Synthesis of new chiral pyrylium salts and their phosphinine and pyridine derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.08.006

Despite their versatility, chiral pyryliums are almost unknown in the literature. Reported here is the synthesis of several new chiral pyrylium salts and the corresponding pyridines and phosphinines. This work more than doubles the number of reported chir

Full text of DOI:10.1016/j.tetlet.2012.08.006

Tetrahedron Letters 53 (2012) 5742–5744
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of new chiral pyrylium salts and their phosphinine and
pyridine derivatives
⇑
Nelson A. van der Velde, Holland T. Korbitz, Charles M. Garner
Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Despite their versatility, chiral pyryliums are almost unknown in the literature. Reported here is the syn-
thesis of several new chiral pyrylium salts and the corresponding pyridines and phosphinines. This work
more than doubles the number of reported chiral pyryliums, and also represents the first racemizable/
Received 27 June 2012
Accepted 4 August 2012
Available online 19 August 2012
epimerizable pyryliums. The derived phosphinines and pyridines represent rare
sition metals.
a-chiral ligands for tran-
In memory of Professor Masahisa Hasegawa
who recently passed away
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Chiral pyrylium
Chiral phosphinine
Chiral pyridine
Epimerization
Introduction
syntheses. The pyrylium products were isolated by simple dilution
with ether, taking advantage of their near-universal insolubility in
that solvent.1 The 13C NMR spectrum exhibited the characteristic
pyrylium peaks (165–185 ppm), further downfield than the typical
aromatic region.
Pyrylium salts are versatile synthetic intermediates, easily
transformed into various heterocycles, including pyridines, phos-
phinines, N-alkyl pyridiniums, and thiopyryliums.1 Pyrylium salts
are also interesting for their electronic properties, being strongly
electron-accepting.2
Pyrylium salts can be synthesized by a variety of methods that
allow various substitution patterns, though in practice aryl substit-
uents are far more common than alkyl groups.2 Polymerization is
often a major problem in the formation of pyryliums, resulting in
tar with little or no product formation in unfavorable cases. Sur-
prisingly, chiral pyrylium salts are almost unknown in the litera-
ture. By our count, only three compounds have been reported to
date (Fig. 1): the C2-chiral pyrylium recently synthesized in our
group (1),3 a racemic atropisomer (2),4 and a C1-chiral camphor
derivative (3).5 We attribute this paucity of examples to difficulties
in the synthesis of non-aryl-substituted pyryliums, having encoun-
tered many tar-forming reactions ourselves.
Pyryliums 4a and 4b were prepared from campholic and fen-
choilic acids, respectively, and derived from (+)-camphor and
(À)-fenchone, respectively, by the method of Whitesides.8 Both
(+)-camphor9 and fenchone10 are regarded as enantiomerically
pure materials. Pyrylium 4c was prepared from ibuprofen. Pyryli-
um 4d was prepared from the commercially available 86:14 mix-
ture of cis:trans 2-methylcyclohexanecarboxylic acid.11 We found
that the cis isomer had a larger coupling (7.1 Hz) for the methyl
doublet than did the trans isomer (6.5 Hz), and this was consistent
(6.3–6.5 Hz) in all of the derivatives 4d, 6d, and 7d, allowing
assignment of the stereochemistry. Also consistent was that the
methyl doublet for the cis isomer was always downfield of that
for the trans. Finally, the benzylic tertiary hydrogen in every case
exhibited two large axial–axial couplings (11–15.6 Hz) consistent
with the trans isomer. Pyrylium 4e was a single diastereomer, even
though it was made from 4-tert-buytlcyclohexane carboxylic acid
which was a 95:5 mixture of trans:cis isomers.
We have found that the reaction of acyl chlorides with dypnone,
first developed by LeFevre6 and modified by Katritkzky and co-
workers,7 is widely applicable to the preparation of simple chiral
pyryliums (Scheme 1). Four chiral pyryliums (4a–d) and two
non-chiral examples (4e,f) were made and characterized (Table 1).
The yields were modest (23–70%), as is typical of many pyrylium
It is evident from this work that pyryliums with a-chiral centers
bearing a hydrogen are relatively easily racemized or epimerized.
To our knowledge, no epimerizable pyryliums have been reported
previously in the literature. The only indication of epimerizability
has been from deuterium exchange experiments.12,13 The diaste-
reomer ratios (39:61 cis:trans) for pyrylium 4d (determined by
⇑
Corresponding author. Tel.: +1 254 710 6862; fax: +1 254 710 4272.
E-mail address: charles_garner@baylor.edu (C.M. Garner).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.006

