Tandem 6π-electrocyclization and cycloaddition of nitrodienes to yield multicyclic nitroso acetals

Article abstract of DOI:10.1021/ja1038819

Upon heating, nitrodienes rearrange through 6π-electrocyclization to form nitronate intermediates, which can be captured through tandem [3 + 2] dipolar cycloadditions to form highly functionalized nitroso acetals. The one-pot, two-step domino process is h

Full text of DOI:10.1021/ja1038819

Published on Web 06/17/2010
Tandem 6π-Electrocyclization and Cycloaddition of Nitrodienes to Yield
Multicyclic Nitroso Acetals
Gardner S. Creech and Ohyun Kwon*
Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles, California 90095-1569
Received May 6, 2010; E-mail: ohyun@chem.ucla.edu
Pericyclic reactions are among the most versatile transformations
in synthetic organic chemistry. In a single step, pericyclic reactions
rapidly generate molecular complexity from simpler starting materials,
often with predictable and well-defined stereochemical outcomes. An
even more powerful effect is generated when more than one pericyclic
reaction is combined in a domino process, wherein the product of the
first reaction serves as a substrate for the subsequent reaction(s).1
Among the known pericyclic reactions, electrocyclization has been
studied relatively less exhaustively than, for example, cycloaddition
or sigmatropic rearrangement, despite its synthetic potential for the
assembly of complex six-membered-ring cyclic compounds.2 In this
context, we became particularly interested in the possible 6π-
electrocyclizations of nitrodienes, examples of which are absent from
the literature.3 The resulting nitronates are well-established substrates
for dipolar cycloaddition,4 suggesting the potential for domino elec-
trocyclization/dipolar cycloaddition. Herein, we disclose the first
example of a 6π-electrocyclization of nitrodienes and subsequent
[3 + 2] cycloadditions of the resulting nitronates to form tricyclic
nitroso acetals with well-defined stereochemistry (eq 1).
R-bromostyrene readily formed their expected nitrodienes (1a and 1b,
respectively); upon heating in the presence of ethyl acrylate at 90 °C,
both nitrodienes underwent rearrangement and exoselective dipolar
cycloaddition13 to form their anticipated nitroso acetal products (entries
1 and 2).14 Unexpectedly, the δ,δ-dimethylnitrodiene prepared from
1-bromo-2-methylpropene spontaneously rearranged to the correspond-
ing nitronate 2 during chromatography over SiO2 (entry 3, 86% isolated
yield); this nitronate smoothly underwent the subsequent [3 + 2]
cycloaddition to produce the nitroso acetal 3c in 91% yield.
Table 1. Syntheses of Nitrodienes, Nitronates, and Nitroso Acetalsa
The closest examples to the 6π-electrocyclization of nitrodienes are
the six-electron, five-atom electrocyclizations of nitrostyrenes, nitros-
tilbenes, and nitrobiphenyls under reductive deoxygenation conditions
to generate indoles and carbazoles.5 Denmark et al. developed a
powerful protocol for the formation of nitronate dipoles through hetero-
Diels-Alder reactions of nitroalkenes and subsequent dipolar cycload-
ditions;6 they have applied this elegant methodology toward the
construction of several multicyclic alkaloid natural products.7 In
addition, formal [4 + 1] cycloadditions of sulfur ylides and nitroalk-
enes, generating nitronate intermediates, have been reported very
recently.8 Finally, there are rare examples of sigmatropic rearrange-
ments of γ,δ-unsaturated nitroalkenes providing cyclic nitronates that
undergo further reactions.9
As we launched our investigation into the possibility of 6π-
electrocyclization of nitrodienes, it immediately became apparent that
the preparation of nitrodienes with the requisite internal cis-olefin
geometry would be a challenge. Locking the internal double bond into
a ring, by tethering the R1 and R2 units, presented itself as a practical
solution. In addition, literature precedents portended that the equilibrium
between the nitrodiene and nitronate would lie unfavorably;10 we
designed to overcome this problem by trapping the nitronate products
in situ with dipolarophiles.
Pleasingly, our synthetic plan was realized as described (Table 1).
Conjugate addition/elimination of zinc cuprates, derived from readily
accessible vinyl halides, into 2-thioethyl nitrocyclohexene11 provided
ready access to the desired nitrodienes.12 Both 2-bromopropene and
a Experimental details are provided in the Supporting Information.
b Reaction performed in CH2Cl2 at 22 °C. c Use of either cis- or
trans-ꢀ-bromostyrene produced 1g.
For mono-δ-substituted nitrodienes, an additional stereogenic center
is formed. For instance, the δ-n-butyl nitrodiene 1d resulted in a 1.6:1
mixture of two diastereoisomers upon reaction with ethyl acrylate (entry
4). Conversely, the 2-cyclohexenyl nitrocyclohexene 1e smoothly
rearranged to the corresponding nitronate and formed the tetracyclic
nitroso acetal 3e with improved selectivity (5.2:1, entry 5). The
nitrodiene 1f, featuring a cyclopentenyl group, provided even better
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10.1021/ja1038819  2010 American Chemical Society

