N-Vinylpyridinium tetrafluoroborate salts as reagents for the stereoselective and regioselective synthesis of symmetrical (2E,4E)-1,6-dioxo-2,4-dienes

Article abstract of DOI:10.1016/j.tetlet.2008.08.076

We had previously demonstrated the utility of N-vinylpyridinium tetrafluoroborate salts as novel electrophilic coupling partners in Pd(0)-catalyzed Suzuki cross-coupling reactions with aryl and vinyl boronic acids. We now report that these crystalline, air-stable, and non-hygroscopic salts are also useful reagents for the synthesis of symmetrical (2E,4E)-1,6-dioxo-2,4-dienes (diene diones), which in turn are valuable starting materials for the synthesis of various five-membered heterocycles. The optimization of reaction conditions and the scope and limitations of the reductive dimerization are discussed.

Full text of DOI:10.1016/j.tetlet.2008.08.076

Tetrahedron Letters 49 (2008) 6491–6494
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Tetrahedron Letters
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N-Vinylpyridinium tetrafluoroborate salts as reagents for the stereoselective
and regioselective synthesis of symmetrical (2E,4E)-1,6-dioxo-2,4-dienes
Ge Gao a, Neil Brown a,b, Machiko Minatoya a, Keith R. Buszek a,b,
*
a Department of Chemistry, University of Missouri-Kansas City, 205 Spencer Chemical Laboratories, 5100 Rockhill Road, Kansas City, MO 64110, USA
b The University of Kansas Center of Excellence in Chemical Methodologies and Library Development, 1251 Wescoe Hall Drive, 4070 Malott Hall, Lawrence, KS 66045, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We had previously demonstrated the utility of N-vinylpyridinium tetrafluoroborate salts as novel electro-
philic coupling partners in Pd(0)-catalyzed Suzuki cross-coupling reactions with aryl and vinyl boronic
acids. We now report that these crystalline, air-stable, and non-hygroscopic salts are also useful reagents
for the synthesis of symmetrical (2E,4E)-1,6-dioxo-2,4-dienes (diene diones), which in turn are valuable
starting materials for the synthesis of various five-membered heterocycles. The optimization of reaction
conditions and the scope and limitations of the reductive dimerization are discussed.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 4 August 2008
Accepted 21 August 2008
Available online 27 August 2008
The ready availability of variously substituted aromatic hetero-
cycles continues to be an important problem in organic chemistry.
In connection with a program of research involving library devel-
opment with novel chemotypes based on our recently reported
indole aryne cycloaddition chemistry,1 we required an efficient
and general route to di-substituted, five-membered ring aromatic
heterocycles.
A potentially attractive avenue for the synthesis of the desired
cycloaddition partners involves the use of 1,6-dioxo-2,4-dienes
(diene diones), as shown in Scheme 1.2–5 Treatment of diene diones
with the appropriate reagents and reaction conditions leads to the
formation of furans 2,2 pyrroles 4,3 or thiophenes 5,4 as well as
dihydrofurans 6.5 However, a review of the literature revealed that
there are only ad hoc methods for the synthesis of the requisite
1,6-dioxo-2,4-dienes.6–11
Most of these methods have significant drawbacks or limita-
tions that detract from their widespread adoption. These include
the use of toxic reagents,6,7 the requirement of harsh reaction
conditions,7 the presence of unstable intermediates,8 or the
involvement of several steps.9 Several of these methods suffer
additionally in that they either give low yields of the diene
dione product or result in mixtures of olefinic regio- and
stereoisomers.10,11
Recently, we showed that N-vinylpyridinium tetrafluoroborate
salts represent an attractive alternative to vinyl halides and
triflates in the Pd(0)-catalyzed Suzuki cross-coupling reaction with
aryl boronic acids (Scheme 2).12 The only other reported use of
these salts is that of a dienophile (Jung’s dienophile) in the
Diels–Alder reaction.13–15 During the course of our investigation
into the application of these salts in the Suzuki reaction, we ob-
served that merely changing the phosphine ligand from PCy3 to
PPh3 in 11 suppressed almost entirely the cross-coupling event
and gave instead in good yield the symmetrical 1,6-dioxo-2,4-
diene 12, presumably via reductive dimerization.
We now report that this one-step, microwave-assisted (heated)
process represents the first general and practical method for the
synthesis of symmetrical, isomerically pure 1,6-dioxo-2,4-dienes.
The N-vinylpyridinium tetrafluoroborate salts used in the present
study are prepared in one-step from the addition of pyridinium
tetrafluoroborate to various ynones14 to afford crystalline, non-
hygroscopic, and indefinitely air-stable components. Besides the
foregoing advantages over the corresponding b-haloenones, the
salts have the additional feature of being appreciably soluble in
many common organic solvents.
O
CH2R
O
O
O
Ar
HCl, AcOH
(ref. 2)
(ref. 3)
Ar
2
CH2R
or
O
O
1
TsOH, CH2Cl2
O
NR3
CH2R2
R1
R3NH2
EtOH
R1
CH2R2
4
3
3
1
O
S
CH2R2
O
O
R1
Ar
(ref. 4)
(ref. 5)
R1
P2S5, EtOH
or
CH2R
CH2R
5
O
Lawesson's
reagent, EtOH
O
R
Ar
KOH
O
6
MeOH
O
Scheme 1. Use of (2E,4E)-1,6-dioxo-2,4-dienes to form aromatic and other
heterocycles.
* Corresponding author. Tel.: +1 816 235 2292; fax: +1 816 235 5502.
E-mail address: buszekk@umkc.edu (K. R. Buszek).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.076