N. A. van der Velde et al. / Tetrahedron Letters 53 (2012) 5742–5744
5743
Figure 1. Existing chiral pyryliums.
Scheme 2. Amine-catalyzed epimerization mechanism.
4d, 4e, or 4f are treated with stoichiometric triethylamine. A de-
tailed study of the epimerization of these and other pyryliums is
in progress.
Scheme 1. Preparation of pyryliums from dypnone.7
Pyrylium salts are partly of interest because of the potential to
convert them into the corresponding phosphinines and pyridines,
which are often good ligands for transition metals. Phosphinines
1H NMR) deviate measurably from the cis:trans ratio (86:14) of the
carboxylic acid starting material.11 This could, of course, be
attributed to several factors: equilibration during acid chloride
formation, differential reactivity in pyrylium formation, or isola-
tion efficiency, especially given the low yields. All of these are
probably occurring to some extent. Indeed, when (S)-ibuprofen
was used to prepare 4c, racemic pyrylium was obtained. More sig-
nificantly, however, we have observed that pyrylium 4d is readily
epimerized by catalytic amounts of N-methylmorpholine, yielding
a 9:91 ratio of cis:trans isomers (Scheme 2). This clearly proceeds
through the well-known7 ‘pseudobase’ intermediates (5), which
can be observed or even isolated when any of the pyryliums 4c,
have a combination of poor
r-donating ability with strong p-
accepting capacity that makes them attractive ligands for the sta-
bilization of highly electron-rich metal centers.14 Interestingly,
only a few examples of chiral phosphinines have been reported
in the literature.3,15,16 Incorporation of chirality directly (i.e.,
a to
the pyrylium ring) in these otherwise planar systems has proven
to be difficult. From our pyrylium salts (6a–f) we have synthesized
new phosphinines with the chirality as close as possible to the
phosphorus center.
The pyrylium salts were converted into the corresponding
phosphinines by treatment with excess of tris-(trimethyl-
Table 1
Yields of pyryliums (4), phosphinines (6), and pyridines (7)
Ph
Ph
Ph
Ph
O
R
Ph
N
R
Ph
P
R
BF4
R =
6
7
4
4a (23%)
6a (46%)
7a (90%)
4b (25%)
4c (23%)
6b (57%)
6c (31%)
7b (98%)
7c (79%)
4d (25%; 39:61)
cis:trans
6d (38%; 10:90)
cis:trans
7d (77%; 22:78)
cis:trans
4e (70%, trans)
6e (70%, trans)
6f (49%)
7e (85%, trans)
7f (80%)
4f (49%)

