a
a,b,c
a
b
c
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.
O
O
LA
O
LA
O
LA
O
LA - H
+ H
+
- LA
R
1
R R
2
R R
3
R R
4
R R
5
R
See: Frontier, A. J.; Collison, C. Tetrahedron 2005 , 61 , 7577
– 7606
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.
NO
2 TMSO O
N LA
-
NO
2
H O
NO
2
O
+
NO
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.
N
R
2
R
1
6
R
1
LA
LA
N
R
2
R
1
7
R
1
LA
N
R
2
R
1
R
1
8
- H
+
LA
N
R
2
H
+
- LA
R
1
9
R
1
N
R
2
R
1
10
R
1
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
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.
Br
Urea, NaNO
2
DMF, -15 °C, 6 hr
NO
2
(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
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.
R
3
N
+
R
4
R
3
N
R
4
R
3
N
R
4
R
1
R
2
R
1
R
2
R
1
11 12
See: Smith, D. A.; Ulmer, C. W. II. J. Org. Chem. 1997, 62 , 5110
– 5115
13
R
2
Phenylnitromethane was then used in a Henry reaction with phenylacetaldehyde in the presence of basic aluminum oxide. This reaction produced the synnitroalcohol in 62%.
NO
2
NO
2 +
O
Al
2
O
3
Neat, 0 °C - R.T.
See: Rosini, G.; Ballini, R.; Sorrenti, P. Synthesis 1983 , 1014
– 1016
OH
(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.
NO
2
OH
Ac
2
O
O
-
N
+
O
O
CH
3
O
-
N
+
O
O
CH
3
O
-
N
+
O
Et
3
N
+
+
1
CHLOROFORM-d
2
3 2
3
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.
TMSO
N
O
-
TMSO
N
+
O
-
1
2
3
2
3
1
Yields:
1 – 11.0 %
2 – 6.2 %
3 – 6.8 %
R
14
R R
15
R
1.00
9.5
9.0
8.5
1.03
1.77
8.0
7.5
7.0
0.88
0.81
6.5
6.0
5.5
5.0
Chemical Shift (ppm)
4.5
4.0
2.09
3.5
3.0
2.51
2.71
2.5
2.0
1.5
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.
NO
2
OH
2 equiv. Ac
2
O
3 equiv. Et
3
N
O
-
N
+
O
O
CH
3
+
1
O
-
N
+
O
O
CH
3
Yields:
1 – 10.8 %
2 – 8.2 %
2
1
2
1,2
1,2
2
1
2.28
10.59
7.5
7.0
0.76
6.5
6.0
1.00
5.5
5.0
Chemical Shift (ppm)
4.5
4.0
3.5
3.0
3.05
2.35
2.5
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.
O
-
N
+
O
O
CH
3
Sc(OTf)
3
X
NO
2