Investigation of the Nitronate-Nazarov Cyclization

Report
Investigation of the Nitronate-Nazarov Cyclization
a
Jaeschke,
Alyssa J.
Ian R. Pottie
a,b,c*
aMount
Saint Vincent University, Department of Chemistry, Halifax, Nova Scotia, B3M 2J6.
bSaint Mary’s University, Department of Chemistry, Halifax, Nova Scotia, B3H 3C3.
cDalhousie University, Department of Chemistry, Halifax, Nova Scotia, B3H 4R2
* corresponding author: [email protected]
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 Brønsted 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.
LA
LA
O
LA
O
O
O
O
+
+
NO 2
H
-H
LA
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.
TMSO
O
N
LA
-
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.
O
NO2
-
O
+
NO 2
R
R
R
R
1
2
R
R
R
3
R
-
O
CH3
+
N
O
3 equiv. Et3N
R
O
N
2 equiv. Ac2O
OH
- LA
R
CH3
O
+
Yields:
1 – 10.8 %
2 – 8.2 %
5
4
1
2
See: Frontier, A. J.; Collison, C. Tetrahedron 2005, 61, 7577 – 7606
NO 2
O
2.32
1
NO 2
HO
+
2.24
2
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.
H
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.
+
- LA
R1
R1
R1
R1
R1
6
7
R1
R1
8
R1
9
1,2
R1
1
2
2.34
+
N
5.74
5.72
-H
LA
N
1,2
R2
6.43
6.40
N
N
R2
7.27
R2
LA
7.58
LA
R2
7.59
N
R2
LA
R1
10
Urea, NaNO2
Br
NO2
2.28 10.59
(45 %)
DMF, -15 °C, 6 hr
7.5
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
0.76
7.0
1.00
6.5
6.0
3.05 2.35
5.5
5.0
4.5
Chemical Shift (ppm)
4.0
3.5
3.0
2.5
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%.
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.
3
+
R
4
R
3
R
1
R
3
N
N
R
4
R
NO2
O
Al2O3
+
(62 %)
Neat, 0 °C - R.T.
OH
See: Rosini, G.; Ballini, R.; Sorrenti, P. Synthesis 1983, 1014 – 1016
4
O
N
+
O
CH3
N
R
2
R
11
1
R
2
R
1
12
R
2
13
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.
See: Smith, D. A.; Ulmer, C. W. II. J. Org. Chem. 1997, 62, 5110 – 5115
O
NO2
-
O
CH3
+
-
O
O
+
R
R
32
2
3
2.28
7.34
7.27
Yields:
1 – 11.0 %
2 – 6.2 %
3 – 6.8 %
3.70
3
5.73
5.71
2
6.43
6.39
2
7.39
3
1
9.77
N
R
14
+
+
1
7.22
N
-
O
7.60
7.58
7.46
TMSO
7.88
-
+
O
CHLOROFORM-d
O
O
N
1
TMSO
O
N
Et3N
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.
-
CH3
+
N
Ac2O
OH
O
2.21
R
NO2
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 Brønsted acid will be optimal in promoting the cyclization.
This will be the first reported example of a nitronate-Nazarov cyclization.
R
15
1.00
1.031.77
9.5
9.0
8.5
8.0
7.5
0.88
7.0
6.5
0.81
6.0
5.5
5.0
Chemical Shift (ppm)
2.09
4.5
4.0
3.5
2.51 2.71
3.0
2.5
2.0
1.5
O
NO2
Sc(OTf)3
X

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