5744
N. A. van der Velde et al. / Tetrahedron Letters 53 (2012) 5742–5744
triphenyl pyrylium salt from dypnone was also reported by
Balaban.20
In summary, we have synthesized six new pyrylium salts, four
of them chiral, and the corresponding phosphinine and pyridine
derivatives. This provides the first racemizable/epimerizable chiral
pyryliums, and kinetic studies of the equilibration of these are in
progress.
Ph
Ph
N
Ph
P(TMS)3
NH4OH
Et2O
CH3CN
heat
Ph
O
R
BF4
Ph
R
Ph
P
R
7a-f
6a-f
4a-f
Scheme 3. Synthesis of substituted C1 phosphinines and pyridines.
Acknowledgments
We would like to thank the Donors of the American Chemical
Society Petroleum Research Fund (Grant #47942-AC1) and the
Robert A. Welch Foundation (Grant #AA-1395) for support of this
work, the National Science Foundation (Award #CHE-0420802)
for funding the purchase of our 500 MHz NMR, and the Mass Spec-
trometry Center at Baylor University for several analysis.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.08.
006.
Figure 2. Acyl chlorides that do not yield the desired pyryliums.
References and notes
1. Balaban, T. S.; Balaban, A. T. Pyrylium Salts in Science of Synthesis—Houben-
Weyl In Methods of Molecular Transformations; Thomas, E. J., Ed.; Thieme
Verlag: Stuttgart, 2004; Vol. 14, pp 11–200.
2. Katritzky, A. R. Pyrylium Salts: Syntheses, Reactions, and Physical Properties;
Academic Press: New York, 1982.
3. Bell, J.; Franken, A.; Garner, C. Tetrahedron 2009, 65, 9368–9372.
4. (a) Müller, C.; Pidko, E.; Totev, D.; Lutz, M.; Spek, A.; van Santen, R.; Vogt, D.
Dalton Trans. 2007, 5372–5375; (b) Müller, C.; Pidko, E.; Staring, A.; Lutz, M.;
Spek, A.; van Santen, R.; Vogt, D. Chem. Eur. J. 2008, 14, 4899–4905.
5. Barnaud, Y.; Maroni, P.; Simalty, M.; Madaule, Y. Bull. Soc. Chim. Fr. 1970, 4,
1398–1403.
6. Hopf, P.; LeFèvre, R. J. Chem. Soc. 1938, 1989.
7. Katritzky, A.; Vassilatos, S.; Alajarin-Ceron, M. Org. Magn. Reson. 1983, 10, 587–
595.
8. McCreary, M.; Lewis, D.; Wernick, D.; Whitesides, G. J. Am. Chem. Soc. 1974,
1038, 96.
9. Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241–1250.
10. Ravid, U.; Putievsky, E.; Katzir, I.; Ikan, R. Flavour Frag. J. 1992, 7, 169–172.
11. Besson, M.; Delbecq, F.; Gallezot, P.; Neto, S.; Pinel, C. Chem. Eur. J. 2000, 6, 949–
958. See Ref.20 in.
12. Stanoiu, I.; Gard, E.; Uncuta, C.; Chiraleu, F.; Balaban, A. Rev. Roum. Chim. 1979,
24, 209–217.
13. Stanoiu, I.; Chiraleu, F.; Gard, E.; Balaban, A. Rev. Roum. Chim. 1977, 22, 117–
126.
14. Mathey, F.; Le Floch, P. Phosphinines In Science of Synthesis: Houben Weyl
Methods of Molecular Transformations, Six Member Hetarenes with One Nitrogen
or One Phosphorus Atom; Black, D., Ed.; Stuttgart: George Thieme Verlag, 2004;
Vol. 15, pp 1097–1155.
15. Breit, B. Chem. Commun. 1996, 2071–2072.
16. Müller, C.; Lopez, L. G.; Kooijman, H.; Spek, A.; Vogt, D. Tetrahedron Lett. 2006,
47, 2017–2020.
17. Breit, B.; Winde, R.; Mackewitz, T.; Paciello, R.; Harms, K. Chem. Eur. J. 2001, 7,
3106–3121.
18. Kwong, H.; Yeung, H.; Wong, W. Coord. Chem. Rev. 2007, 251, 2188–2222.
19. Balaban, A. Org. Prep. Proced. Int. 1977, 3, 125–130.
20. Balaban, A., e-EROS Encyclopedia of Reagents for Organic Synthesis 2001,
10623–10627.
silyl)phosphine (P(TMS)3) in refluxing anhydrous acetonitrile for
24 h (Scheme 3).17 After column chromatography the phosphinines
were obtained as brown oils. The phosphinines showed the typical
downfield resonance at d 180 ppm in the 31P NMR spectrum.
Chiral pyridine ligands have been known for some time but the
development of their applications in asymmetric catalysis had
been lacking until 1981, when the first report of chiral pyridine li-
gands and their application in asymmetric catalysis appeared.18
Interestingly, no examples can be found in the literature that use
the conversion of chiral pyrylium salts to the corresponding chiral
pyridines.
The pyridine derivatives were obtained in high yields by stirring
the pyrylium salts with ammonium hydroxide and diethyl ether
for 30 min. In the case of the most hindered pyrylium salt (4b),
the reaction required reflux with ammonium hydroxide for 6 h.
After acid workup and without further purification the compounds
were obtained as brown oils (Scheme 3).19 The 13C NMR spectrum
displayed downfield aromatic peaks indicative of the trisubstituted
pyridine (five peaks between 140 and 167 ppm).
In the course of our investigation, we found that certain acyl
chlorides did not form the desired pyrylium salt, instead produce
triphenyl pyrylium tetrafluoroborate. We believe that when the
acyl chloride is not reactive enough for reaction, the dypnone
undergoes a retroaldol to produce acetophenone. Excess acetophe-
none in the presence of boron trifluoride is known to yield tri-
phenyl pyrilium salt. We notice that acyl chlorides that bear
ether or ester functionalities (Fig. 2) inevitably fail to produce the
desired pyrylium, perhaps because these functionalities are
reacting with the excess boron trifluoride. The formation of