4 + 2]/[3 + 2] Cycloadditions of
Nitroalkenes
Scott E. Denmark* and Laurent Gomez
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois,
Urbana, Illinois 61801
denmark@scs.uiuc.edu
Received July 4, 2001
ABSTRACT
A new class of tandem [4 + 2]/[3 + 2] cycloadditions of nitroalkenes is described in which both pericyclic processes are intramolecular. Two
subclasses of intra [4 + 2]/intra [3 + 2] cycloadditions have been explored in which the dipolarophile is tethered at either C(5) or C(6) of the
nitronate. For both families of precursors, the cycloadditions occur in good yield and are found to be highly regio- and stereoselective. This
method converts linear polyenes to functionalized polycyclic systems bearing up to six stereogenic centers.
In recent years, the application of tandem reactions has
emerged as a rapid and powerful strategy for the construction
of highly functionalized compounds with high levels of
regio-, diastereo-, and enantiocontrol.1 In these laboratories,
the tandem cycloaddition of nitroalkenes has been investi-
gated as a general approach for the synthesis of various
nitrogen-containing polycyclic compounds.2 The structural
diversity of the tandem [4 + 2]/[3 + 2] cycloaddition
sequence derives from the number of permutations possible
for attachment of the various components (dienophile and
dipolarophile) to the nitroalkene as well as the length of the
tethers. Among these different permutations, both the intra/
inter3 as well as the inter/intra4 tandem [4 + 2]/[3 + 2]
nitroalkene cycloaddition have been extensively documented.
We have begun studies of a new variation on the tandem
sequence, namely, the family of intra [4 + 2]/intra [3 + 2]
cycloadditions. Because of the complementary electronic
demands of the nitroalkene and intermediate nitronate, the
presence of two alkenes in the molecule is not a complication.
Among the different possibilities for dipolarophile attach-
ment, we focused our initial studies on the subclass called
the fused/bridged mode wherein the dipolarophile is tethered
at the C(6) or C(5) position of the nitronate, i.e., the two
ends of the dienophile (i and iv, Scheme 1). The process
involves the Lewis acid promoted intramolecular [4 + 2]
cycloaddition of these nitroalkenes to produce cycloadducts
ii and v. These nitronates are poised to undergo thermal,
intramolecular [3 + 2] cycloaddition to afford unusual
tetracyclic nitroso acetals iii and vi. In this Letter, we report
(1) (a) Ho, T.-L. Tandem Organic Reactions; Wiley: New York, 1992.
(b) Ziegler, F. E. In ComprhensiVe Organic Synthesis, Combining C-C
p-Bonds; Paquette, L. A., Ed.; Pergamon Press: Oxford, 1991; Vol. 5,
Chapter 7.3. (c) Tietze, L. F.; Beifuss, U. A. Angew. Chem., Int. Ed. Engl.
1993, 32, 131. (d) Grigg, R., Ed. Cascade Reactions; Tetrahedron
Symposium in Print; Elsevier: New York, 1996; No. 62.
(2) (a) Denmark, S. E.; Thorarensen, A. Chem. ReV. 1996, 96, 137. (b)
Denmark, S. E.; Thorarensen, A.; Middleton, D. S. J. Am. Chem. Soc. 1996,
118, 8266. (c) Denmark, S. E.; Thorarensen, A. J. Am. Chem. Soc. 1997,
119, 125. (d) Denmark, S. E.; Hurd, A. R.; Sacha, H. J. J. Org. Chem.
1997, 62, 1668. (e) Denmark, S. E.; Marcin, L. R. J. Org. Chem. 1997, 62,
1675. (g) Denmark, S. E.; Dixon, J. A. J. Org. Chem. 1997, 62, 7086. (h)
Denmark, S. E.; Martinborough, E. A. J. Am. Chem. Soc. 1999, 121, 3046.
(3) (a) Denmark, S. E.; Hurd, A. R. J. Org. Chem. 1998, 63, 3045. (b)
Denmark, S. E.; Thorarensen, A. J. Org. Chem. 1994, 59, 5672. (c)
Denmark, S. E.; Herbert, B. J. Am. Chem. Soc. 1998, 120, 7357. (d)
Denmark, S. E.; Hurd, A. R. J. Org. Chem. 2000, 65, 2875. (e) Denmark,
S. E.; Herbert, B. J. Org. Chem. 2000, 65, 2887.
(4) (a) Denmark, S. E.; Stolle, A.; Dixon, J. A.; Guagnano, V. J. Am.