6492
G. Gao et al. / Tetrahedron Letters 49 (2008) 6491–6494
Table 1
O
O
Attempted catalyst optimizationa
+
Pd2(dba)3 (5 mol%)
PCy3 (20 mol%), DIEA
N
R1
(ref. 12)
R1
-
Entry
Catalyst
Ligand
Yield (%)
BF4
8
MW, THF, 150 ºC, 12 min
B(OH)2
R2
7
1
2
3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
PPh3
AsPh3
P-o-tol3
dppf
PCy3
nab
na
na
na
na
27
23
26
15
34
27
24
32
15
15
68-88%
R1 = Me, Ar
R2
R2 = H, Me, OMe
CF3, NO2
4
5
6
7
8
9
10
Pd2(dba)3
+
N
Z
Z
PdCl2[P(tol)3]2
PdCl2[PCy3]2
PdCl2[PPh3]2
Pd(dppe)2
Pd(PPh3)4
(ref. 13-15)
-
BF4
rt, MeCN, 12-24 h
100%
-
BF4
9
+
N
10
Z = COR, CO2R, CN
O
O
a
+
N
Reaction conditions: 5 mol % catalyst, 20 mol % ligand (if applicable), 2.2 equiv
Pd2(dba)3 (5 mol%)
PPh3 (20 mol%), DIEA
Me
Me
(ref. 1)
DIEA, THF/H2O (7:3), MW 150 °C, 10 min.
Me
-
b
BF4
11
na = not applicable.
12
MW, THF, 150 ºC, 10 min
60%
O
Scheme 2. Applications for N-vinylpyridinium tetrafluoroborate salts.
Table 2
Solvent optimizationa
Entry
Solvent
Yield (%)
O
O
1
2
3
4
5
6
7
8
THF
Acetone
CH2Cl2
DMF
MeCN
MeOH
MeCN/H2O (7:3)
THF/H2O (7:3)
34
31
35
19
42
15
21
30
PyH+ BF4
-
+
MgBr
i.
RCHO
13
R
N
R
MeOH, 65 ºC
100%
THF, 0 ºC to rt
ii. Jones reagent
-
14
BF4
11a-j
acetone, 0 ºC to rt
11a R = Me
11b R = i-Pr
11c R = n-Bu
11d R = c-Pr
11e R = Cy
11f R = Bn
11g R = Ph
11h R = 4-MeOPh
11i R = 4-pentenyl
11j R = 2-cyclohexenyl
a
Reaction conditions: 5 mol % Pd2(dba)3, 20 mol % PCy3, 2.2 equiv DIEA, MW
150 °C, 10 min.
Scheme 3. Synthesis of N-vinylpyridinium salts 11a–j.
We next examined the effect of solvent, as shown in Table 2.
Acetonitrile (entry 5) was superior to other strongly coordinat-
ing (DMF) or weakly coordinating (acetone) polar aprotic solvents,
and also showed improved yields compared to weakly polar sol-
vents such as THF or DCM. Interestingly, the use of protic solvents
such as water or methanol alone or in pairs is clearly detrimental
to the reaction as shown in entries 6, 7, and 8. Accordingly, we
employed acetonitrile for the subsequent optimization.
We next examined the choice of base for the reaction, the
results of which are summarized in Table 3. In the absence of base
(entry 1), no reaction takes place. While Hunig’s reagent was used
successfully in our earlier homocoupling work, curiously, the addi-
tion of other common organic bases, such as triethylamine, pyr-
idine, and 2,6-lutidine, failed to give any diene dione (entries 3–5).
However, employing inorganic bases such as lithium carbonate,
potassium bicarbonate, or sodium bicarbonate again gave product,
with sodium carbonate being the best of these three. This observa-
tion stands in contrast to our earlier efforts involving the Suzuki
cross-coupling of N-vinylpyridinium salts in which poor yields
To explore the scope and limitations of this procedure, we com-
menced with a series of commercially available aldehydes having
various aliphatic and aromatic groups (Scheme 3). Reaction with
1.5 equiv of ethynylmagnesium bromide (CCMgBr, THF, 0 °C) fol-
lowed by oxidation with excess Jones reagent (Jones, acetone,
0 °C) afforded the 3-yn-2-ones in good to excellent yields. Reaction
with an equivalent of pyridinium tetrafluoroborate in refluxing
methanol for up to 12 h gave in each case a quantitative yield of
the exclusively trans vinylpyridinium salt.14
The original reductive dimerization conditions failed to give
acceptable or reproducible yields of diene diones for the remaining
vinylpyridinium salts. From our initial efforts at improving the
yield for the other substrates, we determined that the use of a
7:3 mixture of THF/water as the solvent proved to be beneficial,
and generally resulted in a modest yield improvement. Accord-
ingly, we elected to start with this solvent system using 11 as
the test substrate, then to vary the catalyst, ligand, base, solvent,
and temperature in an iterative fashion to find the optimum condi-
tions for the remaining compounds.
Our previous experience in the Suzuki cross-coupling study
involving N-vinylpyridinium salts revealed that the reactions car-
ried out with conventional heating (i.e., reflux) led to prolonged
reaction times and usually significantly diminished yields. For this
reason, along with the observation that microwave use is becom-
ing common in organic synthesis, we continue to use a focused
beam, closed system microwave reactor as the heating method of
choice.16,17
Table 1 shows the attempted optimization of the catalyst using
various palladium sources. The catalyst and ligand combination of
Pd2(dba)3 with PCy3, while affording a modest yield of the diene
dione, was superior to the other entries, and therefore adopted.
Also examined were other metals such as nickel(II)iodide and
copper(I)iodide, but with these catalysts no homocoupling was
observed.
Table 3
Base optimizationa
Entry
Base
Yield (%)
1
2
3
4
5
6
7
8
None
0
42
0
0
0
27
49
56
EtN(i-Pr)2
2,6-Lutidine
Pyridine
NEt3
Li2CO3
KHCO3
NaHCO3
a
Reaction conditions: 5 mol % Pd2(dba)3, 20 mol % PCy3, 2.2 equiv base, MeCN,
MW 150 °C, 10 min.