C O M M U N I C A T I O N S
selectivity: we obtained the tetracycle 3f as a single diastereoisomer
in 79% isolated yield (entry 6). Apparently, ethyl acrylate approached
the nitronate dipole preferentially from the face of its δ-hydrogen
atom.14 The δ-phenyl-substituted nitrodiene 1g was recalcitrant to the
rearrangement, presumably because of its exceptional stability stem-
ming from the extensively conjugated framework (entry 7).
The scope of the dipolarophile partners was further investigated
(Table 2). Another electron-deficient olefin, methyl vinyl ketone, was
smoothly incorporated into the cascade sequence, forming the nitroso
acetal 3g in good yield with reasonable diastereoselectivity (entry 1).
Styrene (electron-neutral) was also an excellent dipolarophile, providing
the nitroso acetal 3h as a single diastereoisomer in 88% yield (entry
2). Allyl bromide also proved to be a viable dipolarophile, albeit with
poorer diastereoselectivity (entry 3). Gratifyingly, ethyl vinyl ether
(electron-rich) was also an excellent dipolarophile, yielding the nitroso
acetal 3j (62%) as a single diastereoisomer (entry 4). N-Methylmale-
imide underwent the dipolar cycloaddition in a highly efficient and
stereoselective manner (entry 5). The trans-disubstituted olefin dimethyl
fumarate was an excellent dipolarophile (entry 6), as was its cis isomer,
dimethyl maleate (entry 7).
the tricyclic amide 5 in 77% isolated yield. Saponification of the ethyl
ester prior to hydrogenolysis precluded amide formation, resulting in
isolation of the amino dihydroxy acid 6 after exposure to Raney Ni.
Therefore, reduction of the nitroso acetal is a versatile and powerful
reaction modality capable of following several potential reaction
pathways without loss of the stereochemical information gained from
the tandem electrocyclization/dipolar cycloaddition.
Scheme 1. Selective Hydrogenolyses of the Nitroso Acetal 3a
In summary, we have developed a new transformation: the 6π-
electrocyclization of nitrodienes and subsequent capture of the
intermediate nitronates through dipolar cycloaddition. In this one-pot
domino process, two rings are formed with one quaternary center
generated; the products are isolated, typically as single diastereoisomers,
in good to excellent yields. Hydrogenolysis of the resulting nitroso
acetal products provides highly functionalized, synthetically useful
structures. We are currently investigating expanding the substrate scope
to acyclic systems, as well as unveiling other latent pericyclic
reactivities of the nitroalkenes.
Table 2. Electrocyclization/Cycloadditions of Nitrodiene 1a
Acknowledgment. Financial support was provided by the NIH
(R01GM071779 and P41GM081282) and Amgen, Inc. We thank Dr.
Saeed Khan for performing the crystallographic analyses.
Supporting Information Available: Representative experimental