Chem. Soc. 1995, 117, 2100. (b) Denmark, S. E.; Schnute, M. E.; Marcin,
L. R.; Thorarensen, A. J. Org. Chem. 1995, 60, 3205. (c) Denmark, S. E.;
Guagnano, V.; Dixon, J. A.; Stolle, A. J. Org. Chem. 1997, 62, 4610. (d)
Denmark, S. E.; Dixon, J. A. J. Org. Chem. 1997, 62, 7086. (e) Denmark,
S. E.; Middleton, D. S. J. Org. Chem. 1998, 63, 1604.
10.1021/ol016385n CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/09/2001

the successful realization of this construction and demonstrate
the potential of this process for the synthesis of highly
functionalized polycyclic compounds (iii f vii and vi f
viii, Scheme 1).5
yield (overall) as a single diastereomer after recrystallization.
The full stereostructure of 3 was confirmed by H NMR
1
spectroscopic analysis. Thus, in just two steps a linear triene
is converted stereoselectively to a tetracyclic compound.
The homologous nitroalkene (E)-2 also reacted cleanly
with SnCl4 within 2 h at -78 °C. The crystalline nitronate
4 could be isolated in 98% yield as a single stereoisomer.
As we had previously established, the intramolecular [4 +
2] cycloaddition reaction is stereospecific with retention of
the dienophile configuration.7 Moreover, on the basis of
previous intramolecular [4 + 2] cycloadditions , we expected
that the nitronate would possess a trans ring fusion from an
exo mode cycloaddition;7 all these features were subsequently
confirmed by 1H NMR spectroscopic analysis. The isolation
of 4 implied that intramolecular [3 + 2] cycloaddition was
considerably slower, presumably due to thermodynamically
disfavored formation of a seven-membered ring.8 Upon
surveying a variety of temperatures and solvents, the rate of
the intramolecular [3 + 2] cycloaddition was indeed found
to be slow. The optimal conditions for converting the
nitronate 4 to the nitroso acetal 5 were found to be heating
a dilute toluene solution at 100 °C for 3 days, in the presence
of NaHCO3 to prevent acidic degradation of the nitronate.
The nitroso acetal 5 was isolated in 44% yield with 40% of
recovered starting material. The regio- and stereochemical
outcome of the intramolecular [3 + 2] cycloaddition is
primarily determined by the constraints imposed by the
tether. Nitroso acetal 5 was isolated as a single isomer and
was shown to possess the fused/bridged tetracyclic structure
indicated by NOE and 2D NMR spectroscopy.9
Scheme 1
To establish the ability of the C(6)-tethered nitroalkenes
to undergo an inverse electron demand intramolecular [4 +
2] cycloaddition, we first selected (E)-1 and (E)-2 as the test
substrates,6 which would create six- and seven-membered
rings in the [3 + 2] process, respectively (Scheme 2). The
intramolecular [4 + 2] cycloaddition of (E)-1 proceeded
readily in the presence of SnCl4 (2 equiv) at -78 °C within
1 h. The nitronate could be isolated, but much to our delight
it was contaminated with the nitroso acetal 3. Thus, we chose
to simply warm the crude nitronate in toluene to effect
dipolar cycloaddition and obtained the nitroso acetal in 82%
Scheme 3
Scheme 2
We next examined the reactivity of the C(5)-tethered
nitroalkenes in the tandem intra [4 + 2]/intra [3 + 2]
cycloaddition (Scheme 3). In this case (as in the inter-
molecular variant of this process4c), we chose to distinguish
the two double bonds by employing a vinyl ether as the
(5) For an early study on the tandem double intramolecular cycloaddition
in a fused/fused mode, see: Moon, Y. C. Ph.D. Thesis, University of Illinois,
Urbana, 1991.
(6) These nitroalkenes were both prepared in nine steps from cyclohexene.
See Supporting Information.
(7) Denmark, S. E.; Moon, Y.-C.; Cramer, C. J.; Dappen, M. S.;
Senanayake, C. B. W. Tetrahedron 1990, 46, 7373.
(8) (a) Padwa, A. In 1,3-DipolarCycloaddition Chemistry; Padwa, A.,
Ed.; Wiley-Interscience: New York, 1984; Vol. 2, Chapter 12. (b)
Confalone, P. N.; Huie, E. M. Org. React. 1988, 36, 1.
2908
Org. Lett., Vol. 3, No. 18, 2001

dienophile. Thus, addition of SnCl4 (1.1 equiv) to a solution
of the nitroalkene 610 at -78 °C resulted in the complete
consumption of the starting material after 20 min and the
formation of a mixture of nitronate 7 and nitroso acetal 8 in
a 3/2 ratio. The intramolecular [3 + 2] cycloaddition was
completed by stirring the mixture in toluene at room
temperature for 1 h. The nitroso acetal could then be isolated
as a single stereoisomer in 87% yield (overall). We were
delighted to find that the unactivated vinyl dipolarophile was
able to undergo intramolecular [3 + 2] cycloaddition very
quickly at room temperature. Clearly, the rate of [3 + 2]
cycloaddition is not only dependent on the reactivity of the
dipolarophile but also on the ability to easily access reactive
conformations in the proximity of the nitronate. The trans
decalin structure of the bicyclic nitronate 7 places the allyl
group in an axial orientation which is apparently favorable
for a 1,3-dipolar cycloaddition.
