New methods of preparing cyclopentenone ketals: The photosolvolysis of 3-alkoxypyridinium tetrafluoroborates

Article abstract of DOI:10.1055/s-1999-2538

A new base catalysed method of ketal formation is reported, such that substituted cyclopentenone ketals are prepared from 3-alkoxypyridinium tetrafluoroborate salts.

Full text of DOI:10.1055/s-1999-2538

LETTER
93
New Methods of Preparing Cyclopentenone Ketals: The Photosolvolysis of
3-Alkoxypyridinium Tetrafluoroborates
C. S. Penkett,* I. D. Simpson
School of Chemistry, Physics and Environmental Science, University of Sussex, Falmer, Brighton, East Sussex BN1 9QJ, UK.
E-mail: c.s.penkett@sussex.ac.uk
Received 20 October 1998
A renaissance of interest in this reaction has led to some
important discoveries by Mariano7 and Burger.8,9 Mariano
reported the results of photosolvolysis of various pyridin-
ium salts and subsequent solvolytic aziridine ring opening
of the products.7 Burger then reported how this reaction
could be used for b-lactam synthesis8 and, more recently,
has shown how polyhydroxylated aminocyclopentanes9
can be made. We were intrigued to know what effect an
electron donating group at the 3 position on the pyridine
ring would have on the photosolvolysis of pyridinium
salts. We reasoned that the incipient cation would be very
stable and should be readily captured by the solvent to
form a geminal bisalkoxy species. To test our hypothesis
various 3-alkoxypyridinium salts 8 were irradiated in dif-
ferent solvents using a 400 W medium pressure mercury
vapour lamp with a pyrex filter. Analysis of the different
products showed that a series of cyclopentenone ketal de-
rivatives 9 had been made (Scheme 3).
Abstract: A new base catalysed method of ketal formation is re-
ported, such that substituted cyclopentenone ketals are prepared
from 3-alkoxypyridinium tetrafluoroborate salts.
Key words: cyclopentenones, photochemistry, pyridinium salts,
tetrafluoroborates, ketalisation
The photochemical properties of aromatic compounds are
a source of amazement to many organic chemists. In par-
ticular the metaphotocyclo addition1 has often been de-
scribed as the reaction that leads to the greatest increase in
molecular complexity. This light induced reaction be-
tween an aromatic ring and an olefin was concurrently
discovered in 1966 by Wilzbach and Kaplan2 and also by
Bryce-Smith, Gilbert and Orger.3 The metaphotocycload-
dition has been very elegantly utilised by Wender for the
synthesis of a number of key natural products, such as (±)-
a-cedrene4 and (±)-modhephene (4)5 (Scheme 1).
Scheme 3
Scheme 1
The pyridinium salts were made according to standard lit-
erature procedures, starting from either 3-hydroxypyri-
dine or 3-hydroxy-6-methylpyridine 10. The hydroxyl
group was initially protected as an ether 11 using an alkyl
halide.10 In order to introduce larger alkyl groups at the 6
position of the pyridine ring, the 6-methylpyridine deriv-
ative was metallated using LDA and quenched with an ap-
propriate alkyl halide.11 The pyridine species were
quaternised by heating in neat alkyl bromide or iodide in-
side a sealed tube and, after filtration, the pyridinium ha-
lides 13 were converted to the tetrafluoroborate salts 14
using silver carbonate and fluoroboric acid. Chloride6,8,9
and perchlorate7 salts have previously been used for pho-
tosolvolysis reactions, although we opted to use tetrafluo-
roborate salts; they were easy to make from the halide salt
(which tended to undergo photoinduced charge transfer
reactions) and were less likely to detonate than perchlor-
ate salts.
As yet there have been no reports of heteroaromatic com-
pounds being involved with similar reaction sequences,
although Wilzbach, Kaplan and Pavlik6 reported an un-
usual photohydration reaction of pyridinium ions in 1972.
These workers described how the irradiation of an alka-
line solution of N-methylpyridinium chloride 5 led to the
formation of a bicyclic aziridinyl alcohol 7. It was pro-
posed that the reaction proceeded via an azabenzvalene 6
cation that was subsequently captured by water from the
least hindered face.
Scheme 2
A series of different pyridinium salts were synthesised
and subsequently irradiated in a solution of sodium hy-
Synlett 1999, No. 1, 93–95 ISSN 0936-5214 © Thieme Stuttgart · New Yorkrk

94
C. S. Penkett, I. D. Simpson
LETTER
4) The alkoxypyridinium salts react in solvents other than
methanol, although lower yields of product were recorded
if the reaction was performed in n-propanol.7
5) The basic conditions under which the reactions take
place do not allow the ketal moiety to equilibrate with the
solvent. This allows the formation of mixed ketals.
6) The reaction shows stereoselective incorporation of the
solvent, as observed by comparing the spectroscopic data
of the two mixed ketals 9i and 9j. The relative stere-
ochemistry of the products has been assigned from NOE
difference data, the most obvious differences being shown
for compound 9h.12
Scheme 4
This last point appears to conflict with the results pub-
lished in earlier papers,6–9 where one might expect the sol-
vent (SolvH) to attack from the opposite side to the newly
formed aziridine. We attribute this unexpected observa-
tion to different stereoelectronic effects controlling the di-
rection of attack. The electron donating alkoxy group will
tend to stabilise adjacent carbocations, making the posi-
tively charged intermediate more carbocation like 17 and
less azabenzvalene like 15. This allows a hydrogen bond-
ing interaction between the solvent and the aziridinyl ni-
trogen, which will direct the solvent to attack the
droxide in either methanol or n-propanol. In one example
(entry 5), the reaction was performed using the perchlora-
te salt as well as the tetrafluoroborate salt to compare the
efficacy of the two counterions. The results are displayed
in the Table.
The points to note from these results are:
1) In entry 5, the perchlorate salt yielded slightly more
product than the tetrafluoroborate salt, although from a
safety point of view it is preferable to use the latter.
2) The yield of cyclopentene product increases up to a cer- carbocation 17 from the same face as the aziridine and so
tain point as the size of the group (R3) at the 6 position of favour the formation of 18 (Scheme 5).
the pyridinium ring increases from hydrogen to n-propyl.
3) The same also appears to be true of the N-alkyl group
(R2) and the O-alkyl group (R1).
Synlett 1999, No. 1, 93–95 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
New Methods of Preparing Cyclopentenone Ketals
95
Acknowledgement
The authors would like to thank Tocris Cookson Ltd and the EPSRC
for funding this work. CSP is very grateful to the Nuffield Founda-
tion for a Newly Appointed Science Lecturer Award, which allo-
wed the purchase of photochemical equipment. We would also like
to thank Dr A Avent for NMR studies and a particularly large debt
of gratitude is extended to Professor Philip Parsons for his continu-
ed support and invaluable advice.
References and Notes
(1) (a) Wender, P. A., Siggel, L., Nuss, J. M., Organic Photo-
chemistry; Padwa, A., Ed.; Marcel-Dekker: New York, 1989;
Vol. 10, Chapter 4. (b) Cornelisse, J., Chem. Rev., 1993, 93,
615.
Scheme 5
(2) Wilzbach, K. E., Kaplan, L., J. Am. Chem. Soc., 1966, 88,
2066.
(3) Bryce-Smith, D., Gilbert, A., Orger, B. H., J. Chem. Soc.,
Chem., Commun., 1966, 512.
(4) Wender, P. A., Howbert, J. J., J. Am. Chem. Soc., 1981, 103,
688.
(5) Wender, P. A., Dreyer, G. B., J. Am. Chem. Soc., 1982, 104,
5805.
(6) Kaplan, L., Pavlik, J. W., Wilzbach, K. E., J. Am. Chem. Soc.,
1972, 94, 3283.
(7) Ling, R., Yoshida, M., Mariano, P. S., J. Org. Chem., 1996,
61, 4439.
(8) Glarner, F., Thornton, S. R., Schärer, D., Bernardinelli, G.,
Burger, U., Helv. Chim. Acta, 1997, 80, 121.
(9) Acar, E. A., Glarner, F., Burger, U., Helv. Chim. Acta, 1998,
81, 1095.
(10) Kohl, B., Sturm, E., Senn-Bilfinger, J., Simon, W. A., Krüger,
U., Schaefer, H., Rainer, G., Figala, V., Klemm, K., J. Med.
Chem., 1992, 35, 1049.
Irradiation of 1-ethyl-3-methoxy-6-methylpyridin-
ium tetrafluoroborate (8e)
A N2-purged solution of 1-ethyl-3-methoxy-6-methyl-
pyridinium tetrafluoroborate (8e) (400 mg, 1.67 mmol)
and sodium hydroxide (308 mg, 7.7 mmol) in methanol
(350 ml) was irradiated for 3 hours in a quartz immersion
well with a pyrex filter using a 400 W medium pressure
mercury vapour lamp. The photolysate was concentrated
in vacuo and the residue was triturated with dichlo-
romethane. The resulting orange solution was concentrat-
ed in vacuo and subjected to column chromatography
(silica gel, dichloromethane:ethanol:ammonia 200/8/1) to
yield 1-methyl-4,4-dimethoxy-6-ethyl-azabicyclo[3.1.0]
hex-2-ene (9e) (197 mg, 1.08 mmol, 65 %) as a yellow oil.
1H-NMR (300 MHz, CDCl3) d: 1.20 (3H, t, J 7), 1.46 (3H,
s), 2.00 (1H, d, J 1.3), 2.42 (2H, m), 3.31 (3H, s), 3.40
(3H, s), 5.70 (1H, dd, J 1.8, 5.8), 6.07 (1H, d, J 5.8). 13C-
NMR (75 MHz, CDCl3 with DEPT 135) d: 9.94 (CH or
CH3), 14.98 (CH or CH3), 46.92 (CH2), 48.59 (CH or
CH3), 49.07 (C), 49.32 (CH or CH3), 51.11 (CH or CH3),
110.49 (C), 131.28 (CH or CH3), 141.56 (CH or CH3). IR:
(thin film) 3054, 2963, 2937, 2873, 2831, 1610 cm-1. EI
MS m/z (rel. intensity): 166 (11), 152 (100, [M-OCH3] +),
137 (10), 124 (37).
(11) Osuch, C., Levine, R., J. Am. Chem. Soc., 1956, 78, 1723.
(12) NOE difference results for compound (9h);
Synlett 1999, No. 1, 93–95 ISSN 0936-5214 © Thieme Stuttgart · New York