G. Gao et al. / Tetrahedron Letters 49 (2008) 6491–6494
6493
Table 4
O
O
Reaction temperature and time optimizationa
+
Pd2(dba)3 (5 mol%)
R
N
R
R
PCy3 (20 mol%), NaHCO3 (2.2 equiv)
MW, MeCN, 160 °C, 18 min
19-74%
-
Entry
Temperature (°C)
Time (min)
Yield (%)
O
BF4
11a-j
12a-j
1
2
3
4
5
6
150
150
170
180
190
160
10
20
10
7
5
18
56
58
53
51
54
74
Scheme 4. Preparation of various 1,6-dioxo-2,4-dienes under optimized homo-
coupling conditions.
a
Reaction conditions: 5 mol % Pd2(dba)3, 20 mol % PCy3, 2.2 equiv NaHCO3,
MeCN, MW temperature and time as shown.
were obtained with inorganic bases, but significantly improved
yields were obtained with organic bases.12
Finally, we looked into the effect of temperature and reaction
time on homodimerization with the catalyst, solvent, and base
system developed thus far (Table 4).
Table 5
The best conditions were achieved by
a combination of
Yields for the formation of 1,6-dioxo-2,4-dienes 12a–j
increased reaction time and slightly increased temperature (entry
6) compared to our original time and temperature profile (entry
1). Increasing the reaction time alone led to only a marginal
improvement (entry 2), whereas increasing the temperature
beyond 160 °C even for much shorter periods resulted in
diminished yields (entries 3–5). The new conditions resulted in a
significantly improved yield of the diene dione 12 to 74% from
the previously reported 60%.12
The other nine N-vinylpyridinium salts, 12b–j, were then
subjected to the same optimized homodimerization conditions as
shown in Scheme 4. The yields for the reactions are summarized
in Table 5.
Overall, the procedure gives fairly uniform and good yields of a
wide variety of relatively unhindered diene diones. The exceptions
include the aryl-substituted ketone products 11g, and 11h, which
are themselves relatively unstable and maybe decomposing or
reacting further (e.g., as a diene) during the course of the reaction.
In spite of this limitation, the reaction seems to be general for alkyl,
branched alkyl, cycloalkyl, and olefin-containing alkyl and cyclo-
alkyl groups.
N-Vinylpyridinium salt
1,6-Dioxo-2,4-diene
Yield (%)
74
O
O
+
N
-
12a
BF4
O
11a
O
O
+
N
52
41
-
BF4
12b
O
11b
O
O
+
N
-
BF4
11c
O
12c
O
O
+
N
61
-
BF4
11d
12d
O
In conclusion, we have discovered a facile and general Pd-(0)
catalyzed method for the stereo- and regioselective synthesis of
symmetrical alkyl-substituted (2E,4E)-1,6-dioxo-2,4-dienes which
are in turn valuable precursors for substituted heterocyclic sys-
tems. This method represents a substantial improvement over pre-
viously reported approaches to diene diones. The advantages of the
current procedure derive from the fact that it is rapid, it involves
only one-step from stable and easily prepared substrates, and it
does not rely upon toxic or other reactive or unstable reagents
during the preparation. Investigation into the mechanism of this
reaction and further efforts to find other applications for N-vinyl-
pyridinium salts are underway, and will be reported as develop-
ments warrant.
O
-
O
+
N
47
52
BF4
11e
12e
O
O
O
+
N
Ph
Ph
Ph
-
BF4
11f
12f
O
O
O
+
N
31
-
BF4
11g
12g
O
Acknowledgment
MeO
O
We acknowledge the support of this work by the National Insti-
tutes of Health (The University of Kansas Chemical Methodology
and Library Development Center of Excellence), P50 GM069663.
O
+
N
19
62
65
-
BF4
12h
OMe
O
11h
OMe
References and notes
O
O
+
N
1. Buszek, K. R.; Luo, D.; Kondrashov, M.; Brown, N.; VanderVelde, D. Org. Lett.
2007, 9, 4135–4137.
2. Ong, C. W.; Chen, C. M. J. Org. Chem. 1995, 60, 3135–3138.
3. Ong, C. W.; Chen, C. M.; Wang, L. H.; Jan, J. J.; Shieh, P. C. J. Org. Chem. 1998, 63,
9131–9134.
4. Ong, C. W.; Chen, C. M.; Wang, L. F. Tetrahedron Lett. 1998, 39, 9191–9192.
5. Ong, C. W.; Chen, C. M.; Juang, S. S. J. Org. Chem. 1994, 59, 7915–7916.
6. Tolstikov, G. A.; Miftakhov, M. S.; Danilova, N. A.; Vel’der, Y. L.; Spirikhin, L. V.
Synthesis 1989, 625–627.
7. Franck-Neumann, M.; Sedrati, M.; Mokhi, M. New J. Chem. 1990, 14, 471–
480.
3
3
-
3
BF4
11i
12i
O
O
O
-
O
+
N
BF4
11j
12j