procedures; spectral data for all new compounds (PDF); crystallographic
data for 2 and 3a (CIF). This information is available free of charge via
the Internet at http://pubs.acs.org.
References
(1) Padwa, A.; Bur, S. K. Tetrahedron 2007, 63, 5341.
(2) Beaudry, C. M.; Malerich, J. P.; Trauner, D. Chem. ReV. 2005, 105, 4757.
(3) Henry, C. E.; Kwon, O. Org. Lett. 2007, 9, 3069.
(4) Denmark, S. E.; Cottell, J. J. Nitronates. The Chemistry of Heterocyclic
Compounds: Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry
Toward Heterocycles and Natural Products; Padwa, A., Pearson, W. H.,
Eds.; Wiley-Interscience: New York, 2002; pp 83-167.
(5) Davies, I. W.; Guner, V. A.; Houk, K. N. Org. Lett. 2004, 6, 743.
(6) Denmark, S. E.; Thorarensen, A. Chem. ReV. 1996, 96, 137.
(7) Select references: (a) Denmark, S. E.; Hurd, A. R.; Sacha, H. J. J. Org.
Chem. 1997, 62, 1668. (b) Denmark, S. E.; Baiazitov, R. Y.; Nguyen, S. T.
Tetrahedron 2009, 65, 6535.
(8) Lu, L.-Q.; Li, F.; An, J.; Zhang, J.-J.; An, X.-L.; Hua, Q.-L.; Xiao, W.-J.
Angew. Chem., Int. Ed. 2009, 48, 9542.
(9) (a) Barco, A.; Benetti, S.; De Risi, C.; Morelli, C. F.; Pollini, G. P.; Zanirato,
V. Tetrahedron 1996, 52, 9275. (b) Baranovsky, A. V.; Bolibrukh, D. A.;
Bull, J. R. Eur. J. Org. Chem. 2007, 445.
(10) (a) Buchi, G.; Yang, N. C. J. Am. Chem. Soc. 1957, 79, 2318. (b) Marvell,
E. N.; Caple, G.; Gosink, T. A.; Zimmer, G. J. Am. Chem. Soc. 1966, 88, 619.
(11) (a) Node, M.; Kawabata, T.; Fujimoto, M.; Fuji, K. Synthesis 1984, 234.
(b) Jung, M. E.; Grove, D. D. J. Chem. Soc., Chem. Commun. 1987, 753.
(12) Jubert, C.; Knochel, P. J. Org. Chem. 1992, 57, 5431.
(13) The presence of both NaHCO3 and methyl hydroquinone (MeHQ) improved
the efficiency of the reaction, presumably because MeHQ acted as a stabilizer
(reducing decomposition of the nitrodiene) and the bicarbonate sequestered
trace acid. Denmark, S. E.; Gomez, L. J. Org. Chem. 2003, 68, 8015.
(14) Structures 2 and 3a were confirmed through X-ray crystallographic analysis.
The relative stereochemistry of 3f (and the major adducts for 3d and 3e)
was rigorously established based on NOE data and comparison to the spectra
of the nitroso acetal 3a. See the Supporting Information for details.
(15) Denmark, S. E.; Moon, Y.-C.; Senanayake, C. B. W. J. Am. Chem. Soc.
1990, 112, 311.
a Isolated yields after chromatographic purification. b The reaction
yielded 3m accompanied by 18% of 3l.
The nitroso acetals served as versatile starting materials for the
construction of complex amino alcohol derivatives. For instance,
subjecting 3a to standard Raney Ni hydrogenolysis conditions, we
generated the spirocyclic amide 4 in 65% yield, along with the tricyclic
minor product 5 (Scheme 1).15 Hydrogenolysis of 3a, followed by
heating the crude reaction mixture under reflux in toluene, produced
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