The Nazarov cyclization is a [2+2] cyclization of a divinyl ketone 1 to a cyclopentenone product 5....
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The Nazarov cyclization is a [2+2] cyclization of a divinyl ketone 1 to a cyclopentenone product 5. This cyclization requires that a pentadienyl cation
The Nazarov cyclization is a [2+2] cyclization of a divinyl
ketone 1 to a cyclopentenone product 5. This cyclization requires
that a pentadienyl cation 2 be formed, and this occurs when the
divinyl cation is in the presence of either a Lewis acid (LA) or
Brnsted acid. The importance of this cyclization is demonstrated by
the fact that it has been used extensively to synthesize natural
products containing one or more cyclic components in their
structure. Investigation of the Nitronate-Nazarov Cyclization
Alyssa J. Jaeschke, a Ian R. Pottie a,b,c * a Mount Saint Vincent
University, Department of Chemistry, Halifax, Nova Scotia, B3M 2J6.
b Saint Marys University, Department of Chemistry, Halifax, Nova
Scotia, B3H 3C3. c Dalhousie University, Department of Chemistry,
Halifax, Nova Scotia, B3H 4R2 * corresponding author:
[email protected] The imino-Nazarov cyclization is similar to the
classic Nazarov cyclization, with the exception that the divinyl
ketone is instead a divinyl imine 6. The product then becomes a
cyclopentenimine 10. This difference in the two cyclizations
creates new possibilities for cyclic products that contain nitrogen
substituents. Despite the potential benefits of the imino-Nazarov
cyclization, it has only been reported three times. The lack of
interest in this cyclization is likely due to the fact that it has
been shown that the energetic barrier for the imino-Nazarov
cyclization is increased with respect to that of the classic
Nazarov. It has been reported that the lone pair of electrons on
the nitrogen atom stabilizes the cation to form the divinyl pi
system 11. This is the favoured resonance structure and therefore
discourages the imino-Nazarov cyclization. See: Frontier, A. J.;
Collison, C. Tetrahedron 2005, 61, 7577 7606 To test this
hypothesis, the imine functionality of the divinyl structure is
replaced with a nitronate functionality. The presence of the two
highly electronegative oxygen atoms could affect the energetic
barrier by changing the population of the resonance structures. It
could decrease the ability of the lone pair of electrons to donate
into the pentadienyl system when a silyl group is bonded to one
oxygen of the nitronate. It is hypothesized that with this
alteration, structure 14 will be more favoured than structure 15,
and cyclization of this pentadienyl cation will occur. To test the
feasibility of the nitronate-Nazarov cyclization, a molecular
skeleton that incorporates the nitro group into the proper divinyl
framework was synthesized. This framework was synthesized using a
Henry reaction between phenylnitromethane and phenylacetaldehyde to
form a nitroalcohol that is then eliminated to the nitroalkene.
This nitroalkene then reacts to form a silyl nitronate that will
undergo the cyclization. To construct the molecular framework
required to test the hypothesis, it was first necessary to
synthesize phenylnitromethane, a compound that is not commercially
available. This compound was produced from benzyl bromide, urea,
and sodium nitrite in 45% yield. The molecular framework that is
necessary to undergo the proposed nitronate-Nazarov cyclization has
successfully been synthesized. The acyl nitronate has been used in
one attempt at the nitronate-Nazarov cyclization using
scandium(III) triflate as a Lewis acid. Unfortunately, this
reaction did not produce the desired cyclic product.. Future work
includes determining which Lewis acid or Brnsted acid will be
optimal in promoting the cyclization. This will be the first
reported example of a nitronate-Nazarov cyclization. See: Tius, M.
A.; Chu, C. C.; Nieves-Colberg, R. Tetrahedron Lett. 2001, 42, 2419
2422, Suarez-Pantiga, S.; Rubio, E.; Alvarez-Rua, C.; Gonzalez, J.
M. Org. Lett. 2009, 11, 13 16, Bow, W. F.; Basak, A. K.; Jolit, A.;
Vicic, D. A.; Tius, M. A. Org. Lett. 2010, 12, 440 443 See: Smith,
D. A.; Ulmer, C. W. II. J. Org. Chem. 1997, 62, 5110 5115 (62 %)
The next step in the synthesis was to form the nitroalkene from the
nitroalcohol. The elimination reaction involved adding an equimolar
amount of acetic anhydride to the nitroalcohol, followed by the
equimolar addition of triethylamine. This reaction gave a mixture
of the desired nitroalkene and the acyl nitronate required for the
cyclization. With the results from the former reaction, it was
hypothesized that the acyl nitronate could be the only product
resulting from the reaction. When reacting the nitroalcohol with
two equivalents of acetic anhydride and three equivalents of
triethylamine, the product isolated was the acyl nitronate; the
nitroalkene did not form. (45 %) See: Kornblum, N.; Larson, H. O.;
Blackwood, R. K.; Mooberry, D. D.; Oliverto, E. P.; Graham, G. E.
J. Am. Chem. Soc. 1956, 78, 1497 1501 Phenylnitromethane was then
used in a Henry reaction with phenylacetaldehyde in the presence of
basic aluminum oxide. This reaction produced the syn-nitroalcohol
in 62%. See: Rosini, G.; Ballini, R.; Sorrenti, P. Synthesis 1983,
1014 1016 Yields: 1 11.0 % 2 6.2 % 3 6.8 % Yields: 1 10.8 % 2 8.2
%