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G. Gao et al. / Tetrahedron Letters 49 (2008) 6491–6494
8. Wenkert, E.; Guo, M.; Pizzo, F.; Ramachandran, K. Hev. Chim. Acta 1987, 70,
1429–1438.
9. Moore, H. W.; West, K. F.; Wriede, U.; Chow, K.; Fernandez, M.; Nguyen, N. V. J.
Org. Chem. 1987, 52, 2537–2549.
10. Ma, S.; Yu, Z. Chem. Eur. J. 2004, 10, 2078–2087.
11. Kovalev, I. P.; Kolmogorov, Y. N.; Strelenko, Y. N.; Ignatenko, A. V.; Vinogradov,
M. G.; Nikishin, G. I. J. Organomet. Chem. 1991, 125–133.
12. Buszek, K. R.; Brown, N. Org. Lett. 2007, 9, 707–710.
13. Jung, M. E.; Buszek, K. R. Tetrahedron Lett. 1986, 27, 6165–6168.
14. Jung, M. E.; Buszek, K. R. J. Am. Chem. Soc. 1988, 110, 3965–3969.
15. Jung, M. E.; Vaccaro, W. D. Tetrahedron Lett. 1989, 30, 1893–1896.
16. Lidström, P.; Tierney, J.; Watney, B.; Westmein, J. Tetrahedron 2001, 57, 9225–
9283.
17. Kappe, C. O. Curr. Opin. Chem. Biol. 2002, 6, 314–320.