Scheme 4
and (E)-2 are converted to functionalized tricyclic compounds
bearing six contiguous stereogenic centers.
Similarly, the nitroso acetal 8 was subjected to hydro-
genolysis (Raney nickel/MeOH/1 atm/rt) to give a highly
polar amino alcohol (Scheme 5). Isolation of the product
was facilitated by acetylation after removal of catalyst and
methanol to afford the tricyclic amine 14 in 81% yield along
with a minor byproduct 15 (6% yield). The byproduct is
generated by over-reduction of the aldehyde derived from
8. On the other hand, nitroso acetal 11 reacted cleanly in
methanol at 1 atm of H2 for 12 h at rt to afford, after
acetylation, the amido acetate 16 in 82% yield (Scheme 5).
The second C(5) nitroalkene studied was the higher
homologue 910 bearing a two methylene tether between the
dienophile and the dipolarophile (Scheme 3). This nitroalkene
was chosen to evaluate the effect of tether length and the
ability to generate different ring sizes. The synthesis of this
nitroalkene provided an inseparable mixture of E and Z vinyl
ethers in a 1/1 ratio. The mixture of nitroalkenes was treated
with SnCl4 (1.1 equiv) in toluene at -78 °C to effect
intramolecular [4 + 2] cycloaddition. Surprisingly, the
nitronate 10 was isolated as a single stereoisomer! On the
basis of previous studies,11 this outcome can be rationalized
by invoking an isomerization of either the starting vinyl ether
or the product acetal in the presence of SnCl4. Intermediate
nitronate 10, in contrast to 7, did not undergo the intra-
molecular [3 + 2] cycloaddition spontaneously at room
temperature, but the reaction could be induced by warming
10 in toluene at 100 °C for 2 h to provide nitroso acetal 11
as a single stereoisomer in 79% yield. The marked difference
in the rate of intramolecular [3 + 2] cycloaddition between
7 and 10 may be rationalized by the greater entropic cost of
achieving suitable alignment that attends the increased length
of the dipolarophile tether from one to two methylene units.
Scheme 5
The synthetic utility of the tandem process is revealed by
the facile transformation of the nitroso acetal by hydro-
genolytic N-O bond cleavage. The conversion of the nitroso
acetals 3 and 5 to the respective R-hydroxy lactams was
accomplished by using a catalytic amount of Raney nickel
in methanol under 160 psi of hydrogen for 12 h to afford 12
and 13 as single isomers in 71 and 78% yields, respectively
(Scheme 4). Thus, in just three steps, linear trienes (E)-1
In summary, we have documented the feasibility of a novel
class of tandem intra [4 + 2]/intra [3 + 2] cycloaddition
called the fused/bridged mode. We have shown that both
families of nitroalkenes bearing dipolarophiles tethered at
C(6) and C(5) are competent. In addition, simple alkenes
and vinyl ethers (both E and Z) can serve as dienophiles
whereas vinyl groups and unsaturated esters (attached with
different chain lengths) both function well as dipolarophiles.
Hydrogenolysis of the nitroso acetal provides functionalized,
nitrogen-containing, polycyclic compounds in high yields.
Extension of the method to incorporate a stereocontrolling
element as well as applications to alkaloid synthesis are in
progress.
(9) The Z isomer of 2 was also investigated (see Supporting Information).
Cycloaddition of (Z)-2 proceeded smoothly in the presence of SnCl4 to
provide the nitronate in 82% yield. However, reaction of the nitronate
bearing a cis dipolarophile in the [3 + 2] cycloaddition was found to be
still slower than that of 4. Heating the nitronate in toluene at 100 °C for 3
days provided the nitroso acetal in 23% yield and 68% of recovered starting
material. The effects of dipolarophile geometry on the rate of the
intramolecular [3 + 2] cycloaddition of cyclic nitronates has been previously
observed. (a) Denmark, S. E.; Senanayake, C. B. W. Tetrahedron 1996,
52, 11579. (b) Denmark, S. E.; Seierstad, M. J.; Herbert, B. J. Org. Chem.
1999, 64, 884.
(10) Nitroalkenes 6 and 9 were prepared in 10 and 11 steps, respectively,
starting from caprolactone. See Supporting Information.
(11) Denmark, S. E.; Dixon, J. A. J. Org. Chem. 1998, 63, 6178.
Acknowledgment. We are grateful to the National
Institutes of Health (GM30938) for generous financial
Org. Lett., Vol. 3, No. 18, 2001
2909

support. L.G. also thanks the Association pour la Recherche
sur le Cancer (ARC) for a postdoctoral fellowship.
experimental procedures, complete spectroscopic and analyti-
cal data for all characterized compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Supporting Information Available: Schemes detailing
the preparation of (E)-1, (E)-2, (Z)-2, 6, and 9, general and
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Org. Lett., Vol. 3, No. 18